Clinical trial NCT02072174
Conditions: Influenza and Acute Respiratory Viral Infections
Sponsor: Materia Medica Holding
Start date: 2014-10-08; Completion date: 2018-04-16
Enrollment: 569 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is:

• To obtain additional data on therapeutic efficacy of Anaferon for children in the treatment of influenza and acute respiratory viral infections in children

Detailed description:
The study will enroll outpatient subjects of both sexes aged 3-12 years with clinical manifestations of influenza/Acute Respiratory Viral Infections (ARVI), including fever

≥ 38.0°С having an appointment with a doctor within the first day after the illness onset.

Тhe physician will collect medical history information, perform an objective examination, record the concomitant therapy, and obtain nasal swab specimens for a rapid diagnostic influenza test. If the swab is positive, the doctor shall obtain swab specimens from the nasal cavity and oropharynx (nasopharyngeal swab) for a subsequent real time reverse transcription-polymerase chain reaction (RT-PCR) to determine the viral load of influenza A and/or B virus. If the swab is negative for influenza the doctor shall collect a nasopharyngeal swab for a subsequent PCR test for other respiratory viruses.

If inclusion criteria are met and exclusion criteria are absent at visit 1 (Day 1), the patient will be enrolled in the trial and randomized into one of the two groups: group 1 patients will take Anaferon for children following a 5-day regimen; group 2 patients will receive Placebo using the Anaferon for children 5-day regimen. The parent/adopter of patient will receive a diary where they should record the child's axillary temperature data in the morning and evening, and score the severity of symptoms.

The subject will be monitored for 14 days (screening, randomization - 1 day, treatment - 5 days, follow-up - 1 day; late-scheduled phone "visit" - day 14).

At Visits 2-4, the physician will document objective examination data; obtain nasopharyngeal swabs from subjects with positive influenza tests for subsequent RT-PCR to determine the viral load and its reduction in the course of treatment; monitor the prescribed and concomitant therapy, and check the patient's diary data. The phone "visit" will be made to elicit information from the parents regarding the patient's general health, presence/absence of secondary bacterial/viral complications, and use of antibacterial drugs.

Interim statistical analysis is stipulated by the study protocol. Interim analysis will be performed using the data obtained from the examination and treatment of the protocol-defined number of patients who completed the study. Based on the expected effect, the minimum required Particular Per Protocol (pPP) sample size will be 254 patients (127 subjects in each group - Anaferon for children and Placebo).

Arms: arm 1: On day 1, five tablets are taken in the first 2 hours (one tablet every 30 min), followed by three more tablets regularly spaced during the rest of the day. From day 2 through 5, one tablet is administered three times daily. arm 2: On day 1, five tablets are taken in the first 2 hours (one tablet every 30 min), followed by three more tablets regularly spaced during the rest of the day. From day 2 through 5, one tablet is administered three times daily.
Interventions: intervention 1: Anaferon for Children
Intervention descriptions: intervention 1: Anaferon for children: For oral use.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
International multicenter double-blind placebo-controlled 
randomized parallel group clinical trial of efficacy of 
Anaferon for children in the treatment of influenza and 
acute respiratory viral infections in children 
 
 
Phase IV 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-AD-004 
Version date: 
August 01, 2016 
ClinicalTrials.gov Id: 
NCT02072174 
 
 


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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. 
Title of Study 
International multicenter double-blind placebo-controlled randomized parallel group clinical trial 
of efficacy of Anaferon for children in the treatment of influenza and acute respiratory viral 
infections in children. 
 
