key: cord-0832788-6xq2h0hp
authors: Efimov, Sergey V; Matsiyeuskaya, Natallia V; Boytsova, Olga V; Akhieva, Luydmila Yu; Kuntsevich, Elena V; Troshina, Anastasia A; Kvasova, Elena I; Tikhonov, Anton A; Khomyakova, Nadezhda F; Harrison, Francisco; Rossi, Jean-François; Hardman, Timothy C
title: Open-label use of an aliphatic polyamine immunomodulator in patients hospitalized with COVID-19
date: 2022-03-03
journal: Drugs Context
DOI: 10.7573/dic.2022-1-1
sha: 16cdfbe56abbd1e7c5d9129307ddc8c74956b9f7
doc_id: 832788
cord_uid: 6xq2h0hp

BACKGROUND: Evidence-based therapies used to treat coronavirus disease (COVID-19) remain limited. Azoximer bromide (AZB; Polyoxidonium(®)) is an immunomodulating molecule frequently used in the Russian Federation. It offers demonstrable therapeutic benefit in upper respiratory tract infections. This study evaluated the safety and efficacy of AZB when used in combination with standard of care treatment in patients hospitalized with COVID-19. METHODS: Hospitalized patients with COVID-19 (n=81; nine sites) received AZB 12 mg intravenously once daily for 3 days then intramuscularly every other day until day 17. The primary endpoint included clinical status at day 15 versus baseline. Historical control data of 100 patients from a randomized, controlled, open-label trial conducted in China were included to serve as a direct control group. RESULTS: Notable clinical improvement, assessed by seven-point ordinal scale (OS) score and National Early Warning Score, was observed. Mean duration of hospitalization was 19.3 days. Indicators of pneumonia and lung function showed gradual recovery to normalization. No patients died but, by day 28, one patient still required respiratory support; this patient died on day 34. A higher proportion of patients receiving AZB required invasive or non-invasive ventilation (OS 5 or 6) at baseline compared with the historical control group. Improvement in mean OS score by day 14/15 was not notable in the control group (OS 3.99–3.87) but was clear in the AZB group (OS 4.36–2.90). Mean duration of hospitalization was similar in the control group (16.0 days); however, day 28 mortality was higher, at 25.0% (n=25). CONCLUSION: AZB combined with standard of care was safe and well tolerated. An apparent clinical improvement could not be fully evaluated due to the lack of a direct control group; further assessment of AZB for the treatment of COVID-19 in a randomized, placebo-controlled study is warranted.

