Clinical trial NCT03455491
Conditions: Acute Respiratory Viral Infections Influenza
Sponsor: PHARMENTERPRISES LLC
Start date: 2018-02-12; Completion date: 2018-06-28
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multicenter double-blinded, randomized, placebo-controlled, parallel-group comparative Phase II clinical study to assess safety, tolerability, efficacy and optimal dose of XC221 vs. placebo in patients with uncomplicated influenza or other ARVI during a 3-day treatment.

The primary objective of the study is to demonstrate the difference in time before the onset of a sustained improvement in clinical symptoms according to the Modified Jackson Scale for ARVI and to determine the optimal dose of XC221 in the treatment of influenza and other ARVI.

Detailed description:
11 Russian centers were planned for participation in this study. The study consists of three periods: screening, treatment and follow-up.

All eligible patients will be randomized into 3 groups (groups A, B and C) in a 1:1:1 ratio:

Group A - XC221 100 mg daily (40 patients); Group B - XC221 200 mg daily (40 patients); Group C - Placebo (40 patients).

During the treatment period (3 days), patients will receive XC221 / placebo daily on a background of standard symptomatic therapy. The follow-up period lasts for 11 days.

Arms: arm 1: XC221 100 mg orally.

1 tablet of XC221 100 mg +1 tablet of Placebo 100 mg (in total 2 tablets) once daily during 3 days of treatment period arm 2: XC221 200 mg orally. 2 tablets of XC221 100 mg once daily during 3 days of treatment period arm 3: Placebo orally. 2 tablets of Placebo 100 mg once daily during 3 days of treatment period
Interventions: intervention 1: XC221 100 mg intervention 2: XC221 200 mg intervention 3: Placebo
Intervention descriptions: intervention 1: once daily during 3 days. intervention 2: once daily during 3 days. intervention 3: once daily during 3 days.

Protocol documents:
Prot_SAP_000.pdf: 
PHARMENTERPRISES LLC 
Investigational medicinal product XC221 
Protocol No.: ARI-XC221-02 
Date: 25-01-2018 
 
 
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Protocol 
A multicenter, double-blind, randomized, placebo-controlled comparison trial 
to evaluate safety, tolerability, and efficacy to choose the optimal dose of 
XC221 at daily doses of 100 and 200 mg in patients with uncomplicated 
influenza or other acute viral upper respiratory infections 
 
 


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Trial title 
A multicenter, double-blind, randomized, placebo-
controlled comparison trial to evaluate safety, 
tolerability, and efficacy to choose the optimal dose of 
XC221 at daily doses of 100 and 200 mg in patients 
with uncomplicated influenza or other acute viral 
upper respiratory infections 
Sponsor 
PHARMENTERPRISES LLC 
Bolshoy Blvd. 42, Building 1, offices 771, 772, 
Skolkovo Innovation Center, Moscow, 143026, 
Russia 
Tel.: +7 (985) 728-75-72 
Manufacturer 
ZAO 
Obninsk 
Chemical 
and 
Pharmaceutical 
Company, Russia 
Investigational medicinal product 
XC221, 100 mg tablets 
Route of administration  
Oral 
Active ingredient 
XC221GI 
Phase of development 
Phase II 
Principal investigators and study 
centers 
Study center 01 
Principal Investigator – Sergey M. Noskov, Dr. Med. 
Sci., Professor; 
State Autonomous Budgetary Healthcare Institution of 
the Yaroslavl Region "Clinical Hospital no. 3"; 
ul. Mayakovskogo 61, Yaroslavl, 150007 Russia 
Tel.: +7 (4852) 24-23-32 
Fax: +7 (4852) 24-23-32 
E-mail: noskov03@gmail.ru 
 
Study center 02 
Principal Investigator – Mikhail E. Statsenko, Dr. 
Med. Sci., Professor; 
Federal State Budgetary Institution of Higher 
Professional Education "Volgograd State Medical 


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University", Ministry of Health of the Russian 
Federation; 
Ploshchad Pavshikh Bortsov 1, Volgograd, 400131, 
Russia 
Tel.: +7 (8442) 38-53-57 
Fax: +7 (8442) 55-17-70 
E-mail: mestatsenko@rambler.ru 
 
Study center 03 
Principal investigator – Vladimir A. Martynov, Dr. 
Med. Sci.; 
Federal State Budgetary Institution of Higher 
Professional Education "Ryazan State Medical 
University named after Academician I.P. Pavlov", 
Ministry of Health of the Russian Federation; 
ul. Vysokovoltnaya 9, Ryazan, 390026, Russia 
Tel.: +7 (4912) 76-55-03 
E-mail: dr.martinov@mail.ru 
 
