EA042665B1 - ANTICORONAVIRUS FOR COMBINATION THERAPY FOR COVID-19 (SARS-CoV-2) - Google Patents

Description

This invention relates to the use of a novel anti-coronavirus agent for the prevention and treatment of COVID-19 (SARS-CoV-2).

The sudden outbreak of the novel coronavirus in 2019, later named SARS-CoV-2, in Wuhan, China, which quickly turned into a global pandemic, marked the third introduction of a virulent Coronavirus into human society, affecting not only the healthcare system, but also the global economy . The total number of people infected with coronavirus in the world by the morning of August 19 exceeded 22.05 million people in 188 countries, more than 14.1 million people recovered and 779,557 infected people died.

Coronavirus SARS-CoV-2 belongs to the group of so-called RNA viruses, which are characterized by high mutation rates during the period of distribution. Despite the fact that SARS-CoV-2 has a relatively low mutation rate, the first reports of a new coronavirus mutation with different immune characteristics and virulence have appeared.

Considering that SARS-CoV-2 poses a serious threat to public health and the economy around the world, it seems appropriate to search for new effective anti-coronavirus drugs.

Effective approaches to the prevention and treatment of SARS-CoV-2 (COVID-19) and epidemiological control are still extremely limited. There is an intensive search for therapeutic agents worldwide for the prevention and treatment of SARS-CoV-2 (COVID-19). In this regard, the World Health Organization and national ministries of health are issuing temporary and constantly updated guidelines for the prevention, diagnosis and treatment of coronavirus infection using existing therapeutic agents previously intended for other viral infections (influenza, AIDS, Ebola, etc.).

One of the first drugs redirected to the treatment of COVID-19 was SARS-CoV-2 replication inhibitors Favipiravir (FVP) [https://static0.rosminzdrav.ru/system/attachments/attaches/000/050/584/original/03062020_%D0 %9CR_COVID-19_v7.pdf] and Remdesivir (RMD) [https://nypost.com/2020/05/01/fda-approves-remdesivir-as-emergency-coronavirustreatment/] and an inhibitor of SARS-CoV-2 entry into the cell Aprotinin (APR) [A. Azimi.TMPRSS2 inhibitors, Bromhexine, Aprotinin, Camostat and Nafamostat as potential treatments for COVID-19 [pfile:///C:/Users/av/Downloads/TMPRSS2inhibitors.pdf].

FVP (6-fluoro-3-hydroxy-2-pyrazinecarboxamide, Favipiravir, has RN: 259793-96-9 CA) has antiviral activity against COVID-19 and is part of a number of preparations, which are tablets containing 200 mg of FVP, including: Avigan

[https://www.cdc.gov.tw/File/Get/ht8jUiB_MI-aKnlwstwzvw], Favilavir

[https://www.singlecare.com/blog/news/favilavir-for-coronavirus/], Avifavir [https://medum.ru/avifavir], Areplivir [https://www.rbc.ru/rbcfreenews/5ef4f1219a7947ef 15с93899 ], Coronavirus

[https://www.rbc.ru/rbcfreenews/5f05d1f69a7947c3dcc66cf7] and Fabiflu

[https://myhep.com.ua/preparaty/oncology/fabiflu/].

The adult dose for COVID-19 is 1600 mg twice on the first day (then on day 1) followed by 600 mg twice for 2-10 days (then on day 2-10) for patients weighing <75 kg, 2000 mg twice on the first day (thereafter day 1) and then 800 mg twice for 2-10 days (then on day 2-10) for patients weighing 75-90 kg (inclusive), and 2400 mg twice a day 1 and 1000 mg twice daily 2-10 for patients weighing >90 kg. All doses are in the range of 44 to 64 mg/kg. Duration of treatment 10 days or less in case of confirmed eradication of the virus

RMD (ethylbutyl(2S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazine-7 -yl)-5-cyano3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-propanoate, Remdesivir (Remdesivir, has RN: 1809249-37-3 CA) is used in the treatment of viral infections (COVID- 19): Injection (100 mg) as a sterile, preservative-free lyophilized powder in single use vials Unopened vials of lyophilized powder can be stored below 30°C (86°F) RMD lyophilized powder is dissolved and diluted with 19 ml before use sterile water for injection and further diluted with saline in an infusion bag [https://www.fda.gov/media/137566/download] RMD is used for injection (5 mg/mL) as a concentrated solution in single dose vials. Adult dose for COVID-19: loading dose of 200 mg IV once daily (Day 1) followed by maintenance dose of 100 mg IV once daily (Days 2 to 5 or 10). membrane oxygenation (ECMO) 10 days or invasive mechanical ventilation and/or ECMO not required - only 5-10 days [https; https://www.drags.com/dosage/remdesivir.html].

