International Multicenter Double-bind Placebo-controlled Randomized Parallel-group Clinical Trial of Anaferon for Children Efficacy in Prevention of Influenza and Other Acute Respiratory Viral Infections in Children During the Peaks of Seasonal Morbidity
Phase: PHASE4
Conditions: Preventive Medicine
Sponsor: Materia Medica Holding

 
 
 
 
 
 
 
 
 
International multicenter double-blind placebo-controlled 
randomized parallel-group clinical trial of Anaferon for children 
efficacy in prevention of influenza and other acute respiratory viral 
infections in children during the peaks of seasonal morbidity 
 
 
 
 
Phase IV 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-AD-008 
Version date: 
August 23, 2018 
ClinicalTrials.gov Id: 
NCT03301155 
 

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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 Anaferon for children efficacy in prevention of influenza and other acute respiratory viral 
infections in children during the peaks of seasonal morbidity. 
 
Phase: IV 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. MMH-AD-008      
 
Objective of the study  
 
To obtain additional data on the efficacy and safety of 12-week course of therapy with 
Anaferon for children for prevention of influenza and other acute respiratory viral 
infections in children during the peaks of seasonal morbidity. 
Endpoints  
Primary endpoint 
1. 
Time from taking the first dose of the study drug to the onset of influenza/ARVI 
symptoms.   
Secondary endpoints 
1. 
Percentage of children not falling ill with influenza or another ARVI during 4, 8, or 12-
week preventive course (based on medical records).  
2. 
Percentage of children with the symptoms of a respiratory or ear-nose-throat bacterial 
infection requiring antibacterial therapy within 12-week preventive course (based on 
medical records). 
3. 
Percentage of children hospitalized for influenza/ARVI or their complications within 12-
week preventive course (based on medical records). 
 
 

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Safety assessment  
 
Presence and type of adverse events, their severity, relation to investigational drug, 
outcomes. 
Study design  
Design: an international, multicenter, double-blind, placebo-controlled, randomized study in 
parallel groups. 
The study will enroll children of both gender from 1 month to 6 years old. Children can 
participate in the study regardless of the frequency of previous ARVI. A potential study 
participant should not be in the incubation (if known), prodromal, acute /subacute periods of any 
infectious disease (except for the recovery period). Schedule for enrollment of participants: 
during the period of a seasonal rise in influenza/ARVI incidence in the Russian Federation and 
the Republic of Uzbekistan. Screening and randomization of participants will be subject to 
availability of official information on the incidence of influenza/ARVI in the relevant study 
region. 
The doctor makes the first visit to the participant in the medical center or at home. After 
parent/adoptive parent signs the information sheet (informed consent form), the doctor evaluates 
the possibility of the participant being included in the trial. If the child meets all the inclusion 
criteria and does not have all non-inclusion criteria, then he/she is included in the study, the 
doctor fills in the Clinical Research Form. At visit 1 (Day 1), the participant is randomized into 
one of two groups: the 1st group participants will take Anaferon for children according to the 
preventive regimen for 12 weeks; the 2nd group participants will take Placebo according to the 
regimen of Anaferon for 12 weeks.  
In total, the study participant will be observed for 12 weeks (screening and randomization up to 1 
day, preventive treatment for 12 weeks). 
During the observation period at 4 (Visit 2), 8 (Visit 3), and 12 (Visit 4) weeks, three visits are 
planned.  
Visits 2 (Week 4 ± 3 days) and 3 (Week 8 ± 3 days) are conducted in the form of a telephone 
survey of parents/adoptive parents about the participant’s health status, presence/absence of 
symptoms of  influenza/ARVI, possible use of antibacterial drugs and/or hospitalization during 
the course preventive therapy. 
Visit 4 (Week 12 ± 3 days) is carried out at home or in a medical center; the doctor collects 
complaints, examines the participant, registers concomitant therapy, assesses the compliance of 
the therapy. 
 

