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Efficacy and safety of Ergoferon versus oseltamivir in adult outpatients with seasonal influenza virus infection: a multicenter, open-label, randomized trial

Open AccessPublished:September 08, 2016DOI:https://doi.org/10.1016/j.ijid.2016.09.002

      Highlights

      • Ergoferon is similar to oseltamivir in terms of efficacy.
      • Ergoferon improves quality of life.
      • There are no serious adverse effects related to Ergoferon intake.

      Summary

      Objectives

      Ergoferon is an antiviral complex drug containing released-active forms of antibodies to interferon gamma, CD4, and histamine. Its efficacy and safety in the treatment of acute respiratory viral infections has been reported previously. The aim of this study was to compare Ergoferon with oseltamivir.

      Methods

      A multicenter, open-label, randomized controlled trial of patients aged 18 to 65 years, who had tested positive for influenza A or B antigens, was performed. A total of 156 patients were enrolled as the intention-to-treat population; these patients were assigned randomly to receive either Ergoferon or oseltamivir (n = 78 in each group).

      Results

      The percentage of patients achieving a normal body temperature (≤37.0°С) following 5 days of treatment did not differ significantly between the groups. The mean duration of fever in the Ergoferon and oseltamivir groups was 2.1 ± 1.5 days and 2.3 ± 1.6 days, respectively (p = 0.01). The average time to the resolution of influenza symptoms was approximately 3 days, with no significant between-group difference. Total quality of life scores were similar in the two groups following 5 days of drug administration. The incidence of adverse events did not differ significantly between the groups, nor were there any serious adverse events.

      Conclusions

      Ergoferon and oseltamivir were equally effective and safe in adult outpatients with seasonal influenza A or B virus infection.
      Clinical trial registration: ClinicalTrials.gov identifier NCT01804946

      Keywords

      1. Introduction

      Influenza is an infection affecting populations worldwide caused by highly contagious, epidemically aggressive and mutagenic viruses.
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      More than 200 000 hospitalizations and an average of 25 470 deaths occur in the USA each year due to seasonal influenza.
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      Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza
      Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection.
      A drug with a high efficacy-to-safety ratio that is able to overcome the virus resistance and that also has advantages from a pharmaco-economic point of view could be attractive as a treatment option. Ergoferon, a drug containing released-active forms of antibodies to interferon gamma (IFN-γ), CD4, and histamine, and whose efficacy and safety against influenza and acute respiratory viral infections has been shown previously, could be considered one such drug.
      • Geppe N.A.
      Ergoferon liquid dosage form—efficacious and safe treatment for childhood acute respiratory infections. Interim outcomes of a multi-center, randomized, double-blind, placebo-controlled clinical trial (In Russian).
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      Ergoferon and improvement of etiopathogenetic therapy of influenza and acute respiratory viral infection in adults (In Russian).
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      Released-active forms of antibodies are produced on the basis of a novel technology (US Patent 8,535,664 B2, 2013) and share a common feature – the ability to modify the initial substance (or biological molecules which are structurally similar to the initial substance) by changing its spatial structure, resulting in alterations to its physical, chemical, and biological properties.
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      The efficacy and safety of these drugs has been studied extensively and has been proven in different experimental and clinical studies.
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      Ultra-low doses (history of one study).
      The superiority of Ergoferon over placebo has been shown in double-blind, placebo-controlled studies in adults and children with acute upper respiratory viral infections and influenza.
      • Geppe N.A.
      Ergoferon liquid dosage form—efficacious and safe treatment for childhood acute respiratory infections. Interim outcomes of a multi-center, randomized, double-blind, placebo-controlled clinical trial (In Russian).
      • Verevschikov V.K.
      • Borzunov V.M.
      • Shemiakina E.K.
      Ergoferon and improvement of etiopathogenetic therapy of influenza and acute respiratory viral infection in adults (In Russian).
      • Kostinov M.P.
      New drug for the treatment of influenza and acute respiratory viral infections (In Russian).
      The objective of this clinical trial was to compare the efficacy and safety of Ergoferon with oseltamivir in the treatment of seasonal influenza in adults.

      2. Methods

      2.1 Study overview

      This study was a multicenter, open-label, randomized controlled trial performed in 12 medical institutions in Russia from February 2011 to April 2014. This period succeeded the emergence of the 2009 pandemic influenza A/H1N1 virus (pH1N1). Furthermore, the influenza morbidity in Russia was low during the study period. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice and was approved by the institutional review boards and the national research ethics committee. Signed informed consent was obtained from all participants prior to enrollment. Due to the open design of the trial, the interim analysis was performed in 2012 to compare the efficacy of the study treatments.
      • Aver’ianov A.V.
      • Babkin A.P.
      • Bart B.I.
      • Volchetskiĭ A.L.
      • Minina E.S.
      • Kozyrev O.A.
      • et al.
      Ergoferon and oseltamivir in treatment of influenza: results of multicentre randomized comparative clinical trial (In Russian).
      Eligible patients were assessed by physicians on days 1, 3, and 7 in the outpatient departments of the study centers involved (see Supplementary Material).

      2.2 Patient selection

      The study enrolled adults aged 18 to 65 years who presented to hospital within 24 h of the onset of influenza symptoms and who had an axillary temperature of ≥37.8 °C at enrollment plus one or more flu-related non-specific symptoms (headache, myalgia, joint pain, sweats and/or chills, malaise, or fatigue) and one or more respiratory symptoms (cough, sore throat, or nasal symptoms). Infection with influenza A or B virus was confirmed by rapid antigen testing (QuickVue Influenza A+B test; Quidel Corporation, San Diego, CA, USA).
      Individuals were excluded from the study if they had an exacerbation or decompensation of a chronic disease that would affect their ability to participate in the clinical trial, chronic renal insufficiency, vaccination against influenza prior to epidemic season onset, medical history of polyvalent allergy, allergy/intolerance to any of the components or medications used in the treatment, suspected or known bacterial infection, a condition requiring antibacterial therapy, or HIV disease. They were also excluded if the were receiving systemic therapy with steroids or other immunosuppressants, or had a history of alcohol or drug abuse. Women were required to have a negative urine pregnancy test before drug administration. Breastfeeding women were not eligible for participation.

