Clinical trial NCT01850446
Conditions: Influenza
Sponsor: Materia Medica Holding
Start date: 2015-02-20; Completion date: 2018-04-16
Enrollment: 184 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is:

* to assess the efficacy of Ergoferon in treatment of influenza;
* to assess the safety of Ergoferon in treatment of influenza;
* to compare the efficacy of Ergoferon and Oseltamivir for treatment of influenza.

Detailed description:
The overall duration of a patient participation in the trial is 6 days (screening/randomization/therapy onset - day 1; study therapy period - day 1-5; follow-up period - day 6).

Arms: arm 1: The treatment period is 5 days. Oral Dose per administration: 1 tablet. The tablet should be kept in the mouth until completely dissolution, the drug is taken without regard to food intake. arm 2: The treatment period is 5 days.

1 capsule (75 mg) twice a day during the meal or regardless of meal.
Interventions: intervention 1: Ergoferon intervention 2: Oseltamivir
Intervention descriptions: intervention 1: Safety and Efficacy intervention 2: Safety and Efficacy

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Comparative Parallel-group Randomized Clinical Trial of 
Efficacy and Safety of Ergoferon Versus Oseltamivir in the 
Treatment of Influenza 
 
Phase IV 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-ER-003 
Version date: 
February 08, 2016 
ClinicalTrials.gov Id: 
NCT01850446 
 


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Protocol Summary 
 
This document represents the protocol summary for the study on human subjects. The study will 
be carried out in accordance with ICH GCP, National Standard of the Russian Federation GOST 
52379-2005 "Good Clinical Practice", Helsinki Declaration of World Medical Association, 
relevant requirements of the regulatory authorities as well as the study procedures. 
Official Title  
Comparative Parallel-group Randomized Clinical Trial of Efficacy and Safety of Ergoferon 
Versus Oseltamivir in the Treatment of Influenza 
 
Phase: IV 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. MMH-ER-003 
 
Study purposes 
 
To assess the efficacy of Ergoferon in the treatment of influenza. 
 
To compare the efficacy of Ergoferon and Oseltamivir in the treatment of influenza. 
 
To assess the safety of Ergoferon in the treatment of influenza. 
Outcome Measures  
Primary Outcome Measure  
1. 
Proportion of patients with recovery/improvement in health1 on days 2-7 − according to the 
patient’s diary; on days 3 and 7 – according to objective examination conducted by a 
physician 
Secondary Outcome Measures  
2. 
Fever changes over time (body temperature change on days 2-7 compared to baseline).  
3. 
Average duration of fever2.  
4. 
Proportion of subjects with normal body temperature (below 37,00С) on days 2-7.  
5. 
Severity of clinical manifestations of influenza (fever3, general symptoms and nasal/ 
throat/chest symptoms) in scores on day 1-7 − according to the patient’s diary; on days 1, 3 
and 7 – according to objective examination by the investigator.  
                                                 
1 Recovery criteria: body temperature <37.00С + no symptoms.  
Improvement criteria: body temperature ≤37.20С + total symptom score (except for fever index) ≤2 scores. 
2 Criteria of no fever - body temperature lower than 37.0° C for 24 hours. 


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6. 
Duration of the major clinical symptoms of influenza (fever, general symptoms and 
(nasal/throat/chest symptoms) in days (according to the patient diary).   
7. 
Severity of influenza course (based on area under curve for total influenza severity score 
on days 1-7 − according to the patient diary; on days 1, 3 and 7 – according to objective 
examination by the physician).   
8. 
 Proportion of patients, who used antipyretics on days 1, 2, 3, 4 and 5 of the treatment.  
9. 
 Proportion of patients with complications requiring antibiotics, aggravation of the disease 
(severe influenza).  
10. 
Proportion of patients with negative results of virology assay on days 3, 5 and 7 (based on 
PCR of nasopharyngeal swabs).  
11. 
Dynamics of Parameters of Immune Status (T-cell and B-cell Immune Response) on days 
1, 3 and 7 of the observation: 
 
Concentration of regulators of the T-cell immune response (IL2, IFN -γ, IL-18), and 
regulators of В-cell immune response (IL-4, IL-16). 
12. 
Dynamics of Parameters of Immune Status ( IFN-α and IFN-γ Production) on days 1, 3 and 
7 of the observation: 
 
