Phase II Multi-center Randomized Double-blind Placebo-controlled Efficacy and Dose Ranging Trial of the Drug Product Seroguard, Solution (JSC Pharmasyntez, Russia) Used for the Prevention of Pelvic Adhesions
Phase: PHASE2
Conditions: Adhesion
Sponsor: Pharmasyntez

Clinical study protocol
Multi-center randomized double-blind placebo-controlled Phase II study of efficacy and selection 
of dose of Seroguard, solution (JSC Pharmasyntez, Russia) used for prevention of pelvic adhesions
Name of the test drug: Seroguard
Dosage form and dosage: Solution, 0.41 mg/mL
Study phase: II
Study Sponsor: JSC Pharmasyntez, Russia
Protocol ID: SG-2/1215
Protocol revision: 3.2 dated 06.03.2017.
Confidentiality agreement
The present document is a confidential intellectual property of JSC Pharmasyntez, Russia. 
Information which is contained in the present document is provided to a Principal Investigator and 
employees of a clinical study site, involved in the study, Independent Ethics Committee and 
regulatory bodies.
Your acceptance of the present document confirms that you agree not to disclose the information 
contained in it to other persons without written approval by JSC Pharmasyntez, Russia, except for 
the information required for obtaining informed consent from persons participating in the study.

Confidential
Seroguard
Protocol ID: SG-2/1215
Revision 3.2 dated 06.03.2017
Page of protocol approval by the study Sponsor
Study title
Multi-center randomized double-blind placebo-controlled 
Phase II study of efficacy and selection of dose of Seroguard, 
solution (JSC Pharmasyntez, Russia) used for prevention of 
pelvic adhesions
Protocol
SG-2/1215
revision 3.2 dated 06.03.2017.
Prepared by
N.A. Dvoynikova, Clinical Pharmacologist
Date 06 March 2017
Signature 
/signed/
Agreed by
A.S. Guschin,
R&D Director Advisor
Date 06 March 2017
Signature 
/signed/
Approved by
M.G. Shurygin, 
R&D Director
Date 06 March 2017
Signature 
/signed/
Page 2 of 85

Конфиденциально
Серогард
Протокол № SG-2/1215
Версия 3.2 от 06.03.2017 г.
Страница утверждения протокола спонсором исследования
Наименование исследования
Протокол
Разработал
Согласовал
Утвердил
Многоцентровое рандомизированное двойное слепое 
плацебо-контролируемое исследование II фазы по 
изучению эффективности и подбору дозы препарата 
Серогард, 
раствор 
(АО 
«Фармасинтез», 
Россия), 
применяемого для профилактики спаечной болезни 
малого таза.
SG-2/1215 
версия 3.2 от 06.03.2017 г.
Двойникова Н. А., клинический фармаколог
Дата &• 0 3 ' 
Подпись^
Гущин А. С., 
советник по науке и инновационной деятельности
Дата G> . £>3 . / 7^~ 
Подпись
Шурыгин М. Г., 
директор по науке и инновационной деятельное
Дата 
2 j £ V  У  
П о д п и с ь
Страница 2 из 95

Confidential
Seroguard
Protocol ID: SG-2/1215
Revision 3.2 dated 06.03.2017
Page of protocol approval by the Principal Investigator
Study title
Multi-center randomized double-blind placebo-controlled 
Phase II study of efficacy and selection of dose of Seroguard, 
solution (JSC Pharmasyntez, Russia) used for prevention of 
pelvic adhesions.
Protocol
SG-2/1215
revision 3.2 dated 06.03.2017.
I, the undersigned, am responsible for conducting the study in this site and agree with the 
following:
I certify that I have read the latest revision of the present protocol, including all the annexures as 
well as Patient information leaflet of the test drug/the reference drug and have understood the 
information specified in these documents.
I have sufficient time for correct performance and completion of the study within the stipulated 
period of the study performance, and I have sufficient number of qualified employees and adequate 
equipment for the planned study procedures.
I agree to perform the study by me and my employees according to conditions, terms and 
procedures of the present protocol, complying with the requirements of national and international 
requirements of ICH GCP (Good Clinical Practice) and all the applicable requirements of 
authorities and government legislation.