      2.3 Patient assessment

      Anterior nose and posterior pharyngeal throat swabs were taken at baseline and assessed with the QuickVue Influenza A+B kit for rapid diagnostic testing for influenza.
      The participants were monitored for a total of 7 days, with hospital visits scheduled for days 1, 3, and 7. All visits included the measurement of axillary temperature, a physical examination, evaluation of influenza symptoms by the physician, and assessment of the intake of concomitant therapies. The laboratory analyses (hematology, blood chemistry, and urinalysis) were performed on days 1 and 7. The severity of each influenza symptom was scored by the physician on a symptom severity scale (0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms). Baseline and end-of-treatment quality of life assessments were based on the first five points of the European Quality of Life Scale (EuroQoL, EQ5D); baseline and end-of-treatment self-reported ‘health-related quality of life’ estimates were obtained using a visual analogue health-rating scale (EQ5D, point 6). The assessment of compliance with the study therapies was done on the last visit (day 7).
      Axillary temperature measurements were taken by the study participants twice daily using a digital thermometer and recorded on a diary card. The names and doses of concomitant medications taken (other than the two drugs specifically assessed during the study) were recorded in the patient diary.
      Safety assessments included examiner-reported adverse events (AEs) and self-reported AEs during the 5 days of treatment and the following 30 days, as well as abnormal laboratory findings on day 7.

      2.4 Treatment

      The participants were assigned randomly to receive Ergoferon (group 1) or oseltamivir (group 2). Randomization occurred at the time of study entry by telephone contact with an automated service (an interactive voice randomization system based on a random number generator).
      Ergoferon (OOO NPF ‘Materia Medica Holding’, Russia) was administered according to the following regimen: on day 1, five tablets were taken in the first 2 h (one tablet every 30 min), followed by three more tablets regularly spaced during the rest of the day. From day 2 through day 5, one tablet was administered three times daily. The efficacy and safety of this specific drug regimen has been assessed and proven in previous clinical trials.
      • Geppe N.A.
      Ergoferon liquid dosage form—efficacious and safe treatment for childhood acute respiratory infections. Interim outcomes of a multi-center, randomized, double-blind, placebo-controlled clinical trial (In Russian).
      • Verevschikov V.K.
      • Borzunov V.M.
      • Shemiakina E.K.
      Ergoferon and improvement of etiopathogenetic therapy of influenza and acute respiratory viral infection in adults (In Russian).
      Each tablet of Ergoferon contains microcrystalline cellulose (30 mg), magnesium stearate (3 mg), and lactose monohydrate (267 mg) saturated with a mixture of affinity purified rabbit polyclonal antibodies to IFN-γ, antibodies to histamine, and antibodies to CD4 receptor, which had previously undergone a process of gradual reduction of their initial concentration (2.0–2.5 mg/ml) by 1024 times at least (mixture of dilutions 10012, 10030, and 10050). This technology conforms to the approach described in the European Pharmacopoeia (general monographs 1038 and 2371) and allows the use of active pharmaceutical ingredients – the released-active form of the above-mentioned antibodies – based on a novel patented biotechnological platform (US Patent 8,535,664 B2, 2013). The initial forms of the antibodies were produced in accordance with the current EU requirements of Good Manufacturing Practice for starting materials (EU Directive 2001/83/EC, as amended in Directive 2004/27/EC) by AB Biotechnology (Edinburgh, UK). The fact that properties of the active pharmaceutical ingredients are based primarily on the technological process of their preparation
      • Kostinov M.P.
      New drug for the treatment of influenza and acute respiratory viral infections (In Russian).
      determines their crucial difference from homeopathic therapy based on other common features (law of similarity, individual hyperergic reactions, and specific methodological principles of personalized indication).
      Oseltamivir (Tamiflu; F. Hoffmann-La Roche, Ltd) was administered at a dose of 75 mg orally twice daily for 5 days; this is the recommended dosing regimen for adults. Tamiflu was obtained from a licensed wholesaler (SIA International Ltd).
      The following concomitant medications were permitted during the study: antipyretic/non-steroidal anti-inflammatory drugs (NSAIDs) (only for patients with a body temperature >38.5 °C), decongestants, drugs for obstructive airway diseases, cough suppressants, expectorants, mucolytics, and medications for the treatment of underlying chronic conditions. The use of other antivirals (except Ergoferon and oseltamivir), antihistamines, antibacterials, and interferons was not permitted. The use of NSAIDs and other medications for symptom relief was recorded by the study researchers (physicians) on the case record form and by the patient on a diary card.

      2.5 Efficacy endpoints

      The percentage of patients with a body temperature ≤37.0 °C following the 5-day treatment was used as the primary efficacy endpoint.
      The secondary efficacy endpoints were: (1) mean body temperature; (2) flu-related non-specific and respiratory symptom severity score; (3) mean duration of fever; (4) time to treatment-associated resolution of influenza symptoms; (5) rates of antipyretic/NSAID use per patient during days 1 to 5 of drug administration; (6) changes in patient quality of life (total EQ5D scores) and self-reported ‘health-related quality of life’ estimates between days 1 and 7; and (7) the percentage of examiner-reported worsening of illness or complications requiring antibacterial therapy during the three medical visits.

      2.6 Statistical methods

      The study was based on a non-inferiority design. Sample size calculations were based on assumed between-group equality of patient proportions with body temperature ≤37.0°С for each of the five treatment days. The level of type I error was set at 5% and the statistical power of the analysis at 80%. A one-tailed Z-test was used. Assuming the most conservative hypothesis that the proportions of patients with body temperature ≤37.0°С in the groups were distributed 50% versus 50%, the minimum sample size required was estimated to be 78 patients in each group. Overall, 156 patients, 78 in each group, were evaluated in this study.

