Types of clinical trials of drugs. Treatment of Acute Respiratory Infection in Adults: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Randomized Trial

Acute respiratory infections (ARIs) of viral etiology, including influenza, are widespread throughout the world and cause significant economic damage to both the healthcare system and the economy as a whole, including due to an increase in the number of days of incapacity for work. The development of new methods for the prevention, control and treatment of ARI and influenza is an urgent medical problem.

The search for new antiviral agents is carried out in two directions: in the first case, the “target” is the pathogen, in the second, the human body into which the virus is introduced. The action of direct antiviral drugs is aimed at blocking viral enzymes that play a key role in the stages of replication, transcription, and release of viruses. Another group of drugs is characterized by a pathogenetic effect aimed at correcting the processes accompanying virus-induced inflammation in the respiratory tract. In this context, it is worth noting that the current WHO influenza strategy draws attention to the need for a more detailed study of immunomodulators. Obviously, this interest is due to the peculiarities of the antiviral immune response associated with the interferon system. It is known that adequate induction of interferon genes in the first 4 days of the disease contributes to a mild course of influenza, while a severe course of infection is noted with insufficient activation of interferons.

One of the drugs that affect the regulation of antiviral reactions due to the targeted effect on the main molecules involved in the immune response is Ergoferon. The drug contains affinity-purified antibodies to interferon gamma, CD4+ receptor and histamine, subjected to technological processing (ultra-high dilutions), as a result of which the active components acquire the ability to modify the activity of their targets by influencing their conformational parameters. As a result, Ergoferon changes the interaction of endogenous molecules with the corresponding receptors, providing a complex antiviral, immunomodulatory, anti-inflammatory and antihistamine action.

The therapeutic efficacy and safety of the use of the complex antiviral drug Ergoferon in adults and children with ARI and influenza has been shown in randomized clinical trials. The drug significantly reduces the duration of fever, intoxication and catarrhal symptoms, and is also effective in eliminating existing complications of SARS and influenza. The purpose of this study was to study the safety and efficacy of a new liquid dosage form of the drug in adults with ARI of the upper respiratory tract.

Material and research methods

Study design

Conducted double-blind, placebo-controlled, randomized clinical trial in parallel groups with a ratio of 1:1 (Phase III).

Eligibility Criteria

The study involved outpatients of both sexes aged 18-60 years with manifestations of ARI of the upper respiratory tract (body temperature> 37.8 ° C, the presence of two or more symptoms of moderate severity (2 points) or three or more symptoms of mild severity (1 score) on the CCQ scale (Common Cold Questionnaire) within ≤ 24 hours from the onset of the disease). The patient was included in the study after signing the informed consent form for participation in compliance with the inclusion / non-inclusion criteria based on the results of screening (history, thermometry and physical examination data). To assess body temperature, tympanic thermometry using an individual electronic infrared thermometer was used, which is a valid method comparable to measurements in other areas of the body. The study did not include patients with suspected invasive bacterial infection or severe disease requiring antibiotics (including sulfonamides); suspicion of the initial manifestations of diseases that have symptoms similar to ARI. In addition, exclusion criteria were exacerbations or decompensation of chronic diseases; mental illness, impaired glucose tolerance, type 1 and type 2 diabetes; oncological diseases; aggravated allergy history, hereditary fructose intolerance (due to the presence of maltitol in the study drug), as well as allergy / intolerance to any of the components of approved drugs, pregnancy, breastfeeding, alcohol abuse, drug use; participation in other clinical trials within the previous 3 months. All participants in the study used contraceptive methods during the study and for 30 days after the end of the study.

Randomization

After the screening procedure, the patients included in the study were randomized using a special Interactive Voice System (IGS) based on a random number generator in a 1:1 ratio into 2 groups: group 1 (Ergoferon) and group 2 (placebo). Block randomization was used with a block size of at least 4 participants. The GHI used ensured uniform inclusion of patients of different age groups in the study, their distribution into groups, and the correct prescription of the study therapy.

Description of the intervention

Patients from the 1st group received the study drug according to the following scheme: on the first day of treatment, 8 doses (in the first 2 hours, 1 scoop every 30 minutes, then, in the remaining time, 3 more times at regular intervals), from 2 on the 5th day - 1 scoop 3 times a day. Patients from the 2nd group received a placebo according to the regimen of Ergoferon. All study participants received symptomatic ARI therapy as needed: cough medications, vasoconstrictive nasal drops, detoxification therapy, and antipyretics (paracetamol 500 mg or Nurofen® 200 mg, provided by the sponsor). 1 month before and during the study, it was forbidden to take antiviral (except for Ergoferon in the framework of this study), antibacterial, antihistamine, antitumor drugs, immunotropic drugs, vaccines, immunoglobulins, sera, etc.

Each patient was observed up to 7 days (screening and randomization - 1st day, treatment - 1-5 days, follow-up at the end of treatment - up to 2 days). In total, 3 visits were made during the treatment and observation (visit 1, visit 2, visit 3, respectively, on the 1st, 3rd and 7th days of observation). At Visits 1 and 3, samples were taken for laboratory testing. At visits 2 and 3, the investigator performed an objective examination, including thermometry and an assessment of the severity of ARI symptoms using the CCQ scale. General symptoms (fever, chills, muscle pain), symptoms associated with the nose (discharge from the nose, sneezing, watery eyes), throat (sore throat) and chest (cough, chest pain) were assessed in points from 0 up to 3. And also, the prescribed and concomitant therapy was monitored, the safety of the treatment was assessed, the patient's diary was checked (in which the patient daily in the morning and evening from the first day of treatment noted the values of tympanic temperature and ARI symptoms according to the WURSS-21 questionnaire (The Wisconsin Upper Respiratory Symptom Survey - 21) This questionnaire allows you to assess the severity of the course of ARI in points from 0 to 7 for each item: the patient's general well-being, the severity of ARI symptoms ("Symptoms" domain), the impact of the disease on the patient's ability to cope with various types of daily activities (domain " ability").

