International Multicenter Double-blind Placebo-Controlled Parallel-Group Randomized Clinical Trial of Efficacy and Safety of Ergoferon in the Treatment of Acute Respiratory Viral Infections in Children
Phase: PHASE4
Conditions: Acute Respiratory Viral Infections
Sponsor: Materia Medica Holding

 
 
 
 
 
 
 
 
 
 
 
 
 
International Multicenter Double-blind Placebo-Controlled Parallel-Group 
Randomized Clinical Trial of Efficacy and Safety of Ergoferon in the 
Treatment of Acute Respiratory Viral Infections in Children 
 
 
 
 
 
Phase IV 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-ER-009 
Version date: 
December 03, 2015 
ClinicalTrials.gov Id: 
NCT03039621 
 

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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 Parallel-Group Randomized Clinical 
Trial of Efficacy and Safety of Ergoferon in the Treatment of Acute Respiratory Viral Infections 
in Children. 
Phase: IV 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. MMH-ER-009 
 
Objective of the study 
 To obtain additional data on the efficacy and safety of Ergoferon in therapy of acute 
respiratory viral infections (ARVI) in children aged 6 months to 6 years old.   
Endpoints  
Primary endpoint 
1. Time to alleviation of all ARVI symptoms1 (time from enrollment in the study to alleviation 
of all ARVI symptoms, according to the patient's diary).  
Secondary endpoints 
1. Time to normalization of body temperature2. 
2. Time to alleviation of flu-like nonspecific symptoms3. 
3. Time to alleviation of respiratory symptoms4. 
4. Flu-like nonspecific and respiratory symptoms total score (TS) for days 2-6 (according to the 
patient's diary). 
5. ARVI severity (based on the area under the curve of TS for days 2-6, according to the 
patient’s diary). 
6. Percentage of patients recovered on day 2, 3, 4, 5, and 6 (according to the patient's diary). 
                                                 
1 Criteria of alleviation of all ARVI symptoms: body temperature ≤37.50С for 24 hours (without subsequent increase within the observation 
period) + absence of ARVI symptoms /presence of ARVI symptoms with ≤3-point of TS. 
2 Oral temperature ≤37.50С for 24 hours (without subsequent increase within the observation period).  
3 Absence of flu-like nonspecific symptoms/presence of one mild flu-like nonspecific symptom.  
4 Absence of respiratory symptoms/presence of one mild respiratory symptom.    

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7. Rates of antipyretic use per patient during days 1 to 5 of therapy (according to the patient's 
diary). 
8. Percentage of patients with worsening of illness (ARVI complications, including those 
requiring antibiotics; hospitalization) for 14 days. 
Safety assessment  
 Presence and type of adverse events during the therapy, their severity, relation to 
investigational drug, outcomes.   
 Dynamics of vital sings. 
Study design  
Study design: multicenter double-blind placebo-controlled randomized clinical study in parallel 
groups.   
The study will enroll patients of either gender aged from 6 months to 6 years old with clinical 
manifestations of ARVI within the first day after the onset of the disease. Patients will be 
included evenly (1:1 ratio) in accordance with the age group:  6 months – 3 years 11 months 29 
days; 4 years – 6 years 11 months 29 days.  Signed information sheet for parents/adopters 
(informed consent form) will be obtained from all participants’ parents/adopters prior to the 
screening procedures. 
Medical history, thermometry, patient examination by a doctor, assessment of ARVI symptoms 
severity, and nasopharyngeal swabs will be performed at screening visit (Day 1). If the inclusion 
criteria are met and exclusion criteria are absent, the patient is included in the study.   
Nasopharyngeal swabs will be analyzed by real-time reverse transcription polymerase chain 
reaction (RT-PCR) to identify the most common respiratory viruses, including (1) Influenza A 
virus; (2) Influenza B virus; (3) Influenza A (H1N1)pdm; (4) Human metapneumovirus; (5) 
Human respiratory syncytial virus; (6) Human rhinovirus; (7) Human adenovirus; (8) Human 
bocavirus; (9) Human parainfluenza virus 1; (10) Human parainfluenza virus 2; (11) Human 
parainfluenza virus 3; (12) Human parainfluenza virus 4; (13) Human coronavirus OC43; (14) 
Human coronavirus 229E; (15) Human coronavirus HKU1; (16) Human coronavirus NL63.   
Patients are randomized into one of two groups:  the 1st group patients will take Ergoferon 
according to the dosage regimen for 5 days; the 2nd group patients will take Placebo according 
to the dosage regimen of Ergoferon for 5 days. 
Patient’s parents/adoptive parents are provided with diaries where daily in the morning and at 
night they record oral temperature (measured by a digital thermometer provided by Sponsor), 
symptoms of ARVI (according to the 4-point scale), administered drug and concomitant therapy. 
Doctors instruct parents/adoptive parents how to fill in diaries; the first scores of ARVI 