APR-aprotinin (RN: 9087-70-1 CA, Polypeptide derived from the lungs of cattle. Blocks the kallikrein-kinin system. Inhibits both total proteolytic activity and the activity of individual proteolytic enzymes. It is a polyvalent inhibitor of proteases (including plasmin , kininogenases, trypsin, chymotrypsin, kallikrein, including activating

- 1 042665 fibrinolysis). Reduces fibrinolytic activity of the blood, inhibits fibrinolysis, has a hemostatic effect in coagulopathy). APR has been used in medical practice for more than 50 years and is recommended for use in doses for intravenous, jet or drip administration from 100,000 to 1,000,000 CIE. Aprotinin activity is expressed in kallikrein inactivating units (KIE or KIU). 100,000 CIE APR corresponds to 14 mg of aprotinin [A.V. Ovcharenko a and O.P. Zhirnov. Antiviral Research 1994, 23, 107-118].

APR is part of a number of preparations, which are lyophilisates for the preparation of solutions for intravenous administration, solutions for intravenous and infusion administration, and aerosols for inhalation, including: Aprox, lyophilisate, 133000 CIE/vial, excipients (BB): lactose, sodium hydroxide; Vero-Narcap, lyophilisate, 30,000 ATP/vial (1 ATP=1.33 CIE), BB: lactose, sodium hydroxide (http://www.webvidal.ru/2011/drug/LP_12027.htm]; Ingitril, lyophilisate, 10000 ATRE/vial [https://www.vidal.ru/drugs/ingitril_6970]; Contrykal, 10000 Atre, BB: mannitol [https://www.vidal.ru/drugs/contrykal_37338]; Contrisel, lyophilisate, 10000 CIE /vial, IV: lactose monohydrate, trisodium citrate for injection, 2 ml ampoule of 0.9% sodium chloride solution as a solvent in ampoules [https://medplaza.uz/drugs/drug/kontrisel]: Trasilol® solution for injection , 500,000 CIE/50 ml bottle), BB: sodium chloride, sodium hydroxide and/or hydrochloric acid solution (to adjust pH), water for injection [https://med.obozrevatel.com/lekarstva/trasilol.htm]; Ingiprol, solution for infusion, 10000 CIE/ml, 2 ml ampoule, and lyophilisate for solution for infusion [https://www.rlsnet.ru/tn_index_id_5562.htm: https://www.webapteka.ru/drugbase/name506 .html]; Aprotimbin, injection, 100,000 CIE and 500,000 CIE, 10 ml ampoules [http://dalinsaat.net/aprotimbin/]; Gordox®, solution for injection, 100,000 CIE, 10 ml ampoule, BB: 85 mg sodium chloride, 100 mg benzyl alcohol, water for injection up to 10 ml. [https://www.eapteka.ru/goods/id21876/; https://pharmacynew.org/gordox-ampoules.]: Contriven, injection, 10,000 cfu/ml aprotinin, 1 ml ampoule, IV: sodium chloride, water for injection

[https://tabletki.ua/%D0%9A%D0%BE%D0%BD%D1%82%D1%80%D0%B8%D0%B2%D0%B5%D0%BD/# %D0% A1%D0%BE% D1%81%D1%82%D0%B0%D0%B2]; Traskolan, solution for injection, 100,000 CIE and 500,000 CIE, 10 ml ampoules [https://www.rlsnet.ru/tn_index_id_3198.htm]; Aerus, dosed aerosol for inhalation, in a metal (aluminum) cylinder with a capacity of 30 or 20 ml, respectively, with a dosing device (valve), 35,000 CIE (350 doses) or 25,000 CIE (250 doses), BB: 0.045 ml propellant HFC-134A (1 ,1,1,2-tetrafluoroethane), 0.000045 ml peppermint leaf oil, 0.0075 ml ethanol 96%, 0.0035 ml glycerol 96% and purified water (EurPh), one dose of Aerus® aerosol is 85 CIE, the recommended daily dose does not exceed 2000 CIE. [https://www.rlsnet.ru/tn_index_id_44141.htm].

The present inventors have found that the use of an antiviral combination agent comprising a SARS-CoV-2 replication inhibitor and aprotinin (APR) or a drug based on it in a therapeutically effective amount and ratio for combination therapy of COVID-19 (SARS-CoV-2) leads to a significant increase in the effectiveness of treatment of patients. In particular, it can significantly reduce the duration of treatment and reduce the risk of unwanted side effects.