Level of spontaneous and induced production of IFN-α and IFN-γ by leukocytes (in 
vitro). 
13. 
Dynamics of Parameters of Immune Status (Absolute Number of Each Type of White 
Blood Cells and Different Lymphocyte Phenotypes) on days 1, 3 and 7 of the observation: 
 
The absolute number of each type of white blood cells (WBC): Absolut Count (AC) of 
leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and CD3, 
CD4, CD8, CD4/CD8, CD16, CD119 leukocytes. 
14. 
Dynamics of Parameters of Immune Status (relative percentage of each type of white blood 
cells and different lymphocyte phenotypes) on days 1, 3 and 7 of the observation: 
 
The relative percentage of each type of white blood cells (WBC): Relative Count (AC) 
of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and CD3, 
CD4, CD8, CD4/CD8, CD16, CD119 leukocytes. 
Safety assessment  
 
Presence and nature of adverse events during the therapy, their association with the drug 
administration and other features. 
                                                                                                                                                             
3 Temperature scoring to determine total disease score will be made at the statistical analysis by OOO “NPF 
“Materia Medica Holding” personnel. To do this, absolute body temperatures (in degrees Celsius) will be converted 
to points (or scores) using the following scale: ≤37.20С=0 points; 37.3-38.00С=1 point; 38.1-39.00С=2 points; 
≥39.10С=3 points.  


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Study design  
Study design: an open-label, comparative, randomized, parallel group clinical study to evaluate 
efficacy of the study treatment.  
The study will enroll outpatient subjects of either gender aged 18-70 years old inclusively with 
clinical manifestations of influenza during seasonal morbidity seeking medical advice within the 
first two days of the disease.  
After signing informed consent to participate in the clinical study baseline examination will be 
initiated including nasal swab for rapid diagnosis and verification of influenza as the cause of the 
disease. In case of positive result of immunochromatographic test the patient will be enrolled. In 
case of negative result of rapid test the patient will be enrolled provided that (1) he/she has 
clinical manifestations of typical influenza; (2) the history evidences contact with a patient with 
influenza; (3) the region has influenza epidemics. Additionally, at the screening (Day 1) all 
patients regardless of the results of rapid test will provide nasopharyngeal wabs for further PCR 
diagnosis and identification of RNA of influenza A and B virus, thermometry, history collection, 
evaluation of vital signs, physical examination will be performed and concomitant therapy will 
be recorded. Females of childbearing potential will undergo pregnancy test. If inclusion criteria 
are met and non-inclusion criteria are absent (Day 1) the patient will be enrolled in the trial and 
randomized into one of the two groups: group 1 will receive Ergoferon as per the selected dosing 
regimen for 5 days; group 2 will be treated with Oseltamivir at 75 mg twice a day for 5 days.  
At Day 1 visit the patient will receive the study product and an antipyretic product approved by 
the study protocol. 
The patient will receive the diary in which he/she will have to record axillary body temperature 
(measured by non-mercuric Geratherm Classic thermometer ) in the morning and evening as well 
as intensity of the disease symptoms and number of doses of the antipyretic product. The 
investigator will train the patient concerning the diary filling. 
In total 3 visits (Days 1, 3 and 7) will be made by the patient/investigator during the treatment 
and follow-up period, on day 5 an additional visit will be made for nasopharyngeal swabs.  
At Day 1, Day 3 and Day 7 visits blood sampling will be made for immunological tests at the 
investigator’s discretion. At Day 3 and Day 7 visits the investigator will collect complaints, 
document examination findings, intensity of influenza symptoms in scores, control the 
prescribed and concomitant medications, assess safety of the study therapy and check the 
patient’s diary. Furthermore, nasopharyngeal swabs (Days 1, 3, 5, 7) and blood samples (Days 1, 
3, 7) will be made for lab tests. The total observation period will be 7 weeks (screening, 
randomization ‒ 1 day, treatment – 5 days, follow-up ‒ 2 days). The patient will keep diary 
throughout the whole 7-day observation period.  


