Clinical trial NCT03039699
Conditions: Viral Intestinal Infection
Sponsor: Materia Medica Holding
Start date: 2016-06-23; Completion date: 2019-06-01
Enrollment: 259 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to obtain additional data on efficacy and safety of Ergoferon in the treatment of viral intestinal infections in inpatient children.

Detailed description:
Design: a multicenter, double-blind, placebo-controlled, randomized clinical trial in parallel groups.

This study will enroll subjects of both sexes aged from 6 months to 6 years who are admitted to hospital within 48 h of the onset of acute intestinal infection (AII), presumably of viral aetiology. Patients to be enrolled in the screening will be children with typical viral gastroenteritis/enteritis symptoms. The key symptom is decreased in the consistency of stools (loose or liquid) and increased in the frequency of its evacuations (at list 3 time daily). Virus detection in stool samples will be performed by polymerase chain reaction (PCR).

After the parent/adopter signs a parents/adopters information sheet (Informed Consent form) for the child's participation in the clinical trial, the recording of medical history data, a medical examination including the evaluation of symptoms on the Clinical Dehydration Scale (CDS) by pediatrician, and laboratory tests will be performed during Visit 1 (Day 1). If inclusion criteria are met and non-inclusion criteria are absent (day 1), the patient will be included in the trial and randomized to administer either Ergoferon or Placebo.

In addition to the standard/pathogenetic therapies, group 1 patients will take Ergoferon following a 5-day regimen, whereas group 2 patients will receive Placebo. The parents/adopters of the patient will be provided with a patient diary and instructed how to complete the diary.

Before treatment stool specimens will be collected from the patients for detection and differentiation of Rotavirus A, Norovirus 2 genotype, Astrovirus, Adenovirus F, Shigella spp., enteroinvasive E.coli (EIEC), Salmonella spp., and thermophilic Campylobacter spp. using a PCR assay to diagnose the etiology of intestinal infection. In total, the patients will be monitored for 10 days (screening, randomization, treatment initiation - Day 1; the treatment on Days 1-5; observation in hospital - Day 6, and follow-up period - Day 7-10). During the treatment and inpatient observation periods (Days 1-6, Visits 1-6), the patients will be examined daily by a pediatrician, and the examination results, including the CDS scores, will be recorded in source documents. The patient's parent/adopter will complete the patient diary every day, recording the presence/absence of diarrhea signs, vomiting, and body temperature. The pediatrician will check them each time for the correctness of completion. On day 10 (after hospital discharge), Visit 7 will be done (as an in-person visit (a hospital or calling a doctor) or a distance, 'phone' visit) to interview the parents/adopters about the patient's health, presence of any complications, and use of medications (the pediatrician will use this information to complete a questionnaire). Collection of stool specimens and repeat PCR for Rotaviruses/Noroviruses/Astroviruses/Adenoviruses, Shigella spp., EIEC, Salmonella spp., and Campylobacter spp. will be performed on Days 3, 4, and 6 of inpatient observation and after discharge from the hospital (Day 10); collection of blood and urine specimens for safety tests will be carried out at baseline and before hospital discharge (day 6). The recording of the intake of study therapies and of concomitant medications as well as the assessment of compliance with and safety of the study therapies will be performed on Days 2-6 and 10.

Patients who recovered while in hospital and are discharged from the unit earlier than at 5 days will undergo the procedures of Visit 6, including the collection of biological specimens for PCR (efficacy evaluation) and biochemistry, blood test and urinalysis (safety assessment). The parents/adopters will be given the blister pack with the remaining study drug so that the patient can continue the treatment.

Arms: arm 1: Tablet for oral use. Dose per administration - 1 tablet per intake (outside a meal/feeding). Within the first 2 hours - 1 tablet every 30 minutes, followed by 3 more tablets at time intervals equally separated throughout the rest of the day; from day 2 to day 5 - 1 tablet 3 times daily. arm 2: Tablet for oral use. Dose per administration - 1 tablet per intake (outside a meal/feeding). Within the first 2 hours - 1 tablet every 30 minutes, followed by 3 more tablets at time intervals equally separated throughout the rest of the day; from day 2 to day 5 - 1 tablet 3 times daily.
Interventions: intervention 1: Ergoferon intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
International Multicenter Double-blind Placebo-Controlled Parallel-Group 
Randomized Clinical Trial of Efficacy and Safety of Ergoferon in the 
Treatment of Viral Intestinal Infections in Children 
 