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If in the period from 2 to 12 weeks a participant falls ill with influenza/ARVI1, then he 
prematurely completes participation in the study (as having reached the primary endpoint). A 
participant is considered fallen ill with influenza/ARVI if the doctor identifies the following 
symptoms: febrile/subfebrile body temperature, presence at least one flu-like nonspecific 
symptom (decreased activity/impaired behavior/weakness; headache; chills) and at least one 
respiratory symptom (runny nose; nasal stuffiness; hoarseness/husky voice; sore throat; cough). 
In this case, the doctor makes an unscheduled visit (at home or in a medical center), which is 
final. During the visit, the doctor carries out the procedures of Visit 4. A nasopharyngeal swab is 
taken to identify the most common pathogens of influenza/ARVI2.  
If ARVI/influenza occurs within the first seven days from the onset of preventive therapy, the 
disease will not be recorded as an adverse event and will not be taken into account to evaluate 
the efficacy of the study drug, since an early manifestation of influenza/ARVI may indicate that 
the participant was included in the study when he/she was in the incubation period of an 
infectious disease. 
During the study, concomitant therapy for underlying chronic conditions, as well as routine 
vaccination of the participant, are allowed, with the exception of the drugs indicated in the 
section “Prohibited Concomitant Treatment”. 
Inclusion and exclusion criteria 
Inclusion criteria 
1. 
Children of either gender aged from 1 month to 6 years old3. 
2. 
The absence of clinical symptoms of any infectious disease, but not earlier than 14 days 
from its onset. 
3. 
Seasonal rise in ARVI incidence, confirmed by official information. 
4. 
An information sheet (Informed Consent form) for the subject participation in the clinical 
trial signed by one parent/adopter of the patient. 
Exclusion criteria 
1. 
Acute or subacute period of infectious disease of any etiology (viral, bacterial, fungal, etc.) 
and localization (including upper and lower respiratory tract infection, meningitis, sepsis, 
otitis media, urinary tract infection, intestinal infection, etc.). 
                                                 
1 The symptoms associated with teething or vaccination (post-vaccination reactions and complications) are not 
considered as manifestations of influenza/ARVI. 
2 PCR-based diagnosis with the AmpliSens Reagent Kit to identify the most common pathogens of ARVI and 
influenza, including (1) Influenza A virus; (2) Influenza B virus; (3) Influenza A (H1N1)pdm, similar to 
A/California/4/2009; (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. 
3 The study participants are aged 1 month to 6 years 11 months and 29 days. 

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2. 
History of (verified previously) or current suspected conditions such as: 
 
primary or secondary immunodeficiency4; 
 
bronchopulmonary dysplasia, primary ciliary dyskinesia, cystic fibrosis, other chronic 
pulmonary diseases; 
 
malformations of the respiratory and ENT organs (ear, throat, mouth, tongue, larynx, 
trachea, neck and salivary and thyroid glands, etc.); 
 
immunopathological diseases (including Marshall syndrome, Behсet's syndrome, 
Kawasaki disease, etc.); 
 
hematological diseases (including agranulocytosis, leukemia); 
 oncologic conditions. 
3. 
Exacerbated or decompensated of chronic diseases affecting the participant's ability to 
participate in the clinical trial. 
4. 
Malabsorption syndrome, including congenital or acquired lactase or another disaccharide 
deficiency, galactosemia. 
5. 
Allergy/intolerance to any component of the study drug. 
6. 
Course administration of the drug products specified in the section ‘Prohibited concomitant 
medications’ within 2 weeks prior to enrollment. 
7. 
Children whose parents/adopter parents will fail to comply with the observation 
requirements of the trial or with the intake regimen of the study drug, from the 
investigator's point of view, 
8. 
Participation in other clinical trials within 3 month prior to enrollment in the study. 
9. 
The patient's parent/adopter parent is a member of the research team of the investigational 
site directly involved in the study or a close relative of an investigator. Close relatives are 
defined as husband/wife, parents, children, brothers (sisters) regardless of whether they are 
biological or adopted. 
10. 
The patient's parent/adopter parent works for OOO "NPF "MATERIA MEDICA 
HOLDING" (i.e., the company's employee, part-time employee under contract or 
appointed official in charge of the trial, or their immediate family). 
Discontinuation criteria  
1. 
Failure or refusal of the child or his/her parents/adopters to comply with the protocol. 
                                                 
4 Primary and secondary immunodeficiencies, regardless of etiology, are characterized by persistent 
immunodeficiency. Transient immunomodulation do not represent immunodeficiency. Children with recurrent 
respiratory infections have transient immunomodulation. High rates of infectious diseases during the first years of 
life should not be considered as a pathology; this condition is not attributable to immunodeficiency and does not 
exhibit negative effect on immunity formation. Such subjects are eligible.  
Subjects with immunodeficiency need complex therapy using the products forbidden within the study. 