Blindness

The double-blind design of the study included identical appearance and organoleptic properties of the study drug and placebo, as well as the absence of information about the therapy received (Ergoferon or placebo) in patients, investigators, employees of research centers and the sponsor's team until the study was completed and the database was closed.

Study Endpoints

The primary efficacy endpoint was the mean duration of fever (body temperature above 37.0°C) as measured by the patient's diary. Its completion was considered the absence of a temperature > 37.0 °C for 24 hours or more. Additionally, we assessed the dynamics of ARI clinical manifestations according to the data of an objective examination by a doctor (the sum of CCQ scores on the 1st, 3rd, and 7th days of treatment), the dynamics of ARI symptoms according to the patient’s daily subjective assessment (total score and domain scores of the WURSS questionnaire -21 according to the patient's diary), the number of antipyretic drugs (on the 1st, 2nd, 3rd, 4th and 5th days of treatment), the proportion of patients with a worsening course of the disease (appearance of symptoms of ARI of the lower respiratory tract development of complications requiring antibiotics or hospitalization). The safety of therapy was assessed taking into account the number and nature of adverse events (AEs), their relationship with the drug; deviations of laboratory indicators in the course of treatment.

Sample size calculation

The sample size was based on a statistical power of 80%, a Type I error rate of less than 5, and the expected effect of the study drug in reducing the mean duration of fever compared with placebo. Considering the study's dropout rate of 1.1, the minimum required sample size was 342 people.

Features of statistical analysis

As part of the study, it was planned to conduct an interim analysis (in order to adjust the sample size or stop the study early) at 2 stages - the inclusion of at least 60 and at least 105 patients in each group who received therapy and completed all visits in full accordance with the protocol. In this regard, the critical value of the error of the first kind for the final analysis was set using the rules of the Pocock criterion (Pocock boundary) at the level α = 0.0221; all results were considered significant only if the p-value was equal to or less than this value. For data processing, the χ 2 test was used, and for multiple comparisons, the χ 2 test modified by Cochran-Mantel-Haenszel (CMH) was used. Analysis of continuous variables was carried out using the nonparametric Kruskal-Wallis test and one-way median analysis (χ 2 Median One-Way Analysis). Multivariate analysis of continuous and polynomial variables was carried out using the analysis of variance for repeated measurements (Repeated Measures Analysis Of Variance, ANOVA, The MIXED Procedure). Numerical data are presented as mean, standard deviation, as well as median, maximum and minimum values. To compare the severity of the course of the disease in the groups, the area under the curve model (Area Under Curve, AUC, conventional units, c.u.) was used for the total score of the CCQ scale and the WURSS-21 questionnaire. This indicator was calculated as the product of the total CCQ/WURSS-21 score by the number of visits/days (n = 3/7) during which symptoms were recorded.

Permission of the Ministry of Health of the Russian Federation No. 835 to conduct the study was received on March 30, 2012, 22 research centers were approved - outpatient bases of medical institutions in Moscow, St. Petersburg, Yaroslavl, Kazan, Chelyabinsk and Voronezh. The study was conducted during the epidemiological seasons of 2012-2015. with the support of LLC NPF Materia Medica Holding. The design of the study is presented in the global database of clinical trials - ClinicalTrials.gov, ST id: NCT01765920.

Research results

Patient characteristics

Patients were randomized to study drug (group 1; n = 169) and placebo (group 2; n = 173). This sample was used to assess the safety of therapy (all included patients who received at least one dose of the study drug/placebo (Safety population, n = 342). Eight patients dropped out during the study (7 patients were included erroneously, in 1 patient the code was disclosed and data were missing after inclusion), an additional 12 participants were excluded during data processing due to major protocol deviations (Fig. 1).

Thus, the Intention to treat (ITT) analysis included data from 167 patients of the 1st group and 167 patients of the 2nd group; 160 patients of the 1st group and 162 patients of the 2nd group completed their participation in the study in accordance with the procedures of the Per protocol (PP-analysis).

The mean age of all included and randomized patients (n = 342) was 36.3 ± 10.6 years in group 1 and 35.1 ± 10.9 years in group 2 (χ 2 = 0.867, p = 0, 35). The groups did not differ in sex ratio: 71 (42.0%) men and 98 (58.0%) women versus 58 (33.5%) men and 115 (66.5%) women in the 1st and 2nd groups, respectively (p = 0.119) (data are presented as the mean value and its standard deviation).

The clinical picture of the disease in patients was manifested by fever in combination with symptoms of intoxication and catarrhal manifestations. The mean body temperature at visit 1 was 38.1 ± 0.3 °C in group 1 and 38.1 ± 0.3 °C in group 2, p = 0.40 (hereinafter, the data are presented in in the form of ITT [PP] samples, respectively). When assessed by a physician, the initial total score for the severity of ARI symptoms on the CCQ scale was 10.4 ± 3.6 points in the Ergoferon group and 10.7 ± 3.9 points in the placebo group (p = 0.72 [p = 0.59]) . As assessed by the patient, the initial WURSS-21 total score was 68.7 ± 25.3 points in the Ergoferon group and 73.4 ± 27.4 points in the placebo group (p = 0.11 [p = 0.07]). The average values of the "Symptoms" domain were registered at the level of 28.3 ± 11.2 and 30.3 ± 11.4 points, the "Ability" domain - 30.0 ± 15.8 and 32.7 ± 17.2 points in two groups respectively, with no significant differences between groups. At baseline, demographic, anthropometric characteristics, and the severity of clinical symptoms of ARI in participants excluded from the analysis were within the range of patients whose data were included in the ITT analysis [PP analysis] and did not differ between groups.

The majority of participants in group 1 (92.3%) and group 2 (94.1%) received concomitant medication (p = 0.502 [p = 0.798]). Most often, vasoconstrictive nasal drops and sprays, antitussive drugs, vitamin and mineral complexes, dental drugs, non-steroidal anti-inflammatory drugs, drugs for the treatment of throat diseases, antiseptics and disinfectants, analgesics were most often used in both groups. Single patients took drugs of other pharmacological groups, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium channel antagonists, diuretics, hemostatic drugs, combined oral contraceptives. There were no statistically significant differences between the groups, as well as between the patients excluded from the efficacy analysis, in terms of the incidence of concomitant diseases in them and the use of concomitant therapy drugs.