The use of said anti-coronavirus agent in combination therapy leads to a new and synergistic effect, unknown from the prior art and not obvious to a person skilled in the art.

Thus, a median improvement in clinical status of 2 points in patients hospitalized with COVID-19 with a clinical status of 4, when using the combined agent of this invention, had a value for 5 days, i.e. 1.6 times faster than in the treatment of FVP (8 days) and 2.2 times faster than in the treatment of APR (11 days), and the median normalization of the concentration of C-reactive protein (CRP - indicating the presence or absence of an acute inflammatory process in the body) had a value 1 day, i.e. 13 times shorter than in the treatment of FVP and 9 times shorter than in the treatment of APR (Table 1).

The time of normalization of the CRP index in the patient's blood, which indicates the presence of synergism, is radically reduced when using the combined agent according to this invention.

The following are definitions of terms that are used in the description of this invention.

The term drug is a substance or mixture of substances with established pharmacological activity, which is used for prophylactic or therapeutic purposes.

The term drug is a drug in the form of a specific dosage form.

The term pharmaceutical composition means a composition comprising a drug and at least one of the additional components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and receiving agents, delivery vehicles such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers,

- 2 042665 suspending agents, thickeners, sweeteners, fragrances, fragrances, antibacterial agents, fungicides, lubricants, sustained delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided with agents that slow down the absorption of the active component, for example, aluminum monostearate and gelatin.

Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.

Examples of grinders and spreaders are starch, alginic acid and its salts, silicates.

Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.

The term excipient as used herein refers to a compound that is used to prepare a pharmaceutical composition and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for use in veterinary, as well as pharmacologically acceptable for human use.

The compounds of this invention may be administered alone, but generally they will be administered in admixture with one or more pharmaceutically acceptable excipients, diluents or carriers, selected in consideration of the intended route of administration and standard pharmaceutical practice.

The term therapeutically effective amount as used herein means the amount of a substance or drug required to reduce the symptoms of a disease in a subject. The dose of the substance or drug will be tailored to the individual requirements in each case. This dosage may vary widely depending on numerous factors such as the severity of the disease being treated, the age and general health of the patient, other drugs the patient is being treated with, the mode and form of administration, and the experience of the attending physician.

Typically, treatment is started with a large initial loading dose to rapidly reduce or eliminate the virus, followed by a tapering dose to a level sufficient to prevent a resurgence of infection.

The term subject means a mammal, which includes, but is not limited to, cattle, pigs, sheep, chickens, turkeys, buffaloes, llamas, ostriches, dogs, cats, and a human, preferably a human.

Below is a detailed description of the implementation of specific embodiments of the present invention. However, these data illustrate the present invention, but do not limit the claims of the applicant. Various modifications of the invention are possible within the scope of the claimed claims.

The median improvement in clinical status of 2 points in patients hospitalized with COVID-19 with clinical status 4 using the combined agent of this invention was significant at 5 days (Table 1), i.e. 1.6 times faster than with FVP treatment (8.0 days) and 2.2 times faster than with APR treatment (11 days).

One of the important indicators indicating the presence or absence of an acute inflammatory process in the body is the concentration of C-reactive protein (CRP, C-Reactives protein - CRP) in the patient's blood. The concentration of CRP = 5 mg/l was taken as the norm, and it does not depend on age and gender [https://sosudinfo.ru/krov/c-reaktivnyj-belok/]. With COVID-19, the appearance and increase in the concentration of CRP is observed, which indicates the presence of an acute inflammatory process in the patient's body.

From Table. Table 5 shows that patients treated with FVP had an initial value of CRP = 67.5 (45.3-108.6) mg/l, and the median of its normalization was 8 days (Table 1).

In the treatment of APR, patients had an initial value of CRP=21.5±8.2 mg/l (Table 8), and the median of its normalization was 11 days (Table 1).

When treated with the combined agent according to this invention, patients had an initial value of CRP=38.7±7.5 mg/l (Table 2) and the median of its normalization was only 1 day, i.e. normalization of CRP when using the combined agent according to this invention is 8 times and 11 times faster than in the treatment of FVP and APR, respectively. This indicates that in the treatment of patients with a combined agent according to this invention, the suppression of an acute inflammatory process in the patient's body proceeds radically more effectively than in the treatment of the components included in the combined agent (FVP and APR) and a synergistic anti-inflammatory effect is observed.