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2. 
The necessity to use medications not permitted within the study. 
3. 
An adverse event requiring discontinuation of the investigational product. 
4. 
The desire of the child or parent/adoptive parent to complete the study ahead of schedule 
for any reason. 
5. 
Cases not specified by the protocol, when the investigator decides that the further 
participation may harm the child. 
6. 
Incorrect inclusion of ineligible child. 
7. 
The patient did not pass the screening procedure. 
8. The participant got influenza/ARVI. 
Number of subjects 
1036 participants of both genders aged 1 month to 6 years old (518 participants in each group) 
are planned to be included and randomized in the clinical trial. It is estimated that approximately 
880 children (440 participants in each group) will complete participation in the study in 
accordance with the protocol. 
Interim analysis 
Since the recruitment of participants covers more than one epidemic season, a blind intermediate 
analysis is carried out in each season (without revealing the participant’s membership in one or 
another experimental group) to possibly clarify a priori research parameters. 
Based on the results of a blind interim analysis, a significant difference between the base 
population frequency of the events studied and the planned one will be revealed, the sample size 
of the study is reassessed. 
Treatment 
 
Group 1 
Name of the medicinal product: Anaferon for children  
Active ingredient: affinity purified antibodies to human interferon-gamma – 0.003 g* 
* applied to lactose monohydrate as water ethanol mixture containing no more than 10-16 ng/g of 
active substance  
Excipients: Lactose monohydrate 0.267 g, microcrystalline cellulose 0.03 g, magnesium stearate 
0.003 g 
Method of administration: Tablet for oral use. One tablet per intake, once daily (approximately 
at the same time). 
The product is administered outside a meal (in the interval between meals or 15 min prior to 
meal or fluid intake), the tablets should be held in mouth until complete dissolution. For young 

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children (aged 1 month to 3 years old), the tablet is recommended to be dissolved in a small 
amount (1 tablespoon) of drinking water of  room temperature.  
Dosage form: Tablets.  
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
Storage conditions: Store at temperature below 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 Anaferon for children scheme. 
Dosage form: Tablets.  
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
Storage conditions: Store at temperature below 25оС. Keep out of the reach of children 
 
Treatment duration 
Anaferon for children/Placebo treatment duration is 12 weeks.  
Observation period 
According to the protocol, the child’s participation in the study lasts 12 weeks, including 
screening and randomization (the first day) and the period of study therapy (12 weeks). 
Basic therapy 
During the entire study period, the participant can receive therapy for the underlying and 
concomitant diseases that are not criteria for non-inclusion. 
Prohibited concomitant therapy 
Two weeks prior to enrollment and during the study the following drugs are prohibited: 
1. Antivirals (J05), except for Anaferon for Children prescribed in this trial.  
2. Immunostimulants (L03), including: 
 
interferon inducers (acridonacetic acid, meglumine acridoacetate/cycloferon®, 
umifenovir/arbidol®, kagocel®, tilorone/amixin®, lavomax®, tilaxin®, polyadenylic acid + 
polyuridylic acid/poludan®, oxodihydroacridinylacetate odium/neovir®, ribonucleate 
sodium/ridostin, etc, deoxyribonucleate sodium/derinat® etc.) 
 
interferons 
 
bacterial immunomodulators (including ribomunyl®, IRS-19, imudon®,  
broncho-munl® and etc.) 

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 
pidotimod/imunorix 
 
interleukins 
 
synthetic immunostimulants (levamisole, alpha-glutamyl-triptophan/thymogen, etc.) 
 
thymus hormone-containing drugs 
 
herbal immunostimulants (immunal®, etc.) 
3. Immunosuppressants (L04). 
4. Antineoplastic agents (L01) and hormones (L02). 
5. Immune sera and immunoglobulins (J06). 
6. Fenspiride (R03DX03), omalizumab (R03DX05). 
7. Systemic corticoids (H02AB). 
8. Homeopathic drugs. 
9. Drugs known to cause allergic reactions in the patient. 
 
