International Observational Non-Interventional Retrospective Program for Studying the Efficiency and Safety of Ergoferon in Patients With Influenza and Acute Respiratory Viral Infection (ARVI).
Conditions: Viral Respiratory Infection
Sponsor: Materia Medica Holding

 
 
 
 
 
 
 
 
 
 
 
 
 
International observational non-interventional retrospective program for 
studying the efficiency and safety of Ergoferon in patients with influenza and 
acute respiratory viral infections  
(HERMITAGE) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
HERMITAGE 
Version date: 
September 30, 2016 
ClinicalTrials.gov Id: 
NCT04413929 
 

Protocol No. HERMITAGE 
30-Sep-2016 
CONFIDENTIAL  
 
Page 2 of 8 
Protocol Summary 
 
This document represents the program 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 observational non-interventional retrospective program for studying the efficiency 
and safety of Ergoferon in patients with influenza and acute respiratory viral infections 
(HERMITAGE). 
Phase: post-registration 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. HERMITAGE 
Objective of the study 
 To study the practice of Ergoferon using in outpatients (adults and children) with influenza / 
acute respiratory viral infections (ARVI). 
 To obtain additional data on the efficacy and safety of Ergoferon in the treatment of 
influenza/ ARVI in outpatients (adults and children). 
 To obtain additional data on the efficacy and safety of Ergoferon for influenza/ARVI in case 
of late initiation of treatment. 
 To obtain additional data on the efficacy and safety of the drug Ergoferon in the treatment of 
influenza/ARVI in patients with an allergic history. 
Endpoints  
Primary endpoint 
1. Duration1 of Influenza/ARVI Symptoms.  
Secondary endpoints 
1. Duration of increased body temperature(>37 °C). 
2. Duration of systemic symptoms (chills, headache, muscle pain, weakness, loss of appetite). 
3. Duration of nose symptoms (nasal congestion, discharge from the nose), other symptoms. 
4. Duration of throat symptoms (sore throat, etc). 
5. Percentage of patients with complications of influenza/ARVI). 
                                                 
1 The time from the onset of treatment with Ergoferon to the resolution of the symptoms, i.e. a body temperature ≤37.0 °С remaining at this level 
for 24 h (with no further increases throughout the rest of the observation period) in the absence of catarrhal signs and systemic symptoms. 

Protocol No. HERMITAGE 
30-Sep-2016 
CONFIDENTIAL  
 
Page 3 of 8 
Safety assessment  
 Adverse events (AE) during the treatment, AEs severity and relations to the study drug, and 
AEs outcomes.  
Study design  
This observational study is aimed to provide additional safety and effectiveness data for 
Ergoferon in the treatment of influenza/ARVI in adult and pediatric outpatients, including cases 
with delayed treatment initiation (after 48 or 72 h of the onset of illness), and in allergy patients. 
Routine clinical practice in the management of outpatients with ARVI is to be studied in 
Azerbaijan, Armenia, Georgia, Kazakhstan, Kyrgyzstan, Mongolia, Tajikistan and Uzbekistan: 
the demographic characteristics of patients, duration and time points of treatment with the use of 
Ergoferon, its safety, and the frequency of additional medication. 
Scope of the study: 519 general practitioners; 8411 patients. 
Physical examinations and tests are performed according to local outpatient clinical practice, and 
to local and international medical care standards. 
Data to be collected and analyzed after the completion of treatment: 
• 
demographics (age, gender, and city/town of residence) 
• 
severity of illness (mild, moderate, or severe) 
• 
comorbidities (chronic ENT conditions, chronic obstructive pulmonary disease (COPD), 
chronic cardiovascular disease, allergic rhinitis/sinusitis, atopic dermatitis/eczema, asthma, or 
other) 
• 
the time of resolution of infection symptoms (absence of fever – a body temperature below 
37.0°С), systemic symptoms (chills, headaches, myalgias, weakness, and loss of appetite), nasal 
symptoms (nasal congestion/ discharge), laryngeal symptoms (a sore throat, or other), and other 
symptoms 
• 
illness time points: onset of illness, first visit to the doctor’s office, and start of treatment. 
• 
symptomatic therapy (drug name, date prescribed, and date discontinued) 
• 
therapy for bacterial complications (date the antimicrobial drug is prescribed, drug name, 
diagnosis, hospitalization or no hospitalization required, date of hospitalization) 
• 
adverse events (description of the event, causality (related/ not related to Ergoferon), 
severity, date of the onset, and actions taken)  
• 
efficacy assessment of the Ergoferon treatment (high efficacy: recovery / satisfactory: 
improvement/ insufficient: no effect) 

Protocol No. HERMITAGE 
30-Sep-2016 
CONFIDENTIAL  
 
Page 4 of 8 
- observational study model: cohort 
Cohort study is an observation of outcomes in a group of individuals linked by shared 
characteristics (an acute respiratory viral infections and use of Ergoferon).  
Inclusion and exclusion criteria 
Inclusion criteria 
1. Data of children from 6 months to 18 years old and adults over 18 years old. 
2. Diagnosis: Flu/ARVI. 
3. Axillary temperature above 37.4 °С. 
4. At least one systemic and/or catarrhal symptom lasting 12 hours to 3 days by the time the 
doctor is consulted, for which treatment with Ergoferon is prescribed.  
5. A specific decision of the doctor to prescribe Ergoferon in strict accordance with the 
indications, regardless of the factor of including patient data in the program. 
6. CRF, filled by a doctor on the basis of medical documentation, at the end of patient 
observation. 
Exclusion criteria 
1. Use for the treatment Flu/ARVI antiviral and immunomodulatory therapy except for 
Ergoferon. 
Criteria for Withdrawal or Termination 
Not applicable. 
 