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Symptomatic therapy of influenza and co-morbidities will be allowed except for the products 
specified in “Forbidden concomitant therapy” section. 
Inclusion and exclusion criteria 
Inclusion criteria 
1. Patients aged from 18 to 70 years.  
2. Patients who were admitted to hospital within 48 hours from the onset of influenza signs.  
3. Patients with body temperature ≥37.8°C when visiting a doctor + severity of influenza 
symptoms ≥4 scores (presence of at least one general symptom ≥2 scores and 1 
nasal/throat/chest symptom ≥2 scores or greater number of symptoms with  the severity ≥1 
point).  
4.  Diagnosed influenza confirmed by rapid diagnostic test (OSOM Influenza A&B Test). 
5. The possibility to start therapy after the onset of the first symptoms of influenza. 
6. Usage of contraceptive methods by both gender patients of reproductive age during the 
trial and within 30 days after ending the participation in the trial. 
7. Availability of signed patient information sheet (Informed Consent form) for participation 
in the clinical trial. 
Exclusion criteria 
1. Suspected pneumonia, bacterial infection or the presence of a severe disease requiring 
usage of antibacterial drugs (including sulphanilamides) starting from Day 1 of the disease. 
2. Severe influenza4 with indications for hospitalization.  
3. Suspected early manifestations of diseases that have symptoms similar to influenza 
symptoms (other acute respiratory and infectious diseases, influenza-like syndrome at the 
onset of systemic connective tissue disorders, hematologic neoplasms and other 
pathology). 
4. Patients requiring concurrent antiviral products forbidden by the study. 
5. Medical history of primary and secondary immunodeficiencies. а) lymphoid 
immunodeficiencies (Т-cell and/or В-cell, immunodeficiencies with predominant antibody 
deficit); b) phagocytic deficits; c) complement factor deficit; d) combined 
immunodeficiencies including AIDS secondary to HIV infection; toxic, autoimmune, 
                                                 
4 Severe influenza criteria (RF MoH, 2009; WHO 2014; CDC 2009-2014): Extreme degree of general intoxication 
syndrome (toxic shock III, vomiting, dehydration symptoms, reduced diuresis/anuria, restlessness or abrupt 
weakness up to complete adynamia, tachypnea, tachycardia inconsistent with temperature, convulsions, meningism 
symptoms), cognitive disorders, hemorrhagic syndrome (epistaxis, dermal and mucosa petechiae), hemodynamic 
instability, expressed obstructive disorders (stenosing laryngotracheitis, bronchial obstruction syndrome), acute 
respiratory failure, primary and secondary pneumonia. Risk factors for severe influenza and complications: chronic 
cardiovascular, respiratory diseases, diabetes mellitus, immunodeficiencies, oncology.  
 


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infectious, radiation panleukopenic syndrome; total lymphocytopenic syndrome; 
polyclonal lymphocyte activation syndrome; postsplenectomic syndrome; congenital 
asplenia; abnormal immune complex syndrome associated with infectious, autoimmune 
and allergic diseases. 
6. Medical history of sarcoidosis 
7. An oncological disease/suspected oncological disease. 
8. Exacerbated or decompensated chronic diseases affecting a patient's ability to participate in 
the clinical trial. 
9. Medical history of polyvalent allergy. 
10. Allergy/intolerance to any of the components of the product used for influenza therapy. 
11. Impaired glucose tolerance, type 1 and type 2 diabetes mellitus. 
12. Malabsorption syndrome, including congenital or acquired lactose deficiency or another 
disaccharide deficiency. 
13. Pregnancy, breast-feeding.  
14. Consumption of narcotics, alcohol > 2 alcohol units per day, mental diseases.  
15. Use of any medicine listed in the section "Prohibited concomitant treatment" within 30 
days preceding the inclusion in this study. 
16. Patients who, from the investigator's point of view, will fail to comply with the observation 
requirements of the trial or with the regimen of the study drugs. 
17. Participation in other clinical studies within 1 month prior to enrollment in the current trial. 
18. Patients related to the research staff of the clinical trial site who are directly involved in the 
trial or are the immediate family member of the researcher. The immediate family 
members include husband/wife, parents, children or brothers (or sisters), regardless of 
whether they are natural or adopted. 
19. Patients employed with OOO "NPF "MATERIA MEDICA HOLDING" (i.e., the 
company's employee, part-time employee under contract, or appointed official in charge of 
the trial, or their immediate family). 
Discontinuation criteria  
1. Participant's failure or decline to comply with the protocol requirements. 
2. Deviation from the schedule of examinations and sampling for lab tests by ≥ 1 day.  
3. The necessity to use medications not permitted in the study. 
4. An adverse event requiring discontinuation of the study drug. 
5. Patients who decide to withdraw early from the study due to lack of treatment efficacy or 
for any other reason. 