Assessment of the safety of therapy

The safety assessment included an analysis of patient complaints, physical examination data, and laboratory data from all patients who received at least one dose of study drug/placebo (n = 342).

The study drug did not adversely affect vital signs, including heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure. The main indicators of the respiratory and circulatory organs in all participants of the study were within the normal range.

A total of 15 AEs were detected in 13 patients, including 8 AEs in 7 patients of the 1st group and 7 AEs in 6 patients of the 2nd group, without significant differences between the number of patients with AEs in the compared groups (Fisher's exact test; p = 0.784) and the frequency of AEs related to a particular Medical Dictionary for Regulatory Activities (MedDRA) code. In the 1st group, 3 AEs of moderate severity were noted in the form of acute bronchitis (n = 1), sinusitis (n = 1) and acute purulent rhinosinusitis (n = 1), which required the appointment of systemic antibiotic therapy; 5 AEs of mild severity in the form of various laboratory abnormalities (uraturia (n = 1), neutropenia (n = 1) and lymphocytosis (n = 1), increased levels of alanine aminotransferase (ALAT) and aspartate aminotransferase (AST) (n = 1)) and acute anal fissure (n = 1). All AEs were unrelated or unlikely to be related to study therapy. In 2 patients of the 2nd group during participation in the study, a worsening of the course of ARI was revealed in the form of generalization of infection with the development of community-acquired lower lobe right-sided pneumonia (n = 1) and acute bronchitis (n = 1), which required antibiotic therapy. The other 5 AEs in the placebo group were represented by abnormalities in laboratory tests - an increase in the number of erythrocytes in the urine (n = 1) and the presence of mucus in it (n = 1), an increase in the level of ALT and AST (n = 1), acute allergic reaction in the form of urticaria (n = 1), facial flushing (n = 1).

The average values of laboratory parameters, both at baseline and at the end of the course of treatment, did not go beyond the reference values. According to statistical analysis, the number of clinically significant abnormalities in blood and urine tests in the 1st and 2nd groups did not differ (p = 1.000).

During the study, no data were obtained on the interaction of the study drug with drugs used as concomitant therapy, no exacerbations of chronic or allergic diseases were registered in the study participants. The treatment was well tolerated by patients, contributing to their high compliance.

Evaluation of the effectiveness of therapy

The duration of the febrile period of ARI in group 1 was 3.1 ± 1.2 days, which was significantly less than in group 2 — 3.6 ± 1.4 days (p = 0.0174 [p = 0, 0136]) (table). Treatment with Ergoferon contributed to a reduction in the febrile period by an average of 0.43 ± 1.30 days, 95% CI 0.15-0.71 (or 10.3 hours).

The study drug group was dominated by patients whose fever was stopped in the first days of therapy. Its duration of no more than 1 day was observed in 11 (6.6%) patients of the 1st group versus 3 (1.8%) patients of the 2nd group. The duration of the febrile period up to 2 days inclusive was noted in 42 (25.1%) patients of the 1st group against 36 (21.7%) of the 2nd group. In addition, there were no patients with fever for more than 6 days in the Ergoferon group. In group 1, only 3 (0.9%) patients had fever on the 6th day of the study, while in group 2, 20 (12.0%) patients had fever for 6 days or more.

According to the objective examination of the doctor on the 3rd day of treatment with Ergoferon, the average value of the total CCQ score from the initial 10.4 ± 3.6 points decreased by more than 50%, amounting to 4.7 ± 2.9 points against 5.3 ± 3, 1 point in the placebo group (p = 0.06 [p = 0.03]). By the 3rd visit, clinical manifestations of ARI were practically absent in patients of both groups and amounted to 0.6 ± 1.1 points in the 1st group and 1.0 ± 1.6 points in the second. When comparing the severity of the course of the disease in groups using AUC for the total CCQ score, a tendency to a milder course for the 1st group was shown - 25.7 ± 12.0 u. e. vs. 28.5 ± 13.9 cu. e. in the 2nd group (p = 0.0719).

According to the daily subjective assessment of the patient, the severity of the course of ARI (AUC for the total WURSS-21 score) in the study drug group was lower - 201.6 ± 106.1 cu. e. against 236.2 ± 127.9 c.u. e. in the placebo group; p = 0.02 [p = 0.015] (Fig. 2).

The results of the analysis of the area under the curve for the points of the "Symptoms" domain of the WURSS-21 questionnaire demonstrated a lower severity of ARI symptoms in the study drug group - 85.2 ± 47.6 cu. e. vs. 100.4 ± 54.0 c.u. e. placebo, p = 0.0099 [p = 0.0063] (Figure 3).

The decrease in the indicators of the "Ability" domain by the end of treatment reflected the restoration of the patient's ability to daily activities. The results of the analysis of the area under the curve for this indicator illustrated the trend of more pronounced dynamics in the 1st group (p = 0.037 [p = 0.029]). Pairwise comparison of the mean values of the total score of the WURSS-21 questionnaire and its individual domains showed a lower severity of ARI symptoms in the study drug group, mainly on days 2-5 of treatment.

When assessing the need for the use of antipyretic drugs, it was noted that in the vast majority of patients, the number of antipyretic doses did not exceed 1 time per day (mainly on days 1-2 of illness). In this connection, the analysis according to this criterion was carried out by comparing the proportions of patients taking antipyretic drugs. On the 1st day of observation, 36.5% of patients in group 1 and 43.4% of patients in group 2 used antipyretics. On the 2nd day, the proportion of patients decreased in both groups to 16.2% and 20.5% (1st and 2nd, respectively). Despite the fact that there were no intergroup differences in the use of antipyretic drugs, the normalization of body temperature in patients of the 1st group occurred faster, as described above. The results obtained confirm the effective effect of the study drug on the course of the infectious and inflammatory process in the respiratory tract in ARI.