The clinical presentation of coronavirus disease 2019 (COVID- 19) ranges from asymptomatic infection to fatal illness and is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 primarily targets the respiratory system and can cause pneumonia and respiratory failure; severe infection is associated with high rates of intensive care admission. [1] [2] [3] Cases of COVID-19 in the Russian Federation have surpassed 4.7 million, with the death toll recently stated to be over 180,000. 4, 5 While almost 200 candidate vaccines are in development and several have been authorized for use, evidence-based therapies are currently limited. 6 These include remdesivir, a broad-spectrum antiviral shown to modestly reduce time to recovery in hospitalized adults; dexamethasone, an anti-inflammatory shown to reduce mortality in patients requiring invasive mechanical ventilation; and tocilizumab, a monoclonal antibody shown to improve survival in hospitalized patients with hypoxia and systemic inflammation. [7] [8] [9] 'Antiviral antibody cocktails' have also demonstrated capacity to reduce viral load in non-hospitalized patients, 10 while combination therapy with the monoclonal antibodies bamlanivimab and etesevimab has been shown to reduce viral load in outpatients with mild-to-moderate disease. 10, 11 In addition, monoclonal antibodies, such as casirivimab and imdevimab, have contributed to the reduction of medical visits in patients with COVID-19 through the successful in vitro activity of REGEN-COV against current SARS-CoV-2 variants of concern. 11 Severe respiratory failure in patients with COVID-19 is associated with complex immune dysregulation or macrophage activation 12 ; immune dysregulation, mediated by overproduction of IL-6, compromises viral clearance. 13 Rapid shedding of endogenous IL-6 receptor (IL-6R) occurs during neutrophil pyroptosis, which affects trans-signalling by augmenting the soluble IL-6R (sIL-6R)/IL-6 complex; this stimulates endothelial cells and ultimately increases the inflammatory response. 14 IL-6 blocks dendritic cell (DC) maturation, which can prevent induction of T cell differentiation. 15 The contribution of immune dysfunction to the progression of COVID-19 highlights the requirement for immunological interventions. Multiple randomized trials indicate that systemic corticosteroid therapy improves clinical outcomes and reduces mortality in hospitalized patients with COVID-19 who require supplemental oxygen, 16 presumably by mitigating the COVID-19-induced systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction. It is also suggested that, as in cases of SARS and Middle-East respiratory syndrome (MERS), regulators and modulators of the immune response, such as interferons, could perhaps alleviate the pathogenesis of SARS-CoV-2. [17] [18] [19] [20] [21] Azoximer bromide (AZB; Polyoxidonium ® ) is an immunomodulator, macromolecular compound successfully indicated as an effective agent for the treatment of infectious and inflammatory diseases of viral, bacterial and fungal origin. AZB is licensed in the Russian Federation, Commonwealth of Independent States (both licensed in 1996) and Slovakia (licensed in 2002) for the treatment of acute and chronic viral and bacterial infections as well as for various other indications, including immunodeficiencies (e.g. infection prophylaxis in rheumatoid arthritis patients taking immunosuppressant medications). 22 Azoximer bromide is generally well tolerated with no major safety concerns. 23 In vitro studies have shown that AZB can induce T cell proliferation, increase natural killer cell degranulation and increase immature DC expansion; in addition, certain DC costimulatory molecules that function to stimulate T cells proliferate following AZB administration. 24 After penetrating leukocytes by endocytosis, AZB localizes in cytosolic endoplasmic vesicles, resulting in significant dosedependent increases in intracellular hydrogen peroxide. 25 Hydrogen peroxide has a role in the activation of NF-κB, which subsequently regulates the transcription of genes involved in the inflammatory and immune responses, thereby coordinating several facets of the immune system necessary for infection resistance. 26, 27 There is a recognized need to find viable treatments for COVID-19. Amongst other indications, including immunodeficiencies, AZB has proven therapeutic benefits in the treatment of upper respiratory tract infections. We therefore conducted an open-label, multicentre study to evaluate the safety and efficacy of AZB in addition to a complex therapy in patients hospitalized with COVID-19.

This was an open-label, multicentre study in patients hospitalized due to COVID-19 conducted between March and July 2020 (ClinicalTrials.gov Identifier: NCT04542226, registered 12 March 2020). The study was exploratory in nature and therefore did not include a placebo group. Eight sites in the Russian Federation and one site in the Republic of Belarus took part. After a screening period (day -1 to day 1), eligible patients were administered AZB for 17 days (day 1 to day 17). Patients were monitored during a planned follow-up period between day 18 and day 29±3; in some patients, the final follow-up visit was performed up to day 73. ISSN: 1740-4398 ORIGINAL RESEARCH -Effects of azoximer bromide in patients with COVID 19 drugsincontext.com parameter National Early Warning Score (NEWS; comprising respiration rate, oxygen saturation (SpO 2 ), supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness); NEWS parameters were also measured individually as absolute values. 30 Other assessments included safety laboratory tests (including C-reactive protein (CRP)), physical examination, clinical signs and symptoms, electrocardiogram, evaluation of chest X-ray/computed tomography scans, nasopharyngeal and/ or oropharyngeal smear assessment for polymerase chain reaction, and bacteriological sputum culture. Adverse events (AEs) and serious adverse events (SAEs) were graded according to The Division of AIDS Outcome measures for safety analysis included the cumulative incidence of AEs/SAEs and the assessment of laboratory parameters. Permanent or temporary discontinuation of infusions and/or injections of the study drug was documented.

Statistical analyses were performed using SAS ® version 9.4 (SAS Institute Inc., Cary, NC, USA). Safety analyses were performed on the intent-to-treat (ITT) population, comprising all patients who received at least one dose of investigational product and had at least one valid post-baseline value for primary endpoint evaluation. All other analyses were performed on the per protocol (PP) population.

Safety outcome measures were presented using frequency counts and percentages. Quantitative data were summarized using descriptive statistics (arithmetic mean and standard Inclusion/exclusion criteria Adults aged ≥18 years hospitalized due to COVID-19 symptoms with a laboratory-confirmed SARS-CoV-2 infection were enrolled after providing informed consent. Infection was confirmed by a polymerase chain reaction from any specimen collected before study enrolment. Patients who were pregnant or breastfeeding, had a history of increased sensitivity to any component of the study treatment, had an acute or chronic renal failure or exhibited pathological conditions judged to make study participation impossible were excluded.

