RU2742116C1 - Anti-coronavirus agent for covid-19 combination therapy (sars-cov-2) - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to medicine. Disclosed is the use in therapeutically effective amounts and ratios of two drugs in COVID-19 combination therapy (SARS-CoV-2). One of these drugs includes aprotinin. The other one includes favipiravir which is SARS-CoV-2 replication inhibitor.EFFECT: invention provides a synergetic effect of two drugs in treatment of COVID-19 and can significantly reduce the duration of treatment and risk of adverse side effects.1 cl, 10 tbl, 3 ex

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 new coronavirus in 2019, later named SARS-CoV-2, in Wuhan, China, which quickly turned into a global pandemic, heralded the third introduction of the 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.

The SARS-CoV-2 coronavirus belongs to the group of so-called RNA viruses, which are characterized by high mutation rates during the period of spread. 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 surfaced.

Given 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. Around the world, there is an intensive search for therapeutic agents for the prevention and treatment of SARS-CoV-2 (COVID-19). In this regard, the World Health Organization and national health ministries 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 reoriented to the treatment of COVID-19 were SARS-CoV-2 replication inhibitors Favipiravir (FVP) [https://static-0.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-emergeney-coronavirus-treatment/] and SARS-CoV entry inhibitor -2 per 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 drugs that are tablets containing 200 mg of FPP, 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/5ef4f1219a7947ef15c93899], Coronavir [https://www.rbc.ru/rbcfreenews/5f05d1dab66c7947c3] https://myhep.com.ua/preparaty/oncology/fabiflu/].

The dose for COVID-19 for adults is 1600 mg twice on the first day (hereinafter on day 1) and then 600 mg twice for 2-10 days (hereinafter day 2-10) for patients weighing <75 kg, 2000 mg twice on the first day (hereinafter 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 range from 44 mg / kg to 64 mg / kg. Duration of treatment is 10 days or less in case of confirmed elimination of the virus [https://static-0.rosminzdrav.ru/system/attachments/attaches/000/050/584/original/03062020_%D0%9CR_COVID-19_v7.pdf].

RMD (ethylbutyl (2S) -2 - (((S) - (((2R, 3S, 4R, 5R) -5- (4-aminopyrrolo (2,1-f) (1,2,4) triazine-7 -yl) -5-cyano-3,4-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): For 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) Lyophilized RMD powder is dissolved and diluted before use 19 ml of sterile water for injection and additionally 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 vials with one Dose for adults with COVID-19: - loading dose of 200 mg intravenously once (day 1) and then a maintenance dose of 100 mg intravenously once a day (days 2 to 5 or 10). apia with invasive mechanical ventilation and / or extracorporeal membrane oxygenation (ECMO) 10 days or with invasive mechanical ventilation and / or ECMO not required - only 5-10 days [https://www.drugs.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 the total proteolytic activity and the activity of individual proteolytic enzymes. Is a polyvalent protease inhibitor (incl. . plasmin, kininogenases, trypsin, chymotrypsin, kallikrein, including activating fibrinolysis). Reduces fibrinolytic activity of blood, inhibits fibrinolysis, has a hemostatic effect in coagulopathies). APR has been used in medical practice for more than 50 years and is recommended for use in doses for intravenous, jet or drip injection from 100,000 to 1,000,000 KIE. The activity of aprotinin is expressed in kallikrein inactivating units (KIE or KIU). 100,000 KIE APR corresponds to 14 mg of aprotinin [A.V. Ovcharenko a and O.R. Zhirnov. Antiviral Research 1994, 23, 107-118].

