A Multicenter, Double-Blind, Randomized, Parallel Group Study of Safety, Reactogenicity, Immunogenicity, and Efficacy of Quadrivalent Influenza Vaccine Grippol Quadri and Trivalent Influenza Vaccine Grippol Plus in Volunteers.
Phase: PHASE2
Conditions: Influenza
Sponsor: NPO Petrovax

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
1 Sosnovaya St., Pokrov village, 142143, Podolsk District, Moscow Region, Russia
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Multicenter, Double-Blind, Randomized, Comparative Study of Safety, Reactogenicity, 
Immunogenicity, and Efficacy of Quadrivalent Inactivated Subunit Influenza Vaccine Grippol® 
Quadri (NPO Petrovax Pharm, LLC, Russia) and Trivalent Inactivated Polymer-Subunit 
Vaccine Grippol® Plus (NPO Petrovax Pharm, LLC, Russia) in Parallel Groups, in Volunteers 
of 18 to 60 Years Old. 
Study ID: GriQv-III-16  
Version of study protocol: 3.0 dated November 18, 2016  
Study phase: Phase II-III 
Study Drug: 
Grippol® Quadri, a quadrivalent inactivated subunit influenza vaccine 
INN or generic name: Influenza vaccine [inactivated] + Azoximer bromide 
Dosage form: suspension for intramuscular and subcutaneous injection. 
Dosage: 0.5 mL (1 dose), active ingredients: type A (H1N1) influenza virus antigen (5 µg), 
type A (H3N2) influenza virus antigen (5 µg), type B (Yamagata lineage) influenza virus 
antigen (5 µg), type B (Victoria lineage) influenza virus antigen (5 µg), and 500 µg of 
Polioxidonium® (Azoximer bromide) 
Manufacturer: NPO Petrovax Pharm, LLC 
Study sponsor: NPO Petrovax Pharm, LLC (1 Sosnovaya St., village of Pokrov, Podolsk district, 
Moscow region, Russia, 142143) Tel/fax: +7 (495) 926-21-07 
 
Confidentiality 
The information contained in this document, especially unpublished data, is the property of NPO Petrovaks Farm, 
LLC (or is under its control) and, therefore, is passed to you — to an investigator, a possible investigator, or  
consultant — under the condition of strict confidentiality to be read by you or your staff, and to Regulatory 
authorities. 
It should be understood that this information cannot be passed to other persons without a written consent from 
NPO Petrovaks Farm, LLC, except for the part that is necessary to obtain informed consent from persons to whom 
the investigational drug may be prescribed. 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
1 Sosnovaya St., Pokrov village, 142143, Podolsk District, Moscow Region, Russia
 
Page 2 of 74 
 
SIGNATURE / APPROVAL PAGE  
(PRINCIPAL INVESTIGATOR, SPONSOR) 
INVESTIGATOR INFORMED CONSENT 
I, 
_____________________________________________________________________________ 
investigator, have reviewed the following protocol provided by NPO Petrovax Pharm, LLC designed 
for the clinical study: Code GriQv-III-16 version dated November 18, 2016 "Multicenter, Double-
Blind, Randomized, Comparative Study of Safety, Reactogenicity, Immunogenicity, and Efficacy of 
Quadrivalent Inactivated Subunit Influenza Vaccine Grippol® Quadri (NPO Petrovax Pharm, LLC, 
Russia) and Trivalent Inactivated Polymer-Subunit Vaccine Grippol® Plus (NPO Petrovax Pharm, 
LLC, Russia) in Parallel Groups, in Volunteers of 18 to 60 Years Old," phase II-III. I affirm that this 
protocol contains all the information necessary to conduct this study. 
I understand that this protocol contains confidential information, which is the property of NPO 
Petrovaks Farm, LLC. I have discussed the objectives of this clinical trial and the content of this 
protocol in full with the representative(s) of the Sponsor. 
I agree to conduct this clinical study in accordance with this protocol, to comply with all the 
requirements of the protocol and all ethical standards and safety matters regarding the drug. 
I understand that the sponsor may decide to prematurely terminate or suspend the study at any time 
and for any reason, and I will be notified about such a decision in writing. If I decide to terminate my 
participation in this clinical study, I will immediately notify the sponsor in writing. 
 
PRINCIPAL INVESTIGATOR  
FULL NAME _______________________ 
Date: _____________  __, 20 __  
SPONSOR'S REPRESENTATIVE 
FULL NAME _______________________ 
Date: _____________  __, 20 __  
 
 
 
Signature______________________ 
 
 
Signature______________________ 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
1 Sosnovaya St., Pokrov village, 142143, Podolsk District, Moscow Region, Russia
 
Page 3 of 74 
 
RESPONSIBLE STUDY PERSONNEL 
 
Sponsor: 
NPO Petrovax Pharm, LLC 
1, Sosnovaya St., Pokrov village, Podolsky District, 
Moscow Oblast, 142143  
President: Arkhangleskaya E. V. 
Sponsor's 
representatives: 
Chirun Natalya Vladimirovna — PhD 
Medical Director of the Medical Department 
NPO Petrovax Pharm, LLC 
Tel.: (495) 730-75-45 (+125) mob.: +7-917-579-57-18 
e-mail: ChirunNV@petrovax.ru 
22, Krasnaya Presnya Str., 123022, Moscow, Russia 
Vera Anatolievna Apryatina, PhD, Head of Clinical Trial Team, Medical 
Affairs Department 
NPO Petrovax Pharm, LLC 
Tel./fax: (495) 744-29-69 (+131), (495) 730-75-45 (+193) 
Mob.: +7-916-220-45-95 
e-mail:ApryatinaVA@petrovax.ru 
24, bldg. 2, Kashirskoye Rd, 115478, Moscow, Russia 
22, Krasnaya Presnya Str., 123022, Moscow, Russia 
Shishimintseva Anastasia Alexandrovna – clinical study monitor of the 
Medical Department 
NPO Petrovax Pharm, LLC 
Tel.: (495) 730-75-45 (+179) mob.: +7-916-385-59-87 
e-mail: ShishmintsevaAA@petrovax.ru 
22, Krasnaya Presnya Str., 123022, Moscow, Russia 
Anna Victorovna Tsymbal — Safety and Pharmacovigilance Specialist, 
Medical Affairs Department 
NPO Petrovax Pharm, LLC 
Tel.: (495) 730-75-45 (+114) 
e-mail: TSymbalAV@petrovax.ru 
22, Krasnaya Presnya Str., 123022, Moscow, Russia 
Trial sites, principal 
investigator, 
laboratories: 
The list of clinical centers participating in this clinical study (indicating the
address and telephone numbers of clinical centers, the name and position of
investigators responsible for conducting the study), detailed information about
the principal investigator, as well as information about central and local
laboratories are presented in a separate document. 
In case of serious 
adverse events, please 
notify: 
Anna Viktorovna Tsymbal 
Tel.: 8-800-234-44-80 
Tel.: (495) 730-75-45 (+114) 
e-mail: TSymbalAV@petrovax.ru 
22, Krasnaya Presnya Str., 123022, Moscow, Russia 
Ethics Board of the MH RF Tel.: (495) 625-44-21 
3, Rakhmanovsky per., 127994, Moscow, Russia 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
1 Sosnovaya St., Pokrov village, 142143, Podolsk District, Moscow Region, Russia
 
Page 4 of 74 
 
CONTENTS 
 
SIGNATURE / APPROVAL PAGE  (PRINCIPAL INVESTIGATOR, SPONSOR) ....................................... 2 
RESPONSIBLE STUDY PERSONNEL ......................................................................................................... 3 
ABBREVIATIONS ........................................................................................................................................ 7 
SYNOPSIS ..................................................................................................................................................... 8 
1. 
STUDY RATIONALE .......................................................................................................................... 17 
1.1. Name and description of study drugs .............................................................................................. 17 
1.2. The results of nonclinical and clinical studies relevant to this study. ............................................... 19 
1.3. Known and potential risks and benefits for study subjects ............................................................... 25 
1.4. Description and justification of the mode of administration, dosage, dosage regimen, and course of 
treatment ....................................................................................................................................... 27 
1.5. Indication that this clinical trial will be conducted in accordance with the protocol, these rules, and 
regulatory requirements. ................................................................................................................ 28 
1.6. Description of study population ...................................................................................................... 28 
1.7. References to literary sources and data relevant to the study that constitute the rationale for this  
study. ............................................................................................................................................ 28 
2. 
OBJECTIVES AND PURPOSES OF THE STUDY .............................................................................. 29 
3. 
STUDY DESIGN .................................................................................................................................. 30 
3.1. Primary and additional study parameters that will be evaluated during the study ............................. 30 
3.2. Description of the type / design of the study and a schematic representation of its design, procedures, 
and stages ...................................................................................................................................... 31 
3.3. Measures for minimization / elimination of subjectivity .................................................................. 37 
3.3.1. Randomization ....................................................................................................................... 37 
3.3.2. Blinding ................................................................................................................................. 38 
3.4. The treatment used in the study, dosages, regimens, dosage form, packaging, labeling, and storage of  
study drugs .................................................................................................................................... 38 
3.5. The duration of participation of subjects in the study, a description of the sequence and duration of all  
study periods ................................................................................................................................. 42 
3.6. “Rules of discontinuation” and “Exclusion criteria” for individual subjects, parts of a study or study 
in general ...................................................................................................................................... 42 
3.7. Procedure for study drug accountability .......................................................................................... 44 
3.8. Storage of randomization codes and unblinding procedures ............................................................ 44 
3.9. The list of all data recorded directly in the CRF and considered as source data ............................... 45 
4. 
SELECTION AND EXCLUSION OF STUDY SUBJECTS .................................................................. 45 
4.1. Subject inclusion criteria ................................................................................................................ 45 
4.2. Subject non-inclusion criteria ......................................................................................................... 46 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
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Medicinal product: Grippol Quadri:
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Page 5 of 74 
4.3. Subject exclusion criteria ............................................................................................................... 47 
5. 
TREATMENT (VACCINATION) OF SUBJECTS................................................................................ 48 
5.1. Treatment (vaccination) with study drugs ....................................................................................... 48 
5.2. Drugs / treatments that are permitted or not permitted before and / or during the study.................... 49 
5.2.1. Contraindicated drugs and treatments ..................................................................................... 49 
5.2.2. Permitted drugs and treatments ............................................................................................... 49 
5.3. Methods of control of compliance with procedures ans subjects...................................................... 49 
6. 
EFFICACY EVALUATION ................................................................................................................. 50 
6.1. List of efficacy parameters ............................................................................................................. 50 
6.2. Methods and terms of evaluation, recording and analysis of efficacy parameters ............................. 50 
7. 
SAFETY EVALUATION...................................................................................................................... 52 
7.1. Review of the safety parameters ..................................................................................................... 52 
7.2. Methods and terms of evaluation, recording, and analysis of safety parameters ............................... 52 
7.3. Reporting requirements, procedures for recording and reporting of adverse events and intercurrent 
diseases ......................................................................................................................................... 56 
7.3.1. Recording of adverse events ................................................................................................... 56 
7.3.2. Serious adverse events............................................................................................................ 58 
7.3.3. The investigator's responsibilities for submission of reports on serious adverse events ............ 59 
7.3.4. The sponsor's responsibilities for submission of SUADR reports and other safety reports ....... 60 
7.3.5. Pregnancy .............................................................................................................................. 62 
7.4. The method and duration of observation of subjects after the occurrence of adverse events ............. 62 
8. 
STATISTICAL ASPECTS OF CLINICAL STUDY .............................................................................. 63 
8.1. Description of statistical methods ................................................................................................... 63 
8.2. Planned number of subjects ............................................................................................................ 66 
8.3. Significance level ........................................................................................................................... 68 
8.4. Statistical criteria for suspension and discontinuation of study ........................................................ 68 
8.5. Selection of study subjects ............................................................................................................. 68 
8.6. Procedures for recording missing, falsified data and data that cannot be analyzed. .......................... 68 
8.7. Procedures for communication on any deviations from the initial statistical plan............................. 69 
9. 
DIRECT ACCESS TO SOURCE  DATA / DOCUMENTS ................................................................... 69 
10. QUALITY CONTROL AND ASSURANCE ........................................................................................ 69 
11. ETHICAL ASPECTS ........................................................................................................................... 70 
11.1. Helsinki Declaration of the World Medical Association .................................................................. 70 
11.2. Approval by the regulatory authorities ............................................................................................ 71 
11.3. Approval by the LEC of a medical institution ................................................................................. 71 
11.4. Informed consent for study participation......................................................................................... 71 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
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Page 6 of 74 
12. DATA PROCESSING AND RECORD KEEPING ............................................................................... 72 
12.1. Baseline data and comparison with baseline data ............................................................................ 72 
12.2. Study archive in the trial site .......................................................................................................... 72 
12.3. Confidentiality of study subject's data............................................................................................. 72 
12.4. Disclosure ...................................................................................................................................... 73 
13. FINANCING AND INSURANCE ........................................................................................................ 74 
13.1. Financing ....................................................................................................................................... 74 
13.2. Insurance ....................................................................................................................................... 74 
14. PUBLISHING OF CLINICAL STUDY RESULTS............................................................................... 74 
 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
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Page 7 of 74 
 
ABBREVIATIONS 
 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
VAS 
Visual Analog Scale 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
HA 
Hemagglutinin 
DBP 
Diastolic Blood Pressure 
BMI 
Body Mass Index 
CRF 
Case report form 
CRO 
Contract Research Organization 
LDH 
Lactate Dehydrogenase 
LEC 
Local Ethics Committee 
INN 
International Non-Proprietary Name 
MoH 
Ministry of Health 
NSAID 
Non-Steroid Anti-Inflammatory Drug 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
POx 
Polyoxidonium® 
HAIR 
Hemagglutination Inhibition Assay 
SBP 
Systolic Blood Pressure 
GMAT 
Geometric Mean Antibody Titer 
SUADR 
Serious Unexpected Adverse Drug Reaction 
SAE 
Serious Adverse Event 
ESR 
Erythrocyte Sedimentation Rate 
CNS 
Central nervous system 
HD 
Human Dose 
AP 
Alkaline phosphatase 
ECG 
Electrocardiography 
CPMP 
Committee for Proprietary Medicinal Products 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IWRS 
Interactive web response system 
Ig 
Immunoglobulin 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
1 Sosnovaya St., Pokrov village, 142143, Podolsk District, Moscow Region, Russia
 
Page 8 of 74 
 
SYNOPSIS 
 
Study Title 
A Multicenter, Double-Blind, Randomized, Comparative Study of Safety,
Reactogenicity, Immunogenicity and Efficacy of Quadrivalent Inactivated
Subunit Influenza Vaccine Grippol® Quadri (NPO Petrovax Pharm, LLC, Russia)
and Trivalent Inactivated Polymer-Subunit Vaccine Grippol® Plus (NPO
Petrovax Pharm, LLC, Russia) in Parallel Groups, in Volunteers of 18 to 60
Years Old. 
Study Design 
A multicenter, double-blind, randomized, comparative study in parallel groups. 
Clinical study phase
Phase II-III 
Number of 
investigation sites 
The list of clinical centers participating in this clinical study (with addresses and
telephone numbers of clinical centers, names and positions of investigators
responsible for conducting the study) is presented in a separate document. Up to
6 study centers in the Russian Federation are to participate in the study. 
Study Drug 
Name: Grippol® Quadri, a quadrivalent inactivated subunit influenza vaccine 
Dosage form: suspension for intramuscular and subcutaneous injection. 
Dosage: 0.5 ml (1 dose) 
Active ingredients: 
- type A (H1N1) influenza virus antigen 5 µg; 
- type A (H3N2) influenza virus antigen 5 µg; 
- type B (Yamagata lineage) influenza virus antigen 5 µg; 
- type B (Victoria lineage) influenza virus antigen 5 µg; 
- immunoadjuvant Polyoxidonium® (azoximer bromide) 500 µg.  
Administration route: intramuscular or deep subcutaneous injection  
Sponsor: NPO Petrovax Pharm, LLC 
Manufacturer: NPO Petrovax Pharm, LLC 
Comparators 
Name: Grippol® Plus, trivalent inactivated polymer-subunit influenza vaccine
containing Yamagata lineage type B influenza virus antigen. 
Dosage form: suspension for intramuscular and subcutaneous injection. 
Dosage: 0.5 ml (1 dose) 
Active ingredients: 
- type A (H1N1) influenza virus antigen 5 µg; 
- type A (H3N2) influenza virus antigen 5 µg; 
- type B (Yamagata lineage) influenza virus antigen 5 µg; 
- immunoadjuvant Polyoxidonium® (azoximer bromide) 500 µg.  
Administration route: intramuscular or deep subcutaneous injection  
Sponsor: NPO Petrovax Pharm, LLC 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
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Page 9 of 74 
 
Manufacturer: NPO Petrovax Pharm, LLC 
Name: Grippol® Plus, trivalent inactivated polymer-subunit influenza vaccine
containing Victoria lineage type B influenza virus antigen. 
Dosage form: suspension for intramuscular and subcutaneous injection. 
Dosage: 0.5 ml (1 dose) 
Active ingredients: 
- type A (H1N1) influenza virus antigen 5 µg; 
- type A (H3N2) influenza virus antigen 5 µg; 
- type B (Victoria lineage) influenza virus antigen 5 µg; 
- immunoadjuvant Polyoxidonium® (azoximer bromide) 500 µg.  
Administration route: intramuscular or deep subcutaneous injection  
Sponsor: NPO Petrovax Pharm, LLC 
Manufacturer: NPO Petrovax Pharm, LLC 
Number of subjects 
The total number of volunteers who will receive the study vaccines is 612 (taking
into account the possible 5 % of volunteers whose data cannot be evaluated). 
It is planned to obtain data on the primary efficacy endpoint that would be
measurable in at least 579 volunteers (193 volunteers in each treatment group). 
Accounting for the possible dropout of volunteers at the screening stage (about
25 %), it is planned to obtain a permission from the Ministry of Health of the
Russian Federation to conduct a clinical study with a total of up to 765 
volunteers. 
Study Objective 
The objective of this study was assessment of safety, reactogenicity,
immunogenicity, and efficacy of quadrivalent inactivated subunit influenza
vaccine Grippol®  Quadri (NPO Petrovax Pharm, LLC, Russia) versus trivalent
inactivated polymer-subunit vaccine Grippol® Plus (NPO Petrovax Pharm, LLC,
Russia) in subjects from 18 to 60 years old. 
Purposes of the 
Study 
1)
Study and comparative assessment of immunogenicity of quadrivalent
inactivated subunit influenza vaccine Grippol® Quadri versus trivalent
inactivated polymer-subunit vaccine Grippol ® Plus in subjects from 18 to
60 years old. 
2) 
Safety and reactogenicity assessment of quadrivalent inactivated subunit
influenza vaccine Grippol® Quadri versus trivalent inactivated polymer-
subunit vaccine Grippol® Plus in subjects from 18 to 60 years old. 
3) 
Study and comparative assessment of immunogenicity of quadrivalent
inactivated subunit influenza vaccine Grippol® Quadri versus trivalent
inactivated polymer-subunit vaccine Grippol® Plus in subjects from 18 to
60 years old. 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
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Page 10 of 74 
 
Treatment groups 
Group А: quadrivalent inactivated subunit influenza vaccine Grippol®  Quadri,
suspension for intramuscular and subcutaneous injections. 
Group B: Grippol® Plus, trivalent inactivated polymer-subunit influenza vaccine,
based on type B influenza virus of Yamagata lineage, suspension for
intramuscular and subcutaneous injections. 
Group C: Grippol® Plus, trivalent inactivated polymer-subunit influenza vaccine,
based on type B influenza virus of Victoria lineage, suspension for intramuscular
and subcutaneous injections. 
Dosing: All the vaccines used in the study are administered as a single
intramuscular injection of 0.5 ml (1 dose) into the upper third of the outer surface
of the shoulder (the deltoid muscle). 
Study duration 
Proposed study duration — 12 months: 
 
Proposed enrollment period — 3 months. 
 