When comparing the proportions of patients with a worsening course of the disease, there were no differences between the groups (p = 0.68 [p = 1.00]). The onset of symptoms of ARI of the lower respiratory tract and paranasal sinuses, which required antibiotic therapy, noted in 5 study participants (n = 3 in group 1 and n = 2 in group 2), are described above as AE. Patients who completed the full course of treatment with study drug did not experience worsening disease, complications, or hospitalizations during treatment and follow-up.

Discussion

A double-blind placebo-controlled study showed the effectiveness of a liquid dosage form of a complex antiviral drug in the treatment of ARI of the upper respiratory tract in adults.

It is known that the main criterion for the resolution of an infectious-inflammatory process in the respiratory tract is the normalization of temperature. It has been established that the use of Ergoferon leads to a reduction in the duration of fever by an average of 10 hours. The average duration of febrile syndrome when taking it was 3 days. There were more cases with an abortive febrile period (1-2 days) compared with placebo. In the placebo group, more than 10% of patients had fever for 6-8 days. And in the Ergoferon group, there were no cases of fever duration of more than 6 days.

The study showed that the use of Ergoferon contributed to a decrease in the severity of an acute infectious and inflammatory process and led to a faster and more effective recovery from ARI. The effective effect of the study drug on the course of the disease was manifested by a positive effect not only on fever, but also on other symptoms of ARI from the nose/throat/chest. According to a medical examination with an assessment on the CCQ scale, on the 3rd day of therapy, the severity of ARI symptoms in patients of the Ergoferon group decreased by more than 50%. The obtained objective data coincided with the subjective assessment by patients in the WURSS-21 questionnaire. Patients who received antiviral therapy noted a significant improvement in well-being, a decrease in the symptoms of ARI and the restoration of daily activity at the very beginning and height of the disease (for 2-5 days). The results obtained are of particular interest due to the fact that during this period, as a rule, there is a maximum severity of the disease in the absence of adequate treatment. It should be noted that the use of symptomatic therapy, including antipyretics, did not differ between the two groups of patients. Participants who completed the full course of therapy with Ergoferon and completed participation in the study in accordance with all protocol procedures did not experience worsening of the course of the disease or the appearance of complications that required antibiotic therapy.

The effectiveness of the drug is explained by its complex composition, which has a targeted effect on “target” molecules: interferon gamma, CD4+ receptor and histamine receptors. The modulating effect of one of the components of the drug on interferon gamma is to change the conformation of the molecule and increase its functional activity, which helps to improve the ligand-receptor interaction of interferon gamma with the receptor, increase the expression of interferon gamma / alpha / beta and their associated interleukins, restore cytokine status; normalization of the concentration and functional activity of natural antibodies to interferon gamma; stimulation of interferon-dependent biological processes. Another component of the drug, acting on the cytoplasmic domain of the CD4+ receptor, causes the activation of T-lymphocytes by increasing the activity of lymphocytkinase and promotes the recognition of antigens by T-helpers together with molecules of the major histocompatibility complex (MHC) class II, which, in turn, triggers cellular and humoral immune response. The third component of the drug modifies histamine-dependent activation of peripheral and central histamine receptors, which leads to a decrease in capillary permeability, a decrease in edema of the respiratory mucosa, and suppression of histamine liberation from mast cells and basophils.

Taking into account the effectiveness of immunotropic drugs in the treatment of acute respiratory viral infections and influenza, it should be noted that the positive effect of Ergoferon on the main clinical manifestations of acute respiratory infections - fever, intoxication and respiratory symptoms - is due to a combination of nonspecific antiviral activity and anti-inflammatory, antihistamine effects.

conclusions

The study found that taking a liquid dosage form of Ergoferon helps the patient recover faster from ARI and facilitates the course of the disease, starting from the very first days of treatment. Based on the results of the study, the following conclusions can be drawn:

The therapeutic efficacy of Ergoferon in the treatment of ARI in adults is manifested by a significant decrease in the duration of the febrile period; the time to complete normalization of body temperature (≤ 37.0 °C) averages about 3 days.
On the 3rd day of treatment with Ergoferon, the severity of symptoms of acute respiratory infection in patients is reduced by more than 50%.
The use of Ergoferon makes it possible to more effectively stop the severity of the symptoms of an acute respiratory infection (the results of the analysis for the "Symptoms" domain), and also leads to a faster recovery of the daily activity of patients (the results of the analysis for the "Ability" domain of the WURSS-21 questionnaire).
The safety of the drug is confirmed by the absence of registered adverse events that have a significant relationship with the study therapy, the absence of deviations from the normal values of biochemical and general clinical parameters of blood and urine.
There were no cases of negative interaction of the drug Ergoferon with drugs of various classes, including antipyretics, decongestants, antitussives, ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium channel antagonists, diuretics, hemostatics, combined hormonal contraceptives, vitamin-mineral complexes, local antiseptics.
Significant efficacy of Ergoferon in the treatment of acute respiratory infections, compared with placebo therapy, is noted in the absence of differences in the use of symptomatic therapy drugs, including antipyretics.
Patients tolerate the drug in a liquid dosage form well and demonstrate a high level of adherence to therapy.

Thus, the liquid dosage form of Ergoferon is safe and effective in the treatment of acute respiratory infections in adults.

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Afinogenova V. P., Lukachev I. V., Kostinov M. P. Immunotherapy: mechanism of action and clinical use of immunocorrective drugs // Attending physician. 2010. 4:9.
Federal Guidelines for the Use of Medicines (formulary system, reference book). Issue XVI. Ed. A. G. Chuchalina (chief editor), V. V. Yasnetsova. M.: "Echo", 2015. 1016 p.
Guidelines for Clinical Immunology in Respiratory Medicine / Ed. M. P. Kostinova, A. G. Chuchalina. 1st ed. M.: ATMO, 2016. 128 p.
Respiratory medicine. Management. / Ed. A. G. Chuchalina, (2nd ed., revised and supplemented). Moscow: Litterra, 2017; T. 2. 544 p.