      2.6.1 Efficacy analysis

      The intention-to-treat (ITT) and per-protocol (PP) analyses were performed in accordance with the current guidelines for evaluating drug efficacy in a clinical non-inferiority trial.

      Guidance for industry non-inferiority clinical trials. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research; March 2010. Available at: http://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf. (accessed July 4, 2016).

      Patient proportions were compared using frequency analysis (Chi-square test or Fisher's exact test) and Wald Z-statistics. For the comparison of means, a modified paired Student t-test was used with the calculation of the confidence interval for differences between sample means. For multiple comparisons, the adaptive Holm procedure was used (the type I error (p-value) used to describe the outcomes was adjusted using this method).

      2.6.2 Safety analysis

      Treatment safety in both groups was assessed in all enrolled and randomized patients who received at least one dose of Ergoferon (n = 81) or oseltamivir (n = 80).
      All recorded AEs, vital signs, clinical laboratory parameters, and physical examination findings were listed, tabulated, and summarized according to the treatment group. The documented AEs were categorized by organ system, preferable terms, severity, and treatment relatedness as determined by the physician.

      3. Results

      3.1 Patient demographics and baseline characteristics

      A total of 161 patients aged 18 to 60 years were enrolled in the study, 81 in group 1 (Ergoferon) and 80 in group 2 (oseltamivir). The date of the first patient enrollment was February 28, 2011; the date on which the last patient completed participation was April 21, 2014.
      Five randomized patients (three in group 1 and two in group 2) were excluded from the full analysis owing to a failure to satisfy the major entry criteria (eligibility violations) (Figure 1). Eligibility violations were the following: absence of the documented axillary temperature of ≥37.8 °C at enrollment (n = 2 in group 1; n = 1 in group 2) or any flu-related symptoms (n = 1 in group 1; n = 1 in group 2). The rest of the participants (n = 156) constituted the ITT set analyzed. Treatment outcomes in this set (78 patients per group) were considered for ITT analysis of efficacy.
      In addition, nine patients (three patients in group 1 and six patients in group 2) had substantial protocol violations: absence of the patient diary (n = 1 in group 1; n = 1 in group 2); temperature gaps in the patient diary for ≥1 day (n = 1 in group 1; n = 2 in group 2); omissions in the case record form (n = 1 in group 1; n = 1 in group 2). In group 2, two additional participants required the administration of non-permitted medications (antibacterials) on day 4. Hence, the PP analysis set included 147 patients: 75 in group 1 and 72 in group 2.
      Basic demographic and clinical parameters (day 1) were comparable between the treatment groups (Table 1, Table 3, Table 4, Table 5). The mean patient age was 34.7 ± 12.1 years (ranging from 18 to 59 years); female patients made up 65% of the study population. The majority of patients presented with typical influenza symptoms (e.g. fever, headache, myalgia) and a predominance of non-specific over respiratory symptoms. On day 1, the mean body temperature was 38.2 ± 0.4 °C in group 1 and 38.3 ± 0.4 °C in group 2 in the ITT set, and 38.3 ± 0.4° C in both groups in the PP set. All patients in both groups complained of moderate to severe headache, chills, fatigue, muscle pain, and malaise. The mean severity score of flu-related non-specific symptoms on day 1 was 18.8 ± 6.2 (19.0 ± 6.7) in group 1 and 18.6 ± 6.2 (18.6 ± 6.3) in group 2 (hereinafter, ITT analysis data are presented first and PP analysis data are given in brackets). The respiratory symptoms score did not differ significantly between the groups: 6.1 ± 3.7 (6.1 ± 3.7) in group 1 and 5.9 ± 3.7 (5.9 ± 3.6) in group 2; these mostly represented moderate symptoms, such as nasal congestion and sore throat.
      Table 1Demographic characteristics of the study participants
      Results are presented as the mean±standard deviation, or number (percentage).
      No.VariableGroup 1Group 2Statistics
      The Statistics column shows the results of the Student t-test (section 1) and frequency analysis (section 2).
      1Age (years), mean ± SD (range)
       Total set (81/80)
      The number of patients in group 1/number of patients in group 2.
      34.5 ± 11.634.9 ± 12.6t = 0.2; p = 0.84
      (18–59)(18–58)
       ITT (78/78)
      The number of patients in group 1/number of patients in group 2.
      34.2 ± 11.735.0 ± 12.7t = 0.41; p = 0.68
      (18–59)(18–58)
       PP (75/72)
      The number of patients in group 1/number of patients in group 2.
      34.4 ± 11.735.5 ± 12.5t = 0.58; p = 0.56
      (18–59)(18–58)
      2Sex, n (%)
       Total set (81/80)
      The number of patients in group 1/number of patients in group 2.
        Male32 (40)25 (31)χ2 = 1.2; p = 0.27
        Female49 (60)55 (69)
       ITT (78/78)
      The number of patients in group 1/number of patients in group 2.
        Male31 (40)24 (31)χ2 = 1.4; p = 0.24
        Female47 (60)54 (69)
       PP (75/72)
      The number of patients in group 1/number of patients in group 2.
        Male30 (40)23 (32)χ2 = 1.03; p = 0.31
        Female45 (60)49 (68)
      ITT, intention-to-treat analysis; PP, per-protocol analysis.
      a Results are presented as the mean ± standard deviation, or number (percentage).
      b The Statistics column shows the results of the Student t-test (section 1) and frequency analysis (section 2).
      c The number of patients in group 1/number of patients in group 2.
      Table 3Body temperature on days 1, 3, and 7
      Results are presented as the mean ± standard deviation.
      DayITT analysisPP analysis
      Group 1 (n = 78)Group 2 (n = 78)Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ° is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      Group 1 (n = 75)Group 2 (n = 72)Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ° is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      138.2 ± 0.438.2 ± 0.4Δ° = 0.0; 95% CI < 0.08

