Clinical trial NCT04542694
Conditions: COVID-19
Keywords: Favipiravir Areplivir COVID-19 SARS-CoV-2 2019-nCoV
Sponsor: Promomed, LLC
Start date: 2020-05-21; Completion date: 2020-08-20
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is open-labe randomized multicenter comparative Phase III study conducted in 5 medical facilities. The objective of the study is to assess the efficacy and safety of Favipiravir compared with the Standard of care (SOC) in hospitalized patients with moderate COVID-19 pneumonia.

Detailed description:
Upon signing the informed consent form and screening, 200 eligible patients with polymerase chain reaction (PCR) confirmed COVID-19 are randomized at a 1:1 ratio to receive either Favipiravir 1600 mg twice a day (BID) on Day 1 followed by 600 mg BID on Days 2-14 (1600/600 mg), or SOC. The course of treatment by Favipiravir is 14 days.

Arms: arm 1: Arm 1 (n=100) receives the study drug Areplivir film-coated tablets:

on day 1 of therapy - 1600 mg (8 tablets) 2 times a day; on days 2-14 of treatment - 600 mg (3 tablets) 2 times a day. The drug is taken orally every 12 hours, swallowing whole tablet without chewing and washing down with a glass of water. The course of treatment is 14 days. The test drug is administered in hospital setting under supervision of a clinical investigator. The test drug is not handed over to the patient. arm 2: Arm 2 (n=100) patients receive standard therapy prescribed in accordance with the recommended treatment regimens included in the Interim Guidelines for the prevention, diagnosis and treatment of new coronavirus infection (COVID-19) approved by the Russian Ministry of Health (but not Favipiravir) by decision of the investigator and taking into account the availability of drugs at the study site. Might include hydroxychloroquine (with or without azithromycin), chloroquine, lopinavir/ritonavir or other recommended schemes.

Standard therapy is administered in hospital setting. Discharge of patients from a hospital is carried out in accordance with the local practice of the study site in compliance with the current sanitary and epidemiological regime.
Interventions: intervention 1: Favipiravir intervention 2: Standard of care
Intervention descriptions: intervention 1: 200 mg coated tablets intervention 2: Drug: Standard of Care Standard of Care will be prescribed in accordance with the recommended treatment regimens presented in the Russian guidelines for the prevention, diagnosis and treatment of COVID-19 according to the decision of the Investigator.

Other Name: Hydroxychloroquine, chloroquine, lopinavir/ritonavir, etc.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical study name: Open randomized multicenter comparative study on the efficacy and safety 
of Areplivir film-coated tablets (PROMOMED RUS LLC, Russia) in patients hospitalized with 
COVID-19 
Investigational product: Areplivir film-coated tablets (PROMOMED RUS LLC, Russia) 
Study indication: COVID-19. 
Study design: open randomized multicenter comparative. 
Study sponsor: PROMOMED RUS LLC, Russia 
Study protocol: No. FAV052020 
NCT number: NCT04542694 
Date and version of the protocol: version 2.0 of 10.06.2020 
Clinical development phase: III 
Study period: 
Q2 2020 - Q4 2020 
Sponsor's responsible person: Director General of the management company of PROMOMED 
RUS, LLC, Smagin Maxim Yurievich 
 
 
This study, including archiving of key study documents, is performed in accordance with the ICH E6 Good 
Clinical Practice recommendations and the Rules of Good Clinical Practice approved by the Eurasian 
Economic Commission. 