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6. Cases not stipulated in the protocol where the investigator decides that further participation 
may harm the patient. 
7. Eligibility error. 
Number of patients 
198 Informed consent forms are supposed to be signed and expected to yield at least 158 patients 
(79 x 2 groups (Ergoferon and Oseltamivir)) completing all the protocol procedures (withdrawal 
index 1,2). 
Treatment 
 
Group 1 
Name: Ergoferon 
Active ingredient: affinity purified antibodies to human interferon-gamma – 0.006 g*, affinity 
purified antibodies to histamine – 0.006 g*, affinity purified antibodies to CD4 - 0.006 g* 
* applied onto lactose as a mixture of three active water-alcohol solutions of the API diluted 
10012, 10030, 10050 times, respectively. 
Excipients: Lactose monohydrate, microcrystalline cellulose, magnesium stearate. 
Dosage: Per os. Dose per administration - 1 tablet (without food) hold in the mouth until 
complete dissolution.  
Dosing scheme: One dose every 30 minutes for the first 2 hours, followed by three more doses 
spaced regularly during the rest of the day. From day 2 to 5: 1 tablet 3 times a day.   
Dosage form: Orally disintegrating tablets.  
Description: White to off-white, circular, flat faced, beveled edge tablets, scored on one side. 
Each tablet is debossed with MATERIA MEDICA on the scored side and ERGOFERON on the 
other flat side. 
Storage conditions: Store in a place protected from light at a temperature below 25ºС. Keep out 
of the reach of children. 
Group 2 
Name: Tamiflu 
Active ingredient: Oseltamivir 75 mg (as oseltamivir phosphate 98.5 mg) 
Excipients: Pregelatinized starch, povidone K30, croscarmellose sodium, talc, sodium stearyl 
fumarate. 
Dosage: Per os, with or  without food. Dosage scheme: Adult patients - 1 capsule (75 mg) twice 
daily. Treatment period - 5 days. 
Dosage form: Capsules 


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Description: Hard, gelatinised capsules, size 2. Grey opaque body; light yellow opaque cap. 
Capsule contents - white to yellowish-white powder. The capsule is engraved with “Roche” 
(body) and “75 mg” (cap) in light blue ink. 
Storage conditions: Store below 25ºС. Keep out of the reach of children. 
 
Treatment period 
Ergoferon/Tamiflu® treatment period is 5 days. 
Observation period 
Overall the patient was observed in the study for 7 days (screening/randomization/prescription of 
treatment - Day 1, study therapy − days 1-5, follow-up − days 6-7). 
Basic therapy 
Throughout the study the patients may receive symptomatic therapy for influenza based on the 
treatment standards including detoxication agents, vitamins, antitussive drugs and expectorants, 
mucolytics, vasoconstrictive nasal drops, where applicable* - antipyretics** except for antiviral, 
antihistamine, immunomodulating and other drugs included into “Forbidden concomitant 
therapy”. 
* Indications for antipyretic therapy:  
Body temperature > 39°С in patients without complications and co-morbidities and > 38°С in patients with co-
morbidities (congestive heart failure, hepatic, renal diseases; mental diseases, diabetes mellitus, history of 
convulsive syndrome).  
Given that congestive heart failure, mental disorders, diabetes mellitus are exclusion criteria for this clinical study, 
these indications need not be considered. 
If antipyretic product was administered by the patient on his/her own (without medical prescription) with no 
indications thereto the patient will not be withdrawn from the study. The patient should record thermometry values 
in the diary before the product administration as well as its name and dose. 
** Products approved as antipyretics (ATC group is specified in brackets): 
1. Paracetamol (N02BE01). 
2. Ibuprofen (М01АЕ01). 
3. Metamizole sodium (N02BB02) – for hyperthermia uncontrolled by paracetamol/ibuprofen as an emergency 
drug.  
The product shall be chosen by the investigator issuing the antipyretic to the patient at Visit 1. 
Prohibited concomitant therapy 
Within one month prior to enrollment* and throughout the study (beginning with signing 
Informed Consent and initiation of screening) patients cannot use any of the following 
medications (ATC group is specified in brackets): 
1. Antiviral drugs (J05) except for Ergoferon and oseltamivir prescribed within the study. 