M. P. Kostinov* , 1 ,
R. F. Khamitov**,doctor of medical sciences, professor
A. P. Babkin***, doctor of medical sciences, professor
E. S. Minina****, Candidate of Medical Sciences
B. Ya. Bart#, doctor of medical sciences, professor
M. P. Mikhailusova#, doctor of medical sciences, professor
M. E. Yanovskaya ##,Candidate of Medical Sciences
A. O. Sherenkov###,Candidate of Medical Sciences
D.V. Petrov####, Candidate of Medical Sciences
D. N. Alpenidze, Candidate of Medical Sciences
Yu. S. Shapovalova&&, Candidate of Medical Sciences
M. V. Chernogorova&&&,doctor of medical sciences, professor
E. F. Pavlysh@, Candidate of Medical Sciences
R. T. Sardinov@@, Candidate of Medical Sciences

* FGBNU NIIVS them. I. I. Mechnikov RAS, Moscow
** Kazan State Medical University of the Ministry of Health of Russia, Kazan
*** BUZ VO VGKP No. 4, Voronezh
**** FGBU PK No. 3 UDP RF, Moscow
# FGBOU VO RNIMU them. N. I. Pirogov of the Ministry of Health of Russia, Moscow
## GBUZ YaO Design Bureau, Yaroslavl
### St. Petersburg GBUZ VFD Krasnogvardeisky district, St. Petersburg
#### FGBOU VO YAGMU of the Ministry of Health of Russia, Yaroslavl
& St. Petersburg GBUZ GP No. 117, St. Petersburg
&& NUZ DKB at the station Chelyabinsk JSC Russian Railways, Chelyabinsk
&&& BUZ MO Podolskaya City Hospital No. 3, Podolsk
@ St. Petersburg GBUZ GP Nevsky district, St. Petersburg
@@ FGBUZ PC No. 1 RAS, Moscow

DOI: 10.26295/OS.2019.29.30.015

Treatment of acute respiratory infection in adults: results of a multicenter, randomized, double-blind, placebo-controlled clinical trial / M. P. Kostinov, R. F. Khamitov, A. P. Babkin, E. S. Minina, B. Ya. Bart, M. P. Mikhailusova, M. E. Yanovskaya, A. O. Sherenkov, D. V. Petrov, D. N. Alpenidze, Yu. S. Shapovalova, M. V. Chernogorova, E. F. Pavlysh, R. T. sardines
For citation: Attending physician No. 10/2019; Page numbers in the issue: 72-79
Tags: influenza, viral infection, antiviral treatment, immune response.

One of the main provisions of the design of a clinical trial is randomization, i.e. the process of random distribution of experience options among objects. A random distribution of treatment options cannot be achieved by random selection. If a person is involved in the selection process, no selection scheme can be considered truly random. It is known from practice that if the participants in the study have the opportunity to influence the results of the study, this opportunity will certainly be used. The task of randomization is precisely to ensure such a selection of patients in which the control group would differ from the experimental group only in the method of treatment.

The word "chance" in its usual colloquial sense is applied to any method of selection that has no definite purpose. However, the choice made by a person is not random in the strict sense, since in practice he does not choose equally often those events that there is reason to consider equally probable.

There is only one way to get a truly random selection procedure - to use some method independent of a person, for example, use a generator (or table) of random numbers.

So, simple randomization is based on the direct application of such a table. The numbers in the table of random numbers are grouped in such a way that the probability for each of the single-digit numbers to be anywhere in the table is the same (uniform distribution). The leftmost column of the table represents the row numbers, the top line - the numbers of columns grouped by 5. The starting point is arbitrarily chosen (the intersection of a row with some number and a column (or columns), depending on how many characters should be in the extracted random numbers) and the direction of movement. The number of patients to be sorted into groups determines which numbers will be selected: P< 10 only single digits; with and = 10-99 - two-digit, etc. For example, to distribute 99 patients into three groups, we select the starting point at the intersection of an arbitrary row and two adjacent columns, as well as the direction of movement. We choose two-digit numbers. Having met the numbers 1-33, we will place the next patient in the first group, the numbers 34-66 - in the second group, 67-99 - in the third group. For distribution into two groups, you can act as follows: having met even numbers, send the next patient to the first group, and odd numbers to the second. However, this method can lead to the formation of groups of different sizes.

The method is free from this shortcoming. consecutive numbers. Each patient is assigned a number which is a random number from a table of random numbers. These numbers are then ranked in ascending order and the treatments are distributed according to the chosen rule. For example, for distribution into two groups: even numbers in a ranked row - the first group, odd - the second. However, the number of patients in the groups is balanced only towards the end of the randomization procedure.

Method adaptive randomization maintains an equal number of patients in groups throughout the randomization procedure. In general terms, such a procedure assumes the following: at the beginning of treatment, patients are distributed equally likely, then, before determining which group to attribute the next patient to, the number of groups already created at the moment is estimated. If the size of the groups is the same, the treatment is distributed equally, if the size of one of the groups exceeds the other, the probability of falling into this group decreases.

Maintains an equal group size throughout the randomization process and the method block randomization. Patients who are supposed to be included in the study are conditionally divided into equal blocks. Within the block, the treatments are distributed so that the same number of patients are treated by different methods, but the sequence of treatment would be different. The blocks are then randomly allocated, for example using a random number table.

In the 6th year at one of the departments, the teacher asked a question to our group: “ On what basis are drugs recommended for the treatment of a particular disease?". Some students suggested that drugs are chosen based on their mechanism of action, disease characteristics, and so on. These are not entirely accurate answers. Nowadays, drugs are chosen primarily for their efficiency. And they do it with rigorous scientific methods. Today you will learn:

which study is cheaper - longitudinal or transverse,
that pacifiers are not only for children,
why blind treatment is considered the most valuable.