Study center 04 
Principal investigator – Yulia V. Drozdova; 
Federal 
State Budgetary 
Institution 
"Research 
Institute of Influenza", Ministry of Health of the 
Russian Federation; 
ul. Prof. Popova 15/17, St. Petersburg, 197376, Russia 
Tel.: +7 (812) 499-15-44 (45) 
Fax: +7 (812) 499-15-44  
E-mail: drozdova-julia78@mail.ru 
 
Study center 05 
Principal investigator – Natal'ya V. Dunaeva, Cand. 
Med. Sci., Associate Professor; 
St. Petersburg State Budgetary Healthcare Institution 
"Center for Prevention and Control of AIDS and 
Infectious Diseases"; 


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nab. Obvodnogo kanala 179, St. Peterburg, 190103, 
Russia 
Tel.: +7 (812) 407-83-49, +7 (812) 251-08-53 
Fax: +7 (812) 251-08-53 
E-mail: nvch@mail.ru 
 
Study center 08 
Principal investigator – Alina S. Agaf'ina, Cand. Med. 
Sci.; 
St. Petersburg State Budgetary Healthcare Institution 
"City Hospital no. 40 of the Kurortnyi District"; 
ul. Borisova 9, lit. B, Sestroretsk, 197706, Russia 
Tel.: +7 (812) 437-35-22 
Fax: +7 (812) 437-31-38 
E-mail: a.agafina@mail.ru 
 
Study center 09 
Principal investigator – Andrey V. Ezhov, Dr. Med. 
Sci., Associate Professor, Professor; 
Budgetary Healthcare Institution of the Udmurt 
Republic "City Clinical Hospital no. 9 of the Ministry 
of Health of the Udmurt Republic"; 
ul. Promyshlennaya 52, Izhevsk, Udmurt Republic, 
426063, Russia 
Tel.: +7 (3412) 66-11-33 
Fax: +7 (3412) 66-11-33 
E-mail: andigel2@rambler.ru 
 
Study center 10 
Principal investigator – Natal'ya Yu. Pshenichnaya, 
Dr. Med. Sci., Professor; 
Municipal Budgetary Healthcare Institution "Rostov-
on-Don City Hospital no. 1 named after N.A. 
Semashko"; 


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pr. Voroshilovskiy, 105/243/264, Rostov-on-Don, 
344000, Russia 
Tel.: +7 (863) 232-08-17 
Fax: +7 (863) 250-07-26 
E-mail: natalia-pshenichnaya@yandex.ru 
 
Study center 11 
Principal investigator – Marina G. Avdeeva, Dr. Med. 
Sci., Professor; 
Federal State Budgetary Institution of Higher 
Professional 
Education "Kuban State Medical 
University", Ministry of Health of the Russian 
Federation; 
ul. Mitrofana Sedina 4, Krasnodar, 350063, Russia 
Tel.: +7 (861) 255-44-23 
E-mail: AvdeevaM@mail.ru 
 
Study center 12 
Principal investigator – Natal'ya N. Burova, Dr. Med. 
Sci.; 
Federal State Budgetary Institution "Diagnostic 
Outpatient Center", Administrative Directorate of the 
President of the Russian Federation; 
Morskoy pr. 3, St. Petersburg, 197110, Russia 
Tel.: +7 (812) 670-09-62 
Fax: +7 (812) 234-68-22 
E-mail: nnburova@rambler.ru 
 
Study center 13 
Principal investigator – Anna V. Snigireva, Cand. 
Med. Sci.; 
Federal State  Budgetary Institution of Higher 
Education "Yaroslavl State Medical University", 
Ministry of Health of the Russian Federation; 
ul. Revolyutsionnaya 5, Yaroslavl, 150000, Russia 


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Tel.: +7 (4852) 24-23-32 
E-mail: n0613@yandex.ru 
 