 
 
 
 
Phase IV 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-ER-008 
Version date: 
November 02, 2015 
ClinicalTrials.gov Id: 
NCT03039699 
 


Protocol No. MMH-ER-008 
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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 viral intestinal infections in children. 
Phase: IV 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. MMH-ER-008 
Objective of the study 
 To obtain additional data on the efficacy and safety of Ergoferon in the treatment of viral 
intestinal infections in inpatient children. 
Endpoints  
Primary endpoint 
1. Average diarrhea duration1.  
Secondary endpoints 
1. Percentage of patients without diarrhea following 48, 72, and 96 hours of treatment. 
2. Percentage of patients with recovery2 following 48, 72, and 96 hours of treatment. 
3. Average illness duration (from the enrollment to the recovery). 
4. Total CDS score at 24, 48, and 72 hours after treatment initiation. 
5. Average vomiting duration (if any). 
6. Percentage of patients with negative PCR tests on Days 3, 4, 6, and 10 of observation versus 
baseline (no RNA detection of rotaviruses/ noroviruses/ astroviruses/ adenoviruses in patients 
who had positive tests at baseline). 
7. Percentage of patients with worsening of illness3 and/or hospital-acquired infection4. 
                                                 
1 Diarrhea duration is considered as the time between receiving the first dose of investigational medicine /placebo and the normal consistency of stool pattern (to the 
previous stool consistency before diarrhea), i.e.  
1) time to the first loose  stool which is followed by two normal consistency stools over 24 h (infants may have three episodes of loose stool over a 24-hour period), or 
2) time to ≤3 episodes of stool occurring over 24 h, at least 2 of which are normal consistency stools, or 
3) time to the absence of stools for ≥12 h which is not followed by new episodes of diarrhea (total stool frequency over 24 h – less than 3 times). 
2 Recovery criteria: absence of diarrhea, vomiting, symptoms of dehydration, and increased body temperature (based on daily examinations by pediatrician). 
3 Worsening of illness: an increase in dehydration scores and worsening of non-specific symptoms, as evidenced by a decline in general appearance, increasing 
fatigue and drowsiness, refusal to eat and drink, severe tachycardia/bradycardia, unstable hemodynamics, tachypnea, hypo- or hyperventilation, circulation disorders, 
peripheral cyanosis, sunken eyes, severe dryness of skin and mucous/tongue, poor tissue turgor, absent tears, persistent vomiting, anuria/acute kidney injury, 
seizure/convulsions, and meningismus. 
4 Hospital-acquired infection: a viral or bacterial infection (intestinal, respiratory or urinary tract infection, etc.) occurring after at least 48 h of hospital stay and 
confirmed by laborator tests.  


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Safety assessment  
 Adverse events (AE) during the treatment, AEs severity and relations to the study drug, and 
AEs outcomes.  
 Changes in vital signs and laboratory parameters (complete blood count test, biochemistry 
blood test and urinalysis). 
 Percentage of patients with abnormal biochemistry. 
Study design  
Study design: an international multicenter, double-blind, placebo-controlled, randomized clinical 
trial in parallel groups. 
The study will enroll patients of either gender aged from 6 months to 6 years old who are 
admitted to hospital within 48 hours of the onset of acute intestinal infection (AII), presumably 
of viral etiology. The children with typical viral gastroenteritis/enteritis symptoms will be 
enrolled in the screening. The key symptom is acute watery diarrhea without visible pathological 
impurities (transparent mucus is possible) at least 3 times a day. Virus detection in stool 
specimens will be performed by polymerase chain reaction (PCR).After the parent/adopter signs 
a parents/adopters information sheet (Informed Consent form) for the child’s participation in the 
clinical trial, the recording of medical history data, a medical examination including the 
evaluation of symptoms on the Clinical Dehydration Scale (CDS) by pediatrician, and laboratory 
examination5 will be performed during Visit 1 (Day 1). If inclusion criteria are met and non-
inclusion criteria are absent (day 1), the patient will be included in the trial and randomized to 
administer either Ergoferon or Placebo. 
In addition to the standard/pathogenetic therapies, group 1 patients will take Ergoferon following 
a 5-day regimen, whereas group 2 patients will receive Placebo. The parents/adopters of patient 
will be provided with patient diary and instructed how to fill it. 
Before treatment stool specimens will be collected from the patients for detection and 
differentiation of Rotavirus A, Norovirus 2 genotype, Astrovirus, Adenovirus F, Shigella spp., 
enterovasive E.coli (EIEC), Salmonella spp., and thermophilic Campylobacter spp. using a PCR 
assay6 to diagnose the etiology of intestinal infection. In total the patients will be monitored for 
10 days (screening, randomization, treatment initiation – Day 1; the treatment on Days 1 – 5; 
observation in hospital – Day 6, and follow-up period – Day 7 – 10). During the treatment and 
inpatient observation periods (Days 1-6, Visits 1-6), the patients will be examined daily by 
                                                 