One of the important markers that predicts the severity of COVID-19 is D-dimer, which is formed during the breakdown of fibrin, a fibrous protein that is the basis of blood clots. An increase in the concentration of D-dimer indicates that small blood clots are forming in the body. An analysis for D-dimer allows you to evaluate 2 factors in a complex at once: coagulation (blood clotting) and fibrinolysis (dissolution of blood clots). The marker makes it possible to timely detect an imbalance between them in case of diseases of the circulatory system (varicose veins, thrombophilia, pulmonary embolism, etc.). A significant increase in D-dimer concentration is a strong predictor of mortality. This indicator is an early and useful marker and should be determined in patients entering dangerous phases of the disease. Normal D-dimer should not exceed 250 ng/mL (0.55 µg FEU/mL). [https://aif.ru/health/coronavirus/pokazateli_smerti_uchenye_obnaruzhili_markery_tyazhelogo_techeniya_covid-19. http://cardiobook.ru/ddimer/. https://www.diagnos.ru/procedures/analysis/koagulogramma/d-dimer].

The initial value of the concentration of D-dimer 855.5±142.5 ng/ml in the blood of hospitalized patients with COVID-19 with clinical status 4 in the treatment with a combined agent according to this invention had a value of 855.5±142.5 ng/ml (Table 2) and returned to normal after 5 days. The elimination of SARS-CoV-2 also proceeded rapidly in patients (median 3.5 days) and the temperature returned to normal within 1 day (Table 1).

When treated with the combined agent according to the invention, all patients (100%) showed an improvement in lung damage according to computed tomography data on day 14, while in the treatment of patients with FVP, this indicator had values of 72.7%, while in 9.1% of patients the damage lungs remained unchanged, and in 18.2% of patients worsening lung damage was observed. In the treatment of patients with APR, this indicator was 60.0%, while in 40.0% of patients, lung damage remained unchanged (Table 1).

Thus, the agent according to this invention has demonstrated high efficiency in the combined therapy of human coronavirus diseases, significantly exceeding the effectiveness of its constituent components.

No serious adverse events were recorded during the study. Adverse reactions noted in some cases were mild or moderate in severity and in most cases did not require additional treatment.

Table 1. Effectiveness of treatment of hospitalized patients with COVID-19 with clinical status 4 with a combined agent according to this invention and its components

Index APR + FVP FVP APR Median improvement in clinical status by 2 points, days 5 (5-5) 8(6-11) 11.0 (6-11) Median CRP normalization, days 1 (1-3) 13(13-) 9(6-0) Median D-dimer normalization, days 5 (4-5) n.k. 4.5 (3-6) Median elimination of SARS-CoV-2, days 3.5 (3-4) 4.5 (4-6) 7.5 (6 - 9) Median normalization of body temperature <37°С, days 1 (1-3) 3 (2-4) 3 (2-4) CT on!4th day: % improvement 10(100.0%) 8 (72.7%) 6 (60.0%) % without change 1 (9.1%) 4 (40.0%) % deterioration 2(18.2%)

The effective amounts of SARS-CoV-2 replication inhibitors and APR administered are indicated above and are traditional for these compounds. The clinical dosage of the components of the drug may vary depending on the age, sex, weight and stage of the disease of the patient. The effective ratio of the components will be determined by the effective amount of the respective active component administered.

As a means for the combined therapy of human coronovirus diseases, a ready-made dosage form containing APR, selected from known drugs, can be used: Aprotex, Vero-Narcap, Ingitril, Contrykal, Contrisel, Trasilol®, Ingiprol, Aprotimbin, Gordox®, Contriven, Traskolan or Aerus.

As inhibitors of SARS-CoV-2 replication, FVP or a finished dosage form containing FVP, which is Avigan, Favilavir, Avifavir, Areplivir, Coronavir or Fabiflu, can be used.

FVP is administered to the patient orally, APR and RMD - parenterally (for example, intravenously, subcutaneously, intraperitoneally, inhalation, in the form of a spray or in the form of drops.

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For APR, the preferred daily dose, depending on the severity of the disease and the route of administration, is from 500,000 to 1,000,000 CIE per day.

For FVP, the preferred adult dose is 1200-1600 mg twice daily on day 1, depending on the severity of the disease, followed by 400-600 mg twice daily 2-10 for patients <75 kg overweight, 2000 mg twice daily 1 and then 800 mg twice daily on day 2-10 for patients weighing 75-90 kg (inclusive), and 2400 mg twice daily on day 1 and 1000 mg twice daily 2-10 for patients weighing > 90 kg. All doses are in the range of 44 to 64 mg/kg. Duration of treatment 10 days or less in case of confirmed eradication of the virus.