Phase: IV 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. MMH-AD-004 
 
Study purposes 
 To obtain additional data on therapeutic efficacy of Anaferon for children in the treatment of 
influenza and acute respiratory viral infections (ARVI) in children. 
Endpoints  
Primary endpoint 
1. Average illness duration (until recovery1 or significant improvement2). 
Secondary endpoints 
1. Percentage of patients with recovery1/improvement2 in health on days 2, 3, 4 and 5 of 
observation treatment (according to the patient’s diary), on days 3 and 5 of therapy 
(according to physician’s objective examination). 
2. Changes in fever (changes in temperature on days 2, 3, 4 and 5 of observation treatment). 
3. Percentage of patients with normal body temperature (≤37.0°С) on days 2, 3, 4 or 5 of 
observation treatment. 
4. Severity of clinical manifestations of influenza/ARVI in scores on days 3 and 5 of 
observation treatment – according to physician’s objective examination; on days 2-6 of 
observation – according to patient’s diary. 
5. Assessment of the Severity of Influenza Virus / ARVI Using the “Area Under the Curve” 
for an Overall Symptom Assessment (based on the results of area under curve for total 
                                               
1 Recovery criteria: temperature ≤ 37.00С + lack of symptoms within 24 hours. 
2 Improvement criteria: temperature ≤37.20С + total symptom score ≤2. 


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symptom score3 and nasal/throat/chest score on days 1, 3, 5 and 7 of observation – 
according to physician’s objective examination; on days 1-7 of observation – according 
to patient’s diary). 
6. Number of intakes of antipyretic drugs  according to indications on days 1, 2, 3, 4 and 5 of 
therapy. 
7. Changes in viral load4 during the treatment and follow-up periods. 
8. Percentage of patients with exacerbation of the disease course (complications requiring 
antibiotic drugs or hospitalization). 
Safety assessment  
 Presence and nature of adverse events during therapy, their relationship with the 
product and other characteristics. 
Study design  
Study design: multicenter double-blind placebo-controlled randomized parallel-group 
study.  
The study will enroll outpatients of both genders aged 3-12 years with clinical signs of 
influenza/ARVI including fever ≥ 38.0°С seeking for medical advice within the first day after 
the disease debut. The first visit shall be made at the subject’s home. After signing patient 
information sheet (informed consent form) by the parent/adoptive parent for the subject’s 
participation in the study his/her medical history will be collected, objective examination will be 
performed and concomitant therapy will be recorded. Nasal swab for rapid influenza diagnostics 
will be collected. In case of positive rapid test the physician will take nasal and oropharyngeal 
swabs (nasopharyngeal swab) for further PCR diagnosis of influenza A and/or B to determine 
the viral load. In case of negative result of rapid test the physician will take nasopharyngeal swab 
for further PCR to detect other respiratory viruses. 
If the subject meets inclusion criteria and has no exclusion criteria at visit 1 (Day 1) he/she 
shall be enrolled and randomized into one of the two groups: group 1 will receive Anaferon for 
children for 5 days; group 2 – placebo according to Anaferon for children for 5 days. 
Parent/adoptive parent will receive a diary to record axillary temperature of the subject on a daily 
basis in the morning and evening (temperature is measured with a standard non-mercuric 
                                               
3 Total symptom score is calculated based on intensity of each influenza symptom at subsequent statistical 
treatment by the experts of OOO “NPF “Materia Medica Holding”. 
4 Viral load will be evaluated in subjects with positive rapid test for influenza A and B. Viral RNA levels [influenza 
А/В] log10 copies/mL in nasal and oral swabs will be determined by real-time RT-PCR.  
 