Number of subjects 
It is planned to enroll 8411 patients. 
Interim analysis 
An interim statistical analysis is not scheduled within the study. 
Treatment 
 
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: Oral administration in the therapeutic dosage specified in the 
instructions for medical use. 

Protocol No. HERMITAGE 
30-Sep-2016 
CONFIDENTIAL  
 
Page 5 of 8 
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 
The duration of the treatment course will be determined by the physician based on the registered 
indications, general clinical experience and treatment tolerance. 
Observation period 
The total duration of the program will be approximately 6 months from October 2016 to April 
2017.  
Symptomatic (Standard) treatment 
Not applicable. 
Prohibited concomitant therapy 
Not applicable. 
Study design scheme 
Ergoferon® therapy will be carried out in accordance with the registered indications in a 
therapeutic dosage (treatment regimen) in accordance with the instructions for medical use. 
Inside, oral use. 1 tablet per intake (outside a meal). The tablet should be kept in the mouth 
without swallowing until it is completely dissolved. Children from 6 months. For young children 
(from 6 months to 3 years), it is recommended to dissolve the tablet in a small amount (1 
tablespoon) of boiled water at room temperature. 
Treatment should be started as early as possible when the first signs of an acute infection appear 
according to the following scheme: in the first 2 hours – 1 tablet every 30 minutes, then 3 more 
intakes are taken at regular intervals during the first day. From the second day onwards, take 1 
tablet three times a day until complete recovery. 
 
Schedule of study procedures  
This program does not provide for additional instrumental or laboratory examination of the 
patient, all necessary, from the point of view of the doctor, examinations will be carried out 
within the framework of the existing practice of managing patients with this pathology, 
regardless of participation in it. 

Protocol No. HERMITAGE 
30-Sep-2016 
CONFIDENTIAL  
 
Page 6 of 8 
Statistical Analyses 
 Samples  
Total set includes all the subjects who have signed ICF. This sample will consider all adverse 
events throughout the study, including those occurred prior to the study therapy.  
The sample including all subjects who received at least one dose of the study product to be used 
for analysis of the study treatment safety and tolerability (Safety population), as all adverse 
events identified after the study product administration will be recorded.  
Full Analysis Set This sample will consist of all enrolled subjects, except for those who met at 
least one of the following criteria:  
1) failure to meet inclusion/non-inclusion criteria;  
2) subject failing to take any dose of the study drug; 
3) absence of any data on the subject after the study drug administration.  
This was the best set for the Intention-to-treat method, so it will be used in the Intention-to-treat 
efficacy analysis of the test therapy. 
Data treatment and all statistical calculations under the protocol will be made using SAS-9.4 
statistical software.2 
Evaluation of sample size 
The sample size was prespecified. 
Statistical criteria  
All statistical calculations will be made using two groups of statistical criteria:  
 
parametric - to evaluate continuous and interval random values;  
 
nonparametric – to obtain: 
 evaluations of equality/inequality of proportions of the subjects upon their comparison 
for various visits,  
 analysis of frequencies of the features compared, 
and 
 evaluation of continuous and interval random values in case of non-compliance with 
normal random distribution. 
Parametric criteria 
Prior to analysis using parametric statistics, data samples under comparison will be tested for 
normality (the Kolmogorov-Smirnov test). Data normalizing transformations (e.g. Box-Cox, 
Yeo-Johnson etc.) would be applied if necessary. 
The following parameters and approaches are to be used: 
                                                 
2 Holder of license: ООО "NPF "Materia Medica Holding", No. 70100045. 

Protocol No. HERMITAGE 
30-Sep-2016 
CONFIDENTIAL  
 
Page 7 of 8 
1. To evaluate the differences in continuous variables obtained in one group at two different 
visits – Student’s test for matched samples. 
2. To evaluate time changes in parameters compared - analysis of variance (ANOVA) or 
modified repeated measures covariance (ANCOVA).  
3. In case of multiple comparisons of the groups various corrections for multiplicity will be 
used, e.g. Dunnett, Tukey, Scheffe, Holm adapted test, etc.  
4. Generalized Linear Models and/or Mixed Linear Models will be used in case of abnormal 
data distribution.  
5. Selection of the type of distribution, specification of factor and covariance structures of the 
model will be made using fit-statistics such as AIC (Akaike information criterion). 
The following SAS software programs are supposed to be applied to the above listed tests and 
techniques:  
 UNIVARIATE: normality verification of the distributions under comparison; 
 CORR, MEANS - calculation of descriptive statistics 
 TTEST – Student’s test with all modifications;  
 GLM – generalized linear models for analysis of time changes (ANOVA, ANCOVA); 
 GENMOD – generalized linear models. 
 MIXED – mixed linear models. 
Non-parametric criteria 
Below are potential types of comparisons with relevant criteria: 
1. To evaluate time changes in the parameters compared – Friedman test, nonparametric 
analogue of repeated measures analysis of variance. 
2. For frequency analysis of contingency tables 2×2 – χ2 (if the frequency under comparison > 
5) or exact Fisher’s test (if one of the frequencies under comparison < 5).  
3. Cochran-Mantel-Haenszel test (modified χ2 test for multiple comparisons) – to perform 
frequency analysis based on independent strata.  
4. For frequency analysis of data on presence/absence of an event or outcome during repeated 
measurements (contingency tables with dependent strata) – survival analysis.  
To perform the above-mentioned nonparametric statistical analysis the following SAS 
procedures are to be used:  
 FREQ – Friedman test, χ2 test and/or exact Fisher’s test; Cochran-Mantel-Haenszel test. 
 LIFETEST – survival analysis.  
 NPAR1WAY - Mann-Whitney test. 

Protocol No. HERMITAGE 
30-Sep-2016 
CONFIDENTIAL  
 
Page 8 of 8 
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 inference 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.