      t = −3.6; p = 0.0002
      38.3 ± 0.438.3 ± 0.4Δ° = 0.0; 95% CI < 0.08

      t = −3.5; p = 0.0003
      337.0 ± 0.537.0 ± 0.5Δ° = 0.01; 95% CI < 0.14

      t = −2.5; p = 0.007
      37.0 ± 0.537.0 ± 0.5Δ° = 0.005; 95% CI <0.14

      t = −2.4; p = 0.008
      736.5 ± 0.236.6 ± 0.3-36.5 ± 0.236.6 ± 0.3-
      ITT, intention-to-treat analysis; PP, per-protocol analysis; CI, confidence interval.
      a Results are presented as the mean ± standard deviation.
      b The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ° is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      Table 4Flu-related non-specific symptom severity scores on days 1, 3, and 7
      Results are presented as the mean±standard deviation.
      DayITT analysisPP analysis
      Group 1 (n = 78)Group 2 (n = 78)Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      Group 1 (n = 75)Group 2 (n = 72)Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      118.8 ± 6.618.6 ± 6.2Δ = 0.2; 95% CI <1.9

      t = −2.7; p = 0.003
      19.0 ± 6.718.6 ± 6.3Δ = 0.4; 95% CI <2.1

      t = −2.5; p = 0.007
      39.2 ± 5.07.7 ± 4.4Δ = 1.5; 95% CI <2.8

      t = −2.0; p = 0.025
      9.2 ± 5.17.8 ± 4.3Δ = 0.45;95% CI <2.8

      t = −2.0; p = 0.02
      72.4 ± 2.92.0 ± 2.5Δ = 0.4; 95% CI <1.1

      t = −5.9; p < 0.0001
      2.3 ± 2.71.9 ± 2.3Δ = 0.39; 95% CI <1.1

      t = −6.3; p < 0.0001
      ITT, intention-to-treat analysis; PP, per-protocol analysis; CI, confidence interval.
      a Results are presented as the mean ± standard deviation.
      b The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      Table 5Respiratory symptom severity scores on days 1, 3, and 7
      Results are presented as the mean±standard deviation.
      DayITT analysisPP analysis
      Group 1 (n = 78)Group 2 (n = 78)Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      Group 1 (n = 75)Group 2 (n = 72)Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      16.1 ± 3.75.9 ± 3.7Δ = 0.2; 95% CI <1.2

      t = 2.1; p = 0.02
      6.1 ± 3.75.9 ± 3.6Δ = 0.2; 95% CI <1.2

      t = −2.1; p = 0.02
      34.3 ± 2.43.9 ± 2.7Δ = 0.4; 95% CI <1.1

      t = −2.7; p = 0.004
      4.3 ± 2.44.0 ± 2.7Δ = 0.3; 95% CI <1.0

      t = −2.8; p = 0.003
      71.3 ± 1.51.4 ± 1.9Δ = −0.1; 95% CI <0.4

      t = −5.8; p < 0.0001
      1.3 ± 1.51.4 ± 1.8Δ = −0.1; 95% CI <0.4

      t = −5.9; p < 0.0001
      ITT, intention-to-treat analysis; PP, per-protocol analysis; CI, confidence interval.
      a Results are presented as the mean ± standard deviation.
      b The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      More than 30% of patients had different underlying chronic conditions that were not reasons for exclusion (see Supplementary Material, Table S1). Most of the patients in both groups received additional permitted concomitant medications (see Supplementary Material, Table S2). Neither the percentage of patients with underlying chronic diseases nor the percentage of patients receiving any additional permitted concomitant medication differed significantly between the groups.

      3.2 Primary efficacy endpoints

      The ITT analysis showed an effect of Ergoferon that was comparable to that of oseltamivir for the 5 days of treatment: 19% of patients in group 1 achieved a normal morning body temperature (≤37.0°С) as early as day 2 (versus 10% in group 2), 46% of patients in group 1 had a normalized body temperature on day 3 (versus 42% in group 2), and 81% of patients in group 1 had a normalized body temperature on day 5 (versus 71% in group 2) (Table 2). At treatment completion (day 6), all patients in group 1 reported a normal morning body temperature (versus 92% in group 2).
      Table 2Percentages of patients with a body temperature ≤37.0°С during the study period
      Treatment dayITT analysisPP analysis
      Group 1Group 2Statistics
      The Statistics column shows the results of the frequency analysis (non-inferiority Wald test) with 95% confidence intervals in parentheses.
      Group 1Group 2Statistics
      The Statistics column shows the results of the frequency analysis (non-inferiority Wald test) with 95% confidence intervals in parentheses.
      (n = 78)(n = 78)(n = 75)(n = 72)
      1Morning0%1%Δ = −1% (−5% to 2%)0%1%Δ = −1% (−5% to 3%)
      Z = 13.7; p < 0.001Z = 12.5; p < 0.001
      Evening4%1%Δ = 3% (−4% to 9%)4%1%Δ = 3% (−4% to 9%)
      Z = 8.4; p < 0.001Z = 8.0; p < 0.001
      2Morning19%10%Δ = 9% (−3% to 21%)19%10%Δ = 9% (−4% to 21%)
      Z = 4.9; p < 0.001Z = 4.8; p < 0.001
      Evening14%15%Δ = −1% (−14% to 11%)15%15%Δ = −1% (−14% to 12%)
      Z = 3.1; p = 0.001Z = 3.1; p = 0.001
      3Morning46%42%Δ = 4% (−13% to 21%)47%43%Δ = 4% (−14% to 21%)
      Z = 2.8; p = 0.002Z = 2.7; p = 0.003
      Evening41%42%Δ = −1% (−18% to 15%)41%43%Δ = −2% (−19% to 16%)
      Z = 2.2; p = 0.014Z = 2.1; p = 0.019
      4Morning81%71%Δ = 10% (−4% to 25%)80%75%Δ = 5% (−10% to 20%)
      Z = 4.2; p < 0.001Z = 3.4; p < 0.001
      Evening68%69%Δ = −1% (−17% to 15%)68%72%Δ = −4% (−20% to 12%)
      Z = 2.3; p = 0.009Z = 1.9; p = 0.028
      5Morning95%83%Δ = 12% (1% to 22%)95%83%Δ = 11% (−0% to 23%)
      Z = 6.2; p < 0.001Z = 5.9; p < 0.001
      Evening85%86%Δ = −1% (−14% to 11%)84%88%Δ = −4% (−16% to 9%)
      Z = 3.1; p = 0.001Z = 2.6; p = 0.004
      6Morning100%92%Δ = 8% (0% to 15%)100%92%Δ = 8% (1% to 16%)
      Z = 8.8; p < 0.001Z = 8.3; p < 0.001
      Evening94%96%Δ = −3% (−11% to 6%)93%96%Δ = −3% (−11% to 6%)
      Z = 4.6; p < 0.001Z = 4.3; p < 0.001
      ITT, intention-to-treat analysis; PP, per-protocol analysis.
      a The Statistics column shows the results of the frequency analysis (non-inferiority Wald test) with 95% confidence intervals in parentheses.
      The percentage of patients with a normal evening body temperature (≤37.0°С) in group 1 was 41% by day 3, 68% by day 4, and 85% by the end of day 5. Group 2 patients had nearly identical values (42%, 69%, and 86%, respectively).
      The PP analysis showed similar normalization rates for morning and evening body temperatures in both groups (Table 2).
      The ITT (PP) analysis demonstrated consistent results, which suggests that the two study treatments have comparable therapeutic effects (Table 2).