Modern methods of treatment are based on positions evidence-based medicine (evidence based medicine). « evidence-based medicine", also referred to as " clinical epidemiology". Evidence-based medicine makes it possible to predict the course of a disease in a particular patient based on the course of many similar cases studied using rigorous scientific methods of mathematical statistics.

To draw any conclusions about the effectiveness or inefficiency of the drug, conduct research. Before a drug gets tested by real patients, it goes through a series of experiments on living tissues, animals, and healthy volunteers. I will talk more about these stages separately in the material "How drugs are developed." In the end, the effectiveness and safety of the drug is tested on a group of sick people, such a test is called clinical.

When preparing a clinical study, scientists determine the contingent of the subjects, the selection and exclusion criteria, the methodology for analyzing the phenomenon under study, and much more. All this together is called study design.

Types of clinical studies

Exists 3 types of clinical trials with its own advantages and disadvantages:

cross-sectional (simultaneous) studies,
longitudinal (prospective, longitudinal, cohort) studies,
retrospective studies ("case - control").

Now more about each type.

1) Cross-sectional (one-shot) study.

it single examination of a group of patients. You can get, for example, statistics on the incidence and current course of the disease in the study group. Reminds me of a photograph taken at a specific point in time. A cross-sectional study is cheap, but it is impossible to understand the dynamics of the disease from it.

Example: preventive examination of a shop doctor at an enterprise.

2) Longitudinal (prospective, longitudinal, cohort) study.

Terminology: from lat. longitudinalis- longitudinal.

Longitudinal research is observation of a group of patients for a long time. To date, such studies are themselves reliable (evidence-based) and therefore are carried out most often. However, they are expensive and most often performed in several countries at the same time (i.e. they are international).

Why are longitudinal studies also called cohort studies? Cohort -

The tactical unit of the legion in ancient Rome (from the 2nd century BC). There were 10 cohorts in the legion, in a cohort - 360-600 people.
In a figurative sense, a tightly knit group of people.
In clinical epidemiology cohort- this is a group of people initially united by some common feature (for example: healthy people or patients at a certain stage of the disease) and observed over a certain period of time.

Scheme of the research model in one group.

Among prospective studies, there are simple and double-blind, open, etc., more on this below.

3) Retrospective studies ("case - control").

These studies are carried out when it is necessary to link risk factors from the past with the current state of the patient. The simplest example: a patient had a myocardial infarction, the district doctor flips through his card and thinks: “ Indeed, high cholesterol for several years does not end well. Patients should be prescribed more statins».

Retrospective studies are cheap but have low evidence. information from the past is not reliable (for example, an outpatient card could be filled out retroactively or without examining the patient).

Double-blind, randomized, multicenter, placebo-controlled study

As I mentioned above the most evidence are prospective (longitudinal) studies, which is why they are carried out most often. The most reliable of all prospective studies to date is double-blind, randomized, multicenter, placebo-controlled trial. The name looks too scientific, but there is nothing complicated about it. Let me explain the term word by word.

What randomized trial? The word comes from English. randomize- arrange in a random order; mix. Since the effectiveness of the tested drug must be compared with something, in every study there are experienced group(the necessary drug is checked in it) and control group, or comparison group(patients in the control group are not given the test drug). Looking ahead, I will say that a study with a control group is called controlled.

Randomization in this case is a RANDOM distribution of patients into groups. It is extremely important that the researchers, for their own selfish purposes, could not collect milder patients in the experimental group, and more severe ones in the control group. There are special methods of randomization, so that in the end the differences between the groups become statistically unreliable. About the concept authenticity» in evidence-based medicine, I will also tell further.

What blind and double blind study? At solitary blind In the study, the patient does not know which group he fell into during randomization and what drug he is given, but the health worker knows this, who may involuntarily or accidentally give out a secret. At double blind study, neither the doctor nor the patient is aware of what exactly a particular patient receives, so such a study is more objective.

Note. If for some reason it is not possible to use a placebo (for example, a doctor or a patient can easily recognize the drug by its effects, for example: MgSO4 when administered intravenously gives a short sensation of intense heat from the inside), open study(both the doctor and the patient know which drug is prescribed). However, the open study is much less reliable.

Interestingly, out of the total number of patients in the hospital placebo(dummy drug; placebo mimics the drug but contains no active ingredient) helps 25-35% , in cases of mental illness - up to 40%. If a patient receiving a placebo has a pronounced positive effect, such patients may be excluded from the study.

Instead of a placebo, a drug can be used that they want to compare with the test. In turn, the tested drug can be taken in one of 2 options:

in parallel groups: i.e. in one group, the study drug is taken, and in the second (control) group, a placebo or a comparator drug is taken.

Outline of the Parallel Group Study Model.

in a cross study: each patient in a certain sequence receives the test and control drug. There should be a free period between taking these drugs, designed to “eliminate” the consequences of taking the previous drug. Such a period is called liquidation", or " laundering».

Scheme of the "cross" research model.

What controlled study? As I mentioned just above, this is a study in which there are 2 groups of patients: experienced group(receiving a new drug or a new treatment) and control group(NOT receiving it). However, there is a small problem. If the drug is not given to patients in the control group, they will decide that they are not being treated, and then become offended and depressed. The results of treatment will definitely be worse. So the researchers give the control group a placebo - a dummy.

Types of control in evidence-based medicine:

In appearance and taste, the placebo, thanks to special excipients without an active substance, resembles the drug being tested. This type of control is called placebo control (negative control).
If a patient taking a placebo could be significantly harmed by the lack of treatment, then the placebo is replaced with an effective comparator drug. This type of control is called active (positive). Active controls are also used for promotional purposes to show that a new drug is superior to existing ones.