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2. OVERVIEW (SYNOPSIS) 
Sponsor: 
PROMOMED 
RUS 
LLC, 
Separate study table relating to part of 
the dossier 
(For use by national authorized bodies 
only) 
Russia 
Volume: 
Pages: 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
Protocol No.: FAV052020 
Clinical study name: 
Open randomized multicenter comparative study on the efficacy and safety of Areplivir film- 
coated tablets (PROMOMED RUS LLC, Russia) in patients hospitalized with COVID-19 
Investigators, Study site: 
The study is conducted at five research centers in the Russian Federation. Detailed information is 
provided in Section 6. 
Publication: 
A list of scientific papers and publications relevant to this study will be presented in the Clinical 
Study Final Report. 
Study period: 
Q2 
2020 
Q4 2020 
– 
Drug development phase: III 
Study purpose: 
Assess the efficacy and safety of Areplivir versus standard therapy in patients hospitalized with 
COVID-19. 
Study objectives: 
 Assess the efficacy of Areplivir versus standard therapy in patients hospitalized with COVID- 
19. 
 Assess the safety of Areplivir versus standard therapy in patients hospitalized with COVID- 
19. 
Methodology: 
an open randomized multicenter comparative study on the efficacy and safety of Areplivir in 
patients hospitalized with COVID-19. 
Number of patients (planned and included in the analysis): 
The study will randomize 200 patients. Given the possible non-inclusion of patients at the 
screening stage, the maximum number of patients to sign the Informed Consent Form in the Patient 
Information Leaflet and to participate in screening can be no more than 210 people. 
This interim report is based on data on 80 patients (40 patients in the Areplivir arm + 40 patients 
in the standard therapy arm). 
Patients who met the inclusion criteria and did not meet the non-inclusion criteria were randomized 
to 2 groups (treatment arms) in a 1:1 ratio: 
Arm 1 (n=100) receives the study drug Areplivir film-coated tablets: 
on day 1 of therapy - 1600 mg (8 tablets) 2 times a day; 
on days 2-14 of treatment - 600 mg (3 tablets) 2 times a day. 
The drug is taken orally every 12 hours, swallowing whole tablet without chewing and washing 
down with a glass of water. The course of treatment is 14 days. 


Confidential 
3 
 
Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
The test drug is administered in hospital setting under supervision of a clinical investigator. The 
test drug is not handed over to the patient. 
Arm 2 (n=100) patients receive standard therapy prescribed in accordance with the recommended 
treatment regimens included in the Interim Guidelines for the prevention, diagnosis and treatment 
of new coronavirus infection (COVID-19) approved by the Russian Ministry of Health (revision 
6 dated 28.04.2020, or current revision at the time of patient enrollment) by decision of the 
investigator and taking into account the availability of drugs at the study site. 
Standard therapy is administered in hospital setting. 
Discharge of patients from a hospital is carried out in accordance with the local practice of the 
study site in compliance with the current sanitary and epidemiological regime. 
Diagnosis and key inclusion criteria: 
The study is conducted with the participation of male and female patients aged 18 to 80 years 
inclusive, hospitalized with COVID-19. 
Inclusion criteria: 
1. Signing and dating of the Informed Consent Form of the Patient Information Leaflet (PIL) by 
patients. 
2. Men and women aged 18 to 80 years inclusive at the time of signing the Informed Consent 
Form in PIL. 
3. No difficulty with oral medication (e.g. swallowing disorder). 
4. Patient diagnosed with "Coronavirus infection caused by SARS-CoV-2 (confirmed)1,  medium 
severity form*" established in accordance with the Interim Guidelines of the Russian Ministry 
of Health for the prevention, diagnosis and treatment of a new coronavirus infection (COVID-
19), (revision 6 of 28.04.2020). 
*Medium severity form: fever above 38 °C, BR above 22/min, dyspnea during exercise, 
pneumonia (confirmed by lung CT), SpO2 < 95%, CRP serum level above 10 mg/l. 
5. Patient should be hospitalized no more than 48 hours before the start of the study therapy. 
6. Positive PCR result for presence of SARS-CoV-2 RNA at screening phase (results obtained 
within 7 days prior to screening are appropriate). 
7. Patient's consent to use reliable contraceptive methods throughout the study and within 1 month 
for women and 3 months for men after its completion. Persons eligible for participation in the 
study: 
 
Women who have a negative pregnancy test and use the following contraceptives: barrier 
method (condom or occlusive cap (diaphragm or cervical/vaulted cap)) or double barrier 
method of contraception (condom or occlusive cap (diaphragm or cervical/vaulted cap) 
plus spermicide (foam/gel/film/cream/suppository)). Women incapable of childbearing 
may 
also 
participate 
in 
the 
study 
 