      3.3 Secondary efficacy endpoints

      The ITT (РР) analysis of mean body temperature showed that the increased baseline values fell to 37.0 ± 0.5 °C by day 3 in both groups and remained consistently below 37.0 °C over the subsequent days of observation (Table 3). Statistical analysis showed mean values of fever in group 1 falling within the acceptable ‘δ’ limits established for treatment outcomes in group 2 (ITT analysis: Δ° = 0.01, 95% confidence interval (CI) <0.14, t =  − 2.5, p = 0.007; РР analysis: Δ° = 0.005, 95% CI <0.14, t = −2.4, p = 0.008), confirming the comparable efficacy of the two drugs (Table 3).
      The ITT analysis showed more than a two-fold reduction in flu-related non-specific symptom severity score in group 1 on the third day, i.e., 9.2 ± 5.0 (versus 7.7 ± 4.4 in group 2) (Table 4). On the last day of observation (day 7), the mean severity score in the Ergoferon group was 2.4 ± 2.9 (versus 2.0 ± 2.5 in the oseltamivir group). The PP analysis yielded almost identical values (Table 4).
      The respiratory symptom scores were significantly reduced on treatment day 3 and this reduction was similar in the two groups (for both ITT and PP data). At the completion of treatment, some patients in both groups reported ‘residual’ catarrhal symptoms, as shown by the mean severity score of over 1.0 (Table 5).
      The mean duration of fever was 2.1 ± 1.5 (2.1 ± 1.4) days in group 1 versus 2.3 ± 1.6 (2.3 ± 1.6) days in group 2. This variable was similar in the two groups (p = 0.01 (p = 0.002)) (Table 6).
      Table 6Duration of fever and time to treatment-associated resolution of influenza symptoms
      Results are presented as the mean ± standard deviation.
      SymptomDuration of symptoms, days
      ITT analysisPP analysis
      Group 1 (n = 78)Group 2 (n = 78)Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The t-test was calculated for differences between means to determine their significance as compared to the pre-defined delta (margin). The p-value stands for type I error.
      Group 1 (n = 75)Group 2 (n = 72)Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The t-test was calculated for differences between means to determine their significance as compared to the pre-defined delta (margin). The p-value stands for type I error.
      Fever2.1 ± 1.52.3 ± 1.6Δ = −0.13; 95% CI <0.28

      t = −2.4; p = 0.01
      2.1 ± 1.42.3 ± 1.6Δ = −0.24; 95% CI <0.17

      t = −2.8; p = 0.002
      Flu-related non-specific symptoms2.7 ± 2.22.4 ± 2.1Δ = 0.29; 95% CI <0.47

      t = −1.7; p = 0.04
      2.6 ± 2.22.4 ± 2.1Δ = 0.26; 95% CI <0.44

      t = −1.96; p = 0.025
      Respiratory symptoms2.8 ± 2.52.6 ± 2.6Δ = 0.15; 95% CI <0.45

      t = −2.1; p = 0.02
      2.7 ± 2.52.6 ± 2.6Δ = 0.09; 95% CI <0.40

      t = −2.3; p = 0.01
      All influenza symptoms2.7 ± 2.32.5 ± 2.2Δ = 0.22; 95% CI <0.37