For completeness, I will also mention two more rare methods of control:

historical control, or archival statistics control. It is used when there are no effective treatments for the disease, and there is simply nothing to compare with. In this case, the results of treatment are compared with the usual survival of such patients.
Examples: some types of cancer treatment, organ transplant operations in the early stages of the development of transplantology.
initial state control. Patients are examined, and the results of treatment are compared with the initial state before the experimental treatment.

multicenter called a study that is performed immediately in several "centers" - clinics. Some diseases are quite rare (for example, certain types of cancer), and at a particular point in time in one center it is difficult to find the right number of volunteer patients that meet the inclusion criteria for the study. Typically, such studies are expensive and are carried out in several countries, being international. For example, many hospitals in Minsk also took part in them.

control period

Every study should have control (introductory) period during which the patient does not receive the test drug or a drug of a similar type of action, except for life-saving ones (for example, nitroglycerin for angina pectoris). In international trials, this period is usually assigned placebo.

Study without control period and randomization(random allocation to groups) cannot be considered controlled, so its results are questionable.

Each study should clearly state inclusion and exclusion criteria patients from the study. The better they are thought out, the more reliable the results will be. For example, when studying the effectiveness of ?-blockers as anti-ischemic drugs, we should exclude from the study patients taking other drugs with a similar effect: nitrates and (or) trimetazidine.

Disadvantages of controlled randomized trials

1) Non-representativeness of the selected group, i.e. the inability of a given sample to correctly reflect the properties of the entire population. In other words, it is impossible to draw true conclusions about all patients with this pathology for this group of patients.

As I pointed out just above, there are strict criteria for inclusion and exclusion of patients from the study. This is needed to get homogeneity groups of patients that can be compared. Usually these are not the most severe patients, because. in seriously ill patients, the strict requirements of controlled trials cannot be met: the presence of a control period, placebo, exercise tests, etc.

For example, in a study RITA(1993) compared results percutaneous transluminal coronary angioplasty(expansion of a narrowed artery by inflating a mini-balloon in its lumen) with coronary artery bypass grafting(creating a bypass for blood to flow past the narrowed portion of the artery). Because the study included only 3% of patients among those subjected to coronary angiography, its results cannot be extended to the remaining 97% of patients. The sample is not representative.

2) Conflict of interests.

When the manufacturer invests a lot of money into the clinical trials of his drug (that is, actually pays for the work of researchers), it is hard to believe that the author will not make every effort to obtain a positive result.

For these reasons the results of single studies cannot be considered absolutely reliable.

randomized controlled trial

Clinical Trial (CT) is a prospective comparative study of the effectiveness of two or more interventions (therapeutic, preventive or diagnostic) that compares outcomes in groups of subjects that differ in the intervention used. This usually tests the hypothesis about the effectiveness of the test method (the effect of the intervention on the outcome), which arose before the study.

In the presence of a control group (comparison), they speak of controlled CI, and when groups are formed by the method of randomization, they speak of randomized controlled test (RCP, randomized controlled trial according to the classification of study types in MEDLINE).

Advantages - results obtained in RCTs better reflect differences in outcomes that are important for patients; systematic errors are the least common; the most objective for evaluating the effectiveness and testing of interventions; the results of the RCP, performed strictly according to the study design, are the most reliable.

Flaws - RCTs take a long time to complete; they are expensive; not suitable for rare disease research cases; these studies have limited generalizability (transferability of results to the population). The last limitation should not be exaggerated, since other types of studies are even worse generalizable.

Patients are selected for the study from a large number of people with the condition being studied. Then these patients are divided randomly into two groups, comparable in terms of the main prognostic signs. One group, called the experimental or treatment group, is given an intervention (such as a new drug) that is expected to be effective. The other group, called the control or comparison group, is in the same conditions as the first, except that its constituent patients do not receive the intervention under study. The validity of clinical trials depends on the extent to which the compared groups managed to ensure the same distribution of all factors that determine the prognosis, except for the therapeutic intervention under study.

Sample formation. Among the many reasons why patients with the disease under study are not included in the study, the main ones are the following three reasons:

1) Patients do not meet the established inclusion criteria. This is an atypical nature of the disease, the presence of other diseases, a poor prognosis of the disease, a high probability of non-compliance with the prescribed treatment by the patient. This limitation increases the reliability of the study: the possibility of outcomes not related to the treatment itself is reduced.
2) In cases where patients refuse to participate in experiments (clinical trials).
3) Excluded are patients who, in the early stages of the trial, showed an inability to strictly follow the prescribed treatment methodology. This will avoid financial and medical wasted efforts and reduce the reliability of the study.

The following options for the structure of RCTs are distinguished.

Parallel- a parallel (simultaneous) study in the active intervention and control groups is carried out independently of each other. This is the most common research structure.

cross- a study conducted in one group of patients with a sequential change in treatment methods, separated by a period of "washout" (for the disappearance of the effect of the previous intervention). Similar studies are carried out in patients with stable and usually chronic pathological conditions.

Steam room - a method of forming groups in a CI, in which each participant in the main group corresponds to a participant in the control group, usually selected according to some common characteristics.

Sequential - way of conducting the study, when the decision to terminate is made when differences between groups are reached (usually the study is terminated at a predetermined period).

Factor protocol - the study is conducted in groups in which combinations of interventions are applied. For example, with a 2x2 factorial protocol (for two types of treatment), four groups are formed, in two of which one of the types of treatment is used, in the third - none of them, in the fourth - both. The factor model is also used to evaluate the effects of different doses of a single drug and combinations of drugs.

Adaptive - enrollment in the group receiving the worst, according to accumulated estimates, treatment decreases over the course of the study.

Zelena design - participants assigned to the intervention being studied are given the opportunity to opt out of the intervention and move on to the control group. It is used when studying interventions for which patients have strong preferences.

Compared to the parallel structure of CI, other options are relatively difficult both to perform and to understand their results and are usually applied when the parallel structure seems inappropriate or impossible. The planning of trials with these types of structures, as well as the analysis of the resulting data, requires the advice of a statistician.

The test is characterized by practical value, complexity and efficiency. The results of treatment should be reproducible and applicable in routine clinical practice. It is necessary to know whether the intervention being studied differs sufficiently from alternative treatments.