APR is a part of a number of drugs, which are lyophilisates for the preparation of solutions for intravenous administration, solutions for intravenous and infusion administration, and aerosols for inhalation, including: Aprotex, lyophilisate, 133000 KIE / vial, excipients (BB): lactose, sodium hydroxide; Vero-Narkap, lyophilisate, 30,000 ATpE / vial (1 ATpE = 1.33 KIE), BB: lactose, sodium hydroxide (http://www.webvidal.ru/2011/drug/LP_12027.htm]; Ingitril, lyophilisate, 10000 ATPE / bottle [https://www.vidal.ru/drugs/ingitril_6970]; Contrikal, 10000 ATPE, BB: mannitol [https://www.vidal.ru/drugs/contrykal_37338]; Contrisel, lyophilisate, 10000 KIE / vial BB: lactose monohydrate, trisodium citrate for injection, an ampoule 2 ml of 0.9% sodium chloride solution as a solvent in ampoules [https://medplaza.uz/drugs/drug/kontrisel]; Trasylol ^® injection. , 500,000 KIE / bottle 50 ml), BB: sodium chloride, sodium hydroxide and / or hydrochloric acid solution (to adjust the pH), water for injection [https://med.obozrevatel.com/lekarstva/trasilol.html; Ingiprol, solution for infusion, 10,000 KIE / ml, ampoule of 2 ml, and lyophilisate for preparation of solution for infusion [https://www.rlsnet.ru/tn_index_id_5562.htm; https://www.webapteka.ru/drugbase/name506.html]; Aprotimbin, solution for injection, 100,000 KIE and 500,000 KIE, 10 ml ampoules [http://dalinsaat.net/aprotimbin/]; Gordox ^® , solution for injection, 100000 KIE, ampoule 10 ml, BB: 85 mg sodium chloride, 100 mg benzyl alcohol, water for injection up to 10 ml. [https://www.eapteka.ru/goods/id21876/; https://pharmacy-new.org/gordox-ampoules]; Contriven, solution for injection, 10000 KIE / ml aprotinin, ampoule 1 ml, BB: 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 KIE and 500,000 KIE, 10 ml ampoules [https://www.rlsnet.ru/tn_index_id_3198.htm]; Aerus, metered dose aerosol for inhalation, in a metal (aluminum) can with a capacity of 30 or 20 ml, respectively, with a dosing device (valve), 35,000 KIE (350 doses) or 25,000 KIE (250 doses), BB: 0.045 ml HFC-134A propellant (1 , 1,1,2-tetrafluoroethane), 0.000045 ml peppermint leaf oil, 0.0075 ml of 96% ethanol, 0.0035 ml of 96% glycerol and purified water (EurPh), one dose aerosol Aerus ^® 85 KIU, the recommended daily dose does not exceed 2000 KIE. [https://www.rlsnet.ru/tn_index_id_44141.htm].

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

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

So, the median improvement in clinical status by 2 points, patients hospitalized with COVID-19 with clinical status 4, when using the combined agent according to this invention, had a value for 5 days, i.e. 1.6 times faster than in the treatment of AFP (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 acute inflammatory process) had a value of 1 day, i.e. 13 times shorter than in the treatment of FP and 9 times shorter than in the treatment of APR (Table 1).

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

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

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

The term "drug" is a drug in a particular dosage form.

The term "pharmaceutical composition" means a composition comprising a drug and at least one of additional components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, dispensing and receiving agents, delivery means such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavorings, 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, and 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 by agents that slow down the absorption of the active ingredient, for example, aluminum monostearate and gelatin.

Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, as well as 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 dispensers 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 to veterinary use as well as pharmacologically acceptable for human use.

The compounds of this invention may be administered alone, but will usually be administered in admixture with one or more pharmaceutically acceptable excipients, diluents or carriers selected based on 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 the drug will be tailored to the individual requirements in each case. This dose can vary widely depending on numerous factors, such as the severity of the disease to be treated, the age and general health of the patient, other drugs with which the patient is being treated, the method 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, accompanying the tapering dose to a level sufficient to prevent an outbreak of infection.

The term "subject" means a mammal that includes, but is not limited to, cattle, pigs, sheep, chickens, turkeys, buffaloes, llamas, ostriches, dogs, cats, and humans, preferably the subject is 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 stated claims.

The median improvement in clinical status by 2 points for patients hospitalized with COVID-19 with clinical status 4 when using the combination agent according to this invention was significant for 5 days (Table 1), i.e. 1.6 times faster than in the treatment of AFP (8.0 days) and 2.2 times faster than in the treatment of APR (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 is taken as the norm, and it does not depend on age and gender [https://sosudinfo.ru/ krov / c-reaktivnyj-belok / 1. 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.