Demographic data and detailed medical history were collected after obtaining informed consent. Eligible patients received AZB 12 mg (lyophilizate for solution for injections and topical application reconstituted in sterile saline) intravenously once daily on day 1 to day 3 then intramuscularly every other day from day 5 to day 17 (maximum 10 injections). Patients also received standard of care (SOC) treatment for COVID-19 in accordance with existing Russian clinical recommendations; this included the use of certain antibiotics, antivirals, anticoagulants, hydroxychloroquine and other drugs, as appropriate. 28, 29 Requirement for oxygen therapy, high flow oxygen devices, non-invasive ventilation, mechanical ventilation (via an endotracheal tube or tracheostomy tube) or extracorporeal membrane oxygenation was assessed daily. Other daily assessments included clinical status as determined by a sevenpoint World Health Organization-recommended Ordinal Scale (OS) ( Table 1 ) and disease severity according to the seven- Historical control data

To address the absence of a direct control group, trends in a control group of patients with COVID-19 receiving SOC treatment from a previously published randomized, controlled, open-label trial were analyzed. 31 The study was identified via conduction of a structured literature search via PubMed and was selected due to the alignment of several outcome measures used in the present study; the search aimed to find clinical trials conducted in patients with COVID-19 with a control arm comprising SOC treatment only (data not published). Standard care included treatment with supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy and extracorporeal membrane oxygenation as necessary. The trial was conducted at a single centre in China between January and February 2020 and recruited 199 patients hospitalized with a confirmed SARS-CoV-2 diagnosis. Patients received lopinavir-ritonavir (400 mg and 100 mg, respectively) twice daily plus SOC for 14 days or SOC alone. The primary endpoint was time to clinical improvement as determined by the same seven-point OS used in the present study. Differences in basic baseline demographics (age, sex, baseline OS score), OS score at the end of study duration, duration of hospitalization and day 28 mortality between the two patient groups (AZB or control) were assessed.

Eighty-one patients were eligible for study inclusion and comprised the ITT population. Eighty patients completed the study. Four patients with very mild COVID-19 symptoms were incorrectly hospitalized and were excluded from the ITT population; they did not require hospital treatment (antibiotics, oxygen support, etc.), had low baseline OS and NEWS values, and recovered by themselves without medical intervention. Seventy-seven patients therefore comprised the PP population.

With the exception of safety analyses, all results are presented for the PP population.

Median age was 53.0 years (range 22-81 years) and 54.5% of patients were men ( was markedly lower on day 15 (n=14, 18.2%) compared with baseline (n=59, 76.6%). Notable improvements in mean (SD) OS score were observed from day 9 (4.08 (1.10)) until the end of the treatment period on day 17 (2.36 (0.71)); this trend continued until the End-of-Study visit (1.12 (0.71)). This improvement was most prominent in patients with 'very severe' or 'severeto-moderate' COVID-19 at baseline ( Figure 1B) ; by day 17, the majority of patients (93.5%; n=72) had an OS score of 2 or 3. Mean (SD) time to an OS score improving to ≤2 was 15.9 (3.72) days. Improvements in observed OS scores were similar between patients <65 years and patients ≥65 years of age ( Figure 1C ).

Improvements in mean NEWS were also observed over time ( Figure 2 ) and were more notable than the improvements in mean OS scores. The most prominent improvement was also observed in the patients with 'very severe' or 'severe-tomoderate' COVID-19 at baseline ( Figure 2B ). Patients with 'mild' COVID-19 at baseline reached NEWS ≤2 (hospital discharge) quicker than patients with more severe disease ( Figure 2E) ; however, all patient groups reached similar scores by day 17 ( Figure 2B ). Mean (SD) NEWS improved from 6.86 (3.14) at baseline to 1.08 (1.18) by the End-of-Study visit with an improvement probability of >80% after 15 days of treatment in all patients. Similar improvements in NEWS were observed between patients <65 years and patients ≥65 years of age ( Figure 2C ) and time to discharge was similar between the two groups ( Figure 2F ). Ordinal Scale scores during treatment phase stratified by patient age: <65 years (n=67), ≥65 years (n=10). D. Improvement probability curve plotted for time to decreasing Ordinal Scale score to ≤2. E. Improvement probability curve plotted for time to decreasing Ordinal Scale score to ≤2 stratified by baseline NEWS severity: 'very severe' (score ≥9), n=30; 'severe or moderate' (score 5-8), n=28; 'mild' (score ≤4), n=19. F. Improvement probability curve plotted for time to decreasing Ordinal Scale score to ≤2 stratified by patient age: <65 years (n=67), ≥65 years (n=10). NEWS, National Early Warning Score; SD, standard deviation. Note: Crosses on the graphs denote censored observations where further data from the patients were not available.