Study population 
Male and female patients aged 18–45 years inclusive, 
diagnosed with uncomplicated influenza or other 
acute viral upper respiratory infections based on 
clinical symptoms only and meeting all the inclusion 
criteria, were enrolled in this trial. 
First patient, first visit – Last 
patient, last visit 
12-Feb-2018 – 28-Jun-2018 
Aim and objectives of the study: 
Study aim: 
The aim of this clinical trial was to evaluate safety, 
tolerability, and efficacy, as well as to determine the 
optimal dose of XC221 co-administered with the 
standard symptomatic therapy to treat influenza and 
acute viral URI. 
Study objectives: 
1. To evaluate the safety of XC221 100 mg and 200 
mg vs placebo, co-administered with the standard 
symptomatic therapy to treat influenza and acute viral 
URI by frequency of adverse events (AEs). 
2. To evaluate the efficacy of XC221 100 mg and 200 
mg vs placebo, co-administered with the standard 
symptomatic therapy to treat influenza and acute viral 
URI by its effect on main manifestations of the disease 
(symptom intensity and duration) using the modified 
Jackson scale. 
3. To determine the optimal dose of XC221 among the 
suggested doses (100 and 200 mg per day) by 
analyzing efficacy, safety, and tolerability of IMP. 
4. To evaluate the dynamics of MxA protein blood 
concentration during the administration of XC221 100 
mg and 200 mg vs placebo. 
5. To evaluate the dynamics of C-reactive protein 
(CRP) blood concentration during the administration 
of XC221 100 mg and 200 mg vs placebo. 
6. To evaluate the dynamics of blood concentrations 
of 6Ckine, BCA-1, CTACK, ENA-78, Eotaxin, 
Eotaxin-2, Eotaxin-3, Fractalkine, GCP-2, GM-CSF, 
Gro-α, Gro-β, I-309, IFN-γ, IL-1β, IL-2, IL-4, IL-6, 
IL-8, IL-10, IL-16, IP-10, I-TAC, MCP-1, MCP-2, 


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MCP-3, MCP-4, MDC, MIF, MIG, MIP-1α, MIP-1δ, 
MIP-3α, MIP-3β, MPIF-1, SCYB16, SDF-1α+β, 
TARC, TECK, and TNF-α cytokines during the 
administration of XC221 100 mg and 200 mg vs 
placebo. 
Methodology (study design and 
procedures): 
A multicenter, double-blind, randomized, placebo-
controlled, comparison trial. 
The trial involved the following periods: screening 
(lasting no longer than 36 hrs after the onset of the 
earliest symptoms), treatment period (3 days), and 
follow-up period (11±1 days after the end of study 
treatment). Duration of participation in the trial for 
each patient was no longer than 16 days and 12 hrs. 
The following visits were performed during the trial: 
Visit 0 (Day 0) (screening); treatment period – Visit 1 
(Day 1) (randomization), Visit 2 (Day 2), Visit 3 (Day 
3), and the follow-up period – Visit 4 (Day 4), Visit 5 
(Day 5), Visit 6 (Day 6), Visit 7 (Day 7), Visit 8 (Day 
8), and the Study Termination Visit 9 (Day 14±1); 
Visit 4, Visit 6, and Visit 9 were performed by the 
patient to the study center in person, while Visit 5, 
Visit 7, and Visit 8 could be made either in person or 
as morning and evening telephone calls. 
Patients receiving both in- and outpatient treatment 
could be enrolled. The investigator made a decision 
regarding whether a patient will be followed up on an 
outpatient or inpatient basis, as well as regarding the 
length of hospital stay for inpatient subjects in 
compliance with the Methodological Guidelines for 
Diagnosis, Treatment, and Prevention of Influenza 
issued by the Ministry of Health of the Russian 
Federation (ed. by A.G. Chuchalin). During the trial, 
Visits 1–3 could be made both on an in- or outpatient 
basis (including at patient's home). If a patient 
underwent a domiciliary screening, samples for all 
laboratory tests could also be collected at home and 
were analyzed at the earliest possible time as the 
patient was supposed to administer the first dose of 
IMP no later than 36 hrs after the onset of the earliest 
disease symptoms. 
During the trial, at Visit 1 (Day 1) all patients meeting 
the inclusion criteria and not meeting any of the 
exclusion criteria were randomly assigned into three 
groups (groups A, B, and C) at a 1:1:1 allocation ratio 
to be treated with the investigational medicinal 


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product/placebo co-administered with the standard 
symptomatic therapy: 
Group A – the IMP was XC221 at a daily dose of 100 
mg, co-administered with the standard symptomatic 
therapy; 
Group B – the IMP was XC221 at a daily dose of 200 
mg, co-administered with the standard symptomatic 
therapy; 
Group C – placebo, co-administered with the standard 
symptomatic therapy. 
During the trial, the randomized patients received the 
study therapy on an in- or outpatient basis during 3 
days under control of an investigator at the following 
visits: Visit 1 (Day 1), Visit 2 (Day 2), and Visit 3 
(Day 3). 
After the 3-day treatment period, the patients were 
followed up for the subsequent 11±1 days (the follow-
up period). 
During the follow-up period, the following visits were 
performed: Visit 4 (Day 4), Visit 6 (Day 6), and Visit 
9 (Day 14±1) – the patient visited the study center in 
person; Visit 5 (Day 5), Visit 7 (Day 7), and Visit 8 
(Day 8) could be made either in person or on an in-
patient/outpatient basis or as morning and evening 
telephone calls to assess patient's wellbeing. Visit 9 
(Day 14±1) was made 14±1 days after treatment 
initiation. After completing Visit 9 (Day 14±1), 
patients' participation in the clinical trial was 
considered completed. 
At Visit 1 (Day 1), diaries were handed over to the 
patients so that they could write down the body 
temperature values. During the treatment period, the 
patient was supposed to measure his/her body 
temperature twice a day: in the morning (at 8–11 a.m.) 
and in the evening (8–11 p.m.). The temperature 
measurements results were written down in the 
patient's temperature diary. 
During the trial, starting with Visit 0 (screening visit) 
through Visit 8 (Day 8), the investigator evaluated the 
severity of the symptoms of influenza/acute viral URI 
daily (in the morning and in the evening) using the 
modified Jackson scale, either in person or in a 
telephone conversation. At Visits 1 (Day 1) through 4 
(Day 4), the first measurement of body temperature 
and evaluation of symptom severity were carried out 