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thermometer Geratherm Classic) as well as intensity of the disease symptoms. Training on the 
diary filling will be performed for parents/adoptive parents.  
The subject will be followed for 14 days (screening, randomization – 1 day, treatment – 5 
days, follow-up − 1 day; delayed phone “visit” – day 14).  
During the treatment and follow-up periods the subject/physician shall make 4 visits, the 
fifth phone “visit” is stipulated additionally: 1) physician/subject visits – on days 1, 3, 5 and 7 
(Visits 1, 2, 3 and 4) – at medical facility or at home; 2) phone “visit” (Visit 5) – on day 14. 
At visits 2-4 the physician shall record objective examination findings, collect 
nasopharyngeal swabs for further PCR diagnosis in subjects with positive rapid test (to 
determine viral load and its reduction against therapy), monitor the prescribed and concomitant 
therapy, revise the patient’s diary. Phone “visit” will be made to inquire on the subject’s 
condition, presence/absence of secondary bacterial/viral complications, administration of 
antibacterial drugs.  
Symptomatic therapy and therapy of co-morbidities is allowed except for the products 
specified in section “Prohibited concomitant therapy”.   
Inclusion and exclusion criteria 
Inclusion criteria 
1. Subjects of both sexes aged 3-12 years inclusively.  
2. Diagnosis of influenza/ARVI according to physician’s examination: body temperature ≥ 
38.0°C at the time of examination + symptom score ≥ 4 (at least 1 systemic symptom ≥2 
and 1 nasal/throat/chest symptom ≥2 or several symptoms ≥ 1 score).  
3. The first 24 hours from the beginning of manifestations of influenza/ARVI.  
4. The possibility to start therapy within 24 hours from the first symptoms of ARVI. 
5. Availability of patient information sheet (informed consent form) for parents/adoptive 
parents for participation in the study signed by one of the parents/adoptive parents. 
Exclusion criteria 
1. Suspected pneumonia, bacterial infection or severe disease requiring antibacterial products 
(including sulfanilamides) starting from the first day of the disease. 
2. Clinical symptoms of severe influenza/ARVI5 requiring hospitalization. 
                                               
5 Severe influenza/ARVI criteria (RF MoH, 2009; WHO 2012; CDC 2009-2013): severe intoxication syndrome 
(toxic shock III, vomiting, dehydration symptoms, reduced urine output/anuria, restlessness, cry or abrupt weakness 
up to full adynamia, tachypnea, tachycardia not correlating with temperature, seizures, meningism symptoms), 
impairment of consciousness, hemorrhagic syndrome (epistaxis, skin 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/ARVI and complications: 
chronic cardiovascular, respiratory diseases, diabetes mellitus, immunodeficiencies, oncology [2, 13, 22, 23, 35, 36].  


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3. Suspected initial manifestations of the diseases having the symptoms similar to the ones of 
influenza/ARVI (other infectious diseases, influenza-like syndrome at debut of systemic 
connective tissue diseases, oncohematological and other diseases). 
4. History of primary 
and secondary 
immunodeficiencies: а) 
lymphoid system 
immunodeficiencies (Т-cell and/or B-cell, immunodeficiencies with predominant antibody 
deficiency); b) phagocytic deficiencies; c) complement factor deficiency; d) combined 
immunodeficiencies including AIDS secondary to HIV-infection; toxic, autoimmune, 
infectious, radiation panleukopenic syndrome; systemic lymphocytopenic syndrome; 
polyclonal lymphocytic activation syndrome; postsplenectomic syndrome; congenital 
asplenia; immune complex pathological syndrome associated with infectious, autoimmune 
and allergic diseases. 
5. Medical history of sarcoidosis. 
6. Oncology. 
7. Exacerbation or decompensation of chronic diseases affecting ability to participate in the 
clinical study.  
8. Medical history of polyvalent allergy. 
9. Allergy/intolerance to any of the components of medications used in the treatment.  
10. Malabsorption syndrome, including congenital or acquired lactase or other disaccharidase 
deficiency, galactosemia. 
11. Intake of medicines listed in the section “Prohibited concomitant therapy” within 1 month 
prior to the inclusion in the study. 
12. Drug addiction, alcohol consumption at more than 2 alcohol units6 per day by the subject's 
parents/adoptive parents. 
13. Mental diseases of the subject, parents/adoptive parents. 
14. Subjects whose parents/adoptive parents, according to the investigator’s point of view, will 
not follow the observation requirements during the study or study product dosing regimen.  
15. Participation in other clinical studies within 3 months prior to the inclusion in the study. 
16. Parent/adoptive parent of the subject is related to the investigator team of medical facility 
directly involved in the study or is a close relative of the investigator. Close relatives 
include spouse, parents, children or brothers (sisters) regardless of whether they are 
biological or adoptive ones. 
17. Parent/adoptive parent of the subject is working in OOO “NPF “Materia Medica Holding”, 
i.e. is the company official, temporary contract worker or an appointed official responsible 
for the study or their close relatives. 
                                               
6 1 alcohol unit – 0.33 L light beer/150 mL of unfortified wine, 40 mL of liquors. 