Mean SpO 2 at baseline was 92.4% and steadily improved over the treatment period ( Figure 3 ). This improvement was most prominent in patients with 'very severe' or 'severeto-moderate' COVID-19 at baseline ( Figure 3B) Figure 4 . The highest recovery probability was in patients with 'mild' COVID-19 at baseline ( Figure 4B ), suggesting a more rapid recovery. The lowest recovery probability was in the 'severe or moderate' group. Patients <65 years and ≥65 years of age had a similar recovery probability ( Figure 4C ). Patients <65 years of age requiring respiratory support (OS 4-6) decreased from 49 (73.1%) patients at baseline to 3 (4.5%) patients by the end of the AZB treatment period; in patients ≥65 years of age, this decreased from 10 (100.0%) patients to 1 (10.0%) patient.

Most patients had elevated body temperatures (>37°C) at baseline ( Figure 5 ). This normalized (≤37°C) in all patients by day 11, and no notable differences were observed when stratified by baseline NEWS severity score ( Figure 5B ). The probability of achieving a normal body temperature after 10 days of treatment was 90% ( Figure 5C ). 

In the ITT population (n=81), six (7.4%) patients each experienced one AE of PQ interval prolongation (two events), fever (two events), intermittent fever and bacterial pneumonia. All AEs resolved and none were considered related to AZB administration. One patient who experienced the event of bacterial pneumonia discontinued from the study after two doses of AZB and required further medication; all other patients completed the study. No deaths were recorded during the study period. One patient experienced an SAE of Klebsiella sepsis (determined to not be related to AZB) and died after study completion (day 34), 17 days after the last AZB injection, due to associated complications, including respiratory distress, disease progression, secondary bacterial infection, sepsis and multiple organ failure. The patient was 30 years old with a body mass index of 46.3 and had a history of hospital admissions due to bacterial pneumonia in the previous 3 years. Data are presented overall and stratified by baseline NEWS severity and age category (per protocol population [n=77]). A. Improvement probability curve plotted for time to vanishing signs of pneumonia. B. Improvement probability curve plotted for time to vanishing signs of pneumonia stratified by baseline NEWS severity: 'very severe' (score ≥9), n=30; 'severe or moderate' (score 5-8), n=28; 'mild' (score ≤4), n=19. C. Improvement probability curve plotted for time to vanishing signs of pneumonia stratified by baseline age category: '<65 years', n=67; '≥65 years', n=10. NEWS, National Early Warning Score; SD, standard deviation. Note: Crosses on the graphs denote censored observations where further data from the patients were not available.

the patients receiving AZB (Table 3) : median age was 58.0 years (range 48.0-68.0 years) with a similarly slightly higher proportion of men (59.0%; n=59) to women (41.0%; n=41). 31 Pre-existing conditions included diabetes (13.0; n=13), cerebrovascular disease (8.0%; n=8) and cancer (1.0%; n=1). All historical control subjects had SpO 2 ≤94% at baseline compared with 59 (76.6%) patients in the AZB-treated patients. Mean baseline OS score was slightly lower in the control group (3.99) compared with the AZB group (4.36). Baseline OS scores ranged from 3 to 5 and the majority of patients (67.0%; n=67) had a score of 4; of patients who received AZB, the majority had a score of 3 (23.4%; n=18), 4 (31.2%; n=24) or 5 (31.2%; n=24), whereas 14.3% (n=11) of patients had a score of 6 ( Figure 7) . A higher proportion of patients receiving AZB therefore required invasive or non-invasive ventilation (OS 5 or 6) compared with the control group. Change in mean OS score from baseline to day 14/15 was not notable in the control group (3.99-3.87) but was more pronounced in the AZB group (4.36-2.90). By day 14 in the control group, most patients had an OS score of 2 (28.0%; n=28), 3 (24.0%; n=24) or 4 (20.0%; n=20) ( Figure 7) . Six (6.0%) and 5 (5.0%) patients had an OS score of 5 and 6, respectively, while 17 (17.0%) patients had died. By day 15 in the AZB group, the majority of patients had an OS score of 2 (35.1%; n=27) or 3 (45.5%; n=35). Three (3.9%) and 2 (2.6%) patients had an OS score of 5 and 6, respectively, 1 (1.3%) patient had an OS score of 1 and no patients had died. By day 28, 25 (25.0%) patients in ISSN: 1740-4398 ORIGINAL RESEARCH -Effects of azoximer bromide in patients with COVID 19 drugsincontext.com Table 3 . Comparison of demographic, baseline and efficacy endpoints with historical control group (per protocol population).