Principal Investigator 
Full name
DESIGNATION, ORGANIZATION 
Phone:
Fax:
E-mail:
Date
Signature
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Protocol ID: SG-2/1215
Seroguard 
Revision 3.2 dated 06.03.2017
Table of Contents
Page of protocol approval by the study Sponsor................................................................................ 2
Page of protocol approval by the Principal Investigator....................................................................3
Synopsis..................................................................................................................................................8
Acronyms............................................................................................................................................ 20
1 
General information..................................................................................................................... 22
1.1 
Protocol title, ID and date....................................................................................................22
1.2 
Name and address of the Sponsor and monitor................................................................. 22
1.3 
Name and designation of persons authorized on behalf of the Sponsor to sign the protocol
and amendments to the protocol.................................................................................................... 22
1.4 
Name, designation, address and phone number of Medical reviewer of the present study
appointed by the Sponsor...............................................................................................................22
1.5 
Name and designation of investigators responsible for the study performance, as well as 
addresses and phone numbers of clinical sites............................................................................. 22
1.6 
Names and addresses of clinical laboratories and other medical and/or technical services
and/or organizations involved into the study................................................................................ 24
2 
Justification of the study..............................................................................................................25
2.1 
Name and description of the study drugs............................................................................27
2.2 
Results of pre-clinical and clinical studies significant for the given study.....................29
2.2.1 
Pre-clinical studies......................................................................................................29
2.2.2 
Clinical studies.............................................................................................................30
2.3 
Known and potential risks and benefit for the study subjects.......................................... 31
2.3.1 
Risks and inconveniences related to participation in the study................................31
2.3.2 
Possible benefit related to participation in the study...............................................32
2.4 
Description and justification of route of administration, dosages, dosage regimen and
therapy course..................................................................................................................................32
2.5 
Normative-regulatory base for conducting the clinical study...........................................34
2.6 
Description of the study population.................................................................................... 34
3 
Purposes and objectives of the study........................................................................................... 34
3.1 
Purpose...................................................................................................................................34
3.2 
Study obj ectives.................................................................................................................... 35
4 
Design of the study...................................................................................................................... 36
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Revision 3.2 dated 06.03.2017
4.1 
Primary and secondary endpoints evaluated in the study................................................. 36
4.2 
Description of the study design, graphical scheme of the study design, procedures and
stages of the study............................................................................................................................ 37
4.2.1 
Description of the study design.................................................................................. 37
4.2.2 
Graphical scheme of the study design.......................................................................38
4.2.3 
Description of the study procedures..........................................................................39
4.2.4 
Description of periods and visits of the study........................................................... 46
4.3 
Measures aimed at minimization of subjectivity...............................................................49
4.3.1 
Randomization procedure...........................................................................................49
4.3.2 
Blinding procedure...................................................................................................... 50
4.4 
Description of the drugs used in the study -  description of the dosage form, packing and
labeling.............................................................................................................................................51
4.4.1 
Dosage form, composition and clinical-pharmacological characteristics............... 51
4.4.2 
Packing and labeling................................................................................................... 53
4.4.3 
Storage conditions........................................................................................................54
4.4.4 
Principles of the study drug dosing............................................................................ 54
4.4.5 
Additional therapy methods........................................................................................54
4.5 
Expected duration of participation of female patients in the study..................................55
4.6 
Description of “termination rules” or “withdrawal criteria” for separate subjects or the
study, in general................................................................................................................................55
4.7 
Procedures for accounting the study drugs.........................................................................56
4.7.1 
Preparation and distribution of the study drugs........................................................ 56
4.7.2 
Supplies, disposal, accounting the study drugs..........................................................57
4.8 
Storage of randomization codes...........................................................................................57
4.9 
List of data recorded directly in the CRF and considered as primary..............................58
5 
Selection and exclusion of the study subjects.......................................................................... 58
5.1 
Inclusion criteria...................................................................................................................58
5.2 
Non-inclusion criteria.......................................................................................................... 58
5.3 
Withdrawal criteria.............................................................................................................. 60
5.3.1 
Early withdrawal..........................................................................................................60
5.3.2 
Collection of data on the study participants early terminated their participation in 
the study 60
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5.3.3 
Substitution procedure................................................................................................ 61
5.3.4 
Follow-up of female patients early terminated the study......................................... 61
6 
Treatment of the study subjects.................................................................................................. 61
6.1 
Dosage regimen of the test drug and the placebo..............................................................61
6.2 
Previous and concomitant therapy...................................................................................... 61
6.2.1 
Permissible previous and concomitant therapy.........................................................62
6.2.2 
Forbidden previous and concomitant therapy...........................................................62
6.3 
Methods of control for compliance with the procedures by the study subjects...............63