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in person by the investigator, while the second 
assessment of symptom severity and obtaining the 
temperature measurement records the same day could 
be performed by the investigator in a telephone 
conversation. All the procedures at Visits 5 (Day 5), 7 
(Day 7), and 8 (Day 8) could be performed either in 
person (on an inpatient/outpatient basis) or as 
telephone conversations, twice daily (in the morning 
and in the evening). Visit 6 (Day 6) was made only on 
an inpatient or outpatient basis (but the second 
assessment of the symptoms severity and obtaining the 
information 
about 
the 
body 
temperature 
measurements results on the same day could be 
performed by the investigator in a telephone 
conversation). 
At Visit 4 (Day 4), the patients brought their diaries 
filled out throughout the period between Visit 1 (Day 
1) and Visit 4 (Day 4) to the investigator; the 
investigator checked whether all necessary records 
were made, discussed the reported complaints, and 
returned the diaries to patients so that they continued 
making records during the follow-up period, starting 
with Visit 5 (Day 5) through Visit 9 (Day 14±1). The 
patient was supposed to write down the body 
temperature values and all his/her complaints and 
symptoms twice daily, in the morning and in the 
evening. 
At Visit 0 (Day 0) (screening) or Visit 1 (Day 1), 
nasopharyngeal and oropharyngeal swabs were taken 
to establish the viral etiology of the disease by PCR (a 
qualitative test to detect the following infectious 
agents: influenza A and B viruses, human respiratory 
syncytial virus, human metapneumovirus, human 
coronavirus, human rhinovirus, human adenovirus 
(subgroups B, C, and E), human bocavirus, human 
parainfluenza viruses 1, 2, 3, and 4) (the samples were 
sent to the central laboratory to be analyzed). The 
therapy prescribed to patients in this trial was not 
supposed to be modified according to the analysis 
results to detect the virus in the biological samples. No 
confirmation of viral nature of the disease was needed 
for patients to be enrolled in this trial. The diagnosis 
of influenza or acute viral URI was made only by 
evaluating the clinical symptoms to recruit the patients 
into the trial and prescribe therapy. 
The viral nature of the disease was taken into account 
when analyzing the data obtained in the trial. 


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At Visit 1 (before the first dose of IMP/placebo was 
taken), Visit 4, and Visit 6, patients' blood samples 
were collected to analyze serum concentrations of 
MxA protein, C-reactive protein, and cytokines 
6Ckine, BCA-1, CTACK, ENA-78, Eotaxin, Eotaxin-
2, Eotaxin-3, Fractalkine, GCP-2, GM-CSF, Gro-α, 
Gro-β, I-309, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-
10, IL-16, IP-10, I-TAC, MCP-1, MCP-2, MCP-3, 
MCP-4, MDC, MIF, MIG, MIP-1α, MIP-1δ, MIP-3α, 
MIP-3β, MPIF-1, SCYB16, SDF-1α+β, TARC, 
TECK, and TNF-α. 
The 
number 
of 
patients 
screened/randomized, and patients 
who completed the study 
Screened patients: 121 
Randomized patients: 120 
Patients who completed the study: 120 
Inclusion criteria: 
1. 
Men and women aged 18 to 45 years 
(inclusive). 
2. 
Clinically diagnosed mild or moderate 
influenza or acute viral URI. 
3. 
Patient's body temperature at screening 
≥37.5°C and at least one intoxication or 
catarrhal symptom from the ones listed in 
the modified Jackson scale, with severity 
grade estimated as score ≥ 2.  
4. 
Uncomplicated course of influenza or 
acute viral URI based on assessment of 
clinical symptoms. 
5. 
The interval between the onset of the 
earliest symptoms of the disease and 
enrollment (administration of the first dose 
of IMP/placebo) is no longer than 36 hrs. 
6. 
Women of reproductive age (who are not 
in menopause and who have not undergone 
surgical sterilization) and men who have 
sexual activity should use a reliable 
method 
of 
contraception 
(acceptable 
methods of contraception in this study are: 
intrauterine devices, oral contraceptives, 
contraceptive patch, long-acting injectable 
contraceptives, a double barrier method 
(condom with spermicide, diaphragm with 
spermicide)) throughout the study period 
and 
30 
days 
after 
the 
last 
dose 
administration of IMP/placebo. 
7. 
A patient agrees to adhere to the treatment 
regimen, 
visits 
and 
laboratory 
examinations provided by the protocol. 