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symptoms severity and oral temperature are made by doctors together with the parents/adoptive 
parents.  
Patients are observed up for 14 days (screening and randomization up to 1 day, therapy for 5 
days, follow-up from 6 to 10 day; delayed telephone “visit” on day 14).  During the observation 
period two visits are planned (at home or at the medical center) on day 3 (Visit 2) and day 6 
(Visit 3).  If patients still have any symptoms of ARVI/complications of ARVI, then an 
additional (unscheduled) Visit 4 is held on Day 10 of the observation (at the medical center).   
During Visits 2, 3 (4), doctors carry out an physical examination, record dynamics of ARVI 
symptoms and concomitant therapy, check patient’s diaries, which parents/adoptive parents 
return back at Visit 3 or 4.  At Visit 3 (after 5 days of therapy), compliance with the treatment is 
additionally assessed. A “telephone visit” (Visit 5, Day 14 ± 1) is carried out to interview parents 
about the patient’s condition, presence/absence of complications, and possible use of antibiotics.  
During the study, symptomatic therapy and therapy for underlying chronic conditions are 
allowed with the exception of the drugs indicated in the section “Prohibited Concomitant 
Treatment”. 
Inclusion and exclusion criteria 
Inclusion criteria 
1. 
Patients of both genders aged 6 months to 6 years old5.  
2. 
ARVI based on medical examination: oral temperature of at least 38.0°C at the time of 
examination + total symptom severity ≥5 points. 
3. 
First 24 hours after ARVI onset6.  
4. 
Seasonal rise in ARVI incidence.  
5. 
Availability of signed information sheet for parents/adopters (informed consent form) for 
participation in the clinical trial. 
Exclusion criteria 
1. 
Suspected pneumonia, bacterial infection (including meningitis, sepsis, otitis media, 
urinary tract infection, etc.) requiring a prescription of antibacterial products from the first 
day of the disease.  
2. 
Suspected initial manifestations of diseases with symptoms similar to ARVI at onset (other 
infectious diseases, flu-like syndrome at the onset of systemic diseases of connective 
tissue, oncohaematological and other diseases). 
3. 
Clinical symptoms of severe influenza/ARVI7 requiring hospitalization. 
                                                 
5 The study participants are aged 6 months to 6 years 11 months 29 days. 
6 Manifestation of fever, or a rise in body temperature to febrile values (≥37.60C for oral and tympanic temperature, ≥37.40C for axillary 
temperature, ≥38.00C for rectal temperature) is considered the onset of ARVI.  

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4. 
Medical history of primary and secondary immunodeficiency; oncologic conditions.  
5. 
Aggravation or decompensation of chronic diseases (diabetes mellitus, cerebral palsy, 
cystic fibrosis, primary ciliary dyskinesia, bronchopulmonary dysplasia, malformations of 
the respiratory and ENT organs/ear, throat, mouth, tongue, larynx, trachea, neck and 
salivary and thyroid glands, etc.), which affect the patient's ability to participate in the 
clinical study.  
6. 
Malabsorption syndrome, including congenital or acquired lactase or other disaccharidase 
deficiency, galactosemia. 
7. 
Allergy/hypersensitivity to any component of the drug product used in the therapy.  
8. 
Course administration of the drug products specified in the section “Prohibited 
Concomitant Therapy” within two weeks prior to inclusion in the study. 
9. 
Patients whose parents/adoptive parents will not fulfill the requirements during the study or 
follow the order of administration of the studied drug products, from the Investigator's 
point of view.  
10. 
Participation in other clinical trials for 3 months prior to enrollment in this study.  
11. 
The patient’s parent/adoptive parent is a study specialist of the centre and is directly 
involved in the study, or is an immediate family member of the Investigator.  Spouses, 
parents, children, or siblings, regardless of whether they are siblings or adopted are 
considered immediate family members. 
12. 
The patient's parent/adoptive parent works at the OOO "NPF "Materia Medica Holding", 
i.e. they are employees of the Company, temporary employees on a contract basis or 
appointed officials responsible for conduction of the study or their immediate family 
members. 
Criteria for Withdrawal or Termination 
1. 
Inability or refusal of patient or parents/adoptive parents to comply the Protocol 
requirements. 
2. 
Necessity in medical products prohibited within the study.  
3. 
Development of adverse event requiring product cancellation. 
4. 
Desire of patient or parent/adoptive patient to complete the study ahead of schedule due to 
inefficacy of therapy or any other reason. 
                                                                                                                                                             