Duration of vaccination period — once (1 day). 
 
Duration of observation period – 180±5 days. 
Visits 
Visit 0 (Days [-3] to [0], inclusion of volunteer into the study, 
assessment of baseline characteristics)  
Visit 1 (Day 0 — vaccination) 
Visit 2–7 (Days 1–22±1 — follow-up) 
Visit 8–11 (Days 43±5–180±5 — telephone calls) 
Methodology 
Study diagram and the order of examinations are presented 
on Figure 1 and in Table 2. 
Within 1–3 days after signing the informed consent, the volunteers will undergo
screening laboratory investigations, and baseline data will be assessed during
physical examination. Upon the screening period and the final confirmation of
compliance with all eligibility criteria, volunteers will be randomized into study
groups of intramuscular injection of 0.5 ml of one of the three study vaccines.
After the vaccination, the volunteers remained under the observation of
investigating physician for 2 hours. The frequency of measurements of vital
functions, body temperature, local and general reactions after vaccination are
described in the procedure table. The volunteers were given diaries for daily
records of the body temperature, concomitant therapy, and adverse events.
Follow up of volunteers includes 7 outpatient visits (up to Day 22±1 post
immunization) and 4 telephone calls (up to Day 180±5 post immunization). 
Randomization: 
The immunization group was determined randomly. Randomization will be
based on a computer-generated randomization algorithm (randomization list),
where each volunteer will be assigned a randomization number. That number
will define the immunization group (A, B, or C) according to the randomization
plan. That number will be assigned to the study subject for the entire period of
the study and will be documented in volunteer's CRF. 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
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Page 11 of 74 
 
The volunteers will be randomized into 3 groups (at a ratio of 1:1:1). 
A block randomization method is used. An interactive web-response system
(IWRS) with technical support service will be used for randomization. 
Investigators will be trained on working with IWRS system, and IWRS user
guide will be handed out to all of them. 
An identification name (ID) and a password will be used to access the system.
These identifiers will be given to the authorized staff member of the investigation
site prior to study initiation. Upon the volunteer randomization, the investigator
receives information through the IWRS system on volunteer assignment to one of
the vaccination groups that will be given to the volunteer during the study. 
Volunteer stratification (by gender and age) will be made in the IWRS system for
uniform assignment to groups. 
Inclusion criteria 
1. Signed and dated volunteer's informed consent for participation in the study.
2. Men and women from 18 to 60 years old. 
3. Healthy volunteers without signs of acute or chronic disorders, without
history of chronic respiratory, cardiovascular, nervous system disorders,
hepatic or renal disorders. 
4. Previously not immunized, or previous influenza immunization occurring ≥ 
12 months before this study. 
5. Subjects without history of influenza within ≥ 12 months before this study. 
6. Consent of volunteers (men and women) to use adequate methods of
contraception (cervical caps with spermicide, diaphragms with spermicide,
condoms with spermicide, intrauterine devices, oral contraceptives) or full
abstinence for the whole period of the study. 
Non-Inclusion 
criteria 
Specific: 
1. Contraindications listed in the protocol and prescribing information for
inactivated influenza vaccines: 
- acute infections and non-communicable disorders, including the period of
reconvalescence of at least one month from the time of clinical and
laboratory evidence of recovery; 
- hepatitis or meningococcal infection occurred less than 6 months after
recovery; 
- exacerbations of chronic disorder or decompensated disorders that may
impact the study (organic central nervous system disorders, decompensated
cardiovascular disorder, acute renal or hepatic failure); 
- malignant neoplasms (including hematological disorders); 
- primary immunodeficiency (laboratory-confirmed); 
- HIV infection or HIV-associated disorders; 
- systemic disorders of connective tissue; 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
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- haemophilia (and other blood coagulation disorders); 
- severe neurological disorders; 
- Guillain–Barré 
syndrome 
(post 
infection 
demyelinating
polyradiculoneuropathy of autoimmune nature with peripheral limb
muscle palsy related to inflammation and destruction of myelin sheath of
peripheral nerves; may acquire an ascending nature, involving muscles of
face, pharynx, larynx); 
- history of severe vaccine-associated reactions (body temperature
exceeding 38.5 °С) or local reactions (hyperemia and/or oedema at the site
of injection of over 5 cm in diameter); 
- history of severe allergic disorders (angioedema, polymorphic exudative
erythema, serum disease, etc.); 
- hypersensitivity to chicken protein or vaccine components; 
- blood and components transfusion within the last 6 months. 
2. Indications for immunomodulating therapy. 
3. Body temperature over 37.0 °С at screening or before injection. 
4. Potential evidence of a chronic infection (periodic episodes of fever within
the last 6 months), or antiviral (and/or antibacterial) treatment indicated. 
5. History of disorders or conditions, which, according to investigator's
judgment may impact the thermal regulation (chronic infections,
neuroendocrine 
disorders 
[thyrotoxicosis, 
pheochromocytoma, 
etc.],
climacteric syndrome, malignant hyperthermia, CNS disorders, malignant
neoplasm, connective tissue disorders, systemic vasculitis, and information
on excessive physical stress or work-rest regimen deviations [within the last
2 months: night shifts, significant change of time zones, overheating]). 
6. Use of antipyretics (including non-steroidal anti-inflammatory drugs and
anilides) within 24 hours before randomization. 
7. Surgical interventions within less than 90 days before the screening visit. 
8. Systolic blood pressure of over 130 mm Hg or less than 100 mm Hg and/or
diastolic blood pressure of over 90 mm Hg or less than 60 mm Hg. 
9. Any other disorder, which, in the opinion of the investigator, may prevent
inclusion of the volunteer due to safety reasons or may impact the study
results. 
General: 
10. Pregnant and nursing women. 
11. Lack of ability to visit daytime inpatient facility according to the study
schedule, unavailability for adequate follow-up of the volunteer. 
12. Body mass index of less than 18.5 or over 30.0 kg/m2 based on the weight-
height Quetelet's index. 
13. Participation in another clinical study of medicinal drugs within 3 months
before the start of this study. 
14. Mental, physical, or other reasons which prevent adequate assessment of
own behavior and prevent from meeting the study protocol conditions. 
15. History of narcotic and/or drug abuse, and/or inhalant addiction, current
signs of alcoholic intoxication. 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
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Page 13 of 74 
16. Intake of at least 5 alcohol units per week or history of alcohol, drug, or
medicinal product abuse. One alcohol unit corresponds to 360 ml of beer,
120 ml of wine, or 30 ml of a strong alcoholic beverage. 
17. Suspected lack of compliance with treatment or inability to undergo
treatment and observe the limitations according to the study protocol. 
18. Volunteers acknowledged by the court to be disabled or under guardianship.
12. Any other conditions that make the volunteer ineligible for the study
according to a justified opinion of the study doctor or Sponsor. 
Criteria of volunteer
drop out from the 
study 
Early withdrawal of the volunteer from the study is possible at any time. The 
study doctor shall withdraw subjects from the study continuation in the following 
cases: 
 Informed consent recall. 
 Occurrence of a severe AEs or serious adverse events. 
 The volunteer is found to meet any of the non-inclusion criteria related to the
safety of the volunteer participation in the study. 
 If a female-volunteer becomes pregnant. 
 The volunteer takes medicines not allowed in this study. 
 The volunteer is lost to follow-up. 
 In a situation which, in investigator's opinion, may adversely impact the
volunteer if he/she continues participation in the study. 
 For administrative reasons (study termination by the Sponsor or regulatory
authorities) or in case of major protocol violations which may significantly
impact the study results. 
Not allowed 
concomitant therapy
During the study, volunteers must not receive: 
 only at screening and on the day of immunization: 
- 
antipyretics (including non-steroidal antiinflammatory drugs and 
anilides); 
- 
any drugs or food supplements which, according to the investigator's 
judgment, may affect the body temperature of the volunteer (including 
caffeine);  
- 
physiotherapeutic procedures. 

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 For the whole period of the study: 
- 
medicinal products suppressing central nervous system functions
(barbiturates, opiates, sedative drugs), tranquilizers, neuroleptics, tricyclic
antidepressants etc.; 
- 
cytotoxic drugs; 
- 
anticoagulants (including warfarin), antiagregants (including clopidogrel,
acetylsalicylic acid). 
Hormonal contraceptives or hormone replacement therapy is only allowed if the
female volunteer has been on a stable dosing regimen maintained for at least 6
months before the screening visit and remains on a stable dosing regimen for the
whole study period. 
Immunogenicity and 
efficacy endpoints 
Primary:  
 The share of subjects achieving seroconversion (the number of volunteers
with antibody titer [of at least 1:40] increased more than 4-fold versus
baseline [assessed by HAIR]) for antigens: influenza virus type А —
H1N1, influenza virus type А — H3N2, influenza virus type В —
Yamagata and Victoria lineage, based on assessment at Day 21 after
immunization (Visit 7). 
Secondary:  
 Coefficient of increase of mean geometric antibody titer (antigens H1N1,
H3N2, Yamagata and Victoria lineages) 
based on assessment data after 21 days following vaccination (visit 7). 
 Geometric mean of serum antibodies to antigens: influenza virus type А —
H1N1, influenza virus type А — H3N2, influenza virus type В —
Yamagata and Victoria lineage, based on assessment at Day 21 after
immunization (Visit 7). 
 Seroprotection: share of subjects achieving protective antibody titer (1:40
and more) to antigens H1N1, H3N2, Yamagata and Victoria lineage, based
on assessment at Day 21 after immunization (Visit 7). 
 Incidence of influenza and ARI based on assessment 180±5 days after
immunization (Visit 11). 
 Severity and duration of reported cases of influenza and ARI,
complications. 
Safety and 
reactogenicity 
parameters 
 Quantitative assessment and nature (severity and duration) of local and 
systemic reactions to vaccine administration. 
 AEs and SAEs associated with the study vaccines. 
 Immediate type AEs, emerging within one hour after immunization. 
 Incidence and nature of intercurrent disorders 
 Vital function assessment results. 
 Results of physical examination. 
 Neurological examination results. 
 Results of blood hematology and biochemistry tests. 

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 Urinalysis results. 
 Immunological parameters evaluation results: serum immunoglobulin content 
(ELISA: IgE). 
Statistical analysis 
See Section 8 of the protocol. 
Determining the 
sample size 
For details see Section 8 of the protocol. 
Calculation of the sample size was performed based on the primary endpoint, the
share of subjects achieving seroconversion according to the evaluation at Day 21
after immunization (Visit 7), and testing of the statistical hypothesis of non-
inferiority of the test vaccine (Grippol® Quadri) versus the reference vaccine
(Grippol® Plus). 
The following non-inferiority margin was used for comparative evaluation of
immunogenic efficacy in the non-inferiority model: 
- upper limit of the two-sided 95 % confidence interval of the difference between
parameters (R-T) of subjects achieving seroconversion in the study quadrivalent
vaccine and reference trivalent vaccine groups shall not exceed 15 %. This value
is selected based on the minimum threshold for influenza vaccines > 40 % of
individuals with seroconversion, established  harmonization requirements for
influenza vaccine of the Committee for Proprietary Medicinal Products (CPMR),
as well as the expected level of seroconversion in comparison groups over 60 %. 
For testing of non-inferiority null hypothesis for Grippol® Quadri and Grippol®
Plus vaccines, taking into account the following parameters: 
 Power: 80 % 
 One-sided significance level: 2.5 % 
 Non-inferiority margin: 15 % 
 Expected share of subjects achieving seroconversion in Grippol® Plus 
group: 60 % 
 Expected actual difference for the parameter in groups: 1 % 
according to the calculation using software package PASS 12, each treatment
group shall have at least 193 volunteers (579 volunteers in total). 
Taking into account the dropout during the study (5 %), the required number of 
volunteers has to be increased to 204 per group (612 in total). Taking into account 
the possible dropout of 25 % of volunteers, up to 765 volunteers are planned to be 
screened during the screening. 
Intermediate data 
analysis 
Not applicable. 
 
 

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Ethical and legal 
aspects 
The study will be conducted in accordance with the Constitution of the Russian 
Federation; the current version of the Federal Law of the Russian Federation of 
April 12, 2010 No. 61-FZ “On Circulation of Medicines”; the current version of 
the Federal Law of the Russian Federation of November 21, 2011 No. 323-FZ 
“Basics of Health Protection of the Citizens in the Russian Federation” 
Guidelines for the Expertise of Medicines (Volume 1.- M .: Grif and K, 2013, p. 
328); GOST R52379-2005 "Good Clinical Practice"; the ethical principles of the 
Helsinki Declaration of the World Medical Association, last revision; 
Government Decree of the Russian Federation of September 13, 2010 No. 714 
“On approval of the Typical rules for compulsory insurance of the life and health 
of a Patient involved in Clinical Trials of a medicinal product” (as amended on 
September 4, 2012); Government Decree of the Russian Federation of May 18, 
2011 No. 393 “On Amendments to the Model Rules for Mandatory Life 
Insurance of a Patient Participating in Clinical Studies of a medicinal product”; 
Order of the Ministry of Healthcare and Social Development of Russia dated 
August 23, 2010 No. 703n “On approval of the reporting form on completion, 
suspension or termination of a clinical trial of a medicinal product for medical 
use”; By order of the Ministry of Health of the Russian Federation dated 
February 8, 2013 No. 58n "On approval of the Regulation on the Ethics Council 
in the field of circulation of medical devices." 
 

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1. STUDY RATIONALE 
1.1. Name and description of study drugs 
Seasonal epidemics of influenza are still a significant public health issue associated with 
significant morbidity and mortality rates in different parts of the globe every year. The illness in 
human is caused by influenza viruses types A/H1N1, A/H3N2, and В. International surveillance over 
influenza demonstrates that seasonal viruses can actively migrate between hemispheres and 
continents. Droplet transmission and high variability of influenza virus poses the whole world 
population at threat as a new variant of the virus emerges in any part of the globe: as it can be seen 
from the practical experience, the virus rapidly spreads within just a few months [1, 2]. 
Influenza A and B viruses belong to orthomixoviruses; however, A strains can infect both 
humans and animals, and birds, while type B is only virulent for humans. Concurrent circulation of 
type A and B influenza viruses in the community has been documented since the 1970s, which 
formed the basis for recommendation of composition of seasonal influenza vaccines based on three 
influenza strains — two A and one B. It has long been conjectured that B influenza virus is 
significantly less virulent and does not cause serious illness or large epidemics, unlike type A viruses. 
Since 1985, experts isolated two phylogenetic lineages of type B virus strains with different antigens 
— Victoria and Yamagata lineages — circulating in different seasons or simultaneously within one 
epidemic period [3]. According to requirements to influenza vaccines, the composition of seasonal 
vaccines still included only one strain of type B virus, which did not always match the seasonal 
circulating strain or both viruses circulated within one epidemiological season. It led to suboptimal 
effectiveness of vaccination in the epidemiological seasons when the vaccine strain B did not match 
the actually circulating strain: the vaccine strain B does not provide full protection against the wild 
strain of another lineage [4, 5, 6, 7]. 
Post-hoc analysis of data on circulation of B viruses of both lineages and of associated 
infections in different populations within different epidemic seasons has shown that the incidence of 
influenza B significantly varies by different years and by continents and may reach high numbers if 
the vaccination strain does not match the wild-type virus. According to the US Centers for Disease 
Control in 2001/2002 to 2010/2011 seasons (including the pandemic season of 2009/2010), in USA 
cases of influenza caused by the type B virus in all populations, predominantly in pediatric 
population, reached 44 % [8]. European data show similar trends: In the Netherlands, the number of 
cases of influenza caused by the type B virus in the period from 1992/1993 to 2006/2007 in various 
seasons reached 82 % [9]; in Finland, the number of confirmed cases of type B influenza reached 20 
% within the period from 1980 to 1999, with most patients affected in the pediatric population of < 17 
years [10]. The analysis of data on influenza virus circulation form 1999 to 2012 by Finnish 
investigators confirmed the epidemic significance for community of mismatch between the vaccine 
and wild type B influenza virus, particularly in children and adolescents [11]. 

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Impossibility to accurately predict the specific type B strain to be prevalent in the next season at a 
specific region and data of monitoring of seasonal epidemics formed the basis for development of 
quadrivalent influenza vaccines, in addition to two type A and one type B virus strains containing the 
second type B virus, the so-called quadrivalent vaccines. 
The first quadrivalent vaccine was launched in Europe in 2012; later, quadrivalent influenza 
vaccines were approved in the US, Canada, Australia, China. Experts expect significant cost 
effectiveness of immunization. European researchers using a mathematic model calculated that using 
quadrivalent influenza vaccine in the UK will help decrease the incidence of seasonal influenza by 
1,393,720 cases; reduce the number of visits by 439,852; complications, by 167,357 cases; 
complication-related hospitalizations, by 26,424; influenza mortality, by 16,471 versus trivalent 
vaccines. The quality of life adjusted incremental cost-effectiveness ratio (ICER) would be £ 5,299 
[12]. 
Currently, only trivalent influenza vaccines have been approved in Russia. No quadrivalent 
influenza vaccines are approved in the Russian pharmaceutical market. There are no local 
developments available either. Development of the first Russian quadrivalent vaccine will help 
improve the effectiveness of vaccination and significantly improve the cost-effectiveness of 
preventive immunization. 
Petrovax Pharm has a rich legacy in the field of development, creation, and manufacture of 
effective subunit influenza vaccines based on highly purified antigens and immunoadjuvant 
Polyoxidonium® (PO). Petrovax Pharm has all the required resources: state-of-art pharmaceutical 
manufacture, competent and qualified personnel, as well as quality assurance service according to 
Good Manufacturing Practice (GMP) standards. 
Many years of positive experience of using local vaccines Grippol® and Grippol® Plus with 
reduced antigenic load and addition of 500 µg of POx further highlights the significance of such 
vaccines and introduction into the practical healthcare in terms of decreased incidence and improved 
cost effectiveness. 
In view of the foregoing, the new development of NPO Petrovax Pharm, LLC — a Russian 
inactivated subunit quadrivalent influenza vaccine containing highly purified antigens of four 
influenza strains and POx as immunoadjuvant — is of significant value. 
The complex of own nonclinical studies of the quadrivalent inactivated influenza subunit 
vaccine Grippol® Quadri confirms the high specific activity and high safety profile of the product 
[13-19]. 
Animal studies on specific activity have shown that Grippol® Quadri vaccine 
has a pronounced immunogenicity comparable with trivalent vaccine Grippol®Plus. The presence of 
the antigen to the fourth B strain of the influenza virus, of Victoria lineage in Grippol® Quadri does 
not reduce the immunogenicity of the other antigens included in the vaccine. 