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8. 
Signed Informed Consent Form. 
Exclusion criteria: 
Patients meeting at least one of these criteria were not 
eligible for the study: 
1. 
Existence of complications of influenza or 
acute 
viral 
URI 
(including 
the 
presence/development 
of 
bacterial 
infection). 
2. 
Hypersensitivity to the active ingredient 
and excipients of IMP or placebo. 
3. 
Administration of antiviral medications 
(antiviral agents, interferons and interferon 
inducers, 
drugs 
that 
have 
immunomodulating action) or systemic or 
local anti-infective agents 7 days prior to 
screening. 
4. 
Severe 
infection 
with 
signs 
of 
cardiovascular insufficiency development 
and other manifestations of infectious-
toxic shock, as well as with the presence of 
neuroinfection syndrome (encephalic and 
meningo-encephalic 
reactions, 
polyradiculoneuritis, neuritis). 
5. 
Signs of the pneumonia development (the 
presence of at least two of the following 
symptoms): dyspnea, chest pain when 
coughing, systemic cyanosis, dullness of 
percussion 
sound 
upon 
symmetrical 
evaluation of the upper and lower sections 
of the lungs). 
6. 
Infectious diseases during the last week 
prior to the Screening visit. 
7. 
History of bronchial asthma. 
8. 
History of increased convulsive activity. 
9. 
Severe, 
decompensated 
or 
unstable 
somatic 
diseases 
(any 
diseases 
or 
conditions that are life-threatening or may 
worsen the patient's prognosis, and make 
him/her ineligible for the clinical study). 
10. 
History of cancer, HIV, tuberculosis. 
11. 
Diabetes mellitus 
12. 
Drug or alcohol abuse. 
13. 
Participation in any other clinical trial in 
the last 90 days prior to the Screening visit. 
14. 
Pregnancy or lactation. 
15. 
Military or prison populations. 
16. 
Impossibility or inability to comply with 
the study procedures. 


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17. 
A member of the investigator's family or 
other person interested in the results of the 
study. 
18. 
Abnormal 
laboratory 
values, 
which, 
according to the study doctor, interfere 
with the patient's inclusion in the study. 
19. 
History of renal insufficiency. 
Withdrawal criteria: 
The Principal Investigator was to withdraw a patient 
from the study at any point in the following situations: 
1. 
Adverse events requiring discontinuation 
of IMP. 
2. 
Patient's enrollment turned out to be a 
protocol deviation. 
3. 
Patient 
needed 
to 
take 
medications 
prohibited by this trial, including the 
situation when the study treatment proved 
ineffective. 
4. 
Investigator 
believed 
that 
further 
participation in the trial contradicted the 
patient's best interest. 
5. 
Patient would like to withdraw his/her 
informed consent. 
6. 
Patient failed to adhere to the protocol. 
7. 
Female patient was pregnant. 
Investigational medicinal product, 
dosage 
schedule, 
route 
of 
administration, lot number 
XC221, 100 mg tablets 
Active ingredient: XC221GI 
Dosage schedule: 
Group A – XC221 at a daily dose of 100 mg co-
administered with the standard symptomatic therapy;  
Group B – XC221 at a daily dose of 200 mg co-
administered with the standard symptomatic therapy; 
(40 patients). 
Route of administration: 
orally, once daily, one tablet from the respective two 
bottles (a total of 2 tablets per day) regardless of 
meals. 
Lot number: 21116 
Duration of therapy with IMP: 
3 days 
Placebo, dosage schedule, route of 
administration, lot number 
Placebo, 100 mg tablets 