      t = −3.0; p = 0.001
      2.6 ± 2.32.5 ± 2.2Δ = 0.17; 95% CI <0.33

      t = −3.4; p = 0.0003
      ITT, intention-to-treat analysis; PP, per-protocol analysis; CI, confidence interval.
      a Results are presented as the mean ± standard deviation.
      b The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The t-test was calculated for differences between means to determine their significance as compared to the pre-defined delta (margin). The p-value stands for type I error.
      The analysis of time to treatment-associated resolution of influenza symptoms showed that the flu-related non-specific symptoms had resolved at 2.7 ± 2.2 days in group 1 and at 2.4 ± 2.1 days in group 2, whereas the improvement in respiratory symptoms was attained by study patients at 2.8 ± 2.5 and 2.6 ± 2.6 days, respectively (Table 6). The mean duration of all influenza symptoms was 2.7 ± 2.3 and 2.5 ± 2.2 days in group 1 and group 2, respectively. The statistical analysis of ITT and РР sets indicated consistent comparability of treatment outcomes in the two groups (Table 6). On average, most influenza symptoms had resolved after approximately 3 days of treatment, without significant differences in either ITT or РР data between the groups (Table 6).
      The mean rate of antipyretic/NSAID intake on day 1 as calculated on a per-patient basis was 0.65 ± 0.48 (0.65 ± 0.48) in group 1 and 0.69 ± 0.46 (0.72 ± 0.45) in group 2 (Table 7). By day 3, this variable was reduced to 0.19 ± 0.40 (0.19 ± 0.39) in group 1 and 0.15 ± 0.36 (0.15 ± 0.36) in group 2. The statistical analysis demonstrated consistent comparability of endpoint values in the treatment groups (p < 0.005 (p < 0.005)).
      Table 7Number of antipyretic and NSAIDs taken
      Results are presented as the mean ± standard deviation.
      DayITT analysisРР analysis
      Group 1

      (n = 78)
      Group 2

      (n = 78)
      Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      Group 1

      (n = 75)
      Group 2

      (n = 72)
      Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      10.65 ± 0.480.69 ± 0.46Δ = −0.04; 95% CI <0.09

      t = −3.16; p = 0.001
      0.65 ± 0.480.72 ± 0.45Δ = −0.07; 95% CI <0.06

      t = −3.5; p = 0.0003
      20.40 ± 0.490.49 ± 0.50Δ = −0.09; 95% CI <0.04

      t = −3.63; p = 0.0002
      0.40 ± 0.490.49 ± 0.50Δ = −0.09; 95% CI <0.05

      t = −3.48; p = 0.0003
      30.19 ± 0.400.15 ± 0.36Δ = 0.04; 95% CI <0.14

      t = −2.65; p = 0.0044
      0.19 ± 0.390.15 ± 0.36Δ = 0.03; 95% CI <0.14

      t = −2.66; p = 0.0043
      40.01 ± 0.110.04 ± 0.19Δ = −0.03; 95% CI <0.02

      t = −8.89; p < 0.0001
      0.01 ± 0.120.04 ± 0.20Δ = −0.03; 95% CI <0.02

      t = −8.48; p < 0.0001
      50.01 ± 0.110.03 ± 0.16Δ = −0.01; 95% CI <0.02

      t = −9.63; p < 0.0001
      0.01 ± 0.120.03 ± 0.17Δ = −0.01; 95% CI <0.02

      t = −9.14; p < 0.0001
      NSAID, non-steroidal anti-inflammatory drug; ITT, intention-to-treat analysis; PP, per-protocol analysis; CI, confidence interval.
      a Results are presented as the mean ± standard deviation.
      b The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      By day 7, the mean EQ5D score in group 1 was 5.4 ± 0.8 (versus a baseline score of 9.4 ± 1.9), indicating a significant improvement in patient health (Δ1–7 = −4.0), and similar results were obtained in group 2 (5.5 ± 0.9 and 9.2 ± 2.3, respectively; Δ1–7 = −3.7) (Table 8).
      Table 8Total EQ5D scores and self-reported health estimates
      Results are presented as the mean ± standard deviation.
      DayITT analysisPP analysis
      Group 1

      (n = 78)
      Group 2

      (n = 78)
      Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the between-group difference in Δ1–7 values. The p-value stands for type I error.
      Group 1

      (n = 75)
      Group 2

      (n = 72)
      Statistics
      The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the between-group difference in Δ1–7 values. The p-value stands for type I error.
      EQ5D Questionnaire, score
      19.4 ± 1.99.2 ± 2.39.6 ± 1.99.4 ± 2.2
      75.4 ± 0.85.5 ± 0.95.3 ± 0.95.4 ± 0.8
      Δ1–7−4.1 ± 1.8−3.7 ± 2.3Δ = −0.4; 95% CI <0.2−4.2 ± 1.8−3.9 ± 2.2Δ = −0.3; 95% CI <0.3
      t = −3.4; p = 0.0005t = −3.2; p = 0.0009
      Health rating scale, score
      142.1 ± 18.446.7 ± 15.141.6 ± 18.246.2 ± 15.4
      787.7 ± 10.687.8 ± 11.487.7 ± 10.788.0 ± 10.6
      Δ1–745.5 ± 20.341.2 ± 16.4Δ = 4.5; 95% CI >−0.546.1 ± 20.041.8 ± 15.7Δ = 4.2; 95% CI >−0.7
      t = 4.3; p < 0.0001t = 4.3; p < 0.0001
      EQ5D, European Quality of Life Questionnaire; ITT, intention-to-treat analysis; PP, per-protocol analysis; Δ1–7, within-group mean difference on days 1 and 7; CI, confidence interval.
      a Results are presented as the mean ± standard deviation.
      b The Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing. Δ is the between-group difference in Δ1–7 values. The p-value stands for type I error.
      Based on patient self-reported health estimates on the health-rating scale, the mean total score in group 1 was increased more than two-fold, from 42.1 ± 18.4 at baseline to 87.7 ± 10.6 (Δ1–7 = 45.6), and an increase from 46.7 ± 15.1 to 87.8 ± 11.4 (Δ1–7 = 41.1) was observed in group 2. These data were consistent with the PP analysis (Table 8). Statistical analysis of variations in total EQ5D score and in patient self-reported health estimates confirmed significant between-group comparability (Table 8).
      In group 1, neither worsening of illness nor complications requiring antibacterial therapy or hospitalization were recorded, whereas two patients in group 2 developed complications (one case of community-acquired pneumonia affecting the lower lobe of the left lung on day 4, and one case of acute maxillary sinusitis on day 5) and were prescribed antibiotic therapy (Table 9).
      Table 9Number of patients with complications requiring antibacterial therapy
      ITT analysisРР analysis
      Group 1 (n = 78)Group 2 (n = 78)Statistics
      The Statistics column shows the results of the frequency analysis for comparability testing (non-inferiority Wald test) with 95% confidence intervals in parentheses.
      Group 1(n = 75)Group 2 (n = 72)Statistics
      The Statistics column shows the results of the frequency analysis for comparability testing (non-inferiority Wald test) with 95% confidence intervals in parentheses.
      02 (3%)Δ = −3% (−7% to 2%)

      Z = 11.9; p < 0.0001
      01 (1%)Δ = −1% (−5% to 3%)

      Z = 14.5; p < 0.0001
      ITT, intention-to-treat analysis; PP, per-protocol analysis.
      a The Statistics column shows the results of the frequency analysis for comparability testing (non-inferiority Wald test) with 95% confidence intervals in parentheses.