7 Criteria of severe influenza/ARVI (RF MH, 2009, 2014; Union of Pediatricians of Russia, 2014; WHO 2011; CDC 20013-2014):  extreme 
severity of disorder (toxic shock syndrome III, critical general condition disorder, decreased activity or weakness up to complete adynamia, 
irritability/cry when touched, lethargy, drowsiness/longer sleep, lack of eye contact during examination, refusal to eat or drink, severe 
tachycardia/bradycardia, tachypnea, hypo- or hyperventilation, microcirculation disorder, peripheral cyanosis, slower capillary filling of the 
nailfold, continuous vomiting, signs of dehydration, decreased diuresis/anuria, convulsions, symptoms of meningism), hemorrhagic syndrome 
(nosebleeds, petechiae on the skin and mucous membranes), hemodynamic instability, severe obstructive disorders (stenosing laryngotracheitis, 
bronchial obstruction syndrome), acute respiratory failure, primary and secondary pneumonia. Risk factors for severe influenza/ARVI and 
development of complications are chronic diseases of the cardiovascular system, respiratory system, diabetes mellitus, immunodeficiency 
conditions, and cancers.  

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5. 
Cases not specified by the protocol when, according to the investigator’s opinion, further 
participation in the study harms the patient. 
6. 
Incorrect inclusion of ineligible patient.   
Number of subjects 
It is planned to include 288 patients, which is expected to allow completion of all protocol 
procedures by at least 216 patients (108 patients in the Ergoferon and Placebo groups, exclusion 
rate is 25%). 
Interim analysis 
An interim statistical analysis is not scheduled within the study.  
Treatment 
 
Group 1 
Name of the medicinal product: Ergoferon 
Active ingredient: affinity purified antibodies to human gamma interferon – 0.006 g*, affinity 
purified antibodies to histamine – 0.006 g*, affinity purified antibodies to CD4 – 0.006 g* 
* Mixture of water-ethanol dilutions 10012, 10030, 10050 of active substance used for saturation of lactose 
monohydrate.   
Excipients: Lactose monohydrate – 0.267 g, microcrystalline cellulose – 0.03 g, magnesium 
stearate – 0.003 g. 
Method of administration: Tablet for oral use, 1 tablet per intake (outside a meal/feeding). 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 (total 8 tablets). From day 2, one tablet is taken 
every 8 hours. The drug is administered outside a meal (in the interval between meals or 15 
minutes before meal or fluid intake). Keep the tablet in the mouth, without swallowing, until 
completely dissolved. For young children (aged 6 months to 3 years old), the tablet is 
recommended to be dissolved in a small amount (1 tablespoon) of drinking water of room 
temperature.  
The therapy lasts for 5 days.   
Dosage form: Tablets. 
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
Storage conditions: Store in a dry place protected from light, at the temperature not exceeding 
25оС. Keep out of the reach of children. 
 