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Active ingredient: none 
Dosage schedule: 
Group C – placebo co-administered with the standard 
symptomatic therapy. 
Route of administration: 
orally, once daily, one tablet from the respective two 
bottles (a total of 2 tablets per day) regardless of 
meals. 
Lot number: 11116 
Duration of placebo therapy: 
3 days 
Efficacy endpoints: 
Efficacy of the investigational medicinal product will 
evaluated according to the primary and secondary 
endpoints. 
Primary endpoint: 
Time to sustained improvement of clinical symptoms 
based on the modified Jackson scale (score ≤ 1 for 
each symptom) measured in hours after administration 
of the first dose of IMP. 
Time to sustained improvement means the time of 
making the first evaluation out of three consecutive 
evaluations based on the modified Jackson scale at 
which all clinical symptoms of acute viral URI and 
influenza corresponded to score 1 or lower. 
Secondary endpoints: 
1. 
The area under the curve "modified 
Jackson scale score" during 3-day therapy; 
2. 
Time to body temperature normalization 
since treatment initiation, measured in 
hours (normalization is regarded as setting 
of body temperature below 37°C without 
elevation above these values during the 
follow-up until Day 14 visit); 
3. 
Time to normalization of body temperature 
since the onset of the earliest symptoms of 
the 
disease, 
measured 
in 
hours 
(normalization is regarded as setting of 
body temperature below 37°C without 
elevation above these values during the 
follow-up until Day 14 visit); 
4. 
The mean modified Jackson scale score on 
days 1, 2, 3, 4, 5, 6, 7, and 8 after treatment 
initiation; 


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5. 
The mean modified Jackson scale score on 
days 1, 2, 3, 4, 5, 6, 7, and 8 after the onset 
of the earliest symptoms of the disease; 
6. 
The percentage of patients in whom the 
sum of modified Jackson scale scores is ≤ 
3 (the score for each symptom is to be ≤ 1) 
on days 1, 2, 3, 4, 5, 6, 7, and 8 after 
treatment initiation; 
7. 
The percentage of patients in whom the 
sum of modified Jackson scale scores is ≤ 
3 (the score for each symptom is to be ≤ 1) 
on days 1, 2, 3, 4, 5, 6, 7, and 8 after the 
onset of the earliest symptoms of the 
disease; 
8. 
The mean body temperature on days 1–14 
after treatment initiation; 
9. 
The mean body temperature on days 1–14 
after the onset of the earliest symptoms of 
the disease; 
10. 
The percentage of patients with normalized 
body temperature on days 1–14 after study 
initiation; 
11. 
The percentage of patients with normalized 
body temperature on days 1–14 after the 
onset of the earliest symptoms of the 
disease; 
12. 
The 
percentage 
of 
patients 
with 
complications of influenza/acute viral URI 
that developed during the period of days 1–
4 and days 1–14 after treatment initiation; 
13. 
The 
percentage 
of 
patients 
with 
complications of influenza/acute viral URI 
that developed during the period of days 1–
4 and days 1–15 after the onset of the 
earliest symptoms of the disease; 
14. 
The percentage of patients with severe 
complications of influenza/acute viral URI 
that developed during the period of days 1–
4 and days 1–14 after treatment initiation; 
15. 
The percentage of patients with severe 
complications of influenza/acute viral URI 
that developed during the period of days 1–
4 and days 1–15 after the onset of the 
earliest symptoms of the disease; 
16. 
Timeframe of developing complications of 
influenza/acute viral URI after treatment 
initiation; 
17. 
Timeframe of developing complications of 
influenza/acute viral URI after the onset of 
the earliest symptoms of the disease; 


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18. 
Time to resolution (score 0) of each 
symptom in the modified Jackson scale 
(sneezing, rhinorrhea, nasal congestion, 
cough, fever, malaise, chills, headache, 
myalgia, sore throat, itchy throat, and 
hoarseness) since treatment initiation in the 
population of patients in whom the 
respective symptom was evaluated as score 
2 or 3 at Visit 0 (Day 0); 
19. 
Time to resolution (score 0) of each 
symptom in the modified Jackson scale 
(sneezing, rhinorrhea, nasal congestion, 
cough, fever, malaise, chills, headache, 
myalgia, sore throat, itchy throat, and 
hoarseness) since the onset of the earliest 
symptoms of the disease in the population 
of patients in whom the respective 
symptom was assessed as score 2 or 3 at 
Visit 0 (Day 0); 
20. 
The percentage of patients having score 0 
for each symptom in the modified Jackson 
scale 
(sneezing, 
rhinorrhea, 
nasal 
congestion, cough, fever, malaise, chills, 
headache, myalgia, sore throat, itchy 
throat, and hoarseness) on days 2, 3, 4, 5, 
6, 7, and 8 after treatment initiation in the 
population of patients in whom the 
respective symptom was evaluated as score 
2 or 3 at Visit 0 (Day 0); 
21. 
The percentage of patients having score 0 
for each symptom in the modified Jackson 
scale 
(sneezing, 
rhinorrhea, 
nasal 
congestion, cough, fever, malaise, chills, 
headache, myalgia, sore throat, itchy 
throat, and hoarseness) on days 2, 3, 4, 5, 
6, 7, and 8 after the onset of the earliest 
symptoms in the population of patients in 
whom the respective symptom was 
evaluated as score 2 or 3 at Visit 0 (Day 0). 
Safety endpoints: 
Secondary endpoint: 
frequency of adverse events (AEs) and serious adverse 
events (SAEs) in the XC221 group and in the placebo 
group. 
Tolerability was evaluated as good, fair, and poor 
based on the presence/absence of adverse drug 
reactions 
causing 
treatment 
suspension 
or 
discontinuation. 