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Discontinuation criteria  
1. Inability or refusal of the subject, his/her parents/adoptive parents to compliance the 
protocol. 
2. Necessity in the medical products not allowed within the study.  
3. Development of adverse event requiring the product discontinuation. 
4. Subject’s or parents’/adoptive parents’ with to terminate the study early due to lack of 
therapeutic efficacy or any other reason. 
5. Cases not specified by the protocol when, according to the investigator, further subject’s 
participation is dangerous. 
6. Enrollment of ineligible subject. 
Number of subjects 
Signed informed consent form is supposed to be obtained from 972 subjects (of them 772 – 
in the Russian Federation, 100 – in Republic of Belarus and 100 – in Ukraine); this would allow 
to complete all protocol procedures by at least 508 subjects (n=254 in Anaferon for children and 
Placebo groups). 
Interim analysis 
An interim statistical analysis is scheduled within the study. The interim analysis will be 
based on the findings from examinations and therapy of the protocol-set number of subjects who 
completed the study. Based on the proposed effect, the minimum required Per Protocol (PP) 
sample size will be 254 subjects (n=127 in Anaferon for children and Placebo groups). 
Treatment 
 
Group 1 
Name: Anaferon for children 
Active ingredient: affinity purified antibodies to human interferon-gamma – 0.003 g* 
* applied to lactose monohydrate as water-alcohol mixture containing no more than 10-16 ng/g 
of the active form of the active ingredient 
Excipients: Lactose monohydrate 0.267 g, microcrystalline cellulose 0.03 g, magnesium stearate 
0.003 g 
Dosage: Per os. One tablet per intake (hold in mouth until complete dissolution – regardless of 
meal). The first 2 hours – every 30 minutes, then 3 additional doses with equal intervals. On days 
2-5 – on tablet 3 times a day.  
Dosage form: Orodispersible tablets 


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Description: Flat cylinder-shaped scored beveled edge white to off-white tablets 
Storage conditions: Store at temperature below 25оС. Keep out of the reach of children. 
 
Group 2 
Name: Placebo 
Active ingredient: NA 
Excipients: Lactose monohydrate 0.267 g, microcrystalline cellulose 0.03 g, magnesium stearate 
0.003 g 
Dosage: Placebo using Anaferon for children scheme 
Dosage form: Orodispersible tablets 
Description: Flat cylinder-shaped scored beveled edge white to off-white tablets 
Storage conditions: Store at temperature below 25оС. Keep out of the reach of children 
 
Treatment period 
Anaferon for children/Placebo treatment period is 5 days. 
Observation period 
Overall the subject is observated for 14 days (screening, randomization, treatment 
initiation – day 1, study therapy period – 5 days, follow-up – 1 day, phone visit – day 14). 
Basic therapy 
Throughout the study the subject may have symptomatic therapy of influenza/ARVI based 
on the accepted treatment standards including expectorants, mucolytics, vasoconstrictive nasal 
drops, where necessary – detoxifying therapy, as indicated* − approved antipyretics**, in case of 
bacterial complications of influenza/ARVI – antibacterial drugs except for antiviral, 
immunomodulating and other products specified in section “Prohibited concomitant therapy”. 
* Indications for antipyretics products [11, 14, 34 ]:  
Body temperature > 38.5°С;  
Body temperature 38.0°С against concomitant chronic pulmonary, cardiac, nervous system 
diseases. 
In case the antipyretic product was prescribed and given to the child by parents/adoptive 
parents on their own (without physician’s prescription) with no indications, the subject will not 
be withdrawn. Parents/adoptive parents should record temperature values in patient’s diary prior 
to the product administration, its name and dose. 
** The products allowed as antipyretics (ATC group is specified in brackets): 
1. Paracetamol (N02BE01). 
2. Ibuprofen (М01АЕ01). 