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2. Immune sera and immunoglobulins (J06).  
3. Vaccines (J07). 
4. Antitumour drugs (L01) and antitumour hormonal products (L02).  
5. Immunostimulants (L03) including: 
 
Colony-stimulating factors (L03AA) – filgrastim, molgramostim, lenograstim, 
pegfigrastim.  
 
Interferons (L03AB) – interferon alpha, interferon gamma, interferon alpha-2a, interferon 
alpha-2b, interferon alpha-n1, interferon beta-1a, interferon beta-1b, peginterferon alpha-
2b, peginterferohn alpha-2a. 
 
Interleukins (L03AC) – aldesleukin. 
 
Other immunostimulants (L03AX) – BCG vaccine; pidotimod; glatiramer acetate. 
 
Interferon inducers (acridonacetic acid, meglumine acridonacetate, complex of 
polyadenylic acid and polyuridylic acid, methylphenylthiomethyl-dimethylaminomethyl- 
hydroxybromindole carboxylic acid ethyl ether, oxodihydroacridinylacetate sodium, 
kagocel, tilorone). 
 
The products containing thymus hormones (alpha-thymosin, alpha-glutamyl-triptophan, 
thymus extract, thymoptin).  
 
В-activin.  
 
Synthetic immunostimulants (levamisole, alpha-glutamyl-triptophan). 
 
Bacterial immunomodulators (ribomunyl, ribonucleate sodium, deoxyribonucleate 
sodium) 
6. 
Immunodepressants (L04).  
7. 
Fenspiride (R03DX03), omalizumab (R03DX05). 
8. 
Antihistamine drugs (R06).  
9. 
Anaferon (L03AX), epigam, rengalin (R05DB). 
10. 
Combined products for symptomatic therapy of acute respiratory diseases containing 
acetylsalicylic acid, diclofenac, propifenazone, metamizole, phenylephrine, Н1-histamine 
blockers (including phenyramine, chlorphenamine).  
11. 
Drugs known to have caused allergic reactions. 
12. 
Products forbidden as antipyretic products:  
 
Butylpyrazolidones (M01AA) including phenylbutazone. 
 
Acetic acid derivatives (M01AB) including indometacin, diclofenac, ketorolac, 
aceclofenac. 
 
Oxicams (M01AC) including piroxicam, meloxicam, tenoxicam, lornoxicam. 


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 
Propionic acid derivatives (M01AE). 
 
Coxibs (M01AH). 
 
Niflumic acid (M01AX02). 
 
Nimesulide (M01AX17) 
 
Acetylsalicylic acid (N02BA01) including in combination with other products. 
 
Pyrazolones (N02BB) including in combination with other products (except for 
metamizole sodium). 
* If a single dose of any of the products from the list “Forbidden concomitant therapy” was administered within 12 
hours prior to the enrollment to the study (except for the products specified in cl. 2-4, 6), it is not an exclusion 
criteria. 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
 
Procedure/visit 
Day 1 
Day 3 
Day 5 
Day 7 
Obtaining informed consent (signing 
informed consent by the patient) 
+ 
 
 
 
Collection of complaints 
+ 
+ 
 
+ 
Collection of medical history data 
+ 
 
 
 
Objective examination 
+ 
+ 
 
+ 
Recording influenza symptoms in 
scores 
+ 
+ 
 
+ 
Collection of nasal swabs and isolation 
of influenza agent antigens 
+ 
 
 
 
Collection of nasopharyngeal swab for 
PCR diagnosis 
+ 
+ 
+ 
+ 
Pregnancy test 
+ 
 
 
 
Information on concomitant medicines 
+ 
+ 
 
+ 
SCREENING 
Ergoferon 
5 days 
7 days 
Oseltamivir 
5 days 
 Day 1 
(Visit 1) 
Day 3  
(Visit 2) 
Day 7 
(Visit 3) 
Day 5  
(Nasopharyngeal swab)  


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Inclusion/exclusion criteria 
+ 
 