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Investigational medicinal product XC221 
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Exploratory endpoints 
1. 
Mean blood concentration of MxA protein 
in patient groups treated with XC221 100 
mg and 200 mg XC221 as compared to the 
placebo group at Visit 4 and Visit 6;  
2. 
Changes in blood concentrations of MxA 
protein in patients at Visit 4 and Visit 6 as 
compared to Visit 1 in treatment groups; 
3. 
Mean blood concentration of C-reactive 
protein in patient groups treated with 
XC221 100 mg and 200 mg as compared to 
the placebo group at Visit 4 and Visit 6; 
4. 
Changes in blood concentrations of C-
reactive protein in patients at Visit 4 and 
Visit 6 as compared to Visit 1 in treatment 
groups; 
5. 
Mean serum concentrations of 6Ckine, 
BCA-1, 
CTACK, 
ENA-78, 
Eotaxin, 
Eotaxin-2, Eotaxin-3, Fractalkine, GCP-2, 
GM-CSF, Gro-α, Gro-β, I-309, IFN-γ, IL-
1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-16, IP-
10, I-TAC, MCP-1, MCP-2, MCP-3, 
MCP-4, MDC, MIF, MIG, MIP-1α, MIP-
1δ, MIP-3α, MIP-3β, MPIF-1, SCYB16, 
SDF-1α+β, TARC, TECK, TNF-α in 
patient groups treated with XC221 100 mg 
and 200 mg as compared to the placebo 
group at Visit 4 and Visit 6; 
6. 
Changes in serum concentrations of 
6Ckine, 
BCA-1, 
CTACK, 
ENA-78, 
Eotaxin, Eotaxin-2, Eotaxin-3, Fractalkine, 
GCP-2, GM-CSF, Gro-α, Gro-β, I-309, 
IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, 
IL-16, IP-10, I-TAC, MCP-1, MCP-2, 
MCP-3, MCP-4, MDC, MIF, MIG, MIP-
1α, MIP-1δ, MIP-3α, MIP-3β, MPIF-1, 
SCYB16, SDF-1α+β, TARC, TECK, 
TNF-α in patients at Visit 4 and Visit 6 as 
compared to Visit 1 in treatment groups;  
7. 
Evaluation of the relationship between 
cytokine concentration and the modified 
Jackson scale score. 
Statistical methods 
Hypothesis testing 
In accordance with the aim and objectives of the trial, 
a hypothesis that time to sustained improvement of 
clinical symptoms based on the modified Jackson 
scale differs between the groups was formulated for 
the primary endpoint. 


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Date: 25-01-2018 
 
 
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The groups were compared for the parameter "time to 
sustained improvement of clinical symptoms" using 
the generalized Wilcoxon test (the Gehan–Wilcoxon 
test). The null hypothesis stated that there were no 
differences between two groups for the hazard 
function assessed for the primary endpoint in each 
IMP group as compared to the placebo group. It was 
assumed that if the Z-score is higher than the selected 
α-quantile of the standard normal distribution, the null 
hypothesis will be rejected in favor of the alternative 
hypothesis stating that there is difference between the 
two groups. 
Sample size justification 
It was expected that the optimal dose of the 
investigational medicinal product (XC221 100 mg or 
XC221 200 mg) would be selected in this trial by 
exploratory data analysis. The optimal IMP dose was 
supposed to be selected by the Sponsor according to 
the treatment group that would have the minimum 
median time to reach the effect for the primary 
endpoint but a similar or superior safety profile 
compared to that in the remaining groups. It was 
assumed that if the median time to reach the effect for 
the primary endpoint in two dose groups was equal, 
the smaller dose would be selected. 
The sample size was calculated using the PASS 14 
software according to the data obtained in the previous 
trial of the same Sponsor (FLU-XC8-01). In it, the 
hazard rates for a similar endpoint were found to be 
0.83 and 1.23 for the placebo and treatment groups, 
respectively. The sample size for the present trial was 
estimated so that the width of 95% two-sided 
confidence interval of hazard rate was no greater than 
the twofold difference in hazard rates between the 
treatment and placebo groups in a similar study (0.8); 
the percentage of censored observations was ≤ 5%. 
Hence, it was found that the sample size required per 
group was 39 subjects. The selected significance level 
α = 0.05; the pre-set power was 80%. Having assumed 
that the percentage of patients withdrawn throughout 
the study was  2.5%, 40 patients needed to be screened 
for each group. Size of the placebo group was equal to 
that of the treatment groups. Hence, a total of 120 
patients were planned to be randomly assigned into 
three groups at a 1:1:1 allocation ratio (40 subjects into 
each group: the placebo group and the groups treated 
with XC221 100 mg or XC221 200 mg). Assuming 