For RMD, the preferred adult dose is 200 mg IV once daily (Day 1) followed by a maintenance dose of 100 mg IV once daily (Days 2 to 5 or 10).

The size of the doses of anti-coronavirus components may vary depending on the severity of the condition to be alleviated. It should be understood that for each particular subject, the specific dosage regimen and schedule may be adjusted in time according to the needs of the individual and the professional judgment of the person who is treating or supervising the combination therapy.

Combination therapy may be sequential, ie. treatment first with one component and then with the other, for example, when each stage of treatment involves a different component of the present invention, or there may be therapy with the introduction of both components at the same time.

Sequential therapy may include a significant time after completion of treatment with one component and before treatment with the second component. Treatment with both components at the same time can be in the same daily dose or in different doses.

More preferred is an agent that includes, in a therapeutically effective amount, the anti-coronavirus components of APR and FVP.

For combination therapy of coronovirus disease, concomitant therapeutic agents may be used, which may be useful when combined and compatible with the anti-coronavirus agent of this invention.

As concomitant therapeutic drugs according to this invention, analgesics (acetylsalicylic acid, paracetamol), angioprotectors (diosmin), antibacterial drugs for systemic use (avelox, azithromycin, amoxicillin), amoxicillin in combination with enzyme inhibitors (levofloxacin, meropenem, metronidazole, cefazolin , Ceftriaxone), antihistamines for systemic action, anticoagulants (fraxiparin, enoxaparin), beta-blockers (bisoprolol, metoprolol), calcium channel blockers (amlodipine, tifedipine), vitamins (ascorbic acid, vitamin C), lipid-lowering drugs (rosuvastatin), diuretics (spironolactone, hypothiazide, indapamide, furosemide), immunosuppressants (tocilizumab, etanercept), systemic corticosteroids (dexamethasone, methylprednisolone, prednisolone), plasma-substituting and perfusion solutions (glucose, sodium chloride, isotonic sterofundin), drugs for the treatment of diseases associated with acid disorders (omeprazole), drugs for the treatment of heart disease (kardiket, nitroglycerin), drugs for the treatment of thyroid diseases (L-thyroxine), drugs for the treatment of obstructive airway diseases (fenoterol), drugs that affect the renin-angiotensin system (valsartan , losartan, lorista, enalapril), antivirals for systemic use (lopinavir, ritonavir), antidiarrheals (Acipol, Diosmectite, sulfosalazine), antitussives and colds (Ambroxol, acetylcysteine, mukaltin), anticancer hormonal drugs (tamoxifen ), other drugs for the treatment of gastrointestinal diseases and metabolic disorders (ademetionine), drugs for the treatment of diabetes mellitus (apidra, levemir, metformin, novomix), etc.

The present invention is illustrated but not limited by the following examples.

Example 1 Efficacy of treatment with a combination agent of this invention in hospitalized patients with moderate COVID-19 and clinical status 4.

The clinical study included 10 hospitalized patients with moderate COVID-19 and clinical status 4 who received separate intravenous APR and oral FVP. Demographic and other baseline characteristics of patients are presented in Table. 2.

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Status Meaning Age(years) 46.7±10.6 18-44 years old 4 (40.0%) 45-59 years old 5 (50.0%) > 60 years old 1 (10.0%) Men 8 (80.0%) Women 2 (20.0%) Body weight (kg) 80.7±6 BMI (kg/m2) 26.4M.5 Duration, ill. (days) 3.4±0.8 < 7 days 10 (100.0%) > 7 days 0 (0.0%) SpO2 (%) 95.0±0.9 >95 6 (60.0%) <95 4 (40.0%)

Table 2. Demographic and other baseline characteristics of 10 hospitalized patients with COVID-19 and clinical status 4 treated with a combined agent of this invention

Status Meaning Temperature (°C) 38.5±0.4 <37 0 (0.0%) 37-38 1 (10.0%) >38 9 (90.0%) NPV (per minute) 21.8±1 <22 7 (70.0%) >22 3 (30.0%) CRP (mg/l) 38.7±7.5 Norm 0 (0.0%) Promoted 7 (70.0%) D-dimer (ng/ml) 855.5±142.5 Norm 0 (0.0%) Promoted 10(100.0%)

Clinical studies were carried out in one of the clinics in Smolensk, Russia, in accordance with the clinical trial protocol.

Primary Objective: To evaluate and compare the efficacy of an anti-coronavirus agent (intravenous APR + oral FVP) in patients hospitalized with COVID-19 and clinical status 4 in terms of the following indicators:

time to elimination of SARS-CoV-2 virus up to day 10;

time to CRP normalization to day 10;

time to D-dimer normalization up to day 10.