 
 
Randomization and prescription of 
study therapy 
+ 
 
 
 
Antipyretic drug dispensing 
+ 
 
 
 
Blood sampling for immunological 
tests 
+ 
+ 
 
+ 
Dispensing of the study drug 
+ 
 
 
 
Drug accountability and return, 
assessment of compliance 
 
 
 
+ 
Distribution of diaries 
+ 
 
 
 
Evaluation of correct diary filling 
 
+ 
 
+ 
Diary return 
 
 
 
+ 
Evaluation of therapeutic safety 
 
+ 
 
+ 
 
Statistical Analyses 
Samples  
 Total set comprised all enrolled patients whose parents/adopters had signed the informed 
consent form for participation of a patient in the trial. This sample will consider all adverse 
events throughout the study, including those occurred prior to the study therapy. Any medically 
unfavourable events (conditions) recorded in patients from Total set after signing informed 
consent but before administration of the study product will be considered as concomitant 
conditions.   
Sample of the patients receiving at least one dose of the study product will be used for the study 
drug safety assessment (Safety population), as any adverse events emerging after administration 
of the product will be recorded.  
Full Analysis Set This sample will consist of all enrolled patients, except for those who met at 
least one of the following criteria: 
1) failure to meet inclusion/non-inclusion criteria;  
2) patient failing to take any dose of the study drug; 
3) absence of any data on the patient after randomization. 
This was the best set for the Intention-to-treat method, so it will be used in the Intention-to-treat 
efficacy analysis of the test therapy.  
Unavailable/missing data (parameters/variants) will be completed by the Last Observation 
Carried Forward method (LOCF). 
Per Protocol set. This sample includes all patients who completed the therapy as per the study 
protocol, without any missing visits or major protocol deviations. This set will be used in the Per 
Protocol efficacy analysis of the test therapy. 


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Evaluation of sample size 
The sample size was assessed in accordance with the following rules and assumptions: 
1. 
Statistical assumptions: 
1.1 
Lack of clinically relevant superiority of reference product (oseltamivir) over test 
product (Ergoferon) is assumed, thus statistically meeting Non-Inferiority design: 
H0: Efcontrol − Eftest ≥ δ 
HА: Efcontrol − Eftest < δ, 
where Efcontrol – effect of reference product (oseltamivir), Eftest – effect of test product 
(Ergoferon), δ –clinically relevant difference; 
1.2 
Clinically relevant difference value “δ” is considered to be equal to 20% (i.e. Ergoferon 
effect is supposed to be comparable to the one of oseltamivir if the effect of test product 
is superior to or inferior to the effect of reference product by no more than 20%); 
1.3 
The power of statistical tests 'P = (1 − β)' is 80% (the probability of correct rejection of 
the null hypothesis is 0.8); 
1.4 
The probability of type 1 error 'a' is less that 5% (the probability of false acceptance of 
the alternative hypothesis is less than 0.05); 
1.5 
Therefore, sample size will be calculated taking into account: 
a. 
assumption on expected effects declared in the main efficacy criterion of 
the protocol; 
1.6 
calculation of sample size of groups 1 and 2 for two-sided test for final analysis will be 
made using the formula5: 
N1=N2=(pa(1 – pa) + pb(1 – pb)) I, 
where N1 and N2 – samples sizes in Ergoferon and Oseltamivit groups 
 pa and pb – expected proportions of the patients with recovery/improvement in these 
groups 
I – Fisher’s information detected using the formula: 
I=(zα + zβ)2/(θ – δ)2, 
where zα and zβ – tabular values of z-test for α and β, θ – difference between proportions 
(pa – pb), δ – clinically relevant difference; 
1.7 
final sample size will be determined using the formula:  
NF = N / (1 − Кв),  
                                                 
5 SAS/STAT(R) 9.2 User`s Guide, Second Edition. 
http://support.sas.com/documentation/cdl/en/statug/63033/HTML/default/viewer.htm#statug_seqdesign_s
ect027.htm 