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that the probability of subject withdrawal at screening 
was ~15%, up to 140 patients were to be screened. 
This was a multicenter trial, with patients recruited on 
a competitive basis. In order to minimize the bias, each 
study center could randomize no more than 30% (36 
patients) of the total sample size. 
Statistical methodology 
All variables for analysis were presented using the 
descriptive statistical methods. An analysis was 
conducted to compare groups at primary and 
secondary endpoints. Categorical variables were 
analyzed using the χ2 test; the two-tailed Fisher's exact 
test was used if more than 20% of expected 
frequencies were < 5. The areas under "variable versus 
time" curves were calculated using the trapezoidal 
rule. Groups were compared in terms of quantitative 
variables 
using 
ANOVA/ANCOVA; 
the 
non-
parametric 
alternative 
was 
employed 
if 
the 
assumptions underlying the method were not met. 
Survival analysis (plotting the Kaplan–Meier curves, 
comparing the hazard functions using the Gehan–
Wilcoxon test) and the stratified Cox regression model 
were used for the censored Time-to-Event data. The 
secondary endpoint data for patients prematurely 
withdrawn from the study were substituted using the 
LOCF algorithm. 
Interim analysis 
Interim analysis was not involved in this study.  
Analysis groups 
Three equal-sized groups, with 40 subjects per group 
(2 groups receiving different doses of IMP and the 
placebo group) were planned for this study. The 
groups treated with IMP were supposed to be 
compared in a pairwise manner to the placebo group; 
it was also planned that the treatment groups would be 
compared to each other. 
Baseline comparability 
The baseline data (demographic and anthropometric 
characteristics, 
as 
well 
as 
disease 
duration 
documented prior to treatment initiation) were 
compared between the groups in the Full Analysis Set 
population. 
If 
significant 
differences 
between 
treatment groups were revealed for any baseline 
parameter, sensitivity analysis was performed to test 


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whether the conclusions about the efficacy remained 
unchanged after applying a correction for different 
baseline parameters in groups. 
Safety analysis 
The safety population consisted of all the patients 
treated with any dose of IMP/placebo. Safety 
parameters (vital signs, laboratory data, and AEs) 
were descriptively analyzed for each group. The 
numbers of AEs and patients with AEs were 
summarized according to their treatment group and 
categorized according to the system organ classes and 
preferred 
terms. 
Additional 
summarizing 
was 
performed for severity of AEs and their relationship to 
IMP. SAE narratives were additionally made in a 
separate analysis. Patients withdrawn prematurely 
from the trial can be found in the list of patients and 
were categorized according to the main reason for 
withdrawal (in each treatment group). 
Tolerability analysis 
Frequency tables were plotted to analyze the 
tolerability data (in the safety population); a 
conclusion regarding the potential differences in 
tolerability between the analyzed samples was drawn 
according to these tables. 
Efficacy analysis 
The main efficacy analysis for the primary endpoint 
was carried out using the Full Analysis Set population. 
Sensitivity analysis in the population of patients with 
verified viral infection and the Per Protocol population 
was conducted. Sensitivity analysis using the stratified 
Cox model was carried out separately for the Per 
Protocol population, with the following covariates: 
"study center", "presence of viral infection", and 
"concomitant treatment with NSAIDs". 
Secondary endpoint analysis was conducted in the Full 
Analysis Set population and the population of patients 
with verified viral infection. Concentrations of C-
reactive protein and 6Ckine, BCA-1, CTACK, ENA-
78, Eotaxin, Eotaxin-2, Eotaxin-3, Fractalkine, GCP-
2, GM-CSF, Gro-α, Gro-β, I-309, IFN-γ, IL-1β, IL-2, 
IL-4, IL-6, IL-8, IL-10, IL-16, IP-10, I-TAC, MCP-1, 
MCP-2, MCP-3, MCP-4, MDC, MIF, MIG, MIP-1α, 
MIP-1δ, MIP-3α, MIP-3β, MPIF-1, SCYB16, SDF-
1α+β, TARC, TECK, and TNF-α cytokines were 
analyzed in the Full Analysis Set population. 


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Investigational medicinal product XC221 
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Date: 25-01-2018 
 
 
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Software 
Specialized SAS software (version 9.4) was used for 
statistical analysis.