1 Positive PCR result for SARS-CoV-2 RNA. 


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Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
(with past history of: hysterectomy, tubal ligation, infertility, menopause more than 1 
year). 
or 
 
men with preserved reproductive function who use barrier contraceptives, as well as men 
with 
infertility 
or 
vasectomy 
in the past medical history. 
Non-inclusion criteria: 
1. Hypersensitivity to favipiravir and/or other components of the study drug. 
2. Impossibility of CT procedure (for example, gypsum dressing or metal structures in the field 
of imaging). 
3. The need to use drugs from the list of prohibited therapy. 
4. Need for treatment in the intensive care unit. 
5. Impaired liver function (AST and/or ALT ≥ 2 UNL and/or total bilirubin ≥ 1.5 UNL) at the 
time of screening. 
6. Impaired kidney function (creatinine clearance according to Cocroft-Gaulth formula less than 
45 ml/min) at the time of screening. 
7. Positive testing for HIV, syphilis, hepatitis B and/or C. 
8. Chronic heart failure FC III-IV according to New York Heart Association (NYHA) functional 
classification. 
9. Malabsorption syndrome or other clinically significant gastrointestinal disease that may affect 
absorption of the study drug (non-correctable vomiting, diarrhea, ulcerative colitis, and others). 
10. Malignancies in the past medical history. 
11. Alcohol, pharmacological and/or drug addiction in the past medical history and/or at the time 
of screening. 
12. Schizophrenia, schizoaffective disorder, bipolar disorder, or other history of mental pathology 
or suspicion of their presence at the time of screening. 
13. Severe, decompensated or unstable somatic diseases (any disease or condition that threaten the 
patient's life or impair the patient's prognosis, and also make it impossible for him/her to 
participate in the clinical study). 
14. Any history data that the investigating physician believes could lead to complication in the 
interpretation of the study results or create an additional risk to the patient as a result of his/her 
participation in the study. 
15. Patient's unwillingness or inability to comply with procedures of the Study Protocol (in the 
opinion of physician investigator). 
16. Pregnant or nursing women or women planning pregnancy. 
17. Participation in another clinical study for 3 months prior to inclusion in the study. 
18. Other conditions that, according to the physician investigator, prevent the patient from being 
included in the study. 


Confidential 
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Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
Investigational medicinal product, dose and mode of administration, batch number: 
Investigational medicinal product: 
Areplivir, film coated tablets (PROMOMED RUS LLC, Russia), batch 010520 (expiry date 
06.2022). 
Patients in Arm 1 take the investigational product Areplivir, film coated tablets: 
on Day 1st of treatment - 1600 mg (8 tablets) 2 times a day; 
on days 2-14 of treatment - 600 mg (3 tablets) 2 times a day. 
The drug is taken orally every 12 hours, swallowing whole tablet without chewing and washing 
down with a glass of water. The course of treatment is 14 days. 
The test drug is administered in hospital setting under supervision of a clinical investigator. The 
test drug is not handed over to the patient. 
Duration of the study: 
The total duration of the study for the patient is not more than 31 days, of which the screening 
period is not more than 2 days. 
Visits: 
Visit 0 (screening, not more than 2 days); 
Visit 1 (randomization, day 1)*; 
Visit 2 (day 5); 
Visit 3 (day 10); 
Visit 4 (day 15)**; 
Visit 5 (day 21±1)***; 
Visit 6 (study completion, day 28±1)***. 
* Visit 1 may coincide with Visit 0. 
** If a patient is discharged from hospital at an earlier date, the visit will be conducted at the time 
of discharge (for Arm 2 patients). 
*** If a patient is discharged from hospital at an earlier date, then this patient does not need to 
visit the study site. Fatalities and serious adverse events (SAE) will be followed-up through 
telephone contact with the patient. 
Discharge of patients from a hospital is carried out in accordance with the local practice of the 
study site in compliance with the current sanitary and epidemiological regime. 
Efficacy criteria: 
The efficacy of therapy is assessed using the following endpoints: 
Primary efficacy criterion: 
 Time (in days) to improvement in clinical status by categorical ordinal scale of clinical status 
improvement. 
 Rate of clinical status improvement by categorical ordinal scale of clinical status 
improvement by 2 or more categories at Visit 3. 
Secondary efficacy criteria: 