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Non-clinical studies have shown that induction of the specific immune response to the vaccination 
does not prevent adequate immune responses to the antigens heterologous to those included into the 
vaccine. 
Phase I safety and tolerability study of quadrivalent inactivated subunit influenza vaccine 
Grippol® Quadri in healthy volunteers was completed [20]. The study included 3 groups of 30 
subjects, overall 90 subjects. Subjects from group 1 (30 volunteers) received a single 0.5 ml dose of 
Grippol® Quadri; Group 2 (30 volunteers) received a single 0.5 ml dose of the reference vaccine 
Grippol Plus; Group 3 (30 volunteers) received a single 0.5 ml dose of placebo (saline solution). 
Overall 53 AEs were reported in the study, including 26 AEs in 11 subjects (36.7 %) in the Grippol® 
Quadri Group, 13 AEs in 9 subjects (30.0 %) in the Grippol® Plus group, and 14 AEs in 6 subjects 
(20.0 %) in the Placebo Group. No serious adverse events (SAE) or AEs leading to withdrawal from 
the study were reported. All the AEs were of a mild to moderate severity. Reactogenicity assessment 
showed mild or indefinite severity local reactions with no significant differences between the groups. 
All systemic reactions were considered to be mild without significant differences between the groups. 
In conclusion, the evidence of non-clinical studies and a phase I clinical study supports safety 
of Grippol® Quadri vaccine (NPO Petrovax Pharm, LLC, Russia) and helps to recommend it for 
further investigation in healthy volunteers to evaluate its immunogenicity, efficiency, safety, and 
reactogenicity. 
The objective of this study was assessment of safety, reactogenicity, immunogenicity, and 
efficacy of quadrivalent inactivated subunit influenza vaccine Grippol®  Quadri (NPO Petrovax 
Pharm, LLC, Russia) versus trivalent inactivated polymer-subunit vaccine Grippol® Plus (NPO 
Petrovax Pharm, LLC, Russia) in subjects from 18 to 60 years old. Due to the identity of antigens 
used in the production of tetravalent and trivalent vaccines, the difference in composition of the 
developed vaccine and the comparator vaccine only in terms of valence, the absence of need to select 
the optimal dose and the possibility 
to adequately assess protective potentials of vaccines on immunological parameters, the proposed 
study belongs to phase II-III and is registrational. 
1.2. The results of nonclinical and clinical studies relevant to this study. 
A detailed description of the results of preclinical and clinical trials of influenza tetravalent 
inactivated subunit vaccine Grippol® Quadri (NPO Petrovaks Farm, Russia) is presented in 
Investigator's Brochure. 
Nonclinical studies  
Antigenic activity (immunogenicity) of Grippol® Quadri [13]. 

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Antigen activity of Grippol® Quadri was assessed by the level of specific antibodies to 
hemagglutinin in serums of immunized mice. The level of antibodies was determined by 
hemagglutination inhibition test (HAIR) and by enzyme-linked immunosorbent assay (ELISA). The 
conducted studies have shown that antibodies to hemagglutinin of each strain of the vaccine are 
produced in mice in response to administration of Grippol® Quadri, as was shown in all the 
performed tests. The geometric mean antibody titers (GMAT) determined in animals after 
administration of Grippol® Quadri did not significantly differ from those for the trivalent vaccine 
Grippol®Plus. In one test, the level of antibodies after administration of quadrivalent vaccine was 
even higher than that for a similar dose of trivalent vaccine. GMAT obtained by HAIR for Grippol® 
Quadri 
were 
1:113, 
1:242, 
1:86, 
1:92 
for 
strains 
A/H1N1/California/07/09, 
A/H3N2 
/Switzerland/9715293/13, B/Phuket/3073/13 and B/Brisbane/60/08 respectively. Equivalent values 
for Grippol Plus: 1:75, 1:80, 1:65. The B/Brisbane/60/08 strain was not included in the trivalent 
vaccine, so the level of antibodies to it was not measured. Thus, it can be concluded that the inclusion 
of additional five micrograms of hemagglutinin strain B/Brisbane/60/08 in the vaccine does not 
reduce the intensity of the immune response to other strains. In addition, the studied vaccines 
provided 100 % seroprotection of animals, i.e. GMAT to hemagglutinin of each strain was ≥ 1:40. 
It was shown that POx acts as an adjuvant in the composition of tetravalent vaccine, in 
particular, it enhances the production of antibodies to hemagglutinin. GMAT for polyoxide-free 
antigens 
was 
1:87, 
1: 
113, 
1:80 
for 
strains 
A/H1N1/California/07/09, 
A/H3N2/Switzerland/9715293/13, B/Phuket/3073/13 respectively. Equivalent values for Grippol® 
Plus: 1:123, 1:247, 1:104. 
ELISA results support the data obtained by HAIR. Immunization of animals led to the 
production of antibodies to hemagglutinin of both IgG1 and IgG2a subclasses. It is known that an 
increase in the level of IgG1 antibodies reflects activation of humoral, and an increase in IgG2a — 
cellular immunity. 
In the second test, the amount of cytokine IL-4 in supernatants of mouse splenocyte pre-
stimulated with a mixture of hemagglutinins was determined. According to the obtained results, it can 
be concluded that the humoral immunity is activated in mice that received Grippol® Quadri. Index of 
Il-4 stimulation was 3.9. Same parameter for trivalent vaccine was 4.3 
During the nonclinical efficacy studies of the Grippol® Quadri influenza vaccine containing 
hemagglutinin and neuraminidase of four influenza virus strains, the antigenic activity of the novel 
product was investigated. In the three studies with laboratory mice it was shown that the Grippol® 
Quadri vaccine represented high antigenic activity comparable or even exceeding that of the trivalent 
vaccine. The presence of the 4th strain B/Brisbane/60/08 Victorian line influenza virus antigens in 
Grippol® Quadri did not reduce immune activity of other vaccine antigens.  

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It should be noted that even considering the 4th strain, the total amount of hemagglutinin in one 
dose of Grippol® Quadri was 20 µg/dose, which is almost twice less than that usually included in the 
trivalent inactivated influenza vaccines without adjuvant (45 µg/dose). Grippol® Quadri vaccine 
includes POx making the antigen dose of 20 μg sufficient and effective. The amount of POx in 
Grippol® Quadri is 500 μg. This amount of POx in the trivalent polymer-subunit vaccines Grippol® 
plus and Grippol® with a total HA content of 15–21 μg has proven its efficacy and safety. The studies 
showed that the "antigen-adjuvant"-related antibody response for each product significantly exceeded 
the antigen-mediated immune response without adjuvant. 
Assessment of administration safety 
Acute toxicity of Grippol® Quadri vaccine [14] 
The acute toxicity of the Grippol® Quadri vaccine was evaluated in 40 male and female white 
mice (10 mice per group) when administered subcutaneously at a single dose of 1,600 and 3,200 μg 
HA/kg that, respectively, 2,000 and 4,000 times exceeds the maximum permitted dose in human 
(based on a child weighing 10 kg, i.e. about 0.8 μg/kg). In the control groups, the animals were 
administered normal saline solution and vehicle (vaccine solvent) — phosphate saline buffer solution. 
The criteria for assessment of toxicity were: indicators of body weight change, signs of 
impaired health in animals during a clinical examination, indicators of changes in peripheral blood, a 
macro- and microscopic picture of cavities and internal organs. 
During the study, no animal death, as well as clinical signs of toxicity following a single-dose 
subcutaneous administration of the Grippol® Quadri vaccine to the male and female mice at the doses 
of 1,600 μg HA/kg and 3,200 μg HA/kg were observed. The necropsy carried out on animals 7 days 
after the administration show no macroscopic changes in the organs or tissues, their location relative 
to each other, size, shape, color, or consistency; no pathological changes in the structure of the walls, 
mucous membranes, intracranial, abdominal, or pleural cavities. As a result of the analysis of 
histological specimens, a moderate reaction of the organs of the immune system (thymus, spleen, 
regional lymph node) was revealed. Thymocyte emigration, delymphatization of thymus-dependent 
areas in the white pulp of the spleen and a regional lymph node, an increase in the number of plasma 
cells in the lymph node medulla were observed. These structural transformations of the lymphoid 
organs are the hallmark of the immune reactions occurring in response to vaccination with significant 
doses. In other organs and tissues, as well as at the administration site no changes were detected. 
Repeat dose toxicity [15] 
Study products were administered to male and female Wistar rats intramuscularly once a week 
for 6 weeks at doses of 20 and 100 HA µg/kg. Animals in control group received in a similar way an 
equivalent amount of saline and the vehicle (vaccine diluent) — phosphate saline buffer. 

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During the observation period, test animals did not show decreased body weight gain, clinically 
significant abnormalities in food and water intake or functional parameters of central nervous system 
and cardiovascular system, as well as changes in the peripheral blood cell counts and serum 
biochemical values. 
Urine biochemical analysis in female rats following 6 intramuscular injections of the 
Grippol® Quadri vaccine at a maximum dose of 100 HA µg/kg revealed a significant decrease of 24-
hour excretion of chlorides and urea along with a decline in the daily urine output. The blood serum 
urea and chlorides levels were within the normal ranges; therefore, there were no reasons to suggest 
any serious tubular reabsorption impairment. 
Histological findings in the liver and kidneys demonstrated moderate vascular reactions and 
changes in convoluted tubules epithelium; in other studied internal organs and tissues, when 
compared to the control, any significant pathological abnormalities have not been revealed. 
Therefroe, the studies showed that there were no significant deviations in the health status of 
study animals following the immunization with Grippol® Quadri vaccine, manufactured by NPO 
Petrovax Pharm, LLC, containing locally produced influenza virus antigens at a dose of 20 μg per 0.5 
ml, which indicates the safety of the study drug. 
Assessment of local effect. 
The assessment of local effect was included in the acute and chronic toxicity studies in mice 
and rats based on the clinical examination data and the results of the histological examination of the 
injection site (muscle and surrounding tissues). 
Macroscopic examination of the injection site after a single subcutaneous injection of Grippol® 
Quadri to mice at doses of 1,600 and 3,200 HA µg/kg and after a course of intramuscular 
administration to the Wistar rats showed no significant differences in the skin, subcutaneous tissue, 
and adjacent tissues condition, following the administration of the investigational product and 
physiological saline solution as a control. 
Histological examination of the injection site after 6 intramuscular administrations of the 
vaccine to male and female rats at doses of 20 and 100 HA µg/kg has shown the presence of small 
haematomas in isolated cases in the control and test groups of males and females. This non-specific 
reaction is a response to the mechanical impact, it is not the result of the local irritant effect. 
Assessment of immunologic safety [16]. 
Immunological safety assessment of the Grippol® Quadri vaccine (in total, 20 µg of HAs of the 
three strains per dose plus 500 µg of Polyoxidonium) consisted of nonclinical investigation of the 
immunoreactivity changes in the experimental animals (mice, guinea pigs) associated with the 
specific immune response to the immunization. The vaccines containing similar hemagglutinin and 
POx levels were used as comparators: commercially available vaccine Grippol® Plus (a total of 15 µg 
HA of the 3 strains per dose and 500 µg of POx) and vaccine Grippol® (a total of 21 µg HA of the 3 
strains per dose and 500 µg of POx). 

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The ability of vaccines to influence the humoral, cellular, and macrophage parts of the immune 
response at different times after vaccination was evaluated in mice. Immunological reactivity of mice 
after the study vaccine administration was estimated according to the accumulation of antibody-
producing cells in mice spleen after their immunization with sheep red blood cells (a model of 
humoral immune response), the development of delayed-type hypersensitivity during the plantar test 
(a model of cell-mediated immune response). Activity of phagocytes was estimated according to the 
respiratory burst process in the spontaneous and induced chemical luminescence setting. Investigators 
also studied the possibility of the polyclonal effect of the study vaccines by the ability to nonspecific 
stimulation of antibody-forming cells to various test antigens. 
The findings of the animal studies performed have demonstrated that the specific immune 
response to the vaccine does not preclude both acute and long-term post-immunization normal 
immune reaction to the antigens heterologous to those presented in vaccines. The stimulating effect of 
the Grippol® Quadri vaccine on the humoral immune response to the heterologous test antigen (the 
ram erythrocytes) has been proven. It was shown that immunoadjuvant action is not associated with 
polyclonal properties, which is the immune system safety indicator. The investigation of the study 
vaccine effect on the multi-local phagocytic activity and the cellular immune response did not reveal 
effects specific for the possible immunotoxic effect of immunization. 
The Grippol® Quadri vaccine allergenic properties [17] were assessed in animals (guinea pigs and 
mice) using the immediate (ITH) and delayed type (DTH) response testing with multiple administrations of 
the product. 
Like the Grippol® vaccine, the Grippol® Quadri vaccine was not found to have any local 
irritative effect (at a dose of 1/10 BH) and did not cause the delayed-type allergic reaction following 
multiple administration of the maximum possible testing amount (1/5 and 1/10 of BH) to mice. 
During evaluation of the possibility to sensitize guinea pigs (the most sensitive animal species) 
in the immediate-type hypersensitivity reaction, there were no signs of sensitization revealed with 
repeated Grippol® Quadri injections, suggesting an extremely low probability of allergic reactions 
associated with the vaccine administration to humans. 
Summarizing the results of the conducted research, we can conclude that the domestic 
tetravalent vaccine for the prevention of influenza Grippol® Plus containing 2 strains of influenza 
virus types A and B in nonclinical studies has shown high efficiency and safety. It can be expected 
that the use of Grippol® Quadri vaccine will provide better protection to the population against 
influenza. 
Clinical studies [20] 
Phase I safety and tolerability study of quadrivalent inactivated subunit influenza vaccine 
Grippol® Quadri was conducted in healthy volunteers [20]. 

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The study included 3 groups of 30 subjects, overall 90 subjects. Subjects from group 1 (30 
volunteers) received a single 0.5 ml dose of Grippol® Quadri; Group 2 (30 volunteers) received a 
single 0.5 ml dose of the reference vaccine Grippol Plus; Group 3 (30 volunteers) received a single 
0.5 ml dose of placebo (saline solution). 
Over the study period, there was a minimum of 1 AE in the Grippol® Quadri group, Grippol® 
Plus group, and Placebo group in 36.7 %, 30.0 %, and 20.0 % of the subjects respectively. The 
majority of all registered AEs were classified as post-immunization reactions (reactogenicity 
symptoms — local and system reactions) and were considered by the Investigator as related to the 
study product (strength of relation: "definite", "probable", and "possible"). 
During the evaluation of the reactogenicity in the Grippol® Quadri group, the local reactions 
were detected in 33.3 % of the subjects, in the group Grippol® Plus, there were 23.3 % of the 
subjects, and in the Placebo group, 13.3 % of the subjects. Among the local reactions, there were 
observed pain at the injection site, erythema, swelling and induration, and itching at the injection site. 
Pain at the injection site was the most common local reaction in all three study groups. No additional 
medical intervention was needed for the local reactions in the subjects. Local reactions were mild to 
non-identified by severity. During the comparative evaluation, there was no evidence of the 
statistically significant difference between the proportion of mild, moderate, and severe local 
reactions in the Grippol® Quadri group, Grippol® Plus group, and Placebo group (p = 1.00 and p = 
1.00 respectively). 
Only the subjects without any intercurrent conditions within the first five days after 
immunization were included in the system reactions analysis: in total 29 of the 30 subjects from the 
group Grippol® Quadri, 28 of 30 subjects from the group Grippol® Plus, and 29 subjects from the 
Placebo group. During the evaluation of the reactogenicity, the general reactions were detected in the 
group Grippol® Quadri in 20.7 % of the subjects, in the group Grippol® Plus in 3.6 % of the subjects, 
and in the Placebo group in 10.3 % of the subjects. Among the general reactions recorded during the 
study, there were the following: rise in body temperature above 37 °C, malaise, headache, nausea, 
myalgia / arthralgia. The most common general reaction in the group Grippol® Quadri was the 
development of headache — in 13.8 % of the subjects, whereas in the group of Grippol® Plus and in 
the Placebo group headache was observed only in 3.6 % and 3.4 % of the subjects respectively. The 
rise in body temperature above 37 °C was recorded in 6.9 % of subjects in the group Grippol® Quadri 
(within subfebrile with a maximum registered value of 37.2 °C), and also in 6.9 % of subjects in the 
Placebo group (within subfebrile with a maximum registered value of 37.5 °C). All the occurred 
systemic reactions were regarded as mild. During the comparative evaluation, there was no evidence 
of the statistically significant difference between the proportion of mild, moderate, and severe local 
reactions in the Grippol® Quadri group, Grippol® Plus group, and Placebo group (p = 0.102 and p = 
0.470 respectively). 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 2016 
 
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The results of the laboratory tests and neurological status assessment did not reveal any 
significant changes over the study period. In addition, the results of the analysis of all vital signs 
excluding body temperature (clinically significant subfebrile increase of body temperature in 2 
subjects during the vital signs assessment) did not reveal any considerable changes over the study 
period. Clinically significant body temperature abnormalities were recorded within the frames of the 
registered AEs. The results of the physical examination evaluations, except for the data on the 
condition of the respiratory system and mucous membranes (in 1 subject diagnosed with respiratory 
tract infection, nasopharyngitis), were within the normal range. Clinically significant abnormalities 
were registered as AEs. 
1.3. Known and potential risks and benefits for study subjects 
Known and potential risks of the study vaccine and comparison vaccine are described below. 
When determining the causal relationship of the adverse events that occur during this study, the 
investigator must take into account all the information described below, as well as information from 
the current version of the draft of the instruction for medical use and information from the latest 
version of the investigator's brochure on the study drug. 
 
Potential risks of using the study drug: 
Inactivated influenza vaccines are highly purified drugs and are well tolerated. Based on the 
published literature, the results of non-clinical studies and the phase I clinical study, it is expected 
that the safety profile of quadrivalent vaccine under investigation will be the same as the profile of 
trivalent comparison vaccines. Adverse events and their frequency are listed below. 
Common (> 1/100, < 1/10). Local reactions in the form of sore, redness, swelling, and itching 
in the administration site. Systemic reactions: malaise, fatigue, subfebrile temperature. 
Infrequent (> 1/1,000, < 1/100). Systemic reactions such as mild runny nose, sore throat, 
headache, temperature above subfebrile. 
Usually the above mentioned reactions pass off in 1–2 days. 
Rare (> 1/10,000, < 1/1,000). Allergic reactions including the immediate ones. 
Very rare (< 1/10,000). 
- nervous system disorders: neuralgia, paresthesia, neurological disorders; 
- locomotor system disorders: myalgia. 
53 adverse events in 26 volunteers have been recorded during phase I clinical study. All the 
AEs were of a mild to moderate severity. None of the adverse events was a reason for the subject's 
withdrawal from the study. Among the AEs, there were no serious adverse events (SAE). 
Characteristics of adverse events (system organ classes and association to the study drug) are 
presented in Table 1. 
 