Additional objectives: Additional objectives of the study include evaluating the following efficacy and safety measures in patients hospitalized with COVID-19:

time to normalization of body temperature (<37°C);

dynamics of changes in laboratory parameters on day 4, day 5, day 6, day 10 and day 14 relative to baseline values: complete blood count (neutrophils, leukocytes and their ratio, platelets), CRP, coagulogram (D-dimer, fibrinogen, prothrombin according to Quick, MHO);

dynamics of changes in laboratory parameters on day 4, day 5, day 6, day 10 and day 14 relative to baseline values: complete blood count (neutrophils, leukocytes and their ratio, platelets), CRP, coagulogram (D-dimer, fibrinogen, prothrombin according to Quick, MHO);

frequency of improvement in clinical status by 2 points on the ordinal scale of clinical improvement or hospital discharge before day 14;

the frequency of transfer to the intensive care unit (ICU), the frequency of non-invasive ventilation (NIVL), the frequency of mechanical ventilation (ALV) and mortality;

the frequency of adverse events (AE) and serious adverse events (SAE) of varying severity according to subjective complaints, physical examination, vital signs, laboratory tests and ECG.

Study design.

All 10 patients received the combined agent (Table 3). APR was administered intravenously drip (slowly over 15-20 minutes) depending on the patient's health, 5000001000000 CIE 1 time per day for 5 days in addition to FVP in tablets: for patients weighing less than 75 kg and depending on state of health, 1200-1600 mg 2 times a day on day 1 and then 400-600 mg 2 times a day on days 2-10; for patients weighing from 75 to 90 kg (inclusive) 2000 mg 2 times a day on day 1 and then 800 mg 2 times a day on days 2-10; for patients weighing more than 90 kg, 2400 mg 2 times a day on day 1 and then 1000 mg 2 times a day on days 2-10 (Table 3).

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Table 3. Daily doses of the components of the combined agent received by patients in the treatment of COVID-19

Patient Age, years Height, cm Weight body, kg Index Masses body Dose of APR (KIE), 1 time per day Dose of FVP (mg) 2 times a day Day 1-5 Day 1 Day 2- 10 16-2 36 181 85.3 26.04 1,000,000 2000 800 17-2 46 182 88.5 26.72 1,000,000 2000 800 21-2 34 172 80.2 27.2 1,000,000 2000 800 22-2 40 175 72.1 23.6 500 000 1200 400 23-2 59 166 77.5 28.2 1,000,000 2000 800 25-2 35 177 78.4 25 1,000,000 2000 800 26-2 48 180 86.3 26.6 1,000,000 2000 800 28-2 65 167 81.2 29.1 1,000,000 2000 800 29-2 52 181 85.9 26.22 1,000,000 2000 800 30-2 52 166 71.1 25.8 1,000,000 1600 600

Depending on the state of health and concomitant COVID-19 diseases, patients received concomitant therapy (Table 4).

Table 4. Concomitant Therapies Used in the Treatment of Hospitalized COVID-19 Patients with Clinical Status 4 ______ Combination Agent of the Invention

A drug X a %* V ^e A drug X a %* ye Paracetamol 1 9.1 1 Spironolactone 1 9.1 9.1 Azithromycin 3 27.3 3 Tocilizumab 1 9.1 9.1 Amoxiclav 1 9.1 1 Dexamethasone 1 9.1 9.1 Imipenem and dehydropeptidase inhibitor 1 9.1 1 Glucose 1 9.1 9.1 Sodium chloride 2 18.2 3 Levofloxacin 1 9.1 1 Omeprazole 1 9.1 1 Meropenem 1 9.1 1 Levothyroxine sodium 1 9.1 1 Sulbactam 1 9.1 1 Drotaverine 1 9.1 1 thiamphenicol 2 18.2 2 Losartan 1 9.1 1 Cefoperazone 2 18.2 2 Losartan in combination with diuretics 1 9.1 1 Ceftriaxone 1 9.1 1 Enoxaparin 4 36.4 4 Hydroxychloroquine 1 9.1 1 Pancreatin 1 9.1 1 bisoprolol 1 9.1 1 Ambroxol 1 9.1 1 Amlodipine 1 9.1 1 Insulin 1 9.1 1 Ascorbic acid 2 18.2 2 insulin glulisine 1 9.1 1 Hydrochlorothiazide 1 9.1 1 insulin detemir 1 9.1 1 Metronidazole 1 9.1 1

X and % - the number and percentage of patients who had at least one event in this group;

Y is the total number of events in this group.