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3. Metamizole sodium (N02BB02) – on prescription only (for emergency assistance in 
case of hyperthermia uncontrolled by paracetamol/ibuprofen able, parenterally).  
The product will be chosen by the investigator who will issue the antipyretic product to the 
subject at Visit 1. 
Prohibited concomitant therapy 
One month prior to enrollment as well as throughout the study (from signing patient 
information sheet (informed consent form) and screening initiation) the following products are 
not allowed (ATC group is specified in brackets): 
1. Antiviral products (J05) except for Anaferon for children prescribed within the study.  
2. Immune sera and immunoglobulins (J06). 
3. Vaccines (J07). 
4. Antitumour products (L01) and antitumour hormonal products (L02). 
5. Immunostimulants (L03) including: 
 
Colony-stimulating factors (L03AA) – filgrastim, molgramostim, lenograstim, 
pegfilgrastim.  
 
Interferons (L03AB) – interferon-alpha, interferon-gamma, interferon alpha-2a, 
interferon alpha-2b, interferon alpha-n1, interferon beta-1a, interferon beta-1b, 
peginterferon alpha-2b, peginterferon alpha-2a. 
 
Interleukins (L03AC) – aldesleukin. 
 
Other immunostimulants (L03AX) – BCG-vaccine; pidotimod; glatiramer acetate. 
 
Interferon inducers (including acridonacetic acid, meglumine acridonacetate, polyadenyl 
and 
polyuridyl 
acid 
complex, 
methylphenylthiomethyl-dimethylaninomethyl-
hydroxybromindole carboxylic acid ethyl ether, oxodihydroacridinylacetate sodium, 
cagocel, tilorone). 
 
Products containing thymus hormones (alpha- thymosin, alpha-glutamyl- tryptophane, 
thymus extract, thymoptin). 
 
В-activin.  
 
Synthetic immunostimulants (including levamisole, alpha-glutamyl- tryptophane). 
 
Bacterial 
immunomodulators 
(including 
ribomuyl, 
sodium 
ribonucleate, 
deoxyribonucleate sodium, IRS-19, imudon, etc.). 
6. Immunodepressants (L04).  
7. Products for which allergic reactions have been recorded previously. 
8. Products forbidden as antipyretic products: 
 Butylpyrazolidones (M01AA) including phenylbutazone. 


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 Acetic acid (M01AB) derivatives including indomethacin, diclofenac, ketorolac, 
aceclofenac. 
 Oxicams (M01AC) including piroxicams, meloxicam, tenoxicam, lornoxicam. 
 Propionic acid (M01AE) derivatives. 
 Coxibs (M01AH). 
 Niflumic acid (M01AX02). 
 Acetylsalicylic acid (N02BA01) including in combination with other products. 
 Pyrazolones (N02BB) including combinations with other products (except for metamizole 
sodium – on prescription). 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
 
Procedure/Visit  
Visit 1 
(Day 1) 
Visit 2 
(Day 3) 
Visit 3 
(Day 5) 
Visit 4 
(Day 7) 
Visit 5  
(Day 
14±1) 
Obtaining signed informed consent 
form (ICF) 
+ 
 
 
 
 
Collection of complaints  
+ 
+ 
+ 
+ 
 
Collection of medical history  
+ 
 
 
 
 
Objective examination  
+ 
+ 
+ 
+ 
 
Recording influenza/ARVI 
symptoms  
+ 
+ 
+ 
+ 
 
Inclusion/exclusion criteria 
assessment  
+ 
 
 
 
 
Recording concomitant therapy  
+ 
+ 
+ 
+ 
 
Rapid test for influenza viruses in 
nasal swabs  
+ 
 
 
 
 
Obtaining nasal and oropharyngeal 
+ 
+ 
+ 
+ 
 
Group 1: Anaferon for children  
SCREENING
Visit 1
(Day 1) 
14±1 days 
Group 2: Placebo
RANDOMIZATION
Visit 2
(Day 3) 
Visit 3
(Day 5) 
Visit 4
(Day 7) 
Visit 5 (phone)
(Day 14±1) 