 
 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
Procedure/visit 
Visit 1 
(Day 1) 
Visit 2  «phone» 
(Week 4±3 days) 
Visit 3 «phone» 
(Week 8±3 days) 
Visit 4  
(Week 12±3 days) 
Obtaining signed informed consent 
+ 
 
 
 
SCREENING 
12 weeks 
Visit 2 
(telephone) 
(Week 4±3 days) 
Visit 4 
(Week 12±3 days) 
RANDOMIZATION 
Group 1:  
Anaferon for children 1 tablet daily during 12 weeks 
Visit 3 
(telephone) 
(Week 8±3 days) 
Visit 1 
(Day 1) 
 
STUDY COMPLETION 
Group 2:  
Placebo 1 tablet daily during 12 weeks 

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form (ICF) 
Eligibility assessment 
+ 
 
 
 
Recording concomitant medications 
+ 
+ 
+ 
+ 
Randomization and prescription of 
study therapy 
+ 
 
 
 
Study drug supply  
+ 
 
 
 
Drug accountability and return, 
assessment of treatment compliance 
 
 
 
+ 
Evaluation of treatment safety 
+ 
+ 
+ 
+ 
Telephone survey 
 
+ 
+ 
 
Collection of nasopharyngeal swabs for 
PCR diagnosis* 
 
* Performed in case the child falls ill with influenza/ARVI during 
unscheduled (additional) visit with Visit 4 procedures  
 
 
Statistical Analysis 
Samples  
Statistical analysis will be carried out in the following sets: 
Total set includes all participants whose parents/adoptive parents signed the Informed Consent 
Form.  
The sample including all enrolled and randomized subjects who received at least one dose of the 
study drug to be used for analysis of safety and tolerability (Safety population), as all adverse 
events identified after the study product administration were recorded.  
Full Analysis Set consists of all enrolled and randomized patients, 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 randomization. 
This is 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. 
Per Protocol set. This sample includes all subjects who completed the therapy as per the study 
protocol, without any missing visits or major protocol deviations. This set will be used in the Per 
Protocol efficacy analysis of the test therapy. 
Evaluation of sample size 
The sample size was assessed in accordance with the following rules and assumptions: 
1. 
Statistical assumptions: 
1.1 
the power of statistical tests 'P = (1 − β)' is 80% (the probability of correct 
rejection of the null hypothesis is 0.8) 

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1.2 
the probability of type 1 error 'a' is less that 5% (the probability of false 
acceptance of the alternative hypothesis is less than 0.05); 
1.3 
statistical criteria of intergroup comparisons will be two-sided;  
1.4 
calculation of sample size is based on the assumptions on the expected effect 
declared in the primary efficacy endpoint; 
1.5 
ratio between Anaferon for children and placebo sample sizes is 1:1 (one 
Anaferon for children subject: one placebo subject). 
1.6 
statistical hypothesis will be as follows: 
null and alternative hypothesis on Anaferon for children superiority using the dosing 
scheme specified: 
H0: T1 – T2≤ Δ 
H1: T1 – T2> Δ, 
in terms of Cox proportional hazard model, 
H0: ln(T1/T2) ≤ δ 
H1: ln(T1/T2) > δ, 
where T1 – median influenza/ARVI time in Anaferon for children group; 
T2 – median influenza/ARVI time in placebo group;  
Δ, δ –minimum clinically relevant effect. 
1.7 
Therefore, sample size will be calculated taking into account 
a. 
Assumption on expected effects declared in the main efficacy criterion; 
1.8 
calculation of sample size for two-sided test for the final analysis will be made 
using the formula: 
 
where n – total sample size of the product and placebo, p1 – proportion of subjects from 
the total sample size in Anaferon for children group, p2 – proportion of subjects from 
the total sample size in placebo group, p1=p2=0.5); b – effect size (calculated as b = 
ln(T1/T2)). δ – minimum clinically relevant effect δ=ln(1+Δ/T2); zα/2 and zβ – relevant 
tabular values of z-test; d – expected proportion of subjects reaching primary endpoint 
during the study. 
1.9 
Final sample size will be determined using the formula:  
NF = NPP / (1 − Кв),  
where NF – final sample size; NPP – result of calculation in cl. 1.8, i.e. scheduled 
number of children completing the study per protocol; Кв – withdrawal coefficient. 
2. 
Assumptions on expected clinical study effects. 