Confidential 
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Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
 Percentage 
of 
patients 
with 
elimination* 
of 
COVID-19 
according 
to 
PCR data at Visit 3. 
 Time (in days) to end of fever (body temperature < 37.2 ° C for 3 consecutive days without 
antipyretic medication). 
 Assessment of lung injury according to CT data at Visits 4, 5 and 6. 
 Percentage of patients transferred to intensive care unit. 
 Percentage of cases with non-invasive lung ventilation. 
 Percentage of cases with mechanical lung ventilation. 
 Incidence of fatal cases. 
* Elimination of the virus is defined as two negative laboratory results for the presence of SARS- 
CoV-2 RNA obtained at an interval of 24 hours. 
Safety criteria: 
 Total number of adverse events (AEs) stratified by severity and incidence; 
 Incidence of adverse drug reactions; 
 Incidence of serious adverse events (SAEs) associated with the use of the study 
drug/standard therapy; 
 Percentage of patients with at least one AE; 
 Percentage of patients who discontinuation treatment due to AE. 
Statistical methods: 
Justification of sample size 
The study will randomize 200 patients. Given the possible non-inclusion of patients at the 
screening stage, the maximum number of patients to sign the Informed Consent Form in the Patient 
Information Leaflet and to participate in screening will be no more than 210 people. 
At the first stage, 40 patients are included in each study arm and the most sensitive efficacy 
criterion of the two selected is determined, or additional analysis is carried out to select the 
criterion from secondary ones. Given 40 patients in each of the study arms, the sensitivity of the 
study to confirm 15% superiority by incidence, supposing the expected response 80% in the test 
drug arm, will exceed 45%. 

 
Two Independent Proportions (Null Case) Power 
Analysis 
 
Numeric Results of Tests Based on the Difference: P1 - P2
 
H0: P1 - P2 ≥ 0. H1: P1 - P2 = D1 < 0. Test Statistic: Z test with pooled variance

 
Sample 
Sample 
Prop|H1 
Prop
 
Size 
Size 
Grp 1 or 
Grp 2 or 
Diff 
Diff
 
Grp 1 
Grp 2 
Trtmnt 
Control 
if H0 
if H1 
Target 
Actu
 
Power    N1 
N2 
P1 
P2 
D0 
D1 
Alpha 
Alph
 
0.4553 
40 
40 
0.6500 
0.8000 
0.0000 
-0.1500 
0.0500 
0.050



Confidential 
7 
 
Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
Said statistical power (45%) is acceptable for exploratory stages of the studies aimed to select the 
duration for endpoint monitoring and to select the endpoint at the second (confirming) stage. 
In case change of the planned endpoints, separate adjustment will be made for the multiplicity of 
comparisons and the required number will be recalculated at the second stage. 
The total planned number of patients before the completion of the first stage will be 100 patients 
in each of the arms. 
The estimated calculation until the data of the first stage are obtained is as follows. Given the 
available data from Chinese researchers, 15% superiority of favipiravir therapy over standard 
therapy without favipiravir is allowed in relation to the rate of improvement by 2 or more 
categories on categorical scale by day 10 of treatment. The adopted higher response to standard 
therapy of 70% is associated with a longer duration relative to the Chinese study (10 days instead 
of 7 days). 
An RCT enrolling patients within 12 days of symptom onset found that favipiravir was superior to 
arbidol in terms of the clinical recovery rate at day 7 in patients with mild illness (62 [56%] of 111 with 
arbidol vs 70 [71%] of 98 with favipiravir), but not in those with critical illness (0 vs 1 [6%]). (Chen C. 
Huang J. Cheng Z. et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiv. 
2020; (published online April 15.) (preprint). 
Tests for Two Proportions 
Numeric Results for Testing Two Proportions using the Z-Test with Unpooled Variance 
H0: P1 - P2 ≥ 0 vs. H1: P1 - P2 = D1 < 0. 
Target   Actual 
Diff 
Power    Power*  N1         N2         N 
P1       P2        D1        Alpha 0.80 
0.80170 107 107 214 0.6500 0.8000 -0.1500 0.0500 
* Power was computed using the normal approximation method. 
Thus, the minimum number of subjects required for a clinical study is 200 with 100 subjects 
randomized to each of the two groups. 
Statistical analysis 
The purpose of statistical analysis is to prove superiority of Areplivir, film-coated tablets 
(PROMOMED RUS LLC, Russia), over standard therapy in patients hospitalized with COVID- 
19. 
The results of statistical analysis, descriptive statistics and illustrative tables, graphs, lists will be 
presented in interim and final clinical study reports. 
General methods of analysis 
Statistical analysis is carried out in accordance with the requirements of the Guideline for Good 
Clinical Practice (ICH 9) approved by the Eurasian Economic Commission, and other applicable 
requirements and laws. 
Statistical  data  processing  is  done  by  staff  not  involved  in  the  management  of  patient 
participating  in  the  study  to  create  conditions  for  independent  evaluation  of  the  findings. 