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Group 2 
Name of the medicinal product: Placebo 
Active ingredient: NA 
Excipients: Lactose monohydrate – 0.267 g, microcrystalline cellulose – 0.03 g, magnesium 
stearate – 0.003 g. 
Method of administration: Placebo using Ergoferon scheme.  
Dosage form: Tablets. 
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
Storage conditions: Store in a dry place protected from light, at the temperature not exceeding 
25оС. Keep out of the reach of children. 
Treatment duration 
Ergoferon/Placebo treatment duration is 5 days.  
Observation period 
In total, the patient is observed up for 14 days (screening and randomization up to 1 day, therapy 
for 5 days, follow-up from 6 to 10 day; delayed telephone “visit” on day 14).  
Symptomatic (Standard) treatment  
Throughout the study, patients can receive symptomatic flu/ARVI therapy based on the approved 
standards of care. 
Indications for prescription of antipyretics:  
 body temperature over 38.5°С;  
 body temperature ≥38.0°C in case of concomitant chronic diseases of the lungs, 
heart, nervous system. 
If an antipyretics was received by the child from parent/adoptive parent independently (without 
any recommendation by the doctor) and in the absence of indications for use, the patient will not 
be excluded from the study. The patient’s parent/adoptive parent is recommended to record the 
thermometry values prior to drug intake, its name and dose in the patient’s diary. 
Drug products allowed for use as antipyretics (the ATC group is indicated in brackets): 
1.  Paracetamol (N02BE01). 
2.  Ibuprofen (M01AE01). 
3. Metamizole sodium (N02BB02) only under prescription (for emergency care at 
hyperthermia resistant to paracetamol/ibuprofen, parenteral).  
The antipyretic drugs (Panadol for children, 120 mg/5 mL or Nurofen® for children, 100 
mg/5 mL, suspension for oral administration) will be provided by the Sponsor for all the 
participants of the study. The doctor prescribes antipyretics which issues to the patient’s 

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parent/adoptive parent at Visit 1. In accordance with the Instruction for Medical Use, the drug 
products are allowed for administration in children aged at least 3 months.   
Prohibited concomitant therapy 
Two weeks before inclusion in the study8, as well as during the study (from signing of the 
information sheet for parents/adopters /informed consent form) it is prohibited to administer the 
following drug products (their ATC group is indicated in brackets): 
1. 
Antivirals (J05), except for Ergoferon prescribed within this study.  
2. 
Immunostimulants (L03), including: 
 
interferon inducers (acridonoacetic acid, meglumine acridone acetate/cycloferon®, 
umifenovir/arbidol®, kagocel®, tiloron/amixin®, polyadenyl acid + polyuridylic 
acid/poludan®, sodium oxodihydroacridinyl acetate/neovir®, lavomax®, tilaxin®, 
etc.)  
 
interferons;  
 
bacterial immunomodulators (including ribomunyl®, sodium ribonucleate/ridostin, 
etc., sodium deoxyribonucleate/derinat®, etc., IRS-19, imudon®, broncho-munal®, 
etc.).  
 
pidotimod/immunorix;   
 
interleukins;  
 
synthetic immunostimulants (levamisole, alpha-glutamyl-tryptophan/thymogen, etc.);  
 
drug products with thymus hormones;  
3. 
Antihistamines (R06). 
4. 
Fenspiride (R03DX03), omalizumab (R03DX05). 
5. 
Steroidal and non-steroidal anti-inflammatory drugs (except for ibuprofen). 
6. 
Analgesics and antipyretics (except for paracetamol, metamizole sodium). 
7. 
Analgesics/antipyretics combinations for symptomatic therapy of acute respiratory 
infections. 
8. 
Drug products based on ultra-low doses of antibodies (anaferon (L03AX), epigam, etc). 
9. 
Homeopathic drug products. 
10. 
Immunosuppressants (L04).  
11. 
Antineoplastic agents (L01) and combined (with hormones) antineoplastic endocrine 
therapy (L02). 
12. 
Immune sera and immunoglobulins (J06). 
13. 
Vaccines (J07).  
                                                 
8 If the patient has taken any drug product listed in “Prohibited Concomitant Therapy” (except for the drugs specified in par. 10-14) once prior to 
the study, it is not considered an exclusion criterion.  