6.3.1 
Measures to provide compliance...............................................................................63
6.3.2 
Evaluation of compliance...........................................................................................63
7 
Efficacy evaluation...................................................................................................................... 63
7.1 
List of efficacy parameters...................................................................................................63
7.2 
Methods and terms of evaluation, recording and analysis of efficacy parameters......... 64
8 
Evaluation of safety..................................................................................................................... 64
8.1 
List of safety parameters......................................................................................................64
8.2 
Methods and terms of evaluation, recording and analysis of safety parameters.............65
8.3 
Requirements to reports, procedures for recording and reporting adverse reactions and
intercurrent diseases........................................................................................................................68
8.4 
Method and duration of follow-up of the study subjects after adverse reactions............69
8.5 
Modification of the study drug dosage regimen................................................................ 69
9 
Statistics........................................................................................................................................ 69
9.1 
Description of statistical methods to be used, including terms of each planned interim
analysis.............................................................................................................................................69
9.1.1 
Demographic data, baseline data and follow-up data.............................................. 70
9.1.2 
Analysis of main efficacy parameters........................................................................70
9.1.3 
Analysis of secondary efficacy endpoints..................................................................70
9.1.4 
Safety analysis.............................................................................................................71
9.2 
Planned number of the study subjects.................................................................................71
9.3 
A significance level used..................................................................................................... 73
9.4 
Study terminati on criteri a .................................................................................................... 73
9.5 
Procedures for accounting absent, unevaluable and doubtful data...................................73
9.6 
Procedures of reporting on any deviations from the primary statistical plan..................74
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9.7 
Selection of the study subjects for the analysis..................................................................74
9.7.1 
Intent-to-treat population (ITT).................................................................................74
9.7.2 
Per protocol population...............................................................................................74
9.7.3 
Safety population.........................................................................................................74
10 Direct access to primary data/documentation............................................................................ 74
11 Quality control and quality assurance........................................................................................75
11.1 Study monitoring..................................................................................................................75
11.2 Amendments to the protocol, deviations and violations of the protocol...........................76
12 Ethics............................................................................................................................................ 77
12.1 General provisions................................................................................................................77
12.2 Procedure of obtaining informed consent...........................................................................77
12.3 Confidentiality and identification of the study subjects....................................................77
12.4 Enrollment of the study subjects from vulnerable and special groups............................. 78
13 Data management and record keeping.......................................................................................78
14 Finance and insurance.................................................................................................................79
15 Publications..................................................................................................................................79
15.1 General provision..................................................................................................................79
15.2 Issues of publication and use of the study results.............................................................. 80
16 Literature......................................................................................................................................81
17 Annexures..................................................................................................................................... 85
17.1 Serious adverse reaction report form...................................................................................85
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Protocol ID: SG-2/1215
Revision 3.2 dated 06.03.2017
Synopsis
Study title
Multicenter randomized double-blind placebo-controlled Phase II 
study of efficacy and selection of dose of Seroguard, solution (JSC 
Pharmasyntez, Russia) used for prevention of pelvic adhesions.
Protocol ID
SG-2/1215
Study purposes and 
objectives
The present study is aimed at evaluation of efficacy of the drug 
Seroguard, solution, used for prevention of pelvic adhesions.
Main study objectives:
1. To determine change in number of pelvic adhesions based on 
MRI data in post-surgical period in comparison to pre-surgical 
MRI data
2. To determine change in thickness of pelvic adhesions based on 
MRI data in post-surgical period in comparison to pre-surgical 
MRI data
3. To determine frequency of limited displaceability of pelvic 
organs in post-surgical period (based on results of transvaginal 
ultrasound investigation).
4. To determine frequency of hyperechoic linear lesions in post- 
surgical period based on results of transvaginal ultrasound 
investigation.
5. To determine changes in frequency of detecting limited 
displaceability in comparison to baseline (absolute change and 
in % of baseline value).
6. To determine changes in frequency of detecting hyperechoic 
linear lesions based on repeated transvaginal ultrasound 
investigation in comparison to baseline.
7. To determine frequency of detecting complete absence of USI -  
signs of adhesion process in pelvis in post-surgical period 
(defined as absence of limited displaceability of pelvic organs 
and absence of hyperechoic linear lesions)
8. To determine number of adhesions during surgery.
9. To determine number of dense adhesions during surgery.
10. To determine percentage of female patients with any adverse 
reactions.
11. To determine percentage of female patients with any serious 
adverse reactions.
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12. To determine percentage of female patients with adverse 
reactions, relation of which to use of the test drug or the placebo 
is “definite”, “probable” or “possible”.
13. To determine percentage of female patients with serious adverse 
reactions, relation of which to use of the test drug or the placebo 
is “definite”, “probable” or “possible”.
14. To determine percentage of female patients with mild adverse 
reactions.
15. To determine percentage of female patients with moderate 
adverse reactions.
16. To determine percentage of female patients with severe adverse 
reactions.
17. To determine percentage of female patients with clinically 
significant changes in results of physical examination.
18. To determine percentage of patients with clinically significant 
changes in vital signs.
19. To determine percentage of female patients with clinically 
significant changes on electrocardiogram (ECG).
20. To determine percentage of female patients with clinically 
significant changes in laboratory parameters.
Study methodology
The present study will be performed as multicenter double-blind 
randomized placebo-controlled Phase II study.