      3.4 Safety analysis

      A total of 25 AEs were reported for 11 subjects in group 1, and 24 AEs were reported for 15 subjects in group 2. No serious AEs were recorded. The incidence of AEs did not differ between the groups (Table 10). The total list of AEs in the safety population is presented in the Supplementary Material (Table S3).
      Table 10Number of patients with AEs and number of AEs per patient
      VariableGroup 1

      (n = 81)
      Group 1

      (n = 80)
      Statistics
      For the number of patients with AEs, the Statistics column shows the results of the frequency analysis (non-inferiority Wald test) with 95% confidence intervals in parentheses. For the number of AEs per patient, the Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing.
      Number of patients with AEs, n (%)11 (14%)15 (19%)Δ = −5% (−18% to 7%)

      Z = 4.1; p < 0.0001
      Number of AEs in group2524NA
      Number of AEs per patient0.30 ± 1.070.28 ± 0.73Δ = 0.02; 95% CI<0.26

      t = −0.2; p = 0.405
      AE, adverse event; NA, not applicable; CI, confidence interval.
      a For the number of patients with AEs, the Statistics column shows the results of the frequency analysis (non-inferiority Wald test) with 95% confidence intervals in parentheses. For the number of AEs per patient, the Statistics column shows the results of the Student t-test modified for comparability (non-inferiority) testing.
      In group 1, all AEs were mild with an uncertain (n = 22) or possible (n = 3) relationship to the study treatment as determined by the physician. Most patients who experienced AEs (n = 10) had some abnormal laboratory findings, as revealed by the examination on day 7. The total number of abnormal laboratory findings in group 1 was 23, and all of them were mild.
      In group 2, a total of five moderate and 19 mild AE cases were reported, including acute pneumonia (n = 1), acute maxillary sinusitis (n = 1), difficulty breathing (n = 1), depressed mood disorder (n = 1), and nausea (n = 2). The total number of abnormal laboratory findings on day 7 in group 2 was 18. Five AEs were unrelated to the treatment; 19 AEs had an uncertain (n = 17) or possible (n = 2) relationship to the treatment.
      Neither Ergoferon nor oseltamivir had negative effects on vital functions (see Supplementary Material, Table S4).
      There was no evidence of any drug–drug interaction with medications administered concomitantly with Ergoferon or oseltamivir (see Supplementary Material, Table S2).
      Patients in both groups had approximately 100% compliance with the therapies (Table 11). Patients in group 1 had good tolerance of Ergoferon and all recovered at the end of treatment. In group 2, two patients had complications requiring antibacterial treatment.
      Table 11Rates of compliance with the study therapies
      Results are presented as the mean ± standard deviation.
      VariableITT analysisPP analysis
      Group 1 (n = 78)Group 2 (n = 78)Statistics
      The Statistics column shows the results of Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      Group 1 (n = 75)Group 2 (n = 72)Statistics
      The Statistics column shows the results of Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.
      Compliance, %101 ± 4100 ± 0Δ = −1; 95% CI >−2

      t = 18.1; p < 0.0001
      101 ± 4100 ± 0Δ = −1; 95% CI >−2

      t = 19.0; p < 0.0001
      ITT, intention-to-treat analysis; PP, per-protocol analysis; CI, confidence interval.
      a Results are presented as the mean ± standard deviation.
      b The Statistics column shows the results of Student t-test modified for comparability (non-inferiority) testing. Δ is the mean difference between group 1 (Ergoferon) and group 2 (oseltamivir). The p-value stands for type I error.

      4. Discussion

      Oseltamivir has been evaluated extensively in randomized controlled trials
      • Geppe N.A.
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      Ergoferon and improvement of etiopathogenetic therapy of influenza and acute respiratory viral infection in adults (In Russian).

      Guidance for industry non-inferiority clinical trials. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research; March 2010. Available at: http://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf. (accessed July 4, 2016).

      and was chosen as the comparator to demonstrate the non-inferiority of Ergoferon in patients with seasonal influenza. At the same time, it should be mentioned that in spite of the fact that the efficacy of oseltamivir has been questioned (Cochrane systematic review, 2014),
      • Jefferson T.
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      Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.
      the World Health Organization (WHO) recommends it as the first-line influenza treatment (http://www.who.int/mediacentre/factsheets/fs211/en/) and the drug is on the WHO List of Essential Medicines.

      World Health Organization. WHO List of Essential Medicines. Geneva: WHO. Available at: http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf. (accessed July 4, 2016).