5 If an eligible patient (not meeting the non-inclusion criteria) is enrolled after the collection of blood and urine specimens for laboratory testing (specifically for the 
current hospitalization), these test results will be considered as the initial variables in the analysis of safety endpoints (i.e., no repeat specimen collection will be 
required provided the laboratory variables evaluated are those defined by this protocol). 
6 The data of a patient whose PCR test indicates a bacterial etiology of acute intestinal infection will not be included in the analysis of treatment efficacy. For the sake 
of sufficiency of data for the efficacy analysis, it is statistically assumed that 50% of patients will test negative for viral etiology of acute intestinal infection. 


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pediatrician, and the examination results, including the CDS scores, will be recorded in source 
documents. The patient’s parent/adopter will fill patient diary on a daily basis, recording the 
presence/absence of diarrhea signs, vomiting, and body temperature. The pediatrician will check 
correctness of diary filling. After discharge on day 10 (±1) Visit 7 is scheduled (personal at the 
site/at home or distant/phone call) to interview the parents/adopters about the patient’s health, 
presence of any complications, and use of medications (the investigator will fill out a 
questionnaire). 
Collection of stool specimens and repeat PCR for Rotaviruses/Noroviruses/Astroviruses/ 
Adenoviruses, Shigella spp., EIEC, Salmonella spp., and Campylobacter spp. will be performed 
on Days 3, 4, and 6 of inpatient observation and after discharge from the hospital (Day 10); 
collection of blood and urine specimens for safety tests will be carried out at baseline and before 
hospital discharge (day 6). The recording of the intake of study therapies and of concomitant 
medications as well as the assessment of compliance with and safety of the study therapies will 
be performed on Days 2-6 and 10. 
Patients who recovered while in hospital and are discharged from the unit earlier than at 5 days 
will undergo the procedures of Visit 6, including the collection of biological specimens for PCR 
(efficacy evaluation) and biochemistry, blood test and urinalysis (safety assessment). The 
parents/adopters will be given the blister pack with the remaining study drug so that the patient 
can continue the treatment. 
Inclusion and exclusion criteria 
Inclusion criteria 
1. Patients of either gender aged from 6 months to 6 years old hospitalized to infectious 
department. 
2. Diarrhea (watery stool without visible abnormal foreign substances [transparent mucus is 
possible] ≥ 3 times a day). 
3. Dehydration symptoms according to CDS scale ≥1. 
4. The first 48 hours from the onset of the first diarrhea episode. 
5. Start of study treatment (Ergoferon/Placebo) within 12 hours after the start of the standard 
hospital therapy. 
6. Availability of a patient information sheet (Informed Consent form) signed by the patient's 
parents/adopters to confirm the child's participation in the clinical trial signed by one 
parent/adopter of patient. 
Exclusion criteria 
1. Suspected bacterial intestinal infection. 


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2. Suspected infectious diseases of another localization including pneumonia, meningitis, 
sepsis, otitis media, urinary tract infection, etc. 
3. Severe intestinal infection7. 
4. Severe dehydration (CDS score ≥7). 
5. Anuria (acute kidney injury). 
6. Medical history or prior diagnosis of serious diseases, including primary/secondary 
immunodeficieny, oncological disease, diabetes mellitus, infantile cerebral palsy, 
mucoviscidosis/cystic fibrosis etc. 
7. Exacerbation or decompensation of a chronic disease, including diseases of the digestive 
system that would affect the patient’s ability to participate in the clinical trial. 
8. Malabsorption syndrome, including congenital or acquired lactose intolerance/lactase 
deficiency or any other disaccharidase deficiency and galactosemia. 
9. Allergy/ intolerance to any of the components of study drugs. 
10. Course administration of any medicines listed in the section "Prohibited concomitant 
treatment" for 2 weeks prior to the enrollment in the trial. 
11. Participation in other clinical trials within 3 months prior to the enrollment in this study. 
12. Patients whose parents/adopters, from investigator's point of view, will fail to comply with 
the observation requirements of the trial or with the dosing regimen of the study drugs. 
13. The patient’s parent/adoptive parent are 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. 
14. The patient's parent/adoptive parent works for 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. The patient`s inability or refusal of the patient or parents/adopters to follow the protocol 
requirements.  
2. The necessity to use medications prohibited within this trial. 
3. An adverse event requiring discontinuation of the study drug. 
4. The patient’s or his/her parent/adopter wish to complete the study ahead of schedule for any 
reason. 
                                                 