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swabs for PCR diagnosis of 
influenza (in case of positive result 
of rapid test for influenza)  
Obtaining nasal and oropharyngeal 
swabs for PCR diagnosis of other 
respiratory viruses (in case of 
negative result of rapid test for 
influenza) 
+ 
 
 
 
 
Randomization and prescription of 
the study therapy  
+ 
 
 
 
 
Issue of the study product  
+ 
 
 
 
 
Issue of antipyretic product  
+ 
 
 
 
 
Accounting and return of the study 
product, determination of 
compliance  
 
 
 
+ 
 
Issue of patient’s diary  
+ 
 
 
 
 
Revision of correctness of diary 
filling  
 
+ 
+ 
+ 
 
Diary return  
 
 
 
+ 
 
Therapy safety assessment  
 
+ 
+ 
+ 
+ 
Phone contact  
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
Statistical Analyses 
Samples  
Statistical analysis will be carried out in the following sets: 
Total set – all enrolled subjects whose parents/adoptive parents had signed ICF. This set 
will take into account all adverse events and related conditions during the study including prior 
to the study therapy initiation.  


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Total set of the subjects receiving at least one dose of the study product will be used for 
safety and tolerability analysis (Safety population), as all adverse events recorded in the subject 
after administration of the product will be taken into account.  
Full Analysis Set. This set includes all enrolled subjects excluding those having at least 
one of the following events: 
1) non-compliance with inclusion/exclusion criteria;  
2) the subject did not receive a single dose of the study product; 
3) lack of any data on the subject after prescription of the study product  
This set most fully conforming to Intention-to-treat principle will be used for Intention-to-
treat analysis (ITT-analysis) of the study product efficacy. 
Per Protocol set. This set includes all subjects receiving per protocol therapy in full, 
completing all scheduled visits and having no major deviations from the protocol. This set will 
be used for Per Protocol analysis (PP-analysis) of the study therapy efficacy. 
Last Observation Carried Forward (LOCF) will be used for filling missing values.  
Evaluation of sample size 
Evaluation of sample size was based on the following rules and assumptions: 
1. 
Statistical provisions. 
1.1 
Power of statistical criteria “P = (1 − β)” is considered to be equal to 80% 
(probability of correct rejection of null hypothesis is 0.8). 
1.2 
Probability of error of the first kind “α” is admitted to be < 5% (probability of 
erroneous acceptance of alternative hypothesis is < 0.05). 
1.3 
The statistical criteria used are two-sided.  
1.4 
Calculation of total sample size was based on the assumptions on expected effects on 
primary endpoint claimed in the protocol.  
1.5 
Effect of interim statistical analyses on probability of error of the first king is 
regulated at each point (interim analysis, final analysis) using O`Brien-Fleming 
boundary. 
2. 
Assumptions on expected clinical study effects. 
It is assumed that the difference between average disease duration (until recovery or 
significant improvement) in Anaferon for children and Placebo groups will be less 
than 0.5 days, while standard deviation in both groups will not exceed 2 days. 


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Taking into account that statistical analysis will be performed twice – at interim analysis 
and at final analysis – based on the assumed effect the minimum required size of each group 
(product and placebo) will be as follows: 
Number of subjects  
Interim analysis  
Final analysis  
Number of subjects in both 
groups  
254 
508 
including  
 
 
- number of subjects in 
Anaferon group 
127 
254 
- number of subjects in 
Placebo group  
127 
254 
 
Given withdrawal at screening, including due to negative rapid influenza test (the ratio is 1 
subject with positive test/5-6 subjects with influenza-like symptoms and negative influenza test) 
and during the study, the final sample size will be 972 subjects to be enrolled.  
This calculation is made using the formula: NT=NPP/(1-Cw), where NT – final sample size; 
NPP – scheduled number of subjects completing the study per protocol (NPP=508); Cw – 
withdrawal coefficient (Cw=0.4774). 
Interim analysis  
Interim analysis of Particular Per Protocol (pPP) is scheduled within the study.  
Purposes of interim analysis: 
 