      The final results of this study support those of the previously published interim analysis in which only about a third of the final number of patients was enrolled.
      • Aver’ianov A.V.
      • Babkin A.P.
      • Bart B.I.
      • Volchetskiĭ A.L.
      • Minina E.S.
      • Kozyrev O.A.
      • et al.
      Ergoferon and oseltamivir in treatment of influenza: results of multicentre randomized comparative clinical trial (In Russian).
      The therapeutic effect of Ergoferon is comparable to that of oseltamivir. The percentage of patients with absence of fever, which is known to correlate with virus clearance and the antiviral efficacy of the therapy,
      • Ison M.G.
      • de Jong M.D.
      • Gilligan K.J.
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      • et al.
      End points for testing influenza antiviral treatments for patients at high risk of severe and life-threatening disease.
      was evaluated as the primary efficacy endpoint. Ergoferon was shown to have the same effect as oseltamivir on the duration of fever: over two-thirds of patients reported a body temperature of ≤37.0 °C by the end of day 4. At treatment completion, the percentages of patients with normal morning and evening body temperatures were similar in the two groups. The mean duration of the febrile period in the Ergoferon group was approximately 2 days without significant difference from the oseltamivir group, and this efficacy is similar to the previously published data.
      Ergoferon intake halved the severity of the influenza symptoms (headache, muscular pain, and joint pain) by day 3. On average, the mean duration of influenza symptoms was about 2 days in the Ergoferon group and was comparable to that in the oseltamivir group. A meta-analysis published in The Lancet demonstrated a median time to influenza symptom alleviation of 97.5 h (or 4.1 days) for ambulant patients receiving oseltamivir.
      • Dobson J.
      • Whitley R.J.
      • Pocock S.
      • Monto A.S.
      Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials.
      In addition, the statistical analysis indicated consistent comparability of the rates of antipyretic use in both groups.
      Furthermore, there were no cases of worsening illness or complications among the study patients. Improved quality of life estimates reported by the patients taking Ergoferon were consistent with the significant improvement in total EQ5D scores and patient health self-assessments from baseline.
      The pharmacological activity of Ergoferon is ensured by the combined action of its components on the antiviral immune response and virus-induced respiratory tract inflammation. Each component of Ergoferon exerts a modulating effect on its respective target, as is a common feature of released-active forms of antibodies.
      • Epstein O.I.
      Phenomenon of release activity and hypothesis of “spatial” homeostasis (in Russian).
      The main component of the drug – technologically treated forms of antibodies to IFN-γ – increases the expression of IFN-γ (a key cytokine participating in the antiviral immune response), IFN-α/β, and associated interleukins (IL-2, IL-4, IL-10). It also improves the ligand–receptor interaction of IFN-γ with its receptor, normalizes the concentration and functional activity of natural antibodies to IFN-γ, induces antigen expression of major histocompatibility complex (MHCI and MHCII) and Fc-receptors, stimulates natural killer (NK) cell and monocyte functional activity, and activates a mixed Th1 and Th2 immune response.
      • Martyushev A.V.
      • Sherstoboev E.J.
      • Pashinskiy V.G.
      • Sergeeva S.A.
      • Epstein O.I.
      Anti-cytokine antibodies in ultra-low doses regulate cytokine expression: experimental and clinical aspects.
      • Zhavbert E.S.
      • Dugina I.L.
      • Épshteĭn O.I.
      Immunotropic properties of anaferon and anaferon pediatric (In Russian).
      Other components of the drug, technologically treated forms of antibodies to histamine and to CD4, have effects on histamine receptor
      • Zhavbert E.S.
      • Dugina Y.L.
      • Epshtein O.I.
      Anti-inflammatory and anti-allergic features of antibodies to histamine in release-active form: review of experimental and clinical researches (In Russian).
      and CD4 receptor,
      • Emelyanova A.G.
      • Grechenko V.V.
      • Petrova N.V.
      • Shilovskiy I.P.
      • Gorbunov E.A.
      • Tarasov S.A.
      • et al.
      Effect of released-active antibodies to CD4-receptor on LCK-kinase level in culture of peripheral blood mononuclear cells (In Russian).
      respectively.
      This study has some limitations that could be considered as sources of bias: the open-label trial design, the absence of a placebo group and an untreated group, the long enrollment period (such that the outcome of many patients was known before others had been enrolled), a number of measurements of key variables performed, and the use of patient self-report.
      In conclusion, Ergoferon and oseltamivir were equally effective and safe in the treatment of adults with seasonal influenza. It is hoped that Ergoferon will become useful in the treatment of patients infected with virus that has developed resistance to current influenza drugs. The cost of a 5-day treatment with Ergoferon is significantly lower than that of a 5-day treatment with Tamiflu.

      Acknowledgements

      The authors thank the research staff at the participating sites. The investigators involved were Babkin A. P. (Burdenko Voronezh State Medical Academy, Voronezh), Kozyrev O. A. (Smolensk State Medical University, Smolensk), Kostinov M. P. (Mechnikov Research Institute for Vaccines and Sera, Russian Academy Medical Sciences, Moscow), Petrov D. V. (Yaroslavl State Medical Academy (government-funded higher professional education institution), Ministry of Healthcare of the Russian Federation), Selkova E. P. (Gabrichevsky Moscow Research Institute of Epidemiology and Microbiology, Moscow), Chernogorova M.V. (municipal health facility City Clinical Hospital No. 3, Podolsk), Chijov D. A. (government-funded health facility City Polyclinic No. 106, St. Petersburg), Barabashkina A. V. (government-funded health facility Clinical Hospital, Vladimir), and Alpenidze D. N. (government-funded health facility City Polyclinic No. 117, St. Petersburg).
      Funding: This study was funded by a grant from OOO NPF ‘Materia Medica Holding’ (Moscow, Russia). The statistical analysis was provided by OOO NPF ‘Materia Medica Holding’.
      Conflict of interest: Vladimir Rafalsky declares no potential conflicts of interest. Alexander Averyanov received an investigator grant from OOO NPF ‘Materia Medica Holding’ to conduct the clinical trial and has received speakers’ honoraria for scientific presentations. Boris Bart and Elena Minina received investigator grants from OOO NPF ‘Materia Medica Holding’ to conduct the clinical trial. Mikhail Putilovskiy and Elena Andrianova are employees of the OOO NPF ‘Materia Medica Holding’. Oleg Epstein is a founder of OOO NPF ‘Materia Medica Holding’.

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