7 Criteria for a severe intestinal infection: sudden patient deterioration, sudden fatigue or even adynamia, marked apathy and drowsiness/excessive sleepiness and 
lethargy, dry mucous membranes, sunken eyes, loss of tearing, pool tissue turgor, lack of eye contact in the child on examination, aversion to food and drink, severe 
tachycardia/bradycardia, unstable hemodynamics, tachypnea, hypo- or hyperventilation, impaired microcirculation, peripheral cyanosis, slow capillary nail refill, 
persistent vomiting, anuria/acute renal disease, convulsions, and meningism. 


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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. 
7. Early discharge of patient from hospital with persisting acute intestinal infection symptoms 
on days 2-5 of hospitalization, before the end of taking the study therapy at the 
parent’s/adopter’s request. 
Number of subjects 
It is planned to enroll 572 patients, which is expected to allow completion of all protocol 
procedures by at least 286 PCR-positive (for viral acute intestinal infection) patients (143 
patients in the Ergoferon and Placebo groups). 
Interim analysis 
An interim statistical analysis will be performed as part of this study. 
The interim analysis will be based on the patient assessment data and treatment outcomes 
recorded for the protocol-defined number of patients who have completed participation in the 
study.  
Number of patients to be evaluated in the interim analysis: 
144 patients (72 in the Ergoferon group and 72 in the Placebo group). 
Number of patients to be evaluated in the final analysis: 
286 patients (143 in the Ergoferon group and 143 in the Placebo group).  
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. Dose per administration - 1 tablet per intake 
(outside a meal/feeding). Within the first 2 hours - 1 tablet every 30 minutes, followed by 3 more 
tablets at time intervals equally separated throughout the rest of the day; from day 2 to day 5 − 1 
tablet 3 times daily. For oral administration to a child aged from 6 months to 3 years old the 


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tablet should be dissolved in 10 mL of boiled water of room temperature (or solution used for 
oral rehydration). 
Dosage form: Tablets. 
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
Storage conditions: Store in a place protected from light, at the temperature not exceeding 
25оС. Keep out of the reach of children. 
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 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 10 days (screening, randomization, treatment initiation – 
day 1, study therapy – days 1-5, hospital follow-up – day 6, personal visit (study 
site/home)/phone call − day 10). 
Symptomatic (Standard) treatment 
Throughout the study the patients can receive pathogenetic therapy for acute intestinal infections 
which includes: 
1. Nutritional Interventions 
Breast-feeding should not be interrupted. The volume and composition of food depends on the 
child’s age, the severity of diarrhea symptoms, and preceding diseases. The frequency of feeding 
and amount of food per meal is determined by the child’s age and presence and frequency of 
vomiting/regurgitation. 
2) Oral rehydration using hypoosmotic rehydration compound Hydrovit ®8.  
3) Intestinal adsorbent (diosmectite − Smecta®). 
4) Probiotic (Linex®). 
                                                 