The value of the studied method of treatment (drug) can only be judged by comparing its results with the effect of other therapeutic measures, i.e. compare between groups receiving different treatments. Or you can compare the effect of a treatment method with the absence of it. The latter method makes it possible to assess the overall effect of medical care, both related to the intervention under investigation and not related to it.

placebo treatment. You can compare the effect of the study treatment (drug) with the appointment of a placebo. A placebo is a dosage form that is indistinguishable from the study drug in appearance, color, taste and smell, but does not have a specific effect (for example, glucose tablets or isotonic saline injections. Placebo effect is a change in the patient's condition (noted by himself or by the attending physician) associated with the fact of treatment rather than the pharmacodynamic effect of the drug The placebo effect is considered by researchers as a baseline for measuring specific treatment effects It is necessary to distinguish between specific and non-specific effects of a treatment intervention in order to objectively evaluate it.

Placebo in clinical drug trials is useful for the following purposes:

3) differentiation of the actual pharmacodynamic and psychological effects of the drug;
4) the difference between the effects of the drug from spontaneous periodic remissions and the influence of other external factors;
5) to avoid obtaining false negative conclusions.

It is possible to compare the investigational treatment with conventional treatment - this is acceptable in cases where the conventional treatment has been shown to be effective.

blind method.

6) researchers who assign patients to intervention groups do not know what treatment will be assigned to each subsequent patient;
7) patients should not know what kind of treatment they receive;
8) supervising physicians should not know what treatment (drug) is prescribed to the patient;

To study the specific therapeutic effect of an intervention (drug), it is necessary to distribute patients into groups randomly, i.e. through randomization. Randomization is the optimal method of choosing a treatment, which avoids bias when dividing patients into groups. Carrying out randomization allows to distribute patients into groups mainly with the same characteristics.

If participants in a trial know who is receiving which type of treatment, there is a chance that their behavior will change, which could lead to bias. To reduce this effect, apply blind method. Blinding in clinical trials can be carried out at the following levels:

9) researchers who assign patients to intervention groups do not know what treatment will be assigned to each subsequent patient;
10) patients should not know what kind of treatment they receive;
11) supervising physicians should not know what treatment (drug) is prescribed to the patient;

A "single-blind" method (not informed by the patient) or "double-blind" method (both the patient and the researcher are not informed) are used. Thus, the "double-blind method" serves as a type of control to prevent the influence of bias on the results of the study.

The results of randomized controlled trials using a blind (masked) method should be given preference over any other information on the effects of treatment. However, such tests have limitations: the high cost of conducting; there may not be enough patients with the disease under study; the duration of the experiment; misunderstanding of doctors and patients about the need for clinical trials and others. For many clinical questions, it is not always possible and practical to rely on the results of randomized clinical trials, so other evidence is used.

Randomization is a key concept in medical data analysis.

The term "randomization" does not refer to the sample, but to the way it was generated.

By saying that a group of a given size is a simple random sample from a larger group, we mean that all possible samples of this size are drawn with equal probabilities.

By saying that treatment is assigned to objects randomly, we mean that the probability of assigning each type of treatment is the same for all objects.

The need for randomization was first pointed out by R. Fisher.

Randomization has three goals:

ensures that our preferences do not affect the formation of groups with different types of processing

prevents the danger associated with choice based on personal judgments

finally, with a random (randomized) distribution of treatments, the most severe critic will not be able to say that the patient groups were treated differently due to our preferences.

Randomization in clinical trials

Suppose a drug needs to be tested in clinical trials to establish its effectiveness.

For this, for example, 50 patients are prescribed a medicine, and another 50 patients are prescribed a neutral drug (“dummy”),

Let us further assume that patients are admitted to trials in series, over a period of time, and not simultaneously.

Let's consider two methods of randomization.

In the first method, it is required to select 50 different numbers between 1 and 100, the active drug must be prescribed to those of the 100 patients whose numbers fall into this set. The remaining 50 patients will receive a neutral drug.

This method has two drawbacks. First, if the study had to be terminated prematurely, then the total number of patients taking the active drug would most likely not be equal to the number of patients taking the neutral drug.

Meanwhile, statistical comparison methods lose sensitivity if the sample sizes differ.

Second, if the clinical status of patients enrolled at one point in time differs from that of patients enrolled at another point in time, or if drug regimens change, then despite randomization, the two groups may differ in patient type or according to the rules for taking medications (see).

The second possible randomization method does not have the disadvantages of the first.

This method independently randomizes patients admitted over short time intervals sequentially to treatment groups.

Assume that ten patients enter the trial each month.

It is reasonable to randomly assign five patients one type of treatment and another five patients another, repeating the random assignment every month as new batches of patients arrive.

The implementation of this procedure can be carried out, for example, using a table of random numbers generated in STATISTICS.

We will browse by ten digits from 0 to 9, since the choice is made from 10 patients. We denote the tenth patient by zero.

If we start from the fifth column, then the first five different numbers will be 2, 5, 4, 8, 6. So, out of ten patients, the second, fifth, fourth, eighth and sixth patients will be assigned the active drug, and the rest - the neutral drug.

Continuing to look at the table, we will see that of the next ten patients, the first, third, fifth, eighth and tenth will take the active drug, and the rest will take the neutral drug. By using the first digits in a column, you can continue browsing through the second digits in that column.

For each subsequent group of patients, a new set of random numbers should be obtained in order to avoid biases that may appear due to the hidden periodicity of the type of patients or because the type of drug will soon be clear to the clinic staff (it should not be known to staff in contact with patients).

A special case of this method is testing on pairs of patients, when one of the two patients receives an active drug and the other receives a neutral drug.

In this case, randomization is very easy to carry out.

First, in some way, for example, in alphabetical order of surnames, one of the two patients is singled out as the first.

This choice must be made prior to randomization. Then, starting from any convenient place, one-digit numbers are looked up in the table of random numbers.

If the number is odd - 1, 3, 5, 7 or 9, then the first patient takes an active, and the second - a neutral drug. If the number is even - 0, 2, 4, b or 8, the active drug is prescribed to the second patient.