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1.8 
where NF – final sample size; N – result of calculation in cl. 1.6, i.e. scheduled number 
of patients completing the study per protocol; Cw – withdrawal coefficient. 
2. 
Assumptions on expected clinical study effects: 
2.1 
The difference between proportions of the patients with recovery/improvement6 on days 
2-7 (according to the patient’s diary) and on days 3 and 7 (according to objective 
medical examination) in Ergoferon group and Oseltamivir is expected to be ≥ 0%.  
The minimum size of each group will be determined as follows: 
Number of patients 
Final analysis 
Number of patients in both groups 
158 
including  
 
- number of patients in 
Ergoferon groups 
79 
- number of patients in 
Oseltamivir group 
79 
 
Taking into account that potential withdrawal of 20% patients during the screening and during 
the study, at least 198 patients (99 in Ergoferon and Oseltamivir group) should sign informed 
consent. 
Statistical criteria  
All statistical calculations will be made using two groups of statistical criteria:  
 parametric - to evaluate continuous and interval random values;  
 non-parametric – to obtain: 
- 
evaluations on equality/inequality of proportions of the patients upon their 
comparison for various visits,  
- 
analysis of frequencies of the features compared, 
and  
- 
to evaluate continuous and interval random values in case of non-compliance 
with normal random distribution. 
Parametric criteria  
Prior to analysis using parametric statistics, data samples under comparison will be tested for 
normality (the Kolmogorov-Smirnov test).  
                                                 
6 Recovery criteria: body temperature <37.00С + no symptoms.  
Improvement criteria: body temperature ≤37.20С + total symptom score (except for fever index) ≤2 scores. 


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The following parameters and approaches are to be used: 
1. 
To evaluate the differences in continuous variables from two different (independent) 
groups – Student’s test for independent samples. 
2. 
To evaluate differences in continuous variables in one group at two different visits - 
Student’s test for paired samples. 
3. 
To evaluate time changes in parameters compared - analysis of variance (ANOVA) or 
modified repeated measures covariance (ANCOVA).  
4. 
In case of multiple comparisons of the groups various corrections for multiplicity will be 
used, e.g. Dunnett, Tukey, Scheffe, Holm adapted test, etc.  
5. 
In case of abnormal data distribution generalized linear models and/or mixed linear models 
will be used.  
6. 
Selection of the type of distribution, specification of factor and covariance structures of the 
model will be made using fit-statistics such as AIC (Akaike information criterion). 
The following SAS software programs are supposed to be applied to the above listed tests and 
techniques:  
 
UNIVARIATE: normality verification of the distributions under comparison 
 
CORR, MEANS - calculation of descriptive statistics 
 
TTEST – Student’s test with all modifications 
 
GLM – generalized linear models for analysis of time changes (ANOVA, 
ANCOVA)  
 
GENMOD – generalized linear models 
 
MIXED – mixed linear models. 
Non-parametric tests: 
Below are potential types of comparisons with relevant criteria: 
1. 
To evaluate difference in continuous variables obtained in two different (independent) 
groups – Mann-Whitney test. 
2. 
To evaluate time changes in the parameters compared – Friedman test, nonparametric 
analogue of repeated measures analysis of variance. 
3. 
For frequency analysis of contingency tables 2×2 – χ2 (if the frequency under comparison 
> 5) or exact Fisher’s test (if one of the frequencies under comparison < 5).  
4. 
Cochran-Mantel-Haenszel test (modified χ2 test for multiple comparisons) – to perform 
frequency analysis based on independent strata.  
5. 
For frequency analysis of data on presence/absence of an event or outcome during repeated 
measurements (contingency tables with dependent strata) – survival analysis.  


Protocol No. MMH-ER-003 
08-Feb-2016 
CONFIDENTIAL  
 
Page 15 of 15 
To perform the above-mentioned nonparametric statistical analysis the following SAS 
procedures are to be used:  
 
FREQ – Friedman test, χ2 test and/or exact Fisher’s test; Cochran-Mantel-Haenszel 
test. 
 
LIFETEST – survival analysis.  
 
NPAR1WAY - Mann-Whitney test. 
Safety parameters  
The AEs recorded throughout the study will be pooled in the frequency tables for severity and 
relationship with the study drug. 
Data presentation 
Descriptive statistics will be given for each continuous/discrete variable tested. Numerical data 
will be presented as mean value, standard deviation, and maximum and minimum values. 
Extreme values (outliers) will be analyzed additionally. The data will be pooled according to 
visits. Categorical variables will be presented as per-visit frequency tables.