8 In medical centers of Uzbekistan the oral rehydration formulations authorized in these countries will be used.  


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In case of special indications and/or complications, the pediatrician may prescribe syndrome-
specific treatments, such as enteral (nasogastric) or pareteral (intravenous) rehydration salt 
formulations and detoxicants, antiemetics (Domperidone/Metoclopramide), antipyretics 
(Paracetamol/Ibuprofen, or Metamizole - for fever not relieved by paracetamol/ibuprofen). 
Prohibited concomitant therapy 
Two weeks prior to enrollment9 and during the study (from the time of signing the information 
sheet (Informed Consent Form) and screening initiation), it is prohibited to administer the 
following medications: 
1. Antibacterials, including enteric antimicrobial agents (sulfonamide and trimethoprim 
preparations). 
2. Antidiarrheal microorganisms (excluding Linex®). 
3. Intestinal antiinflammatory agents. 
4. Intestinal adsorbents (excluding diosmectite). 
5. Antispasmodics and antipropulsives. 
6. Antiemetics (excluding domperidone and metoclopramide). 
7. Laxatives. 
8. Digestives, including enzymes. 
9. Prebiotics. 
10. Nonsteroidal antiinflammatory drugs (excluding ibuprofen). 
11. Analgesics and antipyretics (excluding paracetamol and metamizole). 
12. Antiviral drugs except for Ergofern and Oseltamivir (Tamiflu®), which are prescribed within 
this study. 
13. Immunostimulants, including interferon inducers (acridone acetic acid, meglumine acridone 
acetate, 
polyadenylic 
acid 
+ 
polyuridylic 
acid, 
methylphenylthyomethyl-
dimethylaminomethyl-hydroxybromindol carboxylic acid ethyl ether, sodium oxo-dihydro-
acridinyl acetate, cagocel, tilorone, umifenovir); pidotimod, synthetic immunostimulants 
(levamizol or alfa-glutamyl-tryptophan); bacterial immunomodulators (including ribomunyl, 
ribonucleate sodium, deoxyribonucleate sodium, IRS 19, umudon etc.); 
14. Immune sera and immunoglobulins (J06). 
15. Vaccines. 
16. Antineoplastic agents and antineoplastic endocrine therapy. 
17. Immunosuppressants.  
18. Corticosteroids for systemic use. 
                                                 
9 A single use by a patient of any of the drugs on the ‘non-permitted medications’ list (sections 1-11) in the course of 48 hours prior to enrollment is not considered a 
non-inclusion criterion.  


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19. Homeopathic medicines. 
20. Drugs known to previously cause allergic reactions in the patient. 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
 
Procedure/Day  
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 
Day 
10±1 
Informed consent 
+ 
 
 
 
 
 
 
Collection of complaints 
+ 
+ 
+ 
+ 
+ 
+ 
 
Medical history   
+ 
 
 
 
 
 
 
Physical examination 
+ 
+ 
+ 
+ 
+ 
+ 
 
Body weight measurement 
+ 
 
 
 
 
+ 
 
Body length/height measurement 
+ 
 
 
 
 
 
 
Evaluation of dehydration 
symptoms using CDS  
+ 
+ 
+ 
+ 
+ 
+ 
 
Diary supply 
+ 
 
 
 
 
 
 
Checking the correctness of filling 
the diary 
 
+ 
+ 
+ 
+ 
+ 
 
Parent/adopter inquiry (personal/by 
phone) and filling questionnaire 
“Parent’s/adopter’s inquiry data”  
 
 
 
 
 
 
+ 
Return of patient diary  
 
 
 
 
 
+ 
 
Concomitant therapy 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Eligibility assessment 
+ 
 
 
 
 
 
 
Obtaining stool sample for PCR 
diagnosis 
+ 
 
+ 
+ 
 
+ 
+* 
Safety laboratory tests 
(hematology, serum chemistry, 
+ 
 
 
 
 
+ 
 
Group 1: Ergoferon for 5 days 
SCREENING
Visit 1 
(Day 1) 
10±1 days 
Visit 7  
(Day 10±1) 
Visits 2 − 6 
(Days 2 − 6) 
Group 2: Placebo for 5 days 
RANDOMIZATION
Basic / pathogenetic therapy for groups 1 and 2: 
1) Nutrition therapy. 2) Oral rehydration (Hydrovit®). 3) Enteric sorbent (Smecta®). 4) 
Probiotic 
(Linex®). 
As 
indicated: 
enteric/parentral/parenteral 
rehydration 
and/or 
detoxication, domperidone/metoclopramide, paracetamol/ibuprofen/metamizole sodium.  
 


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urinalysis)  
Randomization and prescription of 
study drug 
+ 
 
 
 
 
 
 
Study drug supply 
+ 
 
 
 
 
 
 
Basic medication supply 
+ 
+ 
+ 
+ 
+ 
 
 
Study drug accountability, 
compliance assessment 
 
 
 
 
 
+** 
+** 
Evaluation of treatment safety 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
* All the subjects will receive sterile containers for stool storage and transportation on day 10. In case of a phone 
visit on day 10 stool samples will be delivered to the local laboratory by a courier. 
** Return of the study product is made after 5-day treatment course (on Day 6). If the subject is discharged sooner 
than on day 6, the parent/adopter will be given a blister with the remaining product to complete outpatient therapy; 
in this case the product return and determination of compliance will be made on Day 10±1. 
 