Ability to adjust sample size in case in minor deviation of the effect achieved from the 
effect specified at baseline; 
 
Ability of early discontinuation of the study in case of major deviation7 of the effect 
achieved from the effect specified at baseline.  
Within the protocol one interim analysis point has been scheduled.  
Interim analysis is scheduled for the time when at least 127 subjects in each group 
complete the study, i.e. receive per protocol therapy in full, undergo all scheduled visits and have 
no major protocol deviations. 
Statistical criteria  
All statistical calculations will be made using the following groups of statistical criteria: 
 
parametric – to assess continuous and interval accidental values; 
 
non-parametric – to obtain: 
                                               
7 Early study termination is possible both on safety reasons in case of lack of efficacy and after the required power 
of statistical efficacy conclusions is achieved.  


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 
evaluations on equality/inequality of proportions of subjects compared for various 
visits, 
 
analysis of frequencies in features compared, 
and 
 
evaluation of continuous and interval accidental values in case of violation of 
requirement on normal sample distribution; 
 
interim analysis procedures. 
Parametric criteria will be checked for normalcy of the samples compared (Kolmogorov-
Smirnov test). 
The following parametric methods and approaches are suggested:  
1. 
To evaluate various continuous variables obtained in two different (independent) groups – 
Student’s test for independent samples. 
2. 
To evaluate differences in continuous variables obtained in one group at two different 
visits – Student’s test for paired samples. 
3. 
For multiple assessment at different visits – Bonferroni’s test (Student’s test modification 
for multiple comparisons). 
4. 
For comparison of several sample means with baseline (control) – Dunnett’s test (Student’s 
test modification for multiple comparisons with control). 
5. 
For evaluation of time changes in parameters under comparison – analysis of variance 
(ANOVA, MANOVA) in modification with repeated measures. 
To carry out the statistical analysis and approaches specified above the following SAS 
procedures are suggested: 
 
UNIVARIATE – check for normalcy of distributions compared; 
 
CORR, MEANS – calculation of descriptive statistics; 
 
TTEST – Student’s test with all modifications; 
 
GLM, GENMOD, GLIMMIX – analysis of variance (ANOVA/ANCOVA, 
MANOVA/MANCOVA). 
Nonparametric criteria: 
1. 
For evaluation of differences in continuous variables obtained in two various (independent) 
groups – Mann-Whitney test; 
2. 
For evaluation of time changes in parameters under comparison – one-way non-parametric 
analysis of variance (ANOVA) in modification with repeated measures; 
3. 
For frequency analysis of contingency tables 2×2 – χ2 test (if the frequencies compared 
exceed 5) of exact Fisher’s test (if one of the frequencies compared is < 5); 


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4. 
For frequency analysis of contingency tables with multiple comparisons – Cochran-
Mantel-Haenszel test (modification of χ2 test for multiple comparisons). 
Non-parametric analysis will be made using SAS procedures: 
 
FREQ – χ2 test and/or exact Fisher’s test; Cochran-Mantel-Haenszel test test; 
 
NPAR1WAY – Mann-Whitney test. 
5. 
Terms for early termination of the study will be established by O`Brien-Fleming boundary. 
Interim analysis procedures: 
Interim analysis will be made using SAS procedure SEQTEST. 
Safety parameters  
Adverse events recorded during the study will be grouped into frequency tables by 
severity, seriousness and relationship with the study product. 
Data presentation 
Descriptive statistics will be provided for each study continuous / interval variable. 
Numerical data will be presented by mean, standard deviation, min and max values. 
Comparisons suggesting statistical conclusion will have the relevant confidence intervals. 
Outliers will be analyzed individually. The data will be grouped by visits. Categorical variables 
will be presented as frequency tables by visits. 
  
SAS-9.3 software will be used for statistical analysis including various parametric and 
nonparametric tests.