Confidential 
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Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
Certified statistical software with validated algorithms is used to perform statistical analyses and 
to ensure proper documenting (StatSoft Statistica 10.0., IBM SPSS Statistics 22). 
Descriptive statistics are provided for all efficacy and safety indicators collected during the study. 
Continuous (quantitative) data are presented using the number of observations, arithmetic mean 
value, confidence interval (CI) 95% for mean, standard (rms) deviation, median, interquartile span 
(25th and 75th centiles), minimum and maximum. 
Ordinal, categorical and qualitative data are presented as absolute frequencies (number of 
observations), relative frequencies (percent) and 95% CI (unless otherwise stated). 
The check for normality of distribution is carried out by one of the generally accepted methods 
(Shapiro-Wilk test, Kolmogorov-Smirnov test). For non-Gaussian distributions, non-parametric 
methods will be used to compare efficacy and safety indicators. 
Significance levels and confidence intervals are calculated as bilateral, the statistical significance 
of differences is two-sided by default and refers to significance level 0.05 (unless specified 
otherwise). 
Analysis of demographics and other source data 
Demographic data (age, sex) and baseline condition data are presented along with summaries in 
the form of absolute frequencies (number of observations), relative frequencies (percent), or using 
the arithmetic mean, confidence interval (CI) 95% for mean, standard deviation, median, 
interquartile span (25th and 75th centiles), minimum and maximum, depending on the type of 
variable. 
To test the study group homogeneity hypothesis, at the baseline zero hypotheses (no differences 
between groups) are tested with Student's t-test (for interval measures with normal distribution in 
the study population), Mann-Whitney's test (for ordinary measures or for interval measures with 
distribution different from normal) or Fisher's exact test and χ2 test (for qualitative indicators). 
If statistically significant differences between study arms are found, the magnitude of differences 
is estimated using confidence intervals. 
Analysis of primary efficacy parameter 
Primary efficacy endpoints: 
One of the primary efficacy parameters is the time (in days) to improvement of patient's clinical 
status according to the categorical ordinal scale of clinical improvement. 
 
Time (in days) to improvement in clinical status on a categorical ordinal scale of clinical 
improvement. 
To compare the primary efficacy indicator between arms, the Student's t-test for independent 
samples is used. If the necessary assumptions about the normality of distribution of this indicator 
are not met, the non-parametric Mann-Whitney test will be used. Also, the Kaplan-Meier 
technique and compilation survival tables can be used as descriptive methods for studying this 
efficiency parameter. Gehan-Wilcoxon test, Cox-Mentel test or Log-Rank test can be used to 
compare the time (in days) to improve the clinical status of the patient between the study groups. 