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It was initially suggested that in Anaferon for children group proportion of subjects falling ill 
with ARVI/influenza in 12 weeks (84 days) after the treatment onset will not exceed 65%, in 
placebo group will be at least 80% (conservative estimate based on the study), therefore the 
difference between the study arms will be less than 15%. Minimum clinically relevant difference 
between the groups will be 5%. 
However, due to essential inability to obtain complete data on all the disease cases in all the 
subjects enrolled during the study (data censored, right) and necessity to determine typical time 
to the disease development, we will reformulate the condition on effects in the assumption of 
exponentially distributed disease cases: 
Pi=1-exp(-λiT), 
where Pi – proportion of ill subjects in I group, λi – risk of disease in I group, Т – follow-
up time. 
Therefore, evaluation of risk for experimental groups is defined as  
λi = ln(1-Pi)/(-T), 
median time to the event 
T1/2,i=ln(2)/λi 
At that the expected median time to the disease in placebo group is 36 days, minimum clinically 
relevant difference is 6 days (therefore, minimum median time for superiority is 42 days). The 
scheduled effect is equal to 19 days (median time to the disease in Anaferon for children group is 
55 days). 
Thus, the intended effect in terms of Cox model will be b= ln(56/36) = ln(1.53) = 0.425, 
minimum clinical effect will be δ=ln(42/36)=0.154. Based on the assumptions on the effects we 
will also take the presumed total proportion of subjects falling ill during the study as equal to 
d=0.725. Therefore, sufficient number of influenza/ARVI cases required to reject null hypothesis 
is 437, the total required number of subjects (PP) is 604 (accurate value 602.75). 
As the subject recruitment covers more than one epidemic season, blind interim analysis will be 
made in each season  to assess nuisance parameters of the study.  
According to the above mentioned statistical terms and assumptions, sample size of each group 
for the final analysis will be 302 subjects for each group (РР set is 604 in total). 
Given potential withdrawal of at least 15% of the subjects at the screening and during the study 
for various reasons, at least 355 subjects should be enrolled in each group (710 subjects in total, 
see 1.9). 
Interim analysis 
The analysis is made in accordance with point 2 without unblinding the treatment group. 

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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: 
 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. 
Parametric criteria will be checked for normality of the samples compared (Kolmogorov-
Smirnov test). 
The following parametric methods and approaches are suggested:  
1. 
To evaluate differences in continuous variables obtained in one group at two different 
visits – Student t-test for paired samples. 
2. 
For evaluation of time changes in parameters under comparison – analysis of variance 
(ANOVA) or covariance (ANCOVA) analysis in a modification with repeated 
measurements (Repeated Measures). 
3. 
In the case of multiple comparisons of groups among themselves, various corrections for 
multiplicity will be applied (Dunnett, Tukey, Scheffe, adapted Holm criterion, etc). 
4. 
For more complex data structures, approaches will be used with the construction of 
Generalized Linear Models and / or Mixed Linear Models. 
5. 
Selection of the type of distribution, refinement of the factor and covariance structures of 
the model is carried out using fit statistics, such as AIC (Akaike Information Criterion). 
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 t-test with all modifications 
 
GLM – analysis of general linear models for studying temporal dynamics (ANOVA, 
ANCOVA) 
 
GENMOD – analysis of generalized linear models 
 
MIXED – mixed linear model analysis 
 
PHREG – survival analysis. 

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Nonparametric criteria: 
Below are the main types of possible comparisons with their respective criteria: 
1. 
For evaluation of time changes in parameters under comparison, the Friedman test, a 
nonparametric analogue of variance analysis with repeated measurements. 
2. 
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). 
3. 
For frequency analysis of contingency tables with multiple comparisons – Cochran-
Mantel-Haenszel test (modification of χ2 test for multiple comparisons). 
4. 
For the frequency analysis of data on the presence / absence of an event or outcome during 
repeated measurements (contingency 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 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-9.45 software will be used for statistical analysis including various parametric and 
nonparametric tests. 
                                                 
5 Licensee: LLC NPF Materia Medica Holding, №70100045.