Table 5 shows that patients treated with FVP had an initial CRP value of 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 CRP value of 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, the patients had an initial CRP value of 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 the combined agent according to this invention, the suppression of the acute inflammatory process in the patient's body proceeds radically more effectively than in the treatment with the components included in the combined agent (FP and APR) and synergism of the anti-inflammatory action is observed.

One of the important markers predicting a severe course of COVID-19 is the D-dimer, which is formed by 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 being formed in the body. The analysis for D-dimer allows in a complex to evaluate 2 factors at once: coagulation (blood clotting) and fibrinolysis (dissolution of blood clots). The marker makes it possible to timely detect the 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 must be determined in patients entering dangerous phases of the disease. Normally the 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/d-imer/. 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 during treatment with a combination agent according to this invention had a value of 855.5 ± 142.5 ng / ml (Table 2) and returned to normal after 5 days. Elimination of SARS-CoV-2 (median 3.5 days) proceeded just as quickly in patients and the temperature returned to normal within 1 day (Table 1).

With the treatment with the combined agent according to the present invention, according to the computed tomography data on Day 14, all patients (100%) showed an improvement in lung damage, while in the treatment of patients with AFP, this indicator was 72.7%, while in 9.1% of patients the lesion was lungs remained unchanged, and in 18.2% of patients worsening of lung lesions was observed. When treating 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 combination therapy of human coronavirus diseases, significantly exceeding the effectiveness of its constituent components.

No serious adverse events were reported during the study. The adverse reactions noted in some cases were mild to moderate and in most cases did not require additional treatment.

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

As a means for the combined therapy koronovirusnyh human diseases can be used finished dosage form containing APR selected from known drugs: Aproteks, Vero Narkap, ingitrila, Contrycal, Kontrisel, Trasylol ^®, Ingiprol, Aprotimbin, Gordoks ^®, Kontriven, Traskolan or Aerus.

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

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

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

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

For RMD, the preferred adult dose is 200 mg IV once (day 1) followed by a maintenance dose of 100 mg IV once a day (days 2 through 5 or 10).

The dose size of the anti-coronavirus components can vary depending on the severity of the condition to be alleviated. It should be understood that for each particular subject, the specific dosing 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 observing the combination therapy treatment.

The combination therapy can be sequential, i.e. 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 may be therapy with the introduction of both components at the same time.

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

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

For combination therapy of coronavirus disease, concomitant therapeutic agents can 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, Merazolefin , Ceftriaxone), antihistamines for systemic action, anticoagulants (fraxiparin, enoxaparin), beta-blockers (bisoprolol, metoprolol), calcium channel blockers (amlodipine, tifedipine), vitamins (ascorbic acid, vitamin C), hypolipine drugs diuretics (spironolactone, hypothiazide, indapamide, furosemide), immunosuppressants (tocilizumab, etanercept), corticosteroids for systemic use (dexamethasone, methylprednisolone, prednisolone), plasma substitutes and steroids for the treatment of svyazofundin sodium chloride from acidity disorders (omeprazole), drugs for the treatment of heart diseases (cardiket, nitroglycerin), drugs for the treatment of thyroid diseases (L-thyroxine), drugs for the treatment of obstructive airways diseases (fenoterol), drugs affecting the renin-angiotensin system (valsartan, losartan, lorista, enalapril), antiviral drugs for systemic use (lopinavir, ritonavir), antidiarrheal drugs (acipol, diosmectite, sulfosalazine), antitussive drugs and drugs for the treatment of colds (ambroxol, acetylcysteine, hormonal drugs, mucousaltin) (tamoxifen), other drugs for the treatment of gastrointestinal diseases and metabolic disorders (ademetionine), drugs for the treatment of diabetes (apidra, levemir, metformin, Novomix), etc.

This invention is illustrated but not limited by the following examples.

Example 1. The efficacy of treatment with a combination agent according to this invention in hospitalized patients with COVID-19 of moderate severity and clinical status 4.

The clinical study included 10 hospitalized patients with COVID-19 of moderate severity and clinical status 4, who received separately intravenous APR and oral FRP. Patient demographics and other baseline characteristics are presented in Table 2.