Confidential 
9 
 
Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
The proof of the superiority hypothesis is the establishment of a statistically significant time 
difference (in days) before patient's clinical status improvement between the Areplivir arm and the 
standard therapy arm. 
The next primary efficacy parameter is the percentage of patients who achieved an improvement 
in clinical status according to the categorical ordinal scale of clinical improvement by 2 or more 
categories at Visit 3. 
 
Rate of clinical status improvement by categorical ordinal scale of clinical status improvement 
by 2 or more categories at Visit 3. 
For the analysis of this parameter, an intergroup comparison of percentages is used using a 
two-sided version of the Fischer's exact test (or a two-sided version of the χ2 (chi-square) test, if 
all the expected values in the cells of the contingency table for this analysis are 5 or more). The 
percentage of patients who achieved improvement in clinical status on a categorical ordinal clinical 
improvement scale by 2 or more categories at Visit 3 is presented with a two-sided 95% confidence 
interval by treatment arm. Hypothesis testing is performed at a 5% significance level. The 
difference in proportion between treatment arms and the 95% bilateral confidence interval for the 
difference in proportion calculated by Newcomb-Wilson technique is presented. 
The proof of the hypothesis of superiority of Areplivir film-coated tablets (PROMOMED RUS 
LLC, Russia) is the establishment of a statistically significant difference in the proportions of 
patients who achieved an improvement in clinical status according to the categorical ordinal scale 
of clinical improvement by 2 or more categories at Visit 3, between Areplivir arm and standard 
therapy arm. 
Analysis of the primary efficacy parameter is performed in the ITT population (main analysis), 
and in the PP population (additional analysis). A summary of all efficacy indicators is provided. 
Analysis of secondary efficacy parameters 
The following efficacy parameters in the protocol are represented by qualitative values: 
 
Percentage of patients with elimination * COVID-19 according to PCR analysis at Visit 3. 
 
Percentage of patients transferred to intensive care unit. 
 
Percentage of cases with non-invasive lung ventilation. 
 
Percentage of cases with mechanical lung ventilation. 
 
Incidence of fatal cases. 
 
Assessment of lung injury according to CT data at Visits 4, 5 and 6.** 
* Virus elimination is defined as two negative laboratory tests for SARS-CoV-2 RNA obtained at intervals of 24 
hours. 
**An "empirical" visual scale will be used to estimate changes in lung involvement from CT data. 
For the analysis of these parameters, an intergroup comparison of shares is used using a two- sided 
version of the Fischer's exact test (or a two-sided version of the χ2 (chi-square) test, if all the 
expected values in the cells of the contingency table for this analysis are 5 or more). 
The protocol also includes the following endpoint: 
 
Time (in days) to fever disappearance (body temperature < 37.2 ° C for 3 consecutive days 


Confidential 
10 
 
Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
without antipyretic medication). 
For the secondary efficacy parameter "time (in days) to fever disappearance (body temperature < 
37.2 °C for 3 consecutive days without antipyretic drugs), a comparison between arms is made 
using the Student's t-test or the Mann-Whitney test (depending on the nature of the distribution 
of quantitative indicators). Also, Kaplan-Meier technique and the construction of survival tables 
can be used as descriptive methods of study. The Gehan-Wilcoxon test, the Cox-Mentel test or 
the Log-Rank test can be used to compare the time (in days) to the disappearance of fever in the 
study arms. 
Analysis of secondary efficacy parameters is performed in the ITT population (main analysis), and 
in the PP population (additional analysis). 
In case of developing acute respiratory distress syndrome and the need to switch patient to 
mechanical ventilation, the investigational drug is canceled, but the patient is not withdrawn from 
the study. Patients are under follow-up until Visit 6, the data are taken into account to assess 
efficacy in the ITT population. 
Safety Analysis 
Safety criteria 
Safety assessment includes the following parameters: 
 Total number of adverse events (AEs) stratified by severity and incidence; 
 Incidence of adverse drug reactions; 
 Incidence of serious adverse events (SAEs) associated with the use of the study 
drug/standard therapy; 
 Percentage of patients with at least one AE; 
 Percentage of patients who discontinuation treatment due to AE. 
Cross-group comparisons are performed for all safety indicators. The comparison of groups on 
frequency indicators is carried out using the Fischer's exact test or the χ2 (chi-square) test, 
depending on the expected value in the cells of contingency table. For quantitative laboratory 
results, comparisons between groups at relevant visits are made using the Student’s t-test or the 
Mann-Whitney test (depending on the nature of the distribution of quantitative indicators). 
For analysis of all safety parameters the safety population was used. 
In case of developing acute respiratory distress syndrome and the need to switch patient to 
mechanical ventilation, the investigational drug is canceled, but the patient is not withdrawn from 
the study. Patients are under follow-up until Visit 6, the data are taken into account to assess 
efficacy in the ITT population. 
Interim analysis 
In the first stage, 40 patients were included in each group (study arm). Given 40 patients in each 
of the study arms, the sensitivity of the study to confirm 15% superiority by incidence, supposing 
the expected response 80% in the test drug arm, will exceed 45%. 