The results of the effectiveness of treatment with a combined agent according to this invention in hospitalized patients with COVID-19 of moderate severity and clinical status 4 are presented in table. 1.

Example 2 Efficacy of Favipiravir (FVP) Treatment in Hospitalized Patients with COVID-19 and Clinical Status 4.

The clinical study included 11 patients receiving oral FVP. Clinical studies were carried out in one of the clinics in Smolensk, Russia, in accordance with the clinical trial protocol. In the studies, identical protocols for all analyzes were used for all patients. Demographic and other baseline characteristics of patients are presented in Table. 5.

Table 5. Demographic and other baseline characteristics of hospitalized COVID-19 patients with clinical status 4 treated with favipiravir FVP)

Status Meaning Age (years) 57.5M5.9 18-44 years old 2(18.2%)

Status Meaning SpO2 (%) 93.4M.8 >95 3 (27.3%)

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45-59 years old 5 (45.5%) > 60 years old 4 (36.4%) Men 3 (27.3%) Women 8 (72.7%) Body weight (kg) 84.0+16.8 BMI (kg/m2) 30.7+5.3 Duration, ill. (days) 7.3±3 < 7 days 3 (27.3%) > 7 days 8 (72.7%)

<95 8 (72.7%) Temperature (°C) 37.5+0.7 <37 2(18.2%) 37-38 7 (63.6%) >38 2(18.2%) NPV (per minute) 20.4+1.5 <22 10 (90.9%) >22 1 (9.1%) CRP (mg/l) 67.5 (45.3-108.6) Norm 0 (0.0%) Promoted 11 (100.0%)

Primary Objective: To evaluate the efficacy of favipiravir (FVP) on the following in patients hospitalized with COVID-19 and clinical status 4:

time to elimination of SARS-CoV-2 virus up to day 10;

time to normalize CRP to day 10. Additional goals are the same as in example 1.

Study design: all 11 patients took oral FVP in tablets: for patients weighing less than 75 kg and depending on the state of health, 1200-1600 mg 2 times a day on day 1 and then 400-600 mg 2 times a day on days 2-10; for patients weighing from 75 to 90 kg (inclusive) 2000 mg 2 times a day on day 1 and then 800 mg 2 times a day on days 2-10; for patients weighing more than 90 kg, 2400 mg 2 times a day on day 1 and then 1000 mg 2 times a day on days 2-10 (Table 6).

Table 6. Daily doses of the components of the combination agent received by patients treated with COVID-19 with favipiravir (FVP)

Patient Age, years Height, cm Weight body, kg Body Mass Index kg/m ² Dose of FVP (mg) 2 times a day Day 1 Day 2-10 02-001 53 170 120 41.52 1800 800 02-003 49 173 95 31.74 1600 600 04-001 83 158 90 May 36 1600 600 04-007 59 158 83 33.25 1600 600 05-001 60 158 70 28.04 1800 800 05-002 36 176 80 25.83 1800 800 05-003 76 160 82 32.03 1800 800 05-005 56 175 92 30.04 1800 800 05-009 56 158 63 25.24 1600 600 05-011 74 170 90 31.14 1800 800 05-012 31 161 59 22.76 1600 600

Depending on the state of health and concomitant COVID-19 diseases, patients received concomitant therapy (Table 7).

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Table 7. Concomitant Therapies Used in the Treatment of Hospitalized COVID-19 Patients with Clinical Status 4 Favipiravir (FVP)

A drug X ^e %* us Chronic pancreatitis 2 18.2 2 Chronic gastritis 1 9.1 1 Pneumonia 9 81.8 9 Pneumonia viral 1 9.1 1 Hyperlipidaemia 1 9.1 1 Dyslipidemia 1 9.1 1 Obesity 6 54.5 6 Type 2 diabetes 4 36.4 4 Bronchitis, chronic 1 9.1 1 Back pain 1 9.1 1 Ostearthritis 1 9.1 1 Osteochondrosis 1 9.1 1 Headache 1 9.1 1 cerebral ischemia 1 9.1 1 Glaucoma 1 9.1 2 Myopia 1 9.1 1 Vertigo 1 9.1 1

Cholecystitis 1 9.1 1 Cholecystitis 1 9.1 1

A drug X ^th %* mustache chronic kidney disease 1 9.1 1 Myocardial ischemia 3 27.3 3 Arteriosclerosis 1 9.1 1 Varicose veins 1 9.1 1 hypertension 6 54.5 6 Deep vein thrombosis 1 9.1 1 Phlebitis 1 9.1 1 Menopause 6 54.5 6 Fracture of the thoracic vertebra 1 9.1 1 tendon rupture 1 9.1 1 Appendectomy 1 9.1 1 Hysterectomy_______ 1 9.1 1 Vein ligation 1 9.1 2 Polypectomy of the stomach I 9.1 1 Retinal laser coagulation 1 9.1 2 Cholecystectomy 1 9.1 1 Endocrine disorders 1 9.1 1 Hypothyroidism 1 9.1 1

The results of the effectiveness of treatment with favipiravir in hospitalized patients with COVID-19 and clinical status 4 are shown in Table. 1.