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Table 1. Number of Volunteers with Adverse Events Associated With the Study Drug (Degree 
of Association: "definite", "probable", and "possible") distributed according to the System 
organ class and the preferred term (MedDRA) 
 
System Organ Class: preferred 
Term, n* (%) 
Degree of 
Association With 
the Study Drug 
Group 
Grippol® 
Quadry  
N = 30 
Group 
Grippol® 
Plus N = 30
Group 
Placebo  
N = 30 
Total number of subjects with adverse events 
(any AEs) 
Definite 
1 (3.3 %) 
1 (3.3 %) 
0 (0.0 %) 
Likely 
9 (30.0 %) 
5 (16.7 %) 
4 (13.3 %) 
Possible 
1 (3.3 %) 
1 (3.3 %) 
1 (3.3 %) 
General disorders and administration site 
conditions: 
Definite 
1 (3.3 %) 
1 (3.3 %) 
0 (0.0 %) 
Likely 
9 (30.0 %) 
5 (16.7 %) 
4 (13.3 %) 
Possible 
0 (0.0 %) 
1 (3.3 %) 
0 (0.0 %) 
Erythema at the injection site
Likely
1 (3.3 %)
1 (3.3 %)
1 (3.3 %)
Pain at the injection site 
Definite
1 (3.3 %)
1 (3.3 %)
0
Likely
9 (30.0 %)
4 (13.3 %)
4 (13.3 %)
Possible
0
1 (3.3 %)
0
Itching at the injection site
Likely
1 (3.3 %)
1 (3.3 %)
0
Swelling at the injection site Malaise 
Likely
0
0
1 (3.3 %)
Possible
2 (6.7 %)
0
1 (3.3 %)
Laboratory and instrumental data: 
Possible 
3 (10.0 %) 
0 
2 (6.7 %) 
Increased body temperature
Possible
3 (10.0 %)
0
2 (6.7 %)
Skeletal muscle and connective tissue 
disorders: 
Possible 
0 
0 
1 (3.3 %) 
Arthralgia
Possible
0
0
1 (3.3 %)
Myalgia
Possible
0
0
1 (3.3 %)
Nervous system disorders: 
Likely 
2 (6.7 %) 
0 
0 
Possible 
3 (10.0 %) 
1 (3.3 %) 
1 (3.3 %) 
Headache 
Likely
2 (6.7 %)
0
0
Possible
3 (10.0 %)
1 (3.3 %)
1 (3.3 %)
Drowsiness
Likely
1 (3.3 %)
0
0
* — number of subjects with adverse events 
The expected benefits from the use of the study drug and the comparator drug:  
For a long time, trivalent influenza vaccines have been successfully used on the territory of the 
Russian Federation and around the world as an efficient and safe measure for prevention of influenza. 
The development of a quadrivalent vaccine containing strains of two lines of influenza B viruses will 
provide for a more reliable protection of the population, thus, increasing the immunization efficiency. 
Several trivalent vaccines (Fluarix Tetra, FluQuadri, Afluria, etc.) produced in Europe and the USA 
have already been successfully used in the world. In the Russian Federation, such drugs are currently 
not available. 

Protocol number: GriQv-III-16 
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Quadrivalent vaccine induces high-level specific anti-influenza immunity formation. Post-
vaccination protective effect usually comes in 8–14 days, and the immunity retains up to 12 months, 
including elderly people. Protective anti-influenza antibody titers are detectable among 75–95 % of 
the vaccinated people of different age. 
Development of the first russian quadrivalent vaccine will help improve the effectiveness of 
vaccination and significantly improve the cost-effectiveness of preventive immunization. 
1.4. Description and justification of the mode of administration, dosage, dosage regimen, 
and course of treatment 
As there are no quadrivalent inactivated influenza vaccines approved on the territory of the 
Russian Federation and also due to similarity of antigens used for manufacture of quadrivalent and 
trivalent vaccines, the use of trivalent inactivated polymer-subunit influenza vaccine Grippol® Plus as 
a reference product is considered to be justified. 
Therefore, to get comparative data for all the four antigens of the quadrivalent vaccine, the 
study will use two trivalent reference vaccines with different type B influenza virus antigens. 
The study will be conducted in three groups (A, B, C): 
Group А: Grippol® Quadri, quadrivalent inactivated subunit influenza vaccine, suspension for 
intramuscular and subcutaneous administration. 
Group B: Grippol® Plus, trivalent inactivated polymer-subunit influenza vaccine, based on type 
B influenza virus of Yamagata lineage, suspension for intramuscular and subcutaneous 
injections. 
Group C: Grippol® Plus, trivalent inactivated polymer-subunit influenza vaccine, based on type 
B influenza virus of Victoria lineage, suspension for intramuscular and subcutaneous injections. 
Dosing: All the vaccines used in the study are administered as a single intramuscular injection 
of 0.5 ml (1 dose) into the upper third of the outer surface of the shoulder (the deltoid muscle). 
The recommended dose and mode of administration of vaccines correspond to those described 
in the instructions for medical use of comparator vaccines. The duration of the observation of 
volunteers to identify adverse events after a single vaccination will be 6 months. A detailed 
description of the vaccination procedure by study vaccines is presented in Section 5.1. 

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1.5. Indication that this clinical trial will be conducted in accordance with the protocol, 
these rules, and regulatory requirements. 
This clinical study will be conducted in accordance with this protocol, current principles of 
good clinical practice (ICH GCP), ethical principles of conducting medical research involving human 
subjects of the Helsinki Declaration of the World Medical Association, as well as all the requirements 
of regulatory authorities of the Russian Federation. 
1.6. Description of study population 
Healthy eligible volunteers will participate in this study.  
1.7. References to literary sources and data relevant to the study that constitute the 
rationale for this study. 
1. R.B. Belshe. The need for quadrivalent vaccine against seasonal influenza.// Vaccine 28S (2010) 
D-45-D53 
2. C.A. Russel et al. Influenza vaccine strain selection and recent studies on the global migration of 
seasonal influenza virus. // Vaccine (2008); 26, Suppl. 4:D31-4. 
3. P.A. Rota et al. Cocirculation of two distinct evolutionary lineages of influenza type B virus 
since 1983.// Virology 1990; 175:59-69. PMID: 23009452; http://dx.doi.org/10.1016/0042-
6822(90)90186-U 
4. R.B. Belshe et. al. Efficacy of live attenuated influenza vaccine in children against influenza B 
viruses by lineage and antigenic similarity. Vaccine 2010; 28:2149-56. 
5. R.B. Couch et al. Background and presentation of possible vaccine options. Presented at: Food 
and Drug administration, Center of Biologics evaluation and research, vaccines and related 
biological products // Advisory Committee meeting: February 27-28, 2007; Washington, DC. 
6. US Centers for Disease control and prevention. Seasonal influenza activity surveillance reports: 
1999 – 2000 to 2010-2011 seasons. // Available at: 
«http://www.cdc.gov/flu/weekly/pastreports.htm%20Accessed%20November%2017», 2011. 
7. World 
Health 
Organization. 
WHO/Europe 
influenza 
surveillance. 
Available 
at: 
http://www.euroflu.org/index.php. Accessed June 20, 2011. 
8. Ch.S. Ambrose and M.J.Levin. The rationale for quadrivalent influenza vaccines. // Human 
vaccines& Immunotherapeutics 2012; January 8:1 81-88; 
9. F. Dijkstra, G.A. Donker et al. Long time trends in influenza-like illness and associated 
determinants in the Netherlands. //Epidemiological infections 2009; 137: 473-9. 
10. V. Petrola, T.Ziegler et al. Influenza A and B virus infection in children.// Clinic Infection 
Diseases 2003: 36:299-305. 
11. T.Heikkinen, N. Ikonen, Th.Ziegler. Impact of influenza B lineage-level mismatch between 
trivalent seasonal influenza vaccines and circulating visuses, 1999-2012. // CID 2014:59 (1 
December). 
12. Joyce H S You et al. Cost-effectiveness of quadrivalent influenza vaccine in Hong Kong – A 
decision analysis.// Human Vaccines & Immunotherapeutics 2015; v.11, No3 
13. Assessment of Grippol® Quadri, a tetravalent inactivated polymer-subunit influenza vaccine, 

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antigen activity. Reg. report code FP- 0575/RNS-Tox-PD-04v1/2016. Study number 19/15, 
33/15, 2016 
14. Nonclinical toxicity study of a tetravalent inactivated polymer-subunit influenza vaccine 
Grippol® Quadri after single subcutaneous dose in male and female (СВАхС57BL/6)F1 mice. 
Reg. report code FP-0575/RNS-Tox-ас-01v1/2016. Study number 69/15, 2016 
15. Nonclinical toxicity study of a tetravalent inactivated polymer-subunit influenza vaccine 
Grippol® Quadri after repeated intramuscular dose in male and female Wistar rats. Reg. report 
code FP-0575/RNS-Tox-chr-02v1/2016. Study number 70/15, 2016 
16. Study of immunological safety of a tetravalent inactivated polymer-subunit influenza vaccine 
Grippol® Quadri. Reg. report code FP-0575/RNS-Tox-it-04v1/2016. Study number 71/15, 2016 
17. Study of a tetravalent inactivated polymer-subunit influenza vaccine Grippol® Quadrivalent 
allergizing effect. Reg. report code FP-0575/RNS-Tox-ар-03v1/2016. Study number 72/15, 2016 
18. Experimental 
study 
of 
embryotoxic 
action 
of 
a 
tetravalent 
inactivated 
polymer-
subunit influenza vaccine Grippol® Quadri, suspension for intramuscular and subcutaneous 
injection, in prenatal period in Wistar rats. Reg. report code FP-0575/RNS-Tox-rpt-09v1/2016, 
2016 
19. Experimental 
study 
of 
embryotoxic 
action 
of 
a 
tetravalent 
inactivated 
polymer-
subunit influenza vaccine Grippol® Quadri in postnatal period in Wistar rats. Reg. report code 
FP- 0575/RNS-Tox-rpt-08v1/2016, 2016 
20. The clinical trial report of phase I to evaluate the safety and tolerability of the influenza vaccine 
tetravalent inactivated polymer-subunit Grippol® Quadri in healthy subjects, 2016. 
21. Instructions for the use of the medicinal product Grippol® plus vaccine influenza trivalent 
inactivated polymer-subunit 
22. Draft instruction for medical use of the medicinal product influenza vaccine tetravalent 
inactivated polymer-subunit Grippol® Quadri. 
2. OBJECTIVES AND PURPOSES OF THE STUDY 
The objective of this study was assessment of safety, reactogenicity, immunogenicity, and 
efficacy of quadrivalent inactivated subunit influenza vaccine Grippol®  Quadri (NPO Petrovax 
Pharm, LLC, Russia) versus trivalent inactivated polymer-subunit vaccine Grippol® Plus (NPO 
Petrovax Pharm, LLC, Russia) in subjects from 18 to 60 years old. 
Study goals: 
 Study and comparative assessment of immunogenicity of quadrivalent inactivated subunit 
influenza vaccine Grippol® Quadri versus trivalent inactivated polymer-subunit vaccine 
Grippol ® Plus in subjects from 18 to 60 years old. 
 Assessment of safety and reactogenicity of the quadrivalent inactivated subunit influenza 
vaccine Grippol® Quadri compared to the influenza vaccine trivalent inactivated polymer 
subunit vaccine Grippol® Plus in volunteers ages 18–60 years old. 
 

Protocol number: GriQv-III-16 
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 Study and comparative assessment of immunogenicity of quadrivalent inactivated subunit 
influenza vaccine Grippol® Quadri versus trivalent inactivated polymer-subunit vaccine 
Grippol® Plus in subjects from 18 to 60 years old. 
3. STUDY DESIGN 
3.1. 
Primary and additional study parameters that will be evaluated during the study 
Primary immunological efficacy endpoint:  
 The share of subjects achieving seroconversion (the number of volunteers with antibody titer 
[of at least 1:40] increased more than 4-fold versus baseline [assessed by HAIR]) for antigens: 
influenza virus type А — H1N1, influenza virus type А — H3N2, influenza virus type В — 
Yamagata and Victoria lineage, based on assessment at Day 21 after immunization (Visit 7). 
Secondary efficacy endpoints:  
 Coefficient of increase of mean geometric antibody titer (antigens H1N1, H3N2, Yamagata 
and Victoria lineage), based on assessment at Day 21 after immunization (Visit 7). 
 
Geometric mean of serum antibodies to antigens: influenza virus type А — H1N1, influenza 
virus type А — H3N2, influenza virus type В — Yamagata and Victoria lineage, based on 
assessment at Day 21 after immunization (Visit 7). 
 Seroprotection: share of subjects achieving protective antibody titer (1:40 and more) to 
antigens H1N1, H3N2, Yamagata and Victoria lineage, based on assessment at Day 21 after 
immunization (Visit 7). 
 Incidence of influenza and ARI based on assessment 180±5 days after immunization (Visit 
12). 
 Severity and duration of reported cases of influenza and ARI, complications. 
Safety parameters: 
The safety parameters of this study are the following: 
 Quantitative assessment and nature (severity and duration) of local and systemic reactions to 
vaccine administration. 
 AEs and SAEs associated with the study vaccines. 
 Immediate type AEs emerging within 60 minutes after immunization. 
 Incidence and nature of intercurrent disorders 
 Vital function assessment results. 
 Results of physical examination. 
 Neurological examination results. 
 Results of blood hematology and biochemistry tests. 
 Urinalysis results. 
 Immunological parameters evaluation results: serum immunoglobulin content (ELISA: IgE). 

Protocol number: GriQv-III-16 
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3.2. 
Description of the type / design of the study and a schematic representation of its 
design, procedures, and stages 
This was a phase II-III, 6-month, multicenter, double-blind, randomized comparative study of 
safety, reactogenicity, immunogenicity and efficacy of quadrivalent inactivated subunit influenza 
vaccine Grippol® Quadri versus trivalent inactivated polymer-subunit influenza vaccine Grippol® 
Plus in parallel groups in volunteers of 18 to 60 years. Study design flow and schedule of procedures 
are shown in Figure 1 and in Table 2. 

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Figure 1. Schematic design of the study 
 
(- 3) ‒ 0 
0 
1 
2 
3 
4 
5 
22 ± 1 
43 ± 5 
64 ± 5 122 ± 5 180 ± 5
Visit
0 
Visit
1 
Visit
2 
Visit
3 
Visit
4 
Visit
5 
Visit
6 
Visit
7 
Telephone calls
(Visits 8–11) 
Screening (n = up to 765) 
Randomization (n = 612) 
Group А (n = 204):
Test Vaccine 
Group B (n = 204):
Reference Vaccine 
Group C (n = 204):
Reference Vaccine 
Immunization
Observation, immunogenicity assessment 
Observation, efficacy 
assessment 
days 

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Table 2. Schematic design of study procedures and stages 
 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 
10 
Visit 
11 
 
Screening
Immunization
Outpatient follow-up
Telephone call
Day after immunization
Day (-3) 
‒ 0 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 
22±1 
Day 
43±5 
Day 
64±5 
Day 
122±5 
Day 
180±5 
Before 
In 2 
hours 
Signing of informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of demographic data and history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Measurement of body weight, height, calculation of BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 
 
Vital signs assessment 
X 
Х 
Х 
 
Х 
 
 
Х 
Х 
 
 
 
 
Body temperature measurement 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 
 
Complete blood count1 
Х 
 
 
 
Х 
 
 
 
Х 
 
 
 
 
Blood biochemistry test2 
Х 
 
 
 
Х 
 
 
 
Х 
 
 
 
 
Urinalysis3 
Х 
 
 
 
Х 
 
 
 
Х 
 
 
 
 
Tests for syphilis, HBV, HCV, HIV 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
Urine test for pregnancy 
Х 
 
 
 
 
 
 
 
Х 
 
 
 
 
Serological test (serum antibody titer test) 
Х 
 
 
 
 
 
 
 
Х 
 
 
 
 
Immunoglobulins (IgE) 
 
Х 
 
 
 
 
 
 
Х 
 
 
 
 
Neurological examination 
 
Х 
 
 
Х 
 
 
 
 
 
 
 
 
Assessment of volunteer's compliance with inclusion and non-
inclusion criteria 
X 
Х 
 
 
 
 
 
 
 
 
 
 
 
Assessment for exclusion criteria 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Randomization 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
Immunization 
 
Х 
 
 
 
 
 
 
 
 
 
 
Distribution of volunteer's diaries and instructions4 
 
 
Х 
 
 
 
 
 
 
 
 
 
 
Review of volunteer's diary 
 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 
 
Return of volunteer's diaries 
 
 
 
 
 
 
 
 
Х 
 
 
 
 
Interviewing on ARI symptoms for the period 
 
 
 
 
 
 
 
 
Х 
Х 
Х 
Х 
Х 
Recording of concomitant therapy 
X 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Recording of local and systemic reactions, adverse events, and 
intercurrent disorders 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
1 - Hemoglobin, RBC, hematocrit, PLT, WBC and WBC differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), ESR. 
2 - Glucose, urea, creatinine, total bilirubin, total protein, ALT, AST, AP. 
3 - Relative density, protein, sugar, RBC, WBC. 
4 - Self-measurement of the body temperature by the volunteer, with the information logged into the diary. 

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2016  
 
 
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Screening (Visit 0 (-3), ‒ 0 days): 
Volunteers will be invited to participate in the study and undergo the corresponding screening 
procedures: 
 Signing of the informed consent form for participation in the study. 
 Collection of demographic data (age, gender, race). 
 Collection of medical history, history of infections and previous immunizations. 
 Physical examination, measurement of height, body weight (calculation of BMI, kg/m2). 
 Measurements of vital functions (pulse, SBP, DBP). 
 Body temperature measurement (t°) 
 Laboratory investigations: 
- Blood hematology (hemoglobin, RBCs, hematocrit, platelets, WBC and WBC differential 
[neutrophils, lymphocytes, monocytes, eosinophils, basophils], ESR). 
- Blood biochemistry (glucose, urea, creatinine, total bilirubin, total protein, ALT, AST, AP). 
- Urine test with sediment microscopy (specific density, protein, sugar, RBC, WBC). 
- Tests for syphilis, HBV, HCV, HIV infection. 
- Urine test for pregnancy (only for female subjects). 
- Blood collection for serology (baseline serum antibody titer). 
 Preliminary assessment of volunteer's compliance with inclusion and non-inclusion criteria. 
 Assessment for exclusion criteria. 
 Recording of concomitant therapy within 3 months prior to screening, including collection of 
information on vaccinations within the last year. 
 Oral instructions (in addition to volunteer's information leaflet) on not allowed medicinal drugs 
during screening and for the whole study period. 
Within the study period, volunteers will not be allowed to take medicinal drugs listed in section  
5.2.1. 
The period of Screening could last up to 3 days. The duration has to be sufficient to obtain all 
the parameters required to assess the selection criteria. In the volunteer's best interests, procedures of 
Visit 0 and Visit 1 can be pooled on condition of collection of all the required parameters within one 
visit. 
Visit 1 (Immunization day): 
Final assessment of volunteer's eligibility, including measurement of the body temperature, is 
performed at Visit 1 before the procedure of randomization and before immunization. 
If the volunteer meets all the inclusion criteria and none of the non-inclusion criteria, and if the 
volunteer did not take any of the unallowed drugs prior to the Screening visit, the volunteer is eligible 
for immunization. 