Clinical studies were carried out in one of the clinics in the city of Smolensk, RF in accordance with the Clinical Trials Protocol.

Primary objective: To evaluate and compare the effectiveness of an anti-coronavirus agent (intravenous APR + oral FP) in patients hospitalized with COVID-19 and clinical status 4 according to the following indicators:

• Time to elimination of SARS-CoV-2 virus up to Day 10;

• Time to CRP normalization up to Day 10.

• Time to D-dimer normalization up to Day 10.

Additional Objectives: Additional objectives of the study include assessing the following indicators of drug efficacy and safety 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 the initial values: complete blood count (the number of neutrophils, leukocytes and their ratio, the number of platelets), CRP, coagulogram (D-dimer, fibrinogen, Quick prothrombin, MHO);

• Dynamics of changes in laboratory parameters on Day 4, Day 5, Day 6, Day 10 and Day 14 relative to the initial values: complete blood count (the number of neutrophils, leukocytes and their ratio, the number of platelets), CRP, coagulogram (D-dimer, fibrinogen, Quick prothrombin, MHO);

• Frequency of improvement in clinical status by 2 points on the Ordinal Clinical Improvement Scale or hospital discharge before Day 14;

• The frequency of transfer to the intensive care unit (ICU), the frequency of non-invasive ventilation (NIV), the frequency of artificial ventilation (ALV) and mortality;

• Frequency of adverse events (AEs) and serious adverse events (SAEs) of varying severity based on subjective complaints, physical examination, vital signs, laboratory tests, and ECG.

Study design:

All 10 patients received the combination medication (Table 3). APR was injected intravenously (slowly over 15-20 minutes), depending on the patient's health status, 500,000 KIE - 1,000,000 KIE 1 time per day for 5 days in addition to FPP in tablets: for patients weighing less than 75 kg and depending on the state of health, 1200 mg - 1600 mg 2 times a day on Day 1 and then 400 mg - 600 mg 2 times a day on days 2-10; for patients weighing from 75 kg 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).

Patients received concomitant therapy depending on their health status and comorbid COVID-19 diseases (Table 4).

The results of the efficacy of treatment with the combination agent according to this invention of 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 FPV. Clinical studies were carried out in one of the clinics in the city of Smolensk, RF in accordance with the Clinical Trials Protocol. The studies used identical protocols for all analyzes for all patients. Patient demographics and other baseline characteristics are presented in Table 5.

Main objective: To evaluate the effectiveness of favipiravir (FVP) according to the following indicators 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 up to Day 10.

Additional goals are the same as in example 1.

Study design: All 11 patients took oral FPP in tablets: for patients weighing less than 75 kg and depending on the state of health, 1200 mg - 1600 mg 2 times a day on Day 1 and then 400 mg - 600 mg 2 times a day on days 2-10; for patients weighing from 75 kg 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).

Patients received concomitant therapy depending on their health status and comorbid COVID-19 diseases (Table 7).

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

Example 3. Efficiency of treatment with aprotinin (APR) in hospitalized patients with COVID-19 and clinical status 4.

The clinical study included 10 patients who received intravenous APR. Patient demographics and other baseline characteristics are presented in Table 8.

Clinical studies were carried out in one of the clinics in the city of Smolensk in the Russian Federation in accordance with the Clinical Trials Protocols. The studies used identical protocols for all analyzes for all patients.

The main goal is to evaluate the effectiveness of intravenous APR according to the following indicators 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 up to Day 10.

• Time to D-dimer normalization up to Day 10.

Additional goals are the same as in example 1.

Study design: All 10 patients received APR intravenously (slowly over 15-20 minutes) at 1,000,000 CIE 1 time per day for 3 days (Table 9).

Patients received concomitant therapy depending on their health status and comorbid COVID-19 diseases (Table 10).

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

Claims (1)

The use of therapeutically effective amounts and ratios of two drugs, one of which includes aprotinin and the other, the SARS-CoV-2 replication inhibitor favipiravir, in combination therapy for COVID-19 (SARS-CoV-2).