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14. 
Drugs that previously caused hypersensitivity/ allergic reactions in patient.   
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
Procedure/ Visit 
Visit 1 
(Day 1) 
Visit 2 
(Day 3) 
Visit 3 
(Day 6) 
Visit 4* 
(Day 10) 
Visit 5 
(Day 14±1) 
Informed consent  
+ 
 
 
 
 
Collection of complaints 
+ 
+ 
+ 
+ 
 
Medical history   
+ 
 
 
 
 
Physical examination 
+ 
+ 
+ 
+ 
 
ARVI symptoms registration  
+ 
 
 
 
 
Inclusion/exclusion criteria 
+ 
 
 
 
 
Concomitant therapy 
+ 
+ 
+ 
+ 
+ 
Nasopharyngeal swabs for RT-PCR 
+ 
 
 
 
 
Randomization and prescription of 
study drug  
+ 
 
 
 
 
Study drug supply 
+ 
 
 
 
 
Antipyretics 
+ 
 
 
 
 
Study drug accountability, 
compliance assessment 
 
 
+ 
 
 
Diary supply  
+ 
 
 
 
 
Checking the correctness of filling 
the diary 
 
+ 
+ 
+ 
 
Diary return 
 
 
+ 
+ 
 
Evaluation of treatment safety  
+ 
+ 
+ 
+ 
 
Telephone survey 
 
 
 
 
+ 
* Visit 4 – unscheduled (additional), provided if the patient still experiences the ARVI symptoms/ complications 
 
RANDOMIZATION
Ergoferon 
5 days 
SCREENING
Visit 3  
(Day 6) 
Visit 2  
(Day 3) 
Visit 1  
(Day 1) 
14±1 days 
Placebo 
5 days 
Visit 5 (telephone) 
(Day 14±1) 
Visit 4, unscheduled 
(Day 10) 

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Statistical Analyses 
Samples  
Total set: all patients included in the study whose parents/adoptive parents signed the Informed 
Consent Form for the patient’s participation in the study. All AEs will be considered throughout 
the study for this sample.  
Safety population:  all patients who received at least one dose of the test drug. This sample will 
be used to analyze the study therapy safety, since all the AEs detected in the patient after 
administration of the drug product will be recorded. The AEs registered in patients of 
the Total set sample from the moment of signing the Informed Consent Form, but before the test 
drug administration will not be taken into account when analyzing the study therapy safety.    
Full Analysis Set. This sample includes all the enrolled patients, except for those who have 
experienced at least one of the following events: 
1) non-compliance with inclusion / exclusion criteria ; 
2) the patient has not taken a single dose of the study drug; 
3) lack of any data of the patient following randomization. 
This sample, the most consistent with the “Intention-to-treat” principle, will be used for 
the Intention-to-treat analysis (ITT analysis) of the the study therapy efficacy. 
To 
fill 
in 
the 
missing 
data 
(indicators/options), 
the 
method 
“LOCF” 
(Last Observation Carried Forward)” will be applied. 
Per protocol set. This sample includes all the patients who have received the complex therapy 
under the Protocol, completed all the scheduled visits and had no significant deviations from the 
Protocol. This sample will be used for the Per Protocol analysis (PP- analysis) of the the study 
therapy efficacy. 
Evaluation of sample size 
The sample size has been assessed on the basis of the following rules and assumptions: 
1. Statistical provisions. 
1.1 
the power of the statistical tests “P = (1 - β )” is assumed to be 80% (the 
probability of correct rejection of the null hypothesis is 0.8); 
1.2 
the probability of a type I error “α” is allowed to be less than 5% (the probability 
of the erroneous acceptance of an alternative hypothesis is less than 0.05); 
1.3 
the statistical criteria used are 2-sided; 
1.4 
the calculation of the sample size is based on the assumptions about the expected 
effects, mainly declared in the primary efficacy criterion of the Protocol; 
1.5 
statistical null and alternative hypotheses are formulated as follows: 

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H0: m2-m1≤0 
H1: m2-m1>0, 
where m1 – time to resolution of all the disease symptoms in 
the Ergoferon group, m2 – time to resolution of all the disease symptoms in 
the Placebo group;  
1.6 
the sample size of the first and second groups for the two-sided criterion is 
calculated with the formula: 
N1=N2=σ2(zα + zβ)2/(m2-m1)2, 
where N1 and N2 – sample sizes of the Ergoferon and Placebo groups; σ– 
expected standard deviation of the first and second groups; zα and  zβ – 
z-criterion values for α and β; m1 – time to resolution of all the disease 
symptoms in the Ergoferon group; m2 – time to resolution of all the disease 
symptoms in the Placebo group; 
1.7 
the final sample size is calculated with the following formula:  
NF=NPP/(1-Кв),  
where NF – final sample size; NPP – result of calculations in par. 1.6, i.e. the planned 
number of patients completing the study in accordance with the Protocol; Кв – 
exclusion rate. 
2. Assumptions about the expected effects of the clinical study. 
It is assumed that the difference between the average duration of the disease (before 
recovery / resolution of the disease) in the Ergoferon group and in the Placebo group will be at 
least 0.5 days, and the standard deviation in both groups will not exceed 1.3 days.  
Based on the above statistical rules and assumptions, the size 9 of each group will account 
for 108 people (sample for the PP analysis).  
Given the possible exclusion of the patients during the screening process, as well as in the 
study for various reasons, it was decided to increase the sample by 25% (Кв=25%) and include at 
least 288 patients (144 patients in each group).  
Statistical criteria  
All the statistical calculations will be performed using two groups of statistical criteria:  
 parametric – to assess continuous and interval random variables;  
 non-parametric – for: 
                                                 