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The volunteer remains under the study doctor's observation within the first 2 hours after 
immunization. 
Therefore, the following procedures are performed at Visit 1: 
 Physical examination before immunization and 2 hours after immunization. 
 Measurement of the body temperature (t°) before immunization and 2 hours after immunization. 
 Measurement of vital signs (pulse, SBP, DBP) before immunization and 2 hours after 
immunization. 
 Neurological examination before immunization. 
 Laboratory investigations: 
- Blood collection prior to immunization to determine the baseline IgE level. 
 Final conclusion on volunteer's compliance with inclusion and non-inclusion criteria. 
 Randomization. 
 Immunization. 
 Provision of a volunteer's diary and instructions on keeping the diary (2 hours after 
immunization). 
 Assessment for exclusion criteria (prior to immunization and 2 hours after immunization). 
 Recording of concomitant therapy. 
 Recording local and systemic reactions, adverse events, and intercurrent disorders. 
After immunization and conclusion of follow-up (2 hours) the volunteer is instructed on how to 
keep a diary. The volunteer has to log the first records (body temperature in the morning) into the 
diary at the trial site to ensure that records in the diary are made correctly. 
Visit 2 (Day 1 after immunization): 
The following procedures are performed at Visit 2: 
 Physical examination. 
 Body temperature measurement (t°). 
 Review of volunteer's diary. 
 Assessment for exclusion criteria. 
 Recording of concomitant therapy. 
 Recording local and systemic reactions, adverse events, and intercurrent disorders. 
Visit 3 (Day 2 after immunization): 
The following procedures are performed at Visit 3: 
 Physical examination. 
 Body temperature measurement (t°). 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 
2016  
 
 
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 Measurements of vital functions (pulse, SBP, DBP). 
 Neurological examination. 
 Laboratory investigations: 
- Blood hematology (hemoglobin, RBCs, hematocrit, platelets, WBC and WBC differential 
[neutrophils, lymphocytes, monocytes, eosinophils, basophils], ESR). 
- Blood biochemistry (glucose, urea, creatinine, total bilirubin, total protein, ALT, AST, AP). 
- Urine test with sediment microscopy (specific density, protein, sugar, RBC, WBC). 
 Review of volunteer's diary. 
 Assessment for exclusion criteria. 
 Recording of concomitant therapy. 
 Recording local and systemic reactions, adverse events, and intercurrent disorders. 
Visit 4 (Day 3 after immunization) and Visit 5 (Day 4 after immunization): 
The following procedures are performed at Visits 4 and 5: 
 Physical examination. 
 Body temperature measurement (t°). 
 Review of volunteer's diary. 
 Assessment for exclusion criteria. 
 Recording of concomitant therapy. 
 Recording local and systemic reactions, adverse events, and intercurrent disorders. 
Visit 6 (Day 5 after immunization): 
The following procedures are performed at Visit 6: 
 Physical examination. 
 Body temperature measurement (t°). 
 Measurements of vital functions (pulse, SBP, DBP). 
 Review of volunteer's diary. 
 Assessment for exclusion criteria. Recording of concomitant therapy. 
 Recording local and systemic reactions, adverse events, and intercurrent disorders. 
Visit 7 (Day 22±1 after immunization): 
The following procedures are performed at Visit 7: 
 Physical examination. 
 Body temperature measurement (t°). 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 
2016  
 
 
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 Measurements of vital functions (pulse, SBP, DBP). 
 Laboratory investigations: 
- Blood hematology (hemoglobin, RBCs, hematocrit, platelets, WBC and WBC differential 
[neutrophils, lymphocytes, monocytes, eosinophils, basophils], ESR). 
- Blood biochemistry (glucose, urea, creatinine, total bilirubin, total protein, ALT, AST, AP). 
- Urine test with sediment microscopy (specific density, protein, sugar, RBC, WBC). 
- Blood collection for IgE test. 
- Blood collection for serology (serum antibody titer). 
- Urine test for pregnancy (only for female subjects). 
 Interviewing on ARI symptoms within the period. 
 Review and return of the volunteer's diary. 
 Assessment for exclusion criteria. 
 Recording of concomitant therapy. 
 Recording adverse events and intercurrent disorders. 
Telephone calls (Visits 8–11): 
Telephone calls are made on Day 43±5 (Visit 8), Day 64±5 (Visit 9), Day 122±5 (Visit 10), 
Day 180±5 (Visit 11) and included the following procedures: 
 Interviewing on ARI symptoms within the period. 
 Assessment for exclusion criteria. 
 Recording of concomitant therapy. 
 Recording adverse events and intercurrent disorders. 
3.3. Measures for minimization / elimination of subjectivity 
Subjectivity in the study is minimized / eliminated due to randomization and the double-blinded 
design of the study. 
3.3.1. 
Randomization 
The immunization group was determined randomly. Randomization will be based on a 
computer-generated randomization algorithm (randomization list), where each volunteer will be 
assigned a randomization number. That number will define the immunization group (A, B, or C) 
according to the randomization plan. That number will be assigned to the study subject for the entire 
period of the study and will be documented in volunteer's CRF. 
The volunteers will be randomized into 3 groups (at a ratio of 1:1:1). A block randomization 
method is used. An interactive web-response system (IWRS) with technical support service will be 
used for randomization. 

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2016  
 
 
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Investigators will be trained on working with IWRS system, and IWRS user guide will be handed out 
to all of them. 
An identification name (ID) and a password will be used to access the system. These identifiers 
will be given to the authorized staff member of the investigation site prior to study initiation. Upon 
the volunteer randomization, the investigator receives information through the IWRS system on 
volunteer assignment to one of the vaccination groups that will be given to the volunteer during the 
study. 
Volunteer stratification will be performed in the IWRS system according to the age and gender. 
In an emergency medical case, the investigator can obtain information about a vaccine received 
by a volunteer through the IWRS system. Information about storage and unblinding of randomization 
codes is provided in Section 3.8. 
3.3.2. 
Blinding 
This study is double-blind, neither the doctor nor the volunteer will know what kind of vaccine 
the study participant will receive. 
3.4. 
The treatment used in the study, dosages, regimens, dosage form, packaging, 
labeling, and storage of study drugs 
All the vaccines related to this study will be stored away from other vaccines and drugs in a 
safe place under relevant storage conditions with temperature control. All vaccines related to this 
study will be checked for the expiry date before use. Study subjects cannot be immunized using 
vaccines with expired date. 
Treatment (immunization), dosages, dosing regimen: 
This study includes 3 study groups: 
 Group А: Grippol® Quadri, quadrivalent inactivated subunit influenza vaccine, suspension for 
intramuscular and subcutaneous administration. 
 
Group B: Grippol® Plus, trivalent inactivated polymer-subunit influenza vaccine, based on 
type B influenza virus of Yamagata lineage, suspension for intramuscular and subcutaneous 
injections. 
 
Group C: Grippol® Plus, trivalent inactivated polymer-subunit influenza vaccine, based on 
type B influenza virus of Victoria lineage, suspension for intramuscular and subcutaneous 
injections. 
Dosing: All the vaccines used in the study are administered as a single intramuscular injection of 0.5 
ml (1 dose) into the upper third of the outer surface of the shoulder (the deltoid muscle). 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 
2016  
 
 
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Description of study vaccines: 
 
Grippol® Quadri, a quadrivalent inactivated subunit influenza vaccine: 
INN or generic name:
Influenza vaccine [inactivated] + Azoximer bromide 
Dosage form: 
suspension for intramuscular and subcutaneous injection. 
Composition: 
One immunizing dose (0.5 ml) contains: 
Active ingredients: 
 Influenza type A virus (H1N1) antigen with hemagglutinin 
- 5 µg. 
 Influenza type A virus (H3N2) antigen with hemagglutinin 
- 5 µg. 
 Influenza type В virus (Yamagata lineage) antigen with hemagglutinin, 5 µg. 
 Influenza type В virus (Victoria lineage) antigen with hemagglutinin, 5 µg. 
 Polyoxidonium®, lyophilizate for the preparation of dosage forms and 
vaccines (Azoximer bromide), supplied by NPO Petrovax Pharm, LLC, 
Russia. 
Russia, 500 µg.  
Excipients: 
 Phosphate saline buffer solution up to 0.5 ml. 
Description: 
Colorless or yellowish, slightly opalescent liquid. 
Presentation: 
0.5 ml (1 dose) in ampules or vials, hermetically sealed with rubber stoppers and
crimped with aluminum caps. 
5 ampoules or vials are placed into a blister packaging of polyvinyl chloride film.
1 or 2 blisters together with Instruction on use per carton pack. 
Or 5 or 10 ampoules or vials without blister packaging are placed into a carton
pack with a package insert. 
Storage conditions: 
Store away from light at the temperature of 2 to 8 °С. 
Keep out of reach of children. Do not freeze! Do not use the product which has 
been frozen. 
Shipping by all the types of roofed transport in lightproof containers temperature
of 2–8 °С in conditions excluding freezing.  Transportation is acceptable at a
temperature of ≤ 25 °C for 6 hours. 
Shelf life: 
1 year. Do not use the product after the expiry date. 
Manufacturer: 
NPO Petrovax Pharm, LLC, Russia 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 
2016  
 
 
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Grippol® Plus is a trivalent inactivated polymer-subunit influenza vaccine: 
INN or generic name:
Influenza vaccine [inactivated] + Azoximer bromide 
Dosage form: 
suspension for intramuscular and subcutaneous injection. 
Composition: 
One immunizing dose (0.5 ml) contains: 
Active ingredients: 
 Influenza type A virus (H1N1) antigen with hemagglutinin 
- 5 µg. 
 Influenza type A virus (H3N2) antigen with hemagglutinin 
- 5 µg. 
 Influenza virus subtype B antigen with hemagglutinin, 5 µg. 
 Polyoxidonium®, lyophilizate for the preparation of dosage forms and 
vaccines (Azoximer bromide), supplied by NPO Petrovax Pharm, LLC, 
Russia. 
Russia, 500 µg. 
Excipients: 
 Phosphate saline buffer solution up to 0.5 ml. 
Description: 
Colorless or yellowish, slightly opalescent liquid. 
Presentation: 
0.5 ml (1 dose) in ampules or vials, hermetically sealed with rubber stoppers and
crimped with aluminum caps. 
5 ampoules or vials are placed into a blister packaging of polyvinyl chloride film.
1 or 2 blisters together with Instruction on use per carton pack. 
Or 5 or 10 ampoules or vials without blister packaging are placed into a carton
pack with a package insert. 
Storage conditions: 
Store away from light at the temperature of 2 to 8 °С. 
Keep out of reach of children. Do not freeze! Do not use the product which has 
been frozen. 
Shipping by all the types of roofed transport in lightproof containers temperature
of 2–8 °С in conditions excluding freezing.  Transportation is acceptable at a
temperature of ≤ 25 °C for 6 hours. 
Shelf life: 
1 year. Do not use the product after the expiry date. 
Manufacturer: 
NPO Petrovax Pharm, LLC, Russia 
 
Packaging and labeling 
Upon arrival to the trial site, the primary and secondary packaging of the study drugs will be 
labeled in accordance with the requirements set forth in Federal Law No. 61 of the Russian 
Federation “On the Circulation of Medicines” and be marked “For clinical studies”. 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 
2016  
 
 
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Study vaccines in 0.5 ml ampoules will be supplied by NPO Petrovaks Farm, LLC in a package 
in accordance with the specification. Packages with the study drug were labeled as follows: 
Protocol: GriQv-III-16 
Study Drug: inactivated influenza vaccine  
Suspension for intramuscular and subcutaneous injection. 
1 ampule = 0.5 ml 
Shake before use 
Code of the study drug: 100, 200, or 300 
Volunteer ID (No.) 
Sponsor: NPO Petrovax Pharm, LLC 
1, Sosnovaya St., Pokrov village, Podolsk district, Moscow region, 142143, Russia  
Tel.: +7 (495) 730-75-45 
Trial site:  
Investigator: 
Batch: 
Date of issue:  
Expiry date: 
Store away from light at the temperature of 2 to 8 °С. 
Labeling: "For clinical studies only" 
Storage of study products 
Vaccines supplied for clinical studies should be kept in a restricted access area (i.e. in a locked 
cabinet) and in strict compliance with the conditions recommended by the manufacturer. The storage 
temperature should be checked and recorded daily. Dispensing and return of the unused product is 
reflected in the reports which were then transferred to NPO Petrovax Pharm, LLC. Vaccines and 
placebo should be stored in a place protected from light and inaccessible to children at a temperature 
of 2 to 8 °C (in the refrigerator). 
Do not use the product that has been frozen.  
Transportation is acceptable at a temperature of ≤ 25 °C for 6 hours. 
Responsibility for storage of the drug 
All vaccine samples for the clinical study are transferred to the trial sites and stored strictly in 
accordance with the documentation. Unused vaccine samples must be returned to NPO Petrovax 
Pharm, LLC. Principal investigator is in charge of the proper product storage at the trial site. 
The investigator should make accurate records of deliveries and release of the drug in a drug 
log. The accurate record containing the date and amount of drug administered to each volunteer 
should be available for inspection at any time. 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 
2016  
 
 
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All delivered drugs should be used only in accordance with this protocol, use for any other purpose is 
prohibited. 
3.5. 
The duration of participation of subjects in the study, a description of the sequence 
and duration of all study periods 
The duration of participation of subjects in the study is 183±5 days. The study includes 
Screening (days (-3)– 0), Vaccination and Post-Vaccination Observation and Efficacy / Safety 
Evaluation (Days 1–180 ± 5). 
3.6. 
“Rules of discontinuation” and “Exclusion criteria” for individual subjects, parts of 
a study or study in general 
Since the present study does not provide for interim analysis of efficacy or safety, the “rules of 
discontinuation” of the entire study are not defined for these parameters. 
If a volunteer withdraws participation from the study early, the investigator must document the 
reason for this withdrawal. Regardless of the reasons for why the volunteers drop out of the study 
early, they are not replaced since the sample size is calculated taking into account the early 
withdrawal of volunteers at a 5 % level. 
In order for the Sponsor to evaluate the benefit and risk ratio for study subjects, an investigator 
is obligated to immediately notify the project manager of the CRO or the Sponsor about all the health 
risks that have arisen for each specific study subject who dropped out of the study. The study subject 
should also be notified about any new information on the study drug. 
Early termination of the entire study: 
Early termination criteria of the study include, but are not limited to: 
 Sponsor's decision for medical or administrative reasons. The current review of medical data and 
information about the safety of study treatment together with the investigator is a standard 
procedure. As a result of this review, it may be decided to discontinue the study before all 
volunteers have completed it. 
 Inability to recruit the needed number of volunteers. 
In the event of early termination of the study, regardless of the reason for such decision, the 
sponsoring company will notify the investigator and the regulatory authorities in writing about study 
termination or suspension, indicating the reasons for its termination or suspension. LEC should be 
immediately notified about termination or suspension of the study with indication of the reasons for 
such decision. The investigator must immediately notify all volunteers and provide them with 
appropriate follow-up and, if necessary, further treatment. 

Protocol number: GriQv-III-16 
Date: version 3.0 dated November 18, 
2016  
 
 
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Early termination of the study in a trial site: 
Criteria for early termination of the study in a trial site include, but are not limited to: 
 The investigator is not complying with protocol requirements, the Helsinki Declaration, standards 
of the good clinical practice (ICH GCP) and the relevant requirements of regulatory authorities. 
 The researcher provides false or incomplete information about the study to the Sponsor, CRO, 
LEC or regulatory authorities (including repeated omission of data entry in the CRF). 
 The investigator cannot recruit the required number of volunteers within a specific period of time. 
 The investigator withdraws his/her consent for study participation. 
If the study is terminated prematurely or suspended for any reason, the investigator or the trial 
site should immediately notify the study subjects, verify the adequacy of their treatment and follow-
ups and, if required by law, inform the regulatory authorities. 
Early termination for separate volunteers: 
Volunteer's informed consent for study participation states that the volunteer has a right to 
terminate his/her participation in the study at any time and for any reason, and that the volunteer may 
terminate his/her participation in the study at the discretion of the investigator or the Sponsor, which 
should not affect the quality of medical care provided to him/her in the future. 
The investigating physician should exclude a volunteer from the study (criteria for early termination 
of study participation) in a case of: 
 Informed consent recall. 
 Occurrence of a severe AE or serious adverse events. 
 The volunteer is found to meet any of the non-inclusion criteria related to the safety of the 
volunteer participation in the study. 
 If a female-volunteer becomes pregnant. 
 The volunteer takes medicines not allowed in this study. 
 The volunteer is lost to follow-up. 
 In a situation, which, to the investigator's judgment, may adversely impact the volunteer if 
he/she continues participating in the study. 
 For administrative reasons (study termination by the Sponsor or regulatory authorities) or in 
case of major protocol violations which may significantly impact the study results. 

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If any of these events occur, the investigator, whenever possible, immediately conducts an early 
study termination visit for the volunteer to evaluate safety and efficacy parameters. 
The date of termination of study participation of a volunteer and the reason for early 
termination must be recorded in source documents and the CRF. 
If a female volunteer drops out due to pregnancy, the investigator provides the sponsor with the 
information about the outcome of pregnancy (see Section 7.3.5). 
Volunteers with unresolved adverse events are observed until the adverse event is resolved or 
until the condition is stabilized. 
3.7. Procedure for study drug accountability 
The investigator is responsible for drug accountability. The pharmacist or another authorized 
employee of the trial site must receive the study drugs, check the inventory, and fill out the drug 
receipt confirmation form. A copy of this form remains at the trial site, and the original must be sent 
to the sponsoring company or an organization authorized by it. In the course of the study, the 
pharmacist or another authorized employee of the trial site keeps records of the release of study drugs 
in a special log on drug release. The following information is recorded in this log for each volunteer: 
 
Volunteer's initials. 
 
Volunteer No. 
 
Study drug code (assigned to a volunteer during randomization). 
 
Time and date when the study drug was dispensed. 
 
Batch numbers of dispensed drugs. 
 
Expiry date of the dispensed drugs. 
 
Time and date when the study drug packages were returned. 
The drug release log is maintained and stored in such a manner that none of unauthorized 
persons have access to the information contained in this log. 
All primary and secondary packaging of study drugs, both used and unused, should be stored at 
the trial site for accounting. After the end of the study, the investigator must return all used or unused 
packages to the study Sponsor or its authorized organization. 
3.8. Storage of randomization codes and unblinding procedures 
The randomization scheme (randomization list in the IWRS system) will only be known to the 
Sponsor, the investigators will not be able to influence the group selection, to which a specific 
volunteer is assigned during randomization. 

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2016  
 
 
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If any of the members of the research team learn about accidental / intentional disclosure of the 
information as to which group a volunteer was randomized into, he/she should immediately notify the 
sponsor company. 
Procedure for unblinding of randomization codes 
In a case of a medical emergency (including pregnancy of a female volunteer), for which 
knowledge of the nature of study investigational drug is critical to further treatment, the investigating 
physician may send a request to the sponsor for disclosure of the code for this volunteer. Unblinding 
can be performed only if it is fully justified. In other cases, especially when an emergency situation is 
not clearly associated with the study drug, the problem should be solved based on the assumption that 
a volunteer is receiving an unauthorized study drug. 
At the request of the Principal Investigator, the sponsor company will inform the investigating 
physician on which vaccine a volunteer is receiving — the emergency unblinding procedure for the 
assigned vaccine through electronic randomization system (IWRS). Instructions for emergency 
unblinding procedure will be provided to the trial site along with guidance for use of IWRS. 
If it is not possible to contact IWRS for emergency unblinding, the Principal Investigator shall 
contact the Sponsor's representative. 
Emergency unblinding of the study therapy should be described and justified in volunteer's 
primary documentation and recorded in the appropriate section of the CRF. 
3.9. 
The list of all data recorded directly in the CRF and considered as source data 
All medical data about volunteers must first be recorded in the source documents on a paper or 
electronic medium and only then entered into the CRF. 
Baseline data is described in detail in Section 12.1. 
4. SELECTION AND EXCLUSION OF STUDY SUBJECTS 
4.1. 
Subject inclusion criteria 
1. Signed and dated volunteer's informed consent for participation in the study. 
2. Men and women from 18 to 60 years old. 
3. Healthy volunteers without signs of acute or chronic disorders, without history of chronic 
respiratory, cardiovascular, nervous system disorders, hepatic or renal disorders. 
4. Previously not immunized, or previous influenza immunization occurring ≥ 12 months before 
this study. 
5. Subjects without history of influenza within ≥ 12 months before this study. 