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 including those occurred prior 
to the study therapy will be considered throughout the study for this sample.  
Safety population:  all patients who received at least one dose of the study drug. This sample will 
be used to analyze the study treatment safety and tolerability, since all the AEs identified after 
the study product administration will be recorded.    
Full Analysis Set. This sample includes all enrolled and randomized 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; 
4) withdrawal of a patient due to early discharge (discharge of patient with persistent 
symptoms of acute intestinal infections on days 2-5 of hospitalization before the study 
treatment is completed at the parent’s/adopter's request). 
This sample is 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. 
Per protocol set. This sample includes all patients who completed the therapy as per the study 
protocol without any missing visits or significant protocol deviations. This sample will be used 
for the Per Protocol analysis (PP- analysis) of the the study therapy efficacy. 
Mean value in Placebo group for the relevant day will be used to fill lacking/missing data. 
Data treatment and all statistical calculations under the protocol will be made using SAS-9.4 
statistical software10. 
                                                 
10 Holder of license: ООО "NPF "Materia Medica Holding", No. 70100045. 


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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 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: 
H0: m2-m1≤0 
H1: m2-m1>0, 
where m1 – mean disease duration in Ergoferon group, 
           m2 – mean disease duration in Placebo group;  
1.6  to assure potential adjustment of sample size or terminate the study due to 
inadequate efficacy/high efficacy, interim analysis will be carried out in which:  
a. 
calculations will be made using O’Brien-Fleming boundary; 
b. 
proportions of the subjects completing the study and yielding the results 
for interim and final analyses, will be taken as 0.5 and 1.0 (i.e. interim 
analysis will be made after recruitment of half of the planned number of 
the clinical study subjects. 
1.7 
therefore, sample size will be calculated taking into account 
a. 
interim analysis; 
b. 
assumption on expected effects declared in the main efficacy criterion of 
the protocol. 
1.8 
calculation of sample size of groups 1 and 2 for two-sided test for interim and 
final analysis will be made using the formula: 
N1=N2=(σ1
2 + σ2
2) I, 
where N1 and N2 are sample sizes in Ergoferon and Placebo groups;  
 σ1 and σ2 are expected standard deviations in groups 1 and 2;  
 I – Fisher's information determined using the formula: 
I=(F-1(1-α)+F-1(1-β))2/θ2, 


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where F-1(1-α) and F-1(1-β) are tabular values of z-test for α and β, а θ =(m1-m2). 
1.9 
final sample size will be determined using the formula:  
NF=NPP/(1-Cw),  
where NF – final sample size;  
           NPP – result of calculation in cl. 1.8, i.e. scheduled number of subjects 
completing the study per protocol; 
          CW – withdrawal coefficient. 
2. Assumptions about the expected effects of the clinical study. 
Given that the results of the previous studies, the difference between Ergoferon effect consisting 
in reduced mean diarrhea duration and Placebo effect is expected to be at least 12 hours in favour 
of Ergoferon with group standard deviation of at least 36 hours11. 
According to the statistical considerations and assumptions above, each group size will be:  
a) at interim analysis - 72 subjects; 
b) at final analysis - 143 subjects.  
Hence, full PP analysis set will included 286 patients. 
Given potential negative results of PCR diagnosis, screening failures and further withdrawals for 
various reasons it was decided to double the sample (Cw=50%) and and enroll at least 572 
subjects (286 per group).  
Statistical criteria  
All the statistical calculations will be performed using two groups of statistical criteria:  
 parametric – to evaluate continuous and interval random variables;  
 non-parametric – for: 
 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. 
The following SAS procedures are supposed to be used for interim analysis:  
 SEQDESIGN, SEQTEST – design and performance of interim analysis. 
 Conditions for early study termination will be established using O’Brien-Fleming 
stopping boundary. 
Parametric criteria 
                                                 
11 According to the report for multicenter double-blind placebo-controlled parallel-group randomized clinical study of therapeutic efficacy and safety of anti-IFN at 
rotavirus infection in children (phase III), mean diarrhea duration in active product group was 1.9±1.2 days, in Placebo group - 2.9±1.8 days. 


Protocol No. MMH-ER-008 
02-Nov-2015 
CONFIDENTIAL  
 
Page 13 of 14 
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: 
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). 


Protocol No. MMH-ER-008 
02-Nov-2015 
CONFIDENTIAL  
 
Page 14 of 14 
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.