9 The formula has been taken from: O’Brien, R. G. and Muller, K. E. (1993), “Unified Power Analysis for t-Tests through Multivariate 
Hypotheses,” in L. K. Edwards, ed., Applied Analysis of Variance in Behavioral Science, 297–344, Section 8.2.1. New York: Marcel Dekker. 

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 assessments of equality / inequality in the proportion of patients when compared for 
different visits,  
 analysis of frequencies of the compared features, 
 assessment of continuous and interval random variables in case of violation of the 
normality assumption. 
Parametric criteria 
The application of parametric criteria will be accompanied by a check for normality of the 
compared samples (Kolmogorov-Smirnov test). 
The following parametric methods and approaches are supposed to be used: 
1. To assess the differences of continuous variables obtained in two different 
(independent) groups –Student t-test for independent samples. 
2. To assess the differences of continuous variables obtained in one group at two 
different visits – Student t-test for for paired samples. 
3. To assess the temporal dynamics of the compared indicators – analysis of variance 
(ANOVA) or covariance (ANCOVA) in the modification with repeated measures. 
4. In case of multiple comparisons between the groups will apply a variety of corrections 
for multiplicity (Dunnett), (Tukey), (Scheffe), Holm adaptive test, etc. 
5. In 
case 
of 
abnormal 
data 
distribution, 
approaches 
with 
the 
Generalized Linear Models and / or Mixed Linear Models will be used.  
6. Selection of the type of distribution, clarification of the factor and covariance 
structures 
of 
the 
model 
is 
carried 
out 
with fit statistics 
such 
as AIC (Akaike information criterion). 
To perform the above-mentioned statistical tests and techniques, it is assumed that the 
following SAS procedures are used:  
 
UNIVARIATE – check for normality of the compared distributions; 
 
CORR, MEANS – calculation of descriptive statistics; 
 
TTEST – Student t-test with all the modifications; 
 
GLM – analysis of Generalized Linear Models for studying temporal dynamics 
(ANOVA, ANCOVA); 
 
GENMOD – analysis of Generalized Linear Models. 
MIXED – analysis of Generalized Linear Models. 
Non-parametric criteria 
Below, there are the main types of possible comparisons with the respective criteria: 

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1. To assess the differences of continuous variables obtained in two different 
(independent) groups – Mann-Whitney U-test. 
2. To assess the temporal dynamics of the compared indicators – Friedman test, non-
parametric analogue of analysis of variance with repeated measures. 
3. For the frequency analysis of 2×2 cross tables – χ2-test (if the compared frequencies are 
greater than 5) or Fisher exact test (if one of the compared frequencies is less than 5). 
4. For the frequency analysis of cross tables with independent strata – Cochran–Mantel–
Haenszel test (modification of the χ2-test for multiple comparisons). 
5. For the frequency analysis of data on the presence / absence of an event or outcome 
during repeated measures (cross tables with dependent strata) – survival analysis. 
To perform the above-mentioned non-parametric statistical analysis options, it is assumed 
that the following SAS procedures are used: 
 FREQ – Friedman test, χ 2-test and / or Fisher exact test; Cochran–Mantel–Haenszel 
test. 
 LIFETEST – survival analysis . 
 NPAR1WAY – Mann-Whitney U-test. 
Safety parameters  
Adverse events recorded during the study will be grouped into frequency tables by severity, 
seriousness and relationship with the study drug. 
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. The categorical variables will be 
presented as frequency tables by visits.