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6. Consent of volunteers (men and women) to use adequate methods of contraception (cervical 
caps with spermicide, diaphragms with spermicide, condoms with spermicide, intrauterine 
devices, oral contraceptives) or full abstinence for the whole period of the study. 
4.2. 
Subject non-inclusion criteria 
Specific: 
1. Contraindications listed in the protocol and prescribing information for inactivated influenza 
vaccines: 
- acute infections and non-communicable disorders, including the period of reconvalescence of 
at least one month from the time of clinical and laboratory evidence of recovery; 
- hepatitis or meningococcal infection occurred less than 6 months after recovery; 
- exacerbations of chronic disorder or decompensated disorders that may impact the study 
(organic central nervous system disorders, decompensated cardiovascular disorder, acute renal 
or hepatic failure); 
- malignant neoplasms (including hematological disorders); 
- primary immunodeficiency (laboratory-confirmed); 
- HIV infection or HIV-associated disorders; 
- systemic disorders of connective tissue; 
- haemophilia (and other blood coagulation disorders); 
- severe neurological disorders; 
- Guillain–Barré syndrome (post infection demyelinating polyradiculoneuropathy of 
autoimmune nature with peripheral limb muscle palsy related to inflammation and destruction of 
myelin sheath of peripheral nerves; may acquire an ascending nature, involving muscles of face, 
pharynx, larynx); 
- history of severe vaccine-associated reactions (body temperature exceeding 38.5 °С) or local 
reactions (hyperemia and/or oedema at the site of injection of over 5 cm in diameter); 
- history of severe allergic disorders (angioedema, polymorphic exudative erythema, serum 
disease, etc.); 
- hypersensitivity to chicken protein or vaccine components; 
- blood and components transfusion within the last 6 months. 
2. Indications for immunomodulating therapy. 
3. Body temperature over 37.0 °С at screening or before injection. 
4. Potential evidence of a chronic infection (periodic episodes of fever within the last 6 months), 
or antiviral (and/or antibacterial) treatment indicated. 
5. History of disorders or conditions, which, according to investigator's judgment may impact 
the thermal regulation (chronic infections, neuroendocrine disorders [thyrotoxicosis, 
pheochromocytoma, etc.], climacteric syndrome, malignant hyperthermia, CNS disorders, 

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2016  
 
 
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malignant neoplasm, connective tissue disorders, systemic vasculitis, and information on 
excessive physical stress or work-rest regimen deviations [within the last 2 months: night 
shifts, significant change of time zones, overheating]). 
6. Use of antipyretics (including non-steroidal anti-inflammatory drugs and anilides) within 24 
hours before randomization. 
7. Surgical interventions within less than 90 days before the screening visit. 
8. Systolic blood pressure of over 130 mm Hg or less than 100 mm Hg and/or diastolic blood 
pressure of over 90 mm Hg or less than 60 mm Hg. 
9. Any other disorder, which, in the opinion of the investigator, may prevent inclusion of the 
volunteer due to safety reasons or may impact the study results. 
 General: 
10. Pregnant and nursing women. 
11. Lack of ability to visit daytime inpatient facility according to the study schedule, 
unavailability for adequate follow-up of the volunteer. 
12. Body mass index of less than 18.5 or over 30.0 kg/m2 based on the weight-height Quetelet's 
index. 
13. Participation in another clinical study of medicinal drugs within 3 months before the start of 
this study. 
14. Mental, physical, or other reasons which prevent adequate assessment of own behavior and 
prevent from meeting the study protocol conditions. 
15. History of narcotic and/or drug abuse, and/or inhalant addiction, current signs of alcoholic 
intoxication. 
16. Intake of at least 5 alcohol units per week or history of alcohol, drug, or medicinal product 
abuse. One alcohol unit corresponds to 360 ml of beer, 120 ml of wine, or 30 ml of a strong 
alcoholic beverage. 
17. Suspected lack of compliance with treatment or inability to undergo treatment and observe the 
limitations according to the study protocol. 
18. Volunteers acknowledged by the court to be disabled or under guardianship. 
19. Any other conditions that make the volunteer ineligible for the study according to a justified 
opinion of the study doctor or Sponsor. 
4.3. Subject exclusion criteria 
Volunteer exclusion criteria are provided in Section 3.6. 

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5. 
TREATMENT (VACCINATION) OF SUBJECTS 
5.1. 
Treatment (vaccination) with study drugs 
Name, description, and dosages of vaccines are provided in Section 3.4. 
The investigator or an authorized person will be responsible for controlling the administration 
of the vaccine to enrolled study participants in accordance with the procedures defined in this study 
protocol. All vaccines will be administered only by staff members that have the right to perform this 
function in accordance with applicable local laws and trial site rules. 
Detailed instructions for preparing and administering the vaccine will be provided to 
investigators in additional documentation prior to study initiation. 
The vaccine cannot be used in the following cases: 
- when the ampoule is damaged; 
- when foreign matter is present; 
- in case of a missing label or missing information from it; 
- in case of violation of storage conditions. 
Dosing: All the vaccines used in the study are administered as a single intramuscular injection 
of 0.5 ml (1 dose) into the upper third of the outer surface of the shoulder (the deltoid muscle). The 
exact anatomical site of each injection must be carefully recorded in the medical record and 
transferred to the CRF. 
Standardized immunization practices should be strictly followed, and the vaccine should be 
administered intramuscularly. DO NOT INJECT intravenously. Before vaccine administration, the 
vaccination site should be disinfected with an appropriate skin disinfectant (70 % ethyl alcohol). Wait 
until the skin is dry. After vaccine injection, the vaccination site shall be wiped again with 70 % ethyl 
alcohol. 
As with all injectable vaccines, trained medical personnel with proper medical treatment should 
be available if anaphylactic reactions should occur after vaccine administration. For example, a 
1:1,000 solution of epinephrine, diphenhydramine, and/or other drugs for the treatment of 
anaphylaxis should be available. 
In case any foreign particles are detected, and/or any changes in the appearance of the vaccine 
are observed, the vaccine should not be administered to the participant, and the issue should be 
reported to the manufacturer. The vaccine should not be discarded without sponsor's permission. Any 
unused medication or waste must be disposed of in accordance with the local regulations. 
Administration error and overdose: 
This study is designed for a one-time intramuscular injection of vaccine. The erroneous 
administration of vaccine is defined as the administration of a the vaccine under study in a dosage 
that does not comply with the instructions or inappropriate mode of administration. An overdose of 
study vaccine (accidental or deliberate) is defined as the administration of a dosage exceeding a 

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single recommended dose of study vaccines. 
Any erroneous administration or an overdose of study vaccine must be registered as an adverse 
event, and if the erroneous administration of the vaccine or an overdose cause a severe response, the 
Sponsor should be informed within 24 hours. 
5.2. 
Drugs / treatments that are permitted or not permitted before and / or during the 
study 
5.2.1. 
Contraindicated drugs and treatments 
The use of the following drugs (regardless of the mode of administration) and treatment methods is 
prohibited during the study: 
 only at screening and on the day of immunization: 
- 
antipyretics (including non-steroidal antiinflammatory drugs and anilides); 
- 
any drugs or food supplements which, according to the investigator's judgment, may affect the 
body temperature of the volunteer (including caffeine); 
- 
physiotherapeutic procedures. 
 For the whole period of the study: 
- 
medicinal products suppressing central nervous system functions (barbiturates, opiates, 
sedative drugs), tranquilizers, neuroleptics, tricyclic antidepressants etc.; 
- 
cytotoxic drugs; 
- 
anticoagulants (including warfarin), antiagregants (including clopidogrel, acetylsalicylic acid). 
Hormonal contraceptives or hormone replacement therapy is only allowed if the female volunteer has 
been on a stable dosing regimen maintained for at least 6 months before the screening visit and 
remains on a stable dosing regimen for the whole study period. 
5.2.2. 
Permitted drugs and treatments 
All unprohibited products and treatments are allowed. 
5.3. 
Methods of control of compliance with procedures ans subjects 
For the whole post-immunization follow-up period, the study subjects had to log in their 
volunteer's diaries information on the body temperature, any adverse events, and treatment with any 
medicinal drugs. At Visits 2–8, the investigator reviews the volunteer's diary and assesses the 
incidence and severity of adverse reactions, as well as the volunteer's compliance with the rules of 
concomitant therapy. 
Additionally, the investigator assesses the regularity of the subject's visits to the trial site. The 
investigator can withdraw the subject from the study in case of subject's non-compliance with the 
requirements to concomitant therapy or if the study subject was not able to comply with the medical 
recommendations, in the investigator's opinion. 

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Study protocol does not provide for self-administration of the study products, the single dose 
immunization is performed at the trial site. The trial site personnel has to ensure that all the 
procedures related to the study product accountability are complied with (see Section 3.7). 
As some of the study procedures (e.g., recording of AEs, blood sample collection, urine sample 
collection, vital signs measurement, physical examination, neurological examination, etc.) are 
performed by the investigator or another authorized personnel of the trial site at the study Visits, no 
methods of compliance control for such procedures are required. 
6. EFFICACY EVALUATION 
6.1. List of efficacy parameters 
Parameters of immunogenic activity and efficacy are listed in Section 3.1. 
6.2. Methods and terms of evaluation, recording and analysis of efficacy parameters 
Evaluation of efficacy parameters includes the following procedures: 
 serum antibody to antigens titer test: influenza virus type А — H1N1, influenza virus type А — 
H3N2, influenza virus type В — Yamagata and Victoria lineages prior to and at Day 21 after 
immunization; 
 influenza and ARI incidence recording within 6 months after immunization; 
 evaluation of severity and duration of reported cases of influenza and ARI, complications. 
Serologic testing (serum antibody titer test): 
Immunological efficacy (antigenic activity) of the vaccine is evaluated by its ability to induce 
the specific immune response, which can be identified under laboratory conditions by serum antibody 
titer to each antigen. 
Antibody titer is determined using the hemagglutination inhibition reaction (HAIR), the method 
recommended by the WHO for influenza vaccine efficacy evaluation. The study is conducted at the 
central laboratory. As an additional method for 150 volunteers (50 volunteers in each group), a 
microneutralization assay is planned (the data will be used to evaluate seroprotection). The detailed 
description of the study methods is provided in the laboratory guide. 
Blood samples for antibody titer test and calculation of mean geometric antibody titer will be 
collected for determination of background antibody titer after the immunization (Visit 0, Screening) 
and evaluation of functional immune reaction three weeks after immunization (Visit 7, Day 22±1). 
Study parameters: 
 The share of subjects achieving seroconversion (the number of volunteers with antibody titer 
[of at least 1:40] increased more than 4-fold versus baseline [assessed by HAIR]) for antigens: 
influenza virus type А — H1N1, influenza virus type А — H3N2, influenza virus type В — 
Yamagata and Victoria lineages. 

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 Coefficient of increase of mean geometric antibody titer (antigens H1N1, H3N2, Yamagata 
and Victoria lineages) (assessed by HAIR). 
 Geometric mean of serum antibody to antigens titer (assessed by HAIR): influenza virus type 
А — H1N1, influenza virus type А — H3N2, influenza virus type В — Yamagata and 
Victoria lineages. 
 Seroprotection: share of subjects achieving protective antibody titer (1:40 and more, assessed 
by HAIR and microneutralization test) to antigens H1N1, H3N2, Yamagata and Victoria 
lineages. 
The detailed instruction on blood and serum sampling, labeling of tubes, storage and 
transportation of samples is presented in a separate laboratory guide provided by the central 
laboratory. 
Influenza and ARI incidence recording: 
Influenza and ARI incidence recording is performed during 6 months after immunization by 
means of follow-up and telephone calls to the study subjects. 
A case of influenza and ARI is considered as a case of flu-like symptoms (according to: ECDC 
TECHNICAL DOCUMENT Protocol for case-control studies to measure pandemic and seasonal 
influenza vaccine effectiveness in the European Union and European Economic Area Member States 
/ European center for Disease Prevention and Control, 2009): 
if a subject seeks physician's advice regarding unexpected occurrence of 
- at least one of four systemic symptoms: 1) chills or fever, 2) distress, 3) headache, 4) myalgia 
and 
- - of at least one of three respiratory symptoms: 1) cough, 2) sore throat, 3) respiratory 
distress. 
Evaluation of severity and duration of reported cases of influenza and ARI, complications: 
When recording a case of influenza or ARI, a study doctor will perform an evaluation of its 
duration, making additional telephone calls, where necessary, and determine its severity. In this 
study, a case with at least one of the complications listed below will be considered severe: 
- the necessity of hospitalization, 
- influenza-associated pneumonia, 
- influenza-associated cardiovascular disorder, 
- death. 

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7. SAFETY EVALUATION 
7.1. Review of the safety parameters 
Safety parameters are listed in Section 3.1. 
7.2. Methods and terms of evaluation, recording, and analysis of safety parameters 
Evaluation of local and systemic reactions, as well as AEs, will be performed from the moment 
of immunization and within 6 months of follow-up. Recording of safety parameters will include the 
following procedures: 
 clinical interview of a study subject; 
 recording of thermometry results and complaints of a study subject related to his/her medical 
condition in a volunteer's diary; 
 physical examination (including neurological status); 
 vital signs; 
 laboratory investigations 
- complete blood count and blood chemistry; 
- urinalysis; 
- evaluation of immunological parameters: serum immunoglobulin content (ELISA: IgE); 
 quantitative assessment and nature (severity and duration) of local and systemic reactions to 
vaccine administration (reactogenicity); 
 recording of AEs and SAEs associated with the study vaccines; 
 recording of immediate type AEs, emerging within one hour after immunization; 
 evaluation of incidence and nature of intercurrent disorders. 
Clinical interview of a study subject: 
During Visits 1–11 (post-immunization) the investigator shall perform a clinical interview of a 
study subject to collect information on the study subject's medical condition. At that, the investigator 
shall ask a study subject the following routine question at every visit: 
"Have there been any changes in your condition since our last conversation / meeting?" 
Clinically significant symptoms will be recorded by the investigator in the source medical 
documentation and CRF as AEs. 
Recording of thermometry results and complaints of a study subject in a volunteer's self-
observation diary: 
A study subject will record axillary temperature in a self-observation diary every day, in the morning 
and in the evening, starting from Visit 1 after immunization and till Visit 7 (further measurements — 
depending on condition). He/she will also record concomitant therapy and complaints related to 
his/her medical condition during the day (if any); to do so, a subject will be offered to answer the 

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following question in the volunteer's diary in writing: 
"Have there been any changes in your condition since yesterday?" 
Clinically significant symptoms will be recorded by the investigator in the CRF as AEs. 
Physical examination (including neurological status): 
The investigator shall perform complete physical examination of a study subject during Visits 
0, 1, 2, 3, 4, 5, 6, and 7. Apart from that, neurological examination (recording of neurological status) 
will be performed by a neurologist during Visits 1 and 3. Height and weight measurements of a 
study subject will only be taken during Screening visit. Clinically significant deviations identified 
during physical and neurological examination will be recorded by the investigator in the primary 
medical documentation and CRF as AEs. 
Vital signs: 
During the Screening visit and Visits 1, 3, 6, and 7, the investigator shall measure the 
following vital signs: SBP, DBP, heart rate. Clinically significant deviations of vital signs will be 
recorded by the investigator in the source medical documentation and CRF as AEs. 
Laboratory investigations: 
Blood and urine samples of a study subject will be collected during the Screening visit and 
Visits 3 and 7 for laboratory safety studies. Valid certificates of laboratories conducting laboratory 
tests and their norms are included in the study archive. The investigator is responsible for evaluation 
of all laboratory investigation results of the study subjects, as well as evaluation of clinical 
significance of any deviations of laboratory parameters. Clinically significant deviations of 
laboratory analyses results are recorded by the investigator in the primary medical documentation 
and CRF as AEs. 
Laboratory investigation parameters for treatment safety evaluation are presented in Table. 
Table 3. Laboratory investigation parameters for treatment safety evaluation. 
 
Laboratory investigation 
Visits 
Parameters 
Complete blood count 
Screening, Visits 3 and 7
hemoglobin, RBC, hematocrit, PLT, WBC and WBC differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), 
ESR 
Blood chemistry 
Screening, Visits 3 and 7
glucose, urea, creatinine, total bilirubin, total protein, ALT, 
AST, AP 
Urinalysis 
Screening, Visits 3 and 7
relative density, protein, sugar, RBC, WBC 

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Table 3. Laboratory investigation parameters for treatment safety evaluation (continued). 
 