Confidential 
11 
 
Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 

 
Two Independent Proportions (Null Case) Power 
Analysis 
 
Numeric Results of Tests Based on the Difference: P1 - P2
 
H0: P1 - P2 ≥ 0. H1: P1 - P2 = D1 < 0. Test Statistic: Z test with pooled variance

 
Sample 
Sample 
Prop|H1 
Prop
 
Size 
Size 
Grp 1 or 
Grp 2 or 
Diff 
Diff
 
Grp 1 
Grp 2 
Trtmnt 
Control 
if H0 
if H1 
Target 
Actu
 
Power    N1 
N2 
P1 
P2 
D0 
D1 
Alpha 
Alph
 
0.4553 
40 
40 
0.6500 
0.8000 
0.0000 
-0.1500 
0.0500 
0.050

Said statistical power (45%) is acceptable for exploratory stages of the studies aimed to select the 
duration for endpoint monitoring and to select the endpoint at the second (confirming) stage. 
In case change of the planned endpoints, separate adjustment will be made for the multiplicity of 
comparisons and the required number will be recalculated at the second stage. 
Significance level used in the clinical study 
Significance levels and confidence intervals are calculated as bilateral, the statistical significance 
of differences is two-sided by default and refers to significance level 0.05 (unless specified 
otherwise). 
Stopping criteria for the clinical study 
This protocol does not contain any statistical criteria for stopping the clinical study. 
Accounting for missing data, data not to be analyzed and questionable data 
In the case of for missing data, data not to be analyzed and questionable data, appropriate statistical 
analysis methods are applied. Patients who will not be able to complete the course of therapy 
according to the protocol are included in the analysis of the main endpoint using the last 
observation carried forward (LOCF) method. This means that measures taken as criteria for 
efficacy will be assessed for such patients at the time of dropping out of the study. 
Procedures for reporting any deviations from the original statistical plan 
All deviations from the final version of the statistical analysis plan will be described and 
substantiated in the final clinical study report. 
Population analysis 
The statistical analysis includes the following patient populations: 
1. Safety population: patients who have received at least one dose of the study drug and for whom 
there is an assessment of condition and/or AE for at least one time point after administration. 
2. Population of all patients included in the study (Intent-to-treat, ITT): patients who received 
at least one dose of the drug in the study and for whom there is data for at least one visit after 
the baseline (Visit 0). 
3. Population    of    patients    who    completed    the    study    as     per     the     Protocol  (Per 
protocol, PP): patients who have completed the study as per the Study Protocol. 
In case of developing acute respiratory distress syndrome and the  need  to  switch  patient to 
mechanical ventilation, the investigational drug is canceled, but the patient is not withdrawn 


Confidential 
12 
 
Sponsor: 
PROMOMED 
RUS 
LLC, 
Russia 
Separate study table relating to part of 
the dossier 
Volume: 
Pages: 
(For use by national authorized bodies 
only) 
Name of finished product: 
Areplivir, film-coated tablets 
Active ingredient: 
Favipiravir 
from the study. Patients are under follow-up until Visit 6, the data are taken into account to 
assess efficacy in the ITT population.