Standard of care (historical control a ) n=100 ORIGINAL RESEARCH -Effects of azoximer bromide in patients with COVID 19 drugsincontext.com with increased mortality in other respiratory illnesses, such as flu, which could be due to the known association between corticosteroids and immunosuppression. 43, 44 With known immunomodulating properties, AZB could be used in place of, or in conjunction with, corticosteroids in patients requiring mechanical ventilation to balance the deleterious effects on the immune system and improve overall recovery. These observations merit further investigation.

Improvements in both OS and NEWS values from baseline to day 17 were observed; however, there were notable differences in the behaviour of the two parameters. Mean OS values were relatively stable during the first 7 days of treatment followed by a prominent decrease. The decrease in mean NEWS values was more pronounced, with improvements noted several days earlier, suggesting that OS score is less responsive to early changes in clinical improvement. We conclude that NEWS may provide a more sensitive interpretation of patient clinical status and better reflect overall recovery. 

COVID-19 has rapidly spread across the globe since December 2019, leading to >225 million confirmed cases and almost 4.7 million fatalities as of 19 September 2021. 32 Although the disease is not as lethal (case fatality ratio (CFR) ~0.3-1%) 33,34 as MERS (CFR ~35%) 35 and SARS (CFR 14-15%), 36 it has become clear that morbidity and mortality are much higher than in pandemic influenza (CFR 0.1%), 37 42 It may therefore have been likely to expect higher mortality in our patient population given that 22.2% and 21.0% of patients required non-invasive and invasive ventilation, respectively. This finding is even more apparent when considering the relatively high incidence of patients exhibiting comorbidities and the number of older patients (≥65 years); comorbidities and age are both known risk factors for severe disease progression and mortality. 40 In a recent study, treatment with the corticosteroid dexamethasone reduced day 28 mortality only in patients requiring mechanical ventilation or oxygen alone, with no significant benefit observed in patients not requiring respiratory support; in patients not receiving respiratory support, day 28 mortality of 17.8% was observed. 8 In contrast, day 28 mortality was not observed in any subgroup of patients in the present study, suggesting a treatment advantage of AZB over dexamethasone, particularly in patients with non-severe COVID-19. Furthermore, corticosteroid use has been associated ISSN: 1740-4398 ORIGINAL RESEARCH -Effects of azoximer bromide in patients with COVID 19 drugsincontext.com conditions, which could serve as an add-on treatment for patients with COVID-19.

The datasets used during the current study are available from the corresponding author upon reasonable request.

The Based on the previous studies of AZB, we can propose several explanations for the nature of the observed effect in patients with COVID-19. First, AZB can cause indirect antiviral activity by stimulating interferon release, antigen presentation and antibody development. 45, 46 Second, the detoxicant effect of AZB can participate in symptom reduction (e.g. temperature) and increased wellbeing in some patients. 47 Another possible explanation of the AZB effect is the prevention of cytokine storm, which serves as a predictive marker of poor COVID-19 outcome.

In conclusion, the devastating impacts of the COVID-19 pandemic are far from over and global collaboration to find effective treatments is paramount. At the time of writing this article, global deaths have surpassed 5.0 million, with the Russian Federation ranking fourth for cases and eighth for deaths worldwide. 48 The recent deployment of approved vaccines in several countries represents a huge milestone; however, continuing research into other treatments is vital. The promising safety and efficacy results presented herein support further assessment of AZB in appropriately controlled

All authors contributed to the study concept and design. SVE, NVM, OVB, LYA, EVK, AAT and EIK enrolled the patients and collected the data. NFK wrote the protocol. AAT and FH managed data collection, monitoring and clean-up. AAT, FH and J-FR analysed the data. TCH, AAT, FH and J-FR wrote the manuscript. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.

Disclosure and potential conflicts of interest: AAT 

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