Laboratory investigation 
Visits 
Parameters 
Infection blood test 
Screening 
RW blood test, HBV, HCV, HIV infection tests 
Determination of blood 
immunoglobulin levels 
Visits 1 and 7 
Immunoglobulin Е (IgE) 
 
Assessment of local and systemic reactions to vaccine administration (reactogenicity) 
For assessment of local and systemic reactions to vaccine administration, the results of daily 
examinations are recorded in a Case Report Form and an Outpatient Medical Record for each 
subject. Particular attention is paid to symptoms corresponding to clinical manifestations of 
influenza, allergic and neurological reactions. A local reaction is evaluated by the diameter of a 
hyperaemic 
skin 
area 
at 
the 
injection 
site, 
skin 
tenderness 
and 
oedema, 
and 
enlargement of regional lymph nodes. 
The assessment is performed before immunization, 2 hours after immunization, then once a 
day for 5 post-immunization days; thermometry is mandatory. Subjects who responded to the 
vaccination are monitored until these reactions pass off completely. In case of development of any 
unusual reactions the subject will be examined by an appropriate specialist. The following 
parameters are used for evaluation of tolerability of the study drugs. 
Local reactions:  
1. Pain at the injection site  
2. Redness (mm)  
3. Swelling, induration (mm)  
4. Infiltrate (mm) 
5. Itch 
6. Enlargement of regional lymph nodes 
Systemic reactions: 
1. Increase of body temperature over 37 ˚С  
2. Malaise 
3. Headache  
4. Sleep disturbance  
5. Appetite disturbance  
6. Nausea 
7. Vomiting 
8. Abdominal pains  
9. Stuffy nose  

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10. Cough  
11. Pharynx hyperaemic 
12. Increased sweating  
13. Tremor 
14. Myalgia, arthralgia. 
The nature and duration of immunization reactions in vaccinated subjects is compared upon 
interpretation of all study materials. An analysis of this data will make it possible to formulate a 
conclusion and resolve the issue of tolerability of study vaccines. 
The course of the post-immunization period is assessed as smooth or complicated. Complicated 
course of the post-immunization period is considered as integration of intercurrent diseases after 
immunization. The absence of intercurrent diseases is considered as smooth post-immunization 
period. Fever responses were classified by temperature increase as follows: mild (low-grade fever up 
to 37.5 °С), moderate (temperature rise from 37.6 °С to 38.5 °С), and severe (temperature rise above 
38.6 °С). 
Local immunization reactions are classified as mild, moderate, and severe. Erythema without 
infiltration up to 50.0 mm in diameter at the injection site or infiltration up to 25.0 mm in diameter is 
estimated as a mild local reaction; erythema with a diameter more than 50.0 mm or an infiltrate with a 
diameter 26.0 to 50.0 mm was estimated as a moderate local reaction; infiltration more than 50.0 mm 
in diameter was estimated as a severe local reaction (Methodological Guidelines MU 3.3.2.1758-03 
"Methods for determination of quality indicators of immunobiological products for prevention and 
diagnostics of influenza"). When the reaction is free of redness and/or infiltration, the reaction 
severity is accepted as indeterminate. 
Local reactions will be assessed in all subjects, since local reactions were directly related to 
the administration of the vaccine. 
Occurrence of general symptoms on the first 3 days after (and even on the day of 
immunization) may be associated with immunization (systemic reactions). However, it does not rule 
out their causal relationship with diseases, accidentally occurring within the first days of post-
immunization period. 
According to the accepted methods of interpretation of the vaccinial process course, assessment 
of general reactions will only be performed in volunteers with a smooth course of vaccinial process, 
because in a complicated course of post-immunization process, the observed symptoms may be 
associated with an intercurrent disease rather than with immunization. Thus, in case of development 
of an infectious intercurrent disease, including ARD/ARI in a volunteer within the first days after 
immunization, the general symptoms observed should be excluded from systemic reactions recorded 
within the first 5 days. 
*List of references: 
Tatochenko V.K., Ozeretskovskiy N.A. Immonoprophylaxis-2009: Reference book. / – М: Publishing 

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and Printing Complex KONTINGENT-PRESS, 9th Edition, 2009 
Lokotkina Е. А., Kharit S.М., Chernyaeva Т. V., Brusov N.К. Post-vaccination complications 
(clinical presentation, diagnosis, treatment, prevention). Physician Guideline. Edited by Ivanova V. 
V. SPb, 2004, p. 79 
Briko N.I. Ensuring the safety of immunization is one of the main criteria for the quality of vaccine 
prevention / Attending Physician. 2015. No. 7. P. 74. 
Kharit S.М. Vaccine prevention: problems and prospects. Infectology Journal. 2009;1(1):61-65. 
7.3. Reporting requirements, procedures for recording and reporting of adverse events 
and intercurrent diseases 
An adverse event (AE) is any adverse change of a study subject's condition upon 
administration of the medicinal product, irrespective of the casual relationship with its administration. 
AEs include all adverse and unintended changes (e.g., deviation of a laboratory parameter), 
symptoms or diseases, where the time of occurrence does not rule out the casual relationship with 
administration of the medicinal product (manifestations absent in a subject prior to enrollment and 
developing during participation in a study, or manifestations observed in a volunteer prior to 
enrollment, the severity of which increases during the study upon administration of study products), 
irrespective of relationship with administration of the medicinal product. 
An adverse drug reaction (ADR), with regard to pre-approval clinical use of a new medicinal 
product, includes all negative reactions associated with administration of any dose of the medicinal 
product. The term "associated with administration of the medicinal product" means at least a 
minimum possibility of presence of a causal relationship between the medicinal product and the 
adverse event, i.e. correlation cannot be excluded. For registered medicinal products, the term 
"adverse drug reactions" means all negative reactions associated with administration of the medicinal 
product in standard doses used for prevention, diagnostics, or treatment of diseases, as well as for 
modification of physiological functions. 
7.3.1. 
Recording of adverse events 
Procedures for recording the AEs are described in Section 7.2. AEs are recorded in the source 
medical documentation of a study subject, as well as in the respective sections of the CRF. Adverse 
events are recorded from the moment of administration of the first dose of the study product till the 
Study end visit. 
The following information should be specified during recording of AEs: 
 Nature of AEs (preferably with indication of the diagnosis, rather than the list of symptoms). 
 Time of AE onset (day, month, year, hour, minute, where possible). 
 Time of AE resolution (day, month, year, hour, minute, where possible). 
 Severity of AE (mild, moderate, severe). 

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 Association with the study drug administration (doubtful, possible, probable, definite). 
 Incidence of AEs (single, intermittent); 
 Measures taken with regard to AE (none, change of the study drugs dosing regimen, suspension of 
the study drugs administration, withdrawal of the study drugs, concomitant therapy); 
 Compliance of AE with SAE criteria (see Section 7.3.2; yes, no). 
 Outcome of AE (resolved without residual complications; resolved with residual complications; 
observed during the Study end visit; death of a study subject; lost to follow-up; stabilization of AE 
and its consequences). 
The investigator should try to establish the diagnosis based on the signs, symptoms, and other 
clinical information. If a diagnosis is determined, then the diagnosis itself should be recorded as an 
AE. If the diagnosis is unknown, then each complaint and symptom must be recorded as a separate 
AE. 
7.3.1.1. 
Evaluation of severity of adverse event 
The investigator should assess the severity of each AE using the following AE severity 
classification: 
 mild: with or without symptoms, which are easily tolerated without treatment; 
 moderate: minimum or local non-surgical treatment is indicated, may interfere with daily 
activities; 
 severe: may interfere with daily activities, may require hospitalization or extension of existing 
hospitalization. 
If severity of the AE changed in the course of its development, maximum severity should be 
reported. 
7.3.1.2. 
Evaluation of casual relationship between the adverse event and 
administration of the study product 
All available information which could help to reveal the causal relationship between the AE and 
the study product should be considered during evaluation of this relationship, namely: 
 mechanism of action of the study product; 
 information on known side effects according to the study protocol, investigator's brochure, and 
draft instruction for medical use of the product; 
 characteristic of AE; 
 temporal association of AE with the product administration; 
 time of AE resolution; 

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 AE resolution upon withdrawal of the product or down titration; 
 administration of other medicinal products or effect of chemical substances; 
 natural course of the main disease or other conditions; 
 study procedures; 
 effect of other factors. 
Based on analysis of the obtained information, the investigator will determine the causal 
relationship between the AE and the study product using one of the following categories: 
 Doubtful: Clinical manifestations of AE occur in absence of a clear temporal association with the 
product administration. Other factors (medicinal products, diseases, chemical substances) which 
may cause their occurrence are observed. 
 Possible: Clinical manifestations of AE have a temporal association with the product 
administration, but they can be attributed to concomitant diseases or administration of other 
medicinal products and to the effect of chemical substances. Information on a reaction to the 
product withdrawal is ambiguous. 
 Probable: Clinical manifestations of AE have a temporal association with the product 
administration, can hardly be attributed to concomitant diseases or other factors and decrease after 
the product withdrawal. The response to re-challenge of the product is unknown. 
 Definite: Clinical manifestations of AE occur during the product administration and cannot be 
attributed to existing diseases and the effect of other factors. Manifestations of ARs decrease after 
the product is discontinued and reoccur upon its re-initiation. 
AEs with a doubtful casual relationship with the study product are considered as not associated 
with the study product administration. AEs with a possible, probable, or definite casual relationship 
with the study product are considered as associated with the study product administration. 
7.3.2. 
Serious adverse events 
A SAE is any AE corresponding to one or several criteria listed below: 
 AE causing death of a volunteer. 
 AE posing a threat to life of a volunteer. 
 AE requiring hospitalization of a study subject or leading to extension of existing hospitalization, 
except for: 
- 
Optional treatment. 
- 
Monitoring of the study disease. 

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- 
For procedures as per the protocol, not associated with a deterioration in a volunteer's condition. 
- 
Treatment of the existing disease, associated or not associated with the study disease, which has 
not worsened after administration of the first dose of the study product. 
- 
Treatment received in an emergency unit due to an event which does not comply with the above 
mentioned criteria and which did not lead to hospitalization. 
 AE leading to permanent or pronounced incapacity for work or disability. 
 AE leading to congenital abnormalities / developmental diseases in children whose parents were 
exposed to the study product. 
Apart from that, SAEs may include important medical manifestations in case when, based on 
the investigator's medical experience, such manifestations, if left untreated, may lead to one of the 
outcomes described above. 
Death of a study subject is considered as an outcome of the AE. In case of death of a study 
subject, the investigator has to report medical condition of the study subject or the event causing the 
death, e.g., a disease, an accident, etc. as an SAE. 
AE is considered as "posing a threat to life of a study subject" if it constitutes immediate danger 
to life of a study subject at the time of its development. This category does not include AEs, which 
could theoretically lead to subject's death if their severity was higher. 
According to SAE criteria, hospitalization is considered as inpatient treatment for more than 
one calendar day, i.e. a hospital stay for at least one night. 
7.3.3. 
The investigator's responsibilities for submission of reports on serious adverse 
events 
Completion of SAE report form: 
In case of development of SAE, the investigator or other authorized employee of the trial site 
has to complete the SAE report form with indication of information on this case. SAE report forms 
will be provided to investigators during the training on completion of SAE report form. The 
information stated in the SAE report has to correspond to the data provided in CRF sections "Adverse 
events", "Concomitant therapy", and "Results of laboratory investigations". SAE has to be included in 
source medical documents of a study subject. 
Report on SAEs: 

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The investigators has to report in a prompt manner on all cases of SAE developing in study 
subjects from the moment of administration of the first dose of the study product until the Study end 
visit. 
When reporting on the SAE, the investigator has to complete an SAE report form and send it to 
the sponsor's contact person by fax or send a scanned copy of the report by e-mail within 24 hours 
from recording of SAE. 
All serious adverse events have to be reported on in a prompt manner by 
sending a completed SAE report form to the sponsor's contact person by fax 
and/or e-mail: 
Anna Viktorovna Tsymbal 
Tel.: 8-800-234-44-80 
Tel.: (495) 730-75-45 (+114) 
e-mail: TSymbalAV@petrovax.ru 
22, Krasnaya Presnya Str., 123022, Moscow, Russia 
 
Before sending a report about an SAE, the study monitor should be notified by phone about the 
submission of the fax. 
The SAE report has to be prepared irrespective of relationship, detected by the investigator or 
an authorized employee, between the observed SAE and administration of the study product. 
After submitting an urgent SAE report, the investigator must, within 48 hours, submit a detailed 
report with detailed information on SAE to the study sponsor, which will allow the latter to make an 
assessment about the need to review the benefit-risk ratio of the clinical study. 
If an SAE associated with administration of the study product is recorded in a study subject, it 
has to be reported even if the study has been completed. 
All SAEs and their complications have to be monitored up to their resolution or stabilization of 
a study subject's condition. 
7.3.4. 
The sponsor's responsibilities for submission of SUADR reports and other 
safety reports 
Reporting of SUADRs: 
A serious unexpected adverse drug reaction (SUADR) is an SAE associated with the study 
product administration, i.e. a reaction the nature and severity of which does not correspond to the 
known information on the medicinal product. The following documents shall be used for 
determination of predictability of the SAE: investigator's brochure, draft instruction for medical use, 
and the study protocol. 

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Pharmacovigilance officer of the sponsor company has to send express reports on SUADR to 
LECs of trial sites and to regulatory authorities. Pharmacovigilance officer of the sponsor company 
also has to inform the investigators on all SUADRs recorded during the study. 
Reports on SUADRs causing death or posing a threat to life of a study subject has to be sent to 
LECs of trial sites and to regulatory authorities within 7 calendar days from the date of receipt of the 
investigator's SAE report. If full information on a death or development of a life-threatening 
condition is not available to the sponsor as of the date of the urgent report, the sponsor has to take all 
measures to obtain full information provided in the form of a subsequent urgent report on identified 
SUADRs within 8 calendar days from the date of submission of initial report. 
Reports on all other SUADRs have to be submitted by the study sponsor to LECs of trial sites 
and to regulatory authorities within 15 calendar days from the date of receipt of the investigator's 
SAE report. 
If new significant information on identified SUADR becomes available to the sponsor, this 
information has to be provided in the form of a subsequent report within 15 calendar days from the 
date of its receipt. 
Requirements to submission of information on SUADR applied to the study product, including 
the study quadrivalent vaccine. 
Submission of other treatment safety reports: 
Within 15 calendar days from the date of receipt of the information, the sponsor has to provide 
regulatory authorities and LECs of trial sites with other safety information which can affect 
evaluation of the risk-benefit balance associated with the treatment performed or can require 
significant modifications of the treatment performed during the study or the study methods. This 
safety information may include: 
 Clinically significant increase of the expected rate and a change in the nature of the expected 
serious adverse reactions. 
 SUADRs that occur in a study subject after completing the participation in a clinical study. 
 New data related to the clinical study that may affect the safety of volunteers, such as: 
- 
Study-related SEAs, on the basis of which changes are required to study protocol. 
- 
The lack of effectiveness of the study drug used in a life-threatening pathology. 
- 
New important safety data from recently completed animal studies (identified carcinogenic 
effects and effects similar in severity and importance). 

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- 
Premature study termination or suspension of the study in another country (countries) due to a 
change in the safety profile of a similar study drug. 
- 
Other safety data that alter the benefit-risk profile for study subjects. 
 Recommendations of the independent evaluation committee of the results of a clinical study 
regarding the safety profile of a study drug. 
Apart from submission of urgent reports, the sponsor company has to submit an annual periodic 
report on safety of the study product to regulatory authorities during the whole period of the clinical 
trial. 
Information on the periodic report on safety of the study product is submitted to LECs of trial 
sites in the form of a brief description of the report basic content with an organized list of serious 
adverse drug reactions attached. 
7.3.5. 
Pregnancy 
If a female volunteer becomes pregnant while participating in the study, administration of the 
study drug must be discontinued immediately. 
Pregnancy as such is not an AE except in cases where there is a reason to believe that the use of 
the study drug led to a decrease in the efficacy of contraceptives. Congenital abnormalities and birth 
defects in children of study subjects are considered SAEs. Medical abortions, as well as any serious 
complications during pregnancy (including spontaneous abortions) should be recorded as SAEs. 
Planned abortions without complications are not considered AEs. 
All cases of pregnancy observed during the study (including cases of pregnancy of sexual 
partners of volunteers participating in the study) should be appropriately recorded. If a pregnancy is 
confirmed, the investigator must notify the sponsor's authorized representative on pharmacovigilance 
in the form of a pregnancy report. Then, the sponsor shall be provided with the information about the 
pregnancy outcome. Pregnancy of a study participant and sexual partners of male volunteers is 
recorded from the moment of the first injection of the study drug and until the Visit of study 
completion. 
The outcome of each pregnancy (spontaneous abortion, elective abortion, birth of a normal 
child or a child with congenital anomalies or birth defects) must be recorded, even if the female 
volunteer has terminated her participation in the study. 
7.4. The method and duration of observation of subjects after the occurrence of adverse 
events 
If AEs or their complications are not resolved, the investigator has to conduct a follow-up of 
study of subject's condition. Follow-up has to be conducted until resolution or stabilization of the AE 
and its consequences in a condition considered as appropriate by the investigator or until the 
identification of the cause of the AE not associated with the study product administration. 

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8. STATISTICAL ASPECTS OF CLINICAL STUDY 
8.1. Description of statistical methods 
Descriptive statistics will be provided for all demographic and other baseline characteristics, 
immunogenicity, efficacy, and safety, as well as for changes (if applicable) in the course of the study 
for the time points of assessment and for therapeutic groups (groups A, B, C, and pooled B and C 
group). Descriptive statistics for quantitative variables will include mean, standard deviation (SD), 
median, first and third quartiles, minimum and maximum, and the number of valid observations. 
Qualitative parameters will be shown as frequencies and shares in per cent. 95 % confidence intervals 
around point estimate are also provided (where applicable). Descriptive statistics for immunogenicity 
and immunological efficacy parameters will be provided for antigens. 
Efficacy analysis 
The following immunogenicity parameters will be presented with the respective two-sided 95 
% confidence intervals for antigens and therapeutic groups: 
Before and after immunization: 
 Geometric mean antibody titers (GMAT). 
 The share of subjects achieving seroconversion.  
After immunization: 
 The share of subjects achieving seroconversion. 
 Coefficient of increase of mean geometric antibody titer versus baseline before immunization 
(GMAT ratio before and after immunization). 
Efficacy parameters will be evaluated by available data, without restoration of missing data. 
Testing of statistical hypotheses will be performed for Group A (Grippol® Quadri vaccine) as 
compared with: 
 pooled data of groups B and C (Grippol® Plus) for antigens H1N1 and H3N2, separately for 
each antigen; 
 data of group B for Yamagata lineage antigen; 
 data of group C for Victoria lineage antigen. 
Primary variable 
For comparison, the primary change in the proportion of persons with seroconversion (the ratio 
of the number of volunteers in whom the antibody titer [at least 1:40] increased by more than 4 times 
compared with the baseline [method of determination — hemagglutination-inhibition reaction]) 
according to an assessment 21 days after vaccination (Visit 7, Day 22 ± 1) the statistical hypothesis 
will be tested that the study vaccine is “not worse than” the comparator vaccines with an established 
15 % limit of “not worse”. 

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H0: π1-π2 ≥ 0.15 HА: π1-π2 < 0.15, 
π1 и π2 – the share of subjects achieving seroconversion for the reference vaccine and the test 
vaccine respectively. 
The numbers of subjects achieving seroconversion according to the evaluation at Day 21 after 
immunization are presented with the respective two-sided 95 % confidence intervals for each antigen, 
by therapeutic groups. Testing of the hypothesis will be performed by calculation of two-sided 95 % 
confidence interval for the difference of shares based on logistic regression with the vaccine as a 
fixed factor and the baseline antibody titer as a covariate. The clinical center, sex, and age will also be 
considered as potential factors of the model. The conclusion that the test vaccine is not inferior to the 
comparator for the primary endpoint, the percentage of subjects achieving seroconversion according 
to the assessment on Day 21 after immunization will be made if the upper limit of the calculated 95 % 
confidence interval does not exceed the established limit of 0.15 (15 %). The calculation of the exact 
two-sided 95 % confidence interval for the difference in proportions will be presented as a supporting 
analysis. In case of proven non-inferiority of the test vaccine versus the reference vaccines for 
Yamagata and Victoria lineages antigens, the same two-sided 95 % confidence interval will be used 
for testing of the hypothesis of predominant efficacy of the test vaccine for the primary endpoint, the 
share of subjects achieving seroconversion according to the evaluation on Day 21 after immunization. 
The conclusion on predominant efficacy of the test vaccine can be made if the upper limit of the 
calculated 95 % confidence interval does not exceed 0. Since a statistically significant conclusion 
when testing "non-inferiority" hypotheses should be obtained in relation to one primary variable, the 
adjustment of significance level due to the presence of one primary variable will not be performed. 
The successive transition from testing of the non-inferiority hypothesis to testing of the statistical 
advantage hypothesis does not require adjustment of the significance level as well. 
Secondary study endpoint 
 Geometric mean titers of serum antibodies to antigens according to assessment at Day 21 after 
immunization (Visit 7) 
The comparison will be performed by calculation of two-sided 95 % confidence interval using 
ANCOVA covariance analysis upon log base 10 transformation. ANCOVA model will include the 
vaccine as a fixed factor and the baseline antibody titer log as a covariate. The clinical center, sex, 
and age will also be considered as potential factors of the model. The difference between mean values 
in the compared groups (comparator test) will be evaluated together with the respective 95 % 
confidence interval. Point estimate of mean differences and the respective confidence interval will be 
subjected to inverse transformation. 