Example 3 Efficacy of Aprotinin (APR) Treatment in Hospitalized Patients with COVID19 and Clinical Status 4.

The clinical study included 10 patients who received APR intravenously. Demographic and other baseline characteristics of patients are presented in Table. 8.

Table 8. Demographic and other baseline characteristics of hospitalized patients with COVID-19 and clinical ________status 4 treated with aprotinin (APR)________

Status Meaning Age (years) 44.9±11.2 18-44 years old 4 (40.0%) 45-59 years old 6 (60.0%) > 60 years old 0 (0.0%) Men 3 (30.0%) Women 7 (70.0%) Body weight (kg) 74.3±4.7 BMI (kg/m2) 25.9±1.7 Duration, ill. (days) 3.4±1.1 < 7 days 10 (100.0%) > 7 days 0 (0.0%) SpO2 (%) 96.7±1.1 >95 10 (100%) <95 0 (0.0%)

Status Meaning Temperature (°C) 38.3±0.1 <37 0 (0.0%) 37-38 0 (0.0%) >38 10 (100%) NPV (per minute) 21.4±1.6 <22 8 (80.0%) >22 2 (20.0%) CRP (mg/l) 21.5±8.2 Norm 0 (0.0%) Promoted 10 (100.0%) D-dimer (ng/ml) 525.4±175.7 Norm 0 (0.0%) Promoted 10 (100.0%)

Clinical studies were carried out in one of the clinics in Smolensk, Russia, in accordance with the Protocols of Clinical Studies. In the studies, identical protocols for all analyzes were used for all patients.

Primary Objective: To evaluate the efficacy of intravenous APR for the following in patients hospitalized with COVID-19 and clinical status 4:

time to elimination of SARS-CoV-2 virus up to day 10;

time to CRP normalization to day 10;

time to D-dimer normalization up to day 10.

Additional goals: the same as in example 1.

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Claims (2)

Study design: all 10 patients received APR intravenously (slowly over 15-20 min) 1,000,000 CIE 1 time per day for 3 days (Table 9). Table 9. Daily doses of the components of the combination agent received by patients treated with COVID-19 with aprotinin (APR) Patient Age, years Height, cm Weight body, kg Index body weight Dose of APR (KIE) 1 time per day 01 56 173 81.4 27.20 1,000,000 02 55 166 72.5 26.31 1,000,000 03 50 169 73.6 25.77 1,000,000 04 24 160 72.1 28.16 0 05 43 176 78.7 25.41 0 06 31 170 75.5 26.12 0 07 41 168 65.2 23.10 0 08 48 179 73.5 22.94 0 09 49 169 79.3 27.77 0 10 60 165 71.4 26.23 0 Depending on the state of health and concomitant COVID-19 diseases, patients received concomitant therapy (Table 10). Table 10. Concomitant Therapies Used in the Treatment of Hospitalized COVID-19 Patients with Clinical Status 4 Aprotinin (APR) A drug X a %* Y with Hydroxychloroquine 9 (90.0% ) 9 Ringer's solution 1 (10.0% ) 1 Lopinavir + Ritonavir 1 (10.0% ) 1 Ritonavir 1 (10.0% ) 1 Preparation X ^e %* us Paracetamol 10 (100.0% ) 10 Azithromycin 9 (90.0%) 9 Levofloxacin 1 (10.0%) 1 Enoxaparin 10 (100.0% ) 10 The results of the effectiveness of treatment with aprotinin in hospitalized patients with COVID-19 and clinical status 4 are shown in Table. 1. CLAIM 1. Use in therapeutically effective amounts of two drugs, one of which includes aprotinin, and the other - an inhibitor of SARS-CoV-2 replication - favipiravir, for combination therapy of COVID-19 (SARS-CoV-2). 2. The use according to claim 1, according to which a drug containing aprotinin in a form suitable for intravenous administration is used, and another drug containing an inhibitor of SARS-CoV-2 replication - favipiravir, in the form of a tablet. 4¾) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2