Study duration
Screening period (up to 15 days before the surgery) 
Treatment period (Day 0)
Interim safety evaluation (Day 6±1)
Evaluation of treatment efficacy (Day 30±4 days)
Number of subjects
1) Placebo group, 1.5 mL/kg -  up to 30 screened female patients 
which corresponds to 26 randomizations and 24 completed 
cases
2) Placebo group, 2.4 mL/kg -  up to 30 screened female patients 
which corresponds to 26 randomizations and 24 completed 
cases
3) Seroguard group, 1.5 mL/kg -  up to 30 screened female 
patients which corresponds to 26 randomizations and 24 
completed cases
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Protocol ID: SG-2/1215
Revision 3.2 dated 06.03.2017
4) Seroguard group, 2.4 mL/kg -  up to 30 screened female 
patients which corresponds to 26 randomizations and 24 
completed cases
Inclusion and non­
inclusion criteria
Inclusion criteria
1. Female patients aged from 18 to 45 years with confirmed 
diagnosis of pelvic adhesions with indications for surgery 
(laparoscopic adhesiolysis)
2. Voluntarily and personally signed and dated Form of Informed 
Consent to participate in the study
3. Female patients with pelvic adhesions confirmed by 
gynecological examination and USI
Non-inclusion criteria
1. Female patients having contraindications to operative treatment 
(including acute or exacerbated chronical adnexal inflammatory 
process)
2. Body mass index 30.0 kg/m2 and more
3. Known hypersensitivity to components of the test drug 
(Seroguard)
4. Pregnancy, lactation or planning for pregnancy during the 
clinical study
5. Refusal to use effective contraception methods throughout the 
study
6. Positive HIV, RW, HBV or HCV test results.
7. Alcohol abuse, drug addiction, and toxicomania (except for 
smoking)
8. Category III and higher by physical status classification of the 
American Society of Anesthesiologists (ASA).
9. Purulent process in the abdominal cavity
10. Disseminated endometriosis
11. Elevated WBC count in complete blood count exceeding 
10*109/L
12. Necessity of using any other drugs during the surgery (except 
for 0.02% chlorhexidine aqueous solution throughout the
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surgery, as well as the test drug or the placebo (0.9% sodium 
chloride) in the end of surgery) administered intraperitoneally
13. Concomitant diseases that may require conversion of the 
surgical intervention by other indications
14. Type I or II diabetes mellitus
15. Deep vein thrombosis and/or PATE at screening or in the 
history
16. Renal impairment (reduced glomerular filtration rate below 60 
mL/min/1.73 m2 evaluated by the CKD-EPI equation)
17. Liver disorders determined as more than 2-fold elevation of the 
upper limit of normal of one of the following enzymes: ALT, 
AST, GGTP, AP, or more than 2-fold elevation of total 
bilirubin level
18. Myocardial infarction within 6 months before screening
19. Any concomitant diseases accompanied by heart failure.
20. Clinically significant changes in ECG (in Investigator’s 
opinion).
21. Any concomitant diseases accompanied by respiratory failure
22. Any oncology disease within 3 years before enrollment into the 
study.
23. Systemic inflammatory diseases.
24. Diseases associated with chronic hemorrhages
25. Blood diseases (anemias of any origin, hemoglobinopathies, 
inherited and acquired coagulopathies, hemostasis disorders, 
thrombocytopenias, and thrombocytopathias, any 
hemoblastoses)
26. Any other disease, that, in the Investigator’s opinion, may 
distort the study results or present an additional threat to well­
being of female patient after administration of the study drug
27. Administration of anticoagulants, antiaggregants (except for 
acetylsalicylic acid at the dose of less than 325 mg/day) at the 
moment of inclusion into the study or planning to do so during 
the study.
28. Administration of drugs with pronounced hemato-, hepato-, or 
nephrotoxic action, drugs of biological origin
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Protocol ID: SG-2/1215
Revision 3.2 dated 06.03.2017
29. Necessity of administration of cytostatics, systemic 
glucocorticosteroids and other immunosuppressive agents in 
the period of participation in the study.
30. Participation in another clinical study within 30 days before 
screening
31. Contraindications for performance of MRI (presence of 
implants or implanted electronic devices)
32. Impossibility or inability to comply with the requirements of 
the protocol, including those for physical, psychic or social 
reasons, in Investigator’s opinion
Withdrawal criteria
1. Withdrawal of informed consent by female patient
2. Female patient’s non-compliance with the rules of participation 
in the study.
3. Pregnancy occurrence.
4. Necessity of conversion during surgical intervention
5. Necessity of surgery during the period between adhesiolysis 
surgery and Visit 3
6. Other reasons occurring during the study and interfering with 
the study performance in accordance with the protocol.
7. Necessity of drain tube installation revealed during the surgery
Study drug
Test drug:
Seroguard, solution 0.41 g/L, JSC Pharmasyntez, Russia, in the volume 
of 1.5 or 2.4 mL/kg
Reference drug:
Sodium chloride, solution for infusion 0.9%, CJSC EAST-PHARM, 
Russia, in the volume of 1.5 or 2.4 mL/kg
Dosage regimen and 
route of
administration of the 
study drug
Administration of the drug is performed at the final stage of surgical 
intervention. After an adequate sanitation of the abdominal cavity with 
warm normal saline in the quantity of 100 mL, the drug Seroguard, 
solution in the concentration of 0.41 g/L or placebo is administered 
through trocar with the help of a metal tube 25 cm long with inner 
diameter of 4 mm with a silicone nozzle 5 cm long, which is tightly
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Protocol ID: SG-2/1215
Revision 3.2 dated 06.03.2017
connected to Janet syringe containing an anti-adhesion 
solution/placebo.
The test drug/placebo should be applied onto the operated surface in 
the quantity of 2.4 mL/kg body weight or 1.5 mL/kg body weight by 
means of forced pressing the plunger of the syringe.
In order to create the maximum afflux of anti-adhesion agent into the 
pelvis, all the patients should be recommended to practice active 
behavior (getting up and walking) in the end of the first day after the 
surgery and supine position with the head kept up by the bed head 
elevation during rest.
At the post-operative period, for all the groups, patient management is 
performed in accordance with the established standards.
Main parameters of 
efficacy and safety 
assessment
Primary efficacy endpoint: achieving clinical efficacy determined as:
Frequency of reducing number of adhesions after repeated MRI by 3 or 
more (in female patients with 10 and less adhesions at the baseline) or 
by 30% and more (in patients with >10 adhesions at the baseline)) in 
comparison to baseline MRI data
Secondary efficacy endpoints:
1. Change in thickness of pelvic adhesions by repeated MRI in 
comparison to baseline MRI data
2. Frequency of limited displaceability of pelvic organs in post- 
surgical period (based on results of transvaginal ultrasound 
investigation) on Day 30±4 after the surgery
3. Frequency of hyperechoic linear lesions in post-surgical period 
based on results of transvaginal ultrasound investigation
4. Change in frequency of detecting limited displaceability of 
pelvic organs in comparison to baseline (absolute change and in 
% of baseline value)
5. Changes in frequency of detecting hyperechoic linear lesions 
based on repeated transvaginal ultrasound investigation in 
comparison to baseline
6. Frequency of detecting complete absence of USI -  signs of 
adhesion process in the pelvis in post-surgical period (defined 
as absence of limited displaceability of pelvic organs and 
absence of hyperechoic linear lesions)
Safety parameters:
7. Vital signs (body temperature, BP, HR, RR)
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Protocol ID: SG-2/1215
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8. Laboratory parameters:
Blood chemistry -  total protein, glucose, ALT, AST, total bilirubin, 
alkaline phosphatase, amylase, creatinine
Complete blood count -  RBC count, WBC count, platelet count, 
hemoglobin, hematocrit, WBC differential, ESR
Coagulogram -  coagulation time, international normalized ratio 
(INR), thrombin time, activated partial thromboplastin time 
(APTT)
Urinalysis -  color, transparency, pH, specific gravity, protein, 
glucose, WBC, RBC, bacteria, casts, salts
9. ECG data -  heart rate [HR], PR, QRS, QT intervals and 
calculated QTc interval.
10. USI data
11. Incidence of adverse reactions
12. Incidence of serious adverse reactions
13. Incidence of unexpected adverse reactions
14. Incidence of adverse and serious adverse reactions caused 
termination/withdrawal from the study
Study procedures
Visit 0 -  Screening
• 
Obtaining informed consent
• 
Collection of history, demographic data
• 
Gynecological history
• 
Collection of previous therapy information
• 
Physical examination with evaluation of vital signs
• 
Laboratory investigation: complete blood count, blood 
chemistry, coagulogram, urinalysis, pregnancy test (performed 
not earlier than on the day 7 before surgical intervention), HIV, 
HBV, HCV and RW blood test
• 
ECG
• 
USI of the abdominal cavity
• 
USI of the pelvic organs (transvaginal) (in the second phase of 
the menstrual cycle)
• 
MRI of the abdominal cavity and the pelvic organs
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• 
Gynecological examination and colposcopy
• 
Cytological examination (Pap-smears)
• 
Microscopic (bacterioscopic examination) examination of the 
smear stained by Gram’s method
• 
Assessment of the inclusion/non-inclusion criteria compliance
• 
Only for female patients included into the study with diagnosis 
“infertility” - hysterosalpingography (Day 7-10 of the 
menstrual cycle), use of hysterosalpingography results obtained 
on Day 7-10 of the menstrual cycle within 6 months before 
screening visit is permissible
Visit 1 (Day 0)
Before the surgery:
• Physical examination with evaluation of vital signs
• Actualization of the information on concomitant therapy
• Actualization of the information on concomitant disease
• Reassessment of inclusion/non-inclusion criteria
• Randomization
• Surgical intervention using the test drug or the placebo
• Evaluating severity of baseline adhesion process 
(intraoperative)
After the surgery:
• Physical examination with evaluation of vital signs
• 
Local status assessment (description of postsurgical wound)
• Adverse reaction assessment
Visit 2 Interim safety assessment (Day 6±1)
• Physical examination with evaluation of vital signs
• Laboratory investigations: complete blood count, blood 
chemistry, urinalysis
• 
Local status assessment (description of postsurgical wound)
• USI of the abdominal cavity
• ECG
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• 
Adverse reaction assessment 
Visit 3 (30±4 days after the surgery)
• 
Physical examination with evaluation of vital signs.
• 
Local status assessment (description of postsurgical wound)
• 
Adverse reaction assessment
• 
Laboratory investigations: complete blood count, blood 
chemistry, coagulogram, urinalysis, pregnancy test
• 
ECG
• 
USI of the pelvic organs (transvaginal) with the adhesion 
severity evaluation
• 
USI of the abdominal cavity
• 
MRI of the abdominal cavity and the pelvis
Statistical analysis 
(sample size 
justification)
In the studies of the drug Adept® (Innoventica plc), maximally close to 
the test drug by mechanism of action (FDA Executive Summary 
(Version 2): P050011 Innovata plc Adept® Adhesion Reduction 
Solution (4% Icodextrin Solution, 2006), a primary endpoint was used. 
It was determined as a decrease in number of adhesions during second 
look diagnostic laparoscopy by 3 or more (in patients with 10 or less 
adhesions at the baseline) or by 30% and more (in patients with >10 
adhesions at the baseline)) is 45%.
Performance of second look laparoscopy under the present study is 
unacceptable from the ethical point of view, MRI will be used for 
evaluation of primary end point. As per the publication (Ghonge, N.P.; 
Ghonge, S.D. Computed tomography and magnetic resonance imaging 
in the evaluation of pelvic peritoneal adhesions: What radiologists 
need to know? Indian J Radiol Imaging. 2014 Apr-Jun; 24(2): 149­
155), MRI data highly correlate with laparoscopy picture (both pre- 
surgical and post-surgical studies during repeated laparoscopies). The 
exclusions are the thinnest adhesions that may not be seen on MRI 
which may be compensated by use of high-field MRI.
As per the above publication, MRI allows to visualize adhesions 
qualitatively and quantitatively and to obtain data with the same degree 
of detalization as during laparoscopic investigation before and after the 
surgery.
Thus, calculation of sample size will be based on efficacy of similar 
drugs studied based on laparoscopic data, however, MRI control will be
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used in the study, first of all due to ethical considerations and due to 
strong correlation between MRI data and laparoscopy data.
Accordingly, as per the above studies of the drug Adept®, efficacy 
related to achieving primary end point (clinical efficacy determined as 
decrease in number of adhesions during repeated diagnostic laparoscopy 
by 3 and more (in patients with 10 or less adhesions at the baseline) or 
by 30% and more (in patients with > 10 adhesions at the baseline)) is 
45%. In the control group (placebo) based on literature review and 
metha-analysis (Ahmad G. et al., Fluid and pharmacological agents for 
adhesion prevention after gynaecological surgery (Review), 2014) 
achieving clinical efficacy is recorded in not more than 10% cases.
Using these baseline data, the following assumptions were introduced 
(as per the method specified in the FDA Guidance for Industry: Non­
Inferiority Clinical Trials):
• 
The study will be conducted as a superiority trial, i.e. at least one 
dosage of Seroguard must be more efficient than the placebo, 
whereby the superiority margin will be 5% and more (definition 
of endpoint and superiority margin from the main study of 
Adept® was used). Comparison with placebo will be performed 
for each dosage of the drug separately. Comparison of dosages 
by efficacy between them is not planned and will be a subject of 
the study in the Phase III of clinical studies of the drug
• 
Expected rates of achieving the primary endpoint in the groups 
with different dosages will be considered initially equal
• 
First type error (a) = 5 % (0.05) for superiority hypothesis
• 
Second type error (P) = 20 % (0.2), that corresponds to 80 % 
power.
• 
Expected withdrawal from the study will make 15% at 
screening and 10% after randomization
Null and alternative hypotheses for the superiority testing stage are 
worded as follows:
1. Null hypothesis (H0) holds that the difference in the rate of the 
primary endpoint achievement for one of the dosages of the drug 
Seroguard and the placebo will not exceed 5% in favor of the 
drug
Но- P1 - P 0 ^  °.°5
2. Alternative hypothesis (Ha ) holds that the difference in the rate 
of the primary endpoint achievement of one of the dosages of the
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drug Seroguard and the placebo will exceed 5% in favor of the
Where p0 and p1 are the rates of the primary endpoint achievement in 
the groups of the placebo and Seroguard (of any dosage), respectively.
For the purpose of calculation of the sample size in each group in this 
case, the formula is applied which is given in Chow S, Shao J, Wang H. 
2008. Sample Size Calculations in Clinical Research. 2nd Ed. Chapman 
& Hall/CRC Biostatistics Series. page 90
where
n is the size of one group;
z is the value of the normal distribution function with the given a and P 
levels;
8 is superiority margin 5%;
p1 is the expected proportion in the active drug group (one of the 
dosages) -  45%
p0 is the expected proportion in the placebo group -  10%
Applying the above data in this formula, we obtain the minimum number 
of patients in the placebo group without considering withdrawal: 24 
completed cases which corresponds to 26 randomizations and 30 
screenings.
Thus, the total number to be enrolled in the study is:
1) Placebo group, 1.5 mL/kg -  up to 30 screened female patients 
that corresponds to 26 randomizations and 24 completed cases
2) Placebo group, 2.4 mL/kg -  up to 30 screened female patients 
that corresponds to 26 randomizations and 24 completed cases
3) Seroguard group, 1.5 mL/kg -  up to 30 screened female 
patients that corresponds to 26 randomizations and 24 
completed cases
4) Seroguard group, 2.4 mL/kg -  up to 30 screened female 
patients that corresponds to 26 randomizations and 24 
completed cases
drug
Pi -P o > 0.05
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Thus, total of 120 female patients are to be screened and at least 104 
female patients are to be randomized for the study.
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Seroguard 
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Acronyms
ALT 
Alanine Aminotransferase
Ap 
Alkaline Phosphatase
APTT 
Activated Partial Thromboplastin Time
AR 
Adverse Reaction
ASA 
American Association of Anaesthetists
AST 
Aspartate Aminotransferase
ATC 
Anatomical Therapeutic Chemical Classification System
BP 
Blood Pressure
CI 
Confidence Interval
CRF 
Case Report Form
CRO 
Contract Research Organization
DP 
Drug Product
ECG 
Electrocardiography
ESR 
Erythrocyte Sedimentation Rate
FDA 
Food and Drug Administration
FL 
Federal Law
GCP 
Good Clinical Practice
GGTP 
Gamma-Glutamyl Transpeptidase
HIV 
Human Immunodeficiency Virus
HR 
Heart Rate
ICD 
International Classification of Diseases
ICH 
The International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
IEC 
Independent Ethics Committee
INR 
International Normalized Ratio
ITT 
Intent-to-treat
LEC 
Local Ethics Committee
MOH 
Ministry of Health
PATE 
Pulmonary Artery Thromboembolism
PP 
Per protocol
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RNA
Ribonucleic Acid
RR
Respiratory Rate
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
USI
Ultrasound Investigation
WHO
World Health Organization
WMA
World Medical Association
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1 
General information 
1.1 
Protocol title, ID and date
Study title 
Multi-center randomized double-blind placebo-controlled Phase II study of efficacy 
and selection of dose of Seroguard, solution (JSC Pharmasyntez, Russia) used for 
prevention of pelvic adhesions
Protocol 
SG-2/1215 
revision 3.2 dated 06.03.2017
1.2 
Name and address of the Sponsor and monitor
Joint Stock Company Pharmasyntez
Legal address: Krasnogvardeyskaya str., 23, off. 3, Irkutsk, 664007, Russia.
Actual address: Rosa Luxemburg str., 184, Irkutsk, 664040, Russia.
Phone: +7(3952)55-03-28 
Fax:(495)737-03-30
1.3 
Name and designation of persons authorized on behalf of the Sponsor 
to sign the protocol and amendments to the protocol
Natalya Anatolyevna Dvoynikova 
Clinical pharmacologist, JSC Pharmasyntez
1.4 
Name, designation, address and phone number of Medical reviewer of 
the present study appointed by the Sponsor
Michael Gennadyevich Shurygin 
R & D Director, JSC Pharmasyntez
Rosa Luxemburg str., 184, Irkutsk, 664040, Russia.
Phone: +7(3952)55-03-28 ext. 189
1.5 
Name and designation of investigators responsible for the study 
performance, as well as addresses and phone numbers of clinical sites
1. Government-Owned Health Institution of Moscow, Municipal clinical hospital No 12,
Moscow City Health Department
Address: Bakinskaya str., 26, Moscow, 115516
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Phone: 8(495)321-54-92
E-mail: gkb12@zdrav.mos.ru
Principal Investigator: Vera Dmitriyevna Petrova
2. State Educational Government-Financed Institution of Higher Professional Education, I.M. 
Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation
Address: Yelanskogo str., 2, bldg. 1, Moscow, 119435
Phone: +7 (499) 372-00-15
E-mail: mgmukliniki@mma.ru
Principal Investigator: Natalya Ivanovna Borisova
3. State Educational Government-Financed Institution of Higher Professional Education, Kazan 
state medical university, Ministry of Health of the Russian Federation (SEGFI of HPE, Kazan 
SMU, Ministry of Health of the Russian Federation)
Address: Butlerova str., 49, Kazan, the Republic of Tatarstan, 420012
Phone: +7 (843) 2360451
E-mail: 
goszak-chief@kgmu.kcn.ru
Principal Investigator: Albir Almazovich Khasanov
4. State Educational Government-Financed Institution of Higher Professional Education, A.I. 
Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of the 
Russian Federation
Address: Delegatskaya str., 20, bldg. 1, Moscow, 127473 
Phone: 8 (495) 609-67-00 
E-mail: msmsu@msmsu.ru
Principal Investigator: Vladimir Nikolayevich Kuzmin
5. Federal state institution, V.I. Kulakov Research Center for Obstetrics, Gynecology, and 
Perinatology, Ministry of Health of the Russian Federation.
Address: Academician Oparin str., 4, Moscow, 117997
Principal Investigator: Inna Anatolyevna Apolikhina.
6. Krai Government-Owned Publicly Funded Health Care Institution, Krai clinical hospital
Address: Partizana Zheleznyaka str., 3 “A”, Krasnoyarsk, 660022
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Principal Investigator: Alexey Ivanovich Gritsan.
7. Federal State Educational Government-Financed Institution of Higher Professional 
Education, I.P. Pavlov Ryazan state medical university, Ministry of Health of the Russian 
Federation (Government-owned health institution, Ryazan regional clinical hospital)
Address: Vysokovltnaya str., 9, Ryazan, 390026
Principal Investigator: Dmitry Viktorovich Seliverstov
8. Government-Owned Health Institution, Leningrad regional clinical hospital
Address: Lunacharskogo prospekt, 45-49, Saint-Petersburg, 194291 
Principal Investigator: Irina Vladimirovna Sergeyeva.
9. State-Funded Health Care Facility of Moscow, V.M. Buyanov Municipal Clinical Hospital, 
Moscow City Health Department
Address: Bakinskaya str., 26, Moscow, 115516
Principal Investigator: Vera Dmitriyevna Petrova.
1.6 
Names and addresses of clinical laboratories and other medical 
and/or technical services and/or organizations involved into the study
Central laboratory for evaluation of MRI data: Center of computed tomography 
Address: Krasnoyarskaya str., 11 B, Irkutsk, 664009 
Tel/fax: (3952) 500-557
responsible person: Viktor Anatolyevich Shanturov, Chief Physician, D. Sc., professor.
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2 
Justification of the study
The seriousness of problematics of serosal injury is related to increase in number of invasive 
medical procedures accompanied by traumatization (surgical procedures in thoracic and 
abdominal cavities, endoscopic diagnostic procedures, etc.). An inflammatory process is 
developed in response to injuries. It leads to formation adhesion which significantly causes 
abnormality of organs covered with serous membrane.
After surgeries, adhesions are formed on the abdominal cavity organs with a rate from 20% to 
80%. Meanwhile, “peritoneal adhesions” are developed with characteristic clinico-morphological 
complex of symptoms. It’s the most common and threatening complication is an acute adhesive 
ileus comprising more than 40% among different types of acquired ileus, lethality for this 
abnormality achieves 8-19%. Formation of adhesions in the pelvis leads to infertility.
Moreover, in 65% cases of infertility, the reason is female reproductive system abnormality, 
whereby one of the most common (30% - 35%) pathogenetic mechanisms of infertility is 
abnormality of transportation of egg, as well as of sperm cell and gestational sac through fallopian 
tubes, including due to pelvic abnormality involving peritoneum and formation of adhesive 
process in the pelvis -  tubal or tubo-peritoneal factor (1,2). Diseases causing such complications, 
first of all, include inflammatory diseases of the pelvis, including acute salpingitis. In their 
etiological structure, infections caused by Chlamydia trachomatis, Neisseria gonorrhea and 
anaerobic bacteria prevail. Infertility risk is increased after each such disease: 10%-12% after the 
first one, 23%-35% - after the second one and 54%-75% - after the third one, and the 6-7 fold risk 
of extrauterine pregnancy after an inflammatory disease of the pelvis (3,4). Other widespread 
reasons of tubo-peritoneal infertility is endometriosis (7%-14%, disease is accompanied by chronic 
inflammation and cicatrization in the pelvis involving Fallopian tubes, similar to that appearing 
after infection diseases) (5), in the developing countries -  tuberculous salpingitis (in 10%-12% 
patients with pulmonary tuberculosis) 
(6), post-surgical adhesive process in the pelvis (in 
particular, after surgeries for perforated appendicitis, the risk of tubo-peritoneal infertility is 
increased by 4.8-fold; in most cases, pelvic surgeries cause development of adhesive process in 
the pelvis) (7,8).
Standard methods of diagnosing infertility reasons are hysterosalpingography, hysteroscopy and 
laparoscopy, whereby the last two methods are also used for treatment (9). In the study by Neerja 
et al. (10), laparoscopy was performed in 140 of 200 women with primary or secondary infertility 
aged from 20 to 30 years. In 38 cases (27.14%), a laparoscopic adhesyolisys was performed, a 
fallopian tube surgery was directly performed in 53 cases (37.86%), electrocoagulation or removal 
of lesions of endometriosis -  in 25 cases (17.86%), drilling of polycystic ovaries -  in 24 cases. 
Laparoscopy allowed to diagnose tubo-peritoneal cause of infertility in 30 women, in which 
abnormality was not found based on hysterosalpingography data, meanwhile the surgery allowed 
64 (45,7%) women to become pregnant. Thus, laparoscopic interventions are one of the most 
efficient methods of diagnostics and treatment of infertility in women.
In the meantime, the most common complication after pelvic surgeries is formation of adhesions. 
After second look laparoscopy in women previously underwent gynecological surgeries, adhesions
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were found in 56%-100