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If the upper limit of the calculated 95 % confidence interval for GMAT1/GMAT2 ratios (GMAT1 
and GMAT2 — geometric mean titers of serum antibodies to antigens for the reference vaccine and 
the test vaccine respectively) does not exceed the limit of 1.5, the test vaccine will be considered as 
not inferior to the comparator for the endpoint, the share of subjects achieving seroconversion 
according to the evaluation at Day 21 after immunization. In case of proven non-inferiority of the test 
vaccine versus the reference vaccines for Yamagata and Victoria lineages antigens the same two-
sided 95 % confidence interval shall be used for testing of the hypothesis of predominant efficacy of 
the test vaccine for this endpoint. This conclusion will be made if the upper limit of the calculated 95 
% confidence interval does not exceed 1. 
 Coefficient of increase of mean geometric antibody titer (antigens H1N1, H3N2, Yamagata 
and Victoria lineages), based on evaluation at Day 21 after immunization versus baseline 
(Visit 7) 
GMAT ratio before and after immunization will be evaluated with the respective two-sided 95 
% confidence interval based on log transformation (log10), point estimate of the difference and the 
confidence interval, and inverse transformation of the obtained values. The lower limit of the 
obtained confidence interval for GMAT ratio shall be positioned to the right of the defined limit of 
2.5. 
 Seroprotection: share of subjects achieving protective antibody titer (1:40 and more) to 
antigens H1N1, H3N2, Yamagata and Victoria lineage, based on assessment at Day 21 after 
immunization (Visit 7). 
The shares of subjects achieving seroprotection will be presented with two-sided exact 95 % 
confidence intervals. Intergroup comparisons will be performed based on the exact Fisher test, as well 
as based on logistic regression with the vaccine as a fixed factor and the baseline antibody titer log as 
a covariate. The clinical center, sex, and age will also be considered as potential factors of the model. 
 Incidence of influenza and ARI based on assessment 180±5 days after immunization (Visit 
11). 
Incidence of the disease will be presented with the respective two-sided 95 % confidence 
interval for therapeutic groups. The parameter will be analyzed using the Kaplan-Meier survival 
method (time to the first episode of the disease). 
 Evaluation of severity and duration of reported cases of influenza and ARI, symptoms and 
complications will be presented descriptively for therapeutic groups. 
Safety analysis 
The safety analysis will be conducted by descriptive methods in the safety population. Adverse 
events will be coded using MedDRA. The number (percentage) of participants with AEs and the 
number of AEs will be presented in tables by system organ class and preferred term, as well as by the 
study therapy and severity. 

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With that, within a system organ class and preferred term, each subject will be considered once with 
regard to study therapy and maximum severity. The number (percentage) of volunteers with local and 
general reactions to vaccination will be presented taking into account severity and duration. 
Laboratory findings and their changes after vaccination compared to the baseline and “shift 
tables” relative to normal values will be tabulated by therapeutic groups and by assessment points. 
The results of the assessment of vital functions will be tabulated by therapeutic groups for each 
assessment point together with changes from the last available measurement prior to vaccination. 
The results of physical examination will be presented descriptively by therapeutic groups and 
by assessment points. 
Immunological parameters evaluation results: serum immunoglobulin content (ELISA: IgE) 
and their changes after vaccination compared to baseline values will be tabulated by therapeutic 
groups. 
8.2. Planned number of subjects 
Sample size was calculated based on the primary endpoint, the percentage of subjects achieving 
seroconversion according to the evaluation at Day 21 after immunization (Visit 7), and testing of the 
statistical hypothesis of non-inferiority of the test vaccine (Grippol® Quadri) versus the reference 
vaccine (Grippol® Plus). 
The following non-inferiority margin was used for comparative evaluation of immunogenic 
efficacy in the non-inferiority model: 
- upper limit of the two-sided 95 % confidence interval of the difference between parameters 
(R-T) of subjects achieving seroconversion in the study quadrivalent vaccine and reference trivalent 
vaccine groups shall not exceed 15 %. 
Justification of the "non-inferiority margin" : 
In placebo-controlled studies of inactivated influenza vaccines, the seroconversion parameter in 
placebo group for the study antigens amounts to 0–1 %. The placebo does not contain the respective 
antigens, so it demonstrates no immunogenic activity [1]. 
Taking into account the expected seroconversion level in reference groups > 60 % and the 
minimum limit for influenza vaccines > 40 % of subjects achieving seroconversion, established by 
the guidelines for harmonization of requirements to influenza vaccine of the Committee for 
Proprietary Medicinal Products (СРМР), the non-inferiority margin 15 % is significantly below the 
superiority of the comparator over the placebo, which is appropriate. 
For testing of non-inferiority null hypothesis for Grippol® Quadri and Grippol® Plus vaccines, 
taking into account the following parameters: 

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 Power: 80 % 
 One-sided significance level: 2.5 % 
 Non-inferiority margin: 15 % 
 Expected share of subjects achieving seroconversion in Grippol® Plus group: 60 % 
 Expected actual difference for the parameter in groups: 1 % 
1 % of the calculated sample size for non-inferiority hypothesis, primary dichotomized parameter and 
uniform assignment into groups (1:1) is based on the following formula [5,6]: 
 
where n — the number of patients in each group being compared; 
π1 — percentage of subjects achieving seroconversion in the reference vaccine group; 
π2 — percentage of subjects achieving seroconversion in the test vaccine group; 
Δ =  π1 – π2 — the expected difference between percentages of subjects achieving seroconversion in 
the reference vaccine and test vaccine groups; 
Z — critical values of standardized normal distribution; 
δ — non-inferiority margin. 
according to the calculation as per the given formula using software package PASS 12, there shall be 
at least 193 volunteers in each therapeutic group (579 volunteers in total). 
Thus, the minimum required sample size should be: 193 volunteers in each of the three groups 
(579 volunteers in total). 
Taking into account the dropout during the study (5 %), the required number of volunteers has 
to be increased to 204 per group (612 in total). 
Accounting for the possible dropout of volunteers at the screening stage (about 25 %), it is 
planned to obtain a permission from the Ministry of Health of the Russian Federation to conduct a 
clinical study with a total of up to 765 volunteers. 
Replacement of discontinued volunteers with backups is not provided for. 
References: 
1. Jackson LA, Gaglani MJ, Keyserling HL, Balser J, Bouveret N, Fries L, Treanor JJ. Safety, efficacy, 
and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized,placebo- 
controlled trial over two influenza seasons. BMC Infect Dis. 2010 Mar 17;10:71. doi: 10.1186/1471-
2334- 10-71. 
2. Clinical study report "Clinical trials of influenza trivalent inactivated polymer-subunit influenza 
vaccine Grippol plus (phase II)", GOU VPO St. Petersburg State Medical University named after Acad. 
I.P. Pavlov, 2008. 

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3. Committee for Proprietary Medicinal Products (CPMP). Note for guidance on harmonization of 
requirements for influenza vaccines. CPMP/BWP/214/96. The European Agency for the Evaluation of 
Medicinal Products (EMEA), March 1997. 
4. FDA Guidance for Industry Clinical Data Needed to Support the Licensure of Seasonal Inactivated 
Influenza Vaccines, 2007. 
5. Chow S-Ch., Shao J., Wang H., "Sample Size Calculations in Clinical Research", 2003. 
6. Fleiss, J. L., Levin, B., Paik, M.C. 2003. Statistical Methods for Rates and Proportions. Third Edition. 
John Wiley & Sons. New York 
8.3. Significance level 
Level of statistical significance: bilateral 5 %. 
8.4. Statistical criteria for suspension and discontinuation of study 
Not provided by the protocol. 
8.5. Selection of study subjects 
Data analysis is performed in the following populations: 
Safety analysis population. This population will include all volunteers who received a dose of 
the vaccine. The whole safety analysis will be provided in that population of volunteers. 
Full Analysis Set (FAS). This analysis set will include all volunteers from the safety analysis 
set who had at least one measurement of serum antibody titer to antigens made. This analysis set was 
used for the analysis of efficacy and immunogenicity. 
Per-protocol population. This population includes all the volunteers from the full analysis set 
meeting the inclusion / non-inclusion criteria, having received a dose of the vaccine according to the 
randomization, who provided data before and after vaccination to asses immunogenicity according to 
the study schedule, who did not receive any of the prohibited drugs, and who completed the study 
without any significant protocol deviations. This analysis set will be used for the analysis of 
immunogenicity parameters. 
8.6. Procedures for recording missing, falsified data and data that cannot be analyzed. 
The employee who maintains the database, after entering all the data checks the database for 
inconsistencies, erroneously entered and missing data. If questions arise, the investigator will be sent 
a form “Questions for investigators”, the request for which must be answered in writing within 7 
business days after receipt. After receiving answers to the questions, the officer responsible for 
maintaining the study database checks for inconsistencies, erroneously entered data, and missing data. 
After the final completion of the collection and data entry of all centers, the database is closed, after 
which statistical processing can begin. 

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8.7. Procedures for communication on any deviations from the initial statistical plan 
If the application of initially defined statistical methods is not possible, the statistical report and 
the final report on the study will provide a justification for making changes, with references to the 
calculations made, statistical indicators and a general analysis of the reasons for these changes. The 
decision to make extraordinary deviations (assumptions, modifying data) is the competence of the 
study Sponsor, and must be explained and justified, including in the text of the final report on the 
clinical study. 
9. DIRECT ACCESS TO SOURCE  DATA / DOCUMENTS 
The investigator and the medical institution where the study is conducted are obligated to 
provide direct access to source documents (original records or certified copies) to study monitors, 
auditors, representatives of the medical unit of LEC, as well as to representatives of regulatory 
authorities. 
Direct access to source documents is granted to specified persons for the purpose of verifying 
the data entered in the CRF, assessing the compliance of the study with the protocol and normative 
documents, as well as protecting the rights of study subjects. To accomplish these goals, these 
individuals may conduct study-related monitoring, audits, ethical examinations, and inspections. 
10. QUALITY CONTROL AND ASSURANCE 
The quality control of this study is provided through monitoring, verification of data against the 
baseline, audits by representatives of the sponsoring company, standardized data entry and 
processing. All the above procedures are carried out according to sponsor's standard operating 
procedures that have been composed in accordance with the requirements of ICH GCP. 
Training of investigators 
During the initial visit, the trial site monitor will conduct a training on the clinical trial protocol, 
as well as on all procedures and materials required for appropriate conduct of the study with the study 
team members. 
Monitoring of the study 
Study monitors must regularly contact the investigator and visit the trial site. Upon request, the 
investigator and the medical institution that conducts the study should provide them with direct 
access to all study documents (CRFs and other documents relevant to the study), subject to the 
requirements of confidentiality of the personal data of volunteers and conducting an audit in 
accordance with legal regulations. 

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The duties of the monitor of the trial site include verification of data entered in the CRF against 
the baseline data, monitoring of the compliance of the study center with the requirements of the study 
protocol, monitoring of the compliance with the requirements of the good clinical practice, and 
monitoring of the compliance with the applicable legal requirements. 
The investigator and other staff members at the trial site participating in the clinical study must 
be prepared to allow time to discuss the data with the clinical study monitor. The investigator should 
assist the monitor and cooperate with him/her in order to resolve any problems identified during the 
visits to the trial site. 
The frequency of monitor's visits to a trial site depends on a set of study subjects; at the 
beginning and end of the study, more frequent visits of the monitor to the trial site are possible as 
compared to the middle of the study. 
Before initiation of the study, the monitor verifies that the trial site complies with all of the 
study requirements and discusses the clinical study protocol and the CRF with the investigator and 
the rest of the trial site staff responsible for the implementation of key study elements. 
During the study, the monitor checks the compliance of the study with all the requirements 
specified above, including checking the informed consents, records and storage conditions of the 
study drugs, study documentation, baseline data, and reports on AEs. 
When data inconsistencies are identified during the validation of study database, the description 
of these inconsistencies is addressed to the investigator in a form of data correction forms. 
Monitors will be provided with separate guidelines for monitoring the study, containing 
additional instructions on monitoring procedures. 
Audits: 
The purpose of the audit by the study sponsor is an assessment of the conduct of study and its 
compliance with the requirements of the protocol, standard operating procedures, standards for good 
clinical practice, and applicable legal requirements independent of normal monitoring and quality 
control procedures. An audit can be conducted in all trial sites and orgaizations participating in the 
study. 
11. ETHICAL ASPECTS 
11.1. Helsinki Declaration of the World Medical Association 
The investigator is obligated to ensure that the study is conducted in strict accordance with the 
Helsinki Declaration of the World Medical Association, adopted in 1964, in a 2013 edition. 

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11.2. Approval by the regulatory authorities 
This study will be conducted in compliance with the requirements of the regulatory authorities 
of the Russian Federation. In addition to the approval of LEC trial sites before initiation of the study, 
a study permission must be obtained from relevant regulatory authorities, including the Ethics 
Council. In addition, all amendments to study documents must be submitted to the regulatory 
authorities for approval, as well as reports on SUADR, annual reports on the safety of study treatment 
and notification of the completion of the study. 
11.3. Approval by the LEC of a medical institution 
Before study drugs are sent to the trial site, and the site begins recruiting study subjects, the 
LEC of the medical institution must receive a documented approval to conduct the said study, as well 
as approval of the study protocol, amendments to it (if any), volunteer information sheet and the 
informed consent form for participation in the study, any other documents provided to the volunteers 
for promotional purposes, as well as information on payments and compensation to volunteers in the 
study. 
Amendments to study documents, which must be approved by the LEC, take effect only upon 
receipt by the sponsoring company of a copy of the written approval of the LEC amendment. 
If an amendment to the study protocol is necessary in order to eliminate the obvious and 
immediate risk to volunteers, it can be enforced before the approval of the LEC of the medical 
institution. However, in this case the approval has to be obtained within the shortest possible period 
of time after introduction of the amendment. 
11.4. Informed consent for study participation 
The investigator is responsible for obtaining the written consent from study subject to 
participate in the study. Consent from the study subject must be obtained before the start of any study 
procedures and after the study subject has been provided with adequate information about the 
objectives and methods of the study, the expected benefits and possible risks associated with study 
participation. The study subject must be issued one copy of the information leaflet and the informed 
consent form for the volunteer to participate in the study in his/her native language. The signed and 
dated informed consent form should be kept in the archives of the trial site and may be requested by 
the study monitor, employees of the sponsoring company or representatives of regulatory authorities 
during monitoring, audits, and inspections. 

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12. DATA PROCESSING AND RECORD KEEPING 
12.1. Baseline data and comparison with baseline data 
Source documents and source records with the results of all assessments and surveys conducted 
as part of this study should be kept in the study archive. The source medical records in the study 
archive are the source of baseline data of the study subject. The investigator is responsible for 
complete and accurate filling out of CRF. All data registered in the CRF must also be reflected in the 
source medical documentation of the study subject in the form of records made by the investigator or 
other authorized person according to the form on assignment of responsibilities. The data in the CRF 
must correspond to the source documentation from which they are transferred; discrepancies should 
be explained. 
12.2. Study archive in the trial site 
The investigator must keep an archive of the study, where all documentation is stored. The 
investigator shall store the documents related to the study until the sponsor company notifies him that 
further storage of these documents is no longer required. All primary medical documentation, drug 
registration logs, correspondence, confirmation of receipt of participation consent, and other 
documents related to the conduct of the study should be kept in the medical institution for as long as 
possible. 
Essential study documents, including informed consent forms and primary medical records, 
must be kept for at least 15 years after the end of the study. 
It is the sponsor's responsibility to inform the investigator / medical institution about the end of 
the period of documentation storage. 
Documents must be stored in such a way as to be accessed later and easily identified in case of 
an inspection. Special attention should be paid to document storage conditions. 
The destruction of study documents is possible only after the written approval  by the sponsor 
and investigator. If the investigator wishes to delegate the duties for document archiving to another 
person or change the archive storage location, he/she must obtain written permission from the 
sponsoring company. 
12.3. Confidentiality of study subject's data 
The investigator shall ensure subject's confidentiality. Only subject's ID number is used in CRF 
and other documents submitted to the sponsoring company, to a laboratory and to safety and 
efficiency assessment commissions. Documents that are not forwarded to the study sponsor (for 
example, signed informed consent forms for participation in the study) must be kept by the 
investigator in compliance with confidentiality requirements 

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When a volunteer is included in the study, the investigator is assigned a unique number 
(screening number) consisting of numbers and letters, having the following structure: eight 
consecutive ranks placed from left to right 
 
G
R 
I 
 
Ranks from 1 to 3 are defined for this study with the following sequence: GRI (where GRI is 
the first letter of the protocol number) and the same for all volunteers, the next two digits correspond 
to the number of the trial site (for example, 01, 02, etc.), and the last three digits are the volunteer's 
number at the screening stage (numerical values of 001, 002, 003, etc.). 
Based on the unique screening number, the investigator generates an individual volunteer 
identification code to record it in "Volunteer Information Sheet and the Informed Consent for 
Participation in a Clinical Study" and its medical documentation. 
Individual identification code of the volunteer looks as follows: 
 
G R I
Number of 
permission for 
study 
participation 
Permission issue date 
MM.DD.YYYY 
Serial number of 
the medical 
organization 
specified in the 
permit 
Volunteer's 
initials 
Volunteer's date of 
birth MM.DD.YYYY
Unique volunteer number 
assigned at screening 
 
The investigator must maintain a separate Identification Log containing individual numbers, 
surnames, addresses, telephone numbers and medical record numbers (if available). The investigator 
must keep documents that are not intended to be submitted to the Sponsor in strict confidentiality, in 
particular, the signed Informed Consent Forms and the Identification Log. 
The investigator is obligated to provide access to CRFs and primary medical documentation of 
study subjects to the authorized representatives of the sponsoring company, regulatory authorities 
and LEC of the medical institution for the purpose of their inspection during monitoring visits, 
audits, and inspections. 
12.4. Disclosure 
Information about the study, patent applications, procedures, as well as data of a scientific 
nature, and other information relevant to the study are the property of the sponsoring company. The 
investigator must understand that the sponsoring company may use the information obtained during 
this study to further develop the study drug, and therefore this information may be passed on to other 
researchers participating in clinical trials, as well as to regulatory authorities. 

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NPO Petrovax Pharm, LLC 
Medicinal product: Grippol Quadri:
Strictly confidential. Proprietary Information.
1 Sosnovaya St., Pokrov village, 142143, Podolsk District, Moscow Region, Russia
 
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In order to make it possible to use the information obtained during this study, the investigator obliges 
to provide the sponsor with the results of all tests conducted during the study, as well as any other 
information obtained during the study. Discussion of the study results in oral or written form until 
study completion and registration of all data is possible only with the written permission of the 
sponsoring company. 
13. FINANCING AND INSURANCE 
13.1. Financing 
Financing terms are described in a separate contract. 
13.2. Insurance 
The sponsoring company provides the necessary insurance for the study subjects required in 
accordance with the national legislation on clinical studies. Insurance conditions for study subjects 
are described in a separate contract. 
14. PUBLISHING OF CLINICAL STUDY RESULTS 
Study results are planned to be published in specialized scientific publications after the 
completion of final report on the clinical study. 
The investigator has no right to publish the study results without prior consent of the sponsoring 
company. The investigator obliges to submit a manuscript or draft report containing the results of this 
study to the sponsor in order to obtain consent from the sponsor for publication or public presentation 
of these results. In this case, the investigator shall submit to the sponsor a manuscript or draft report 
no less than 30 days prior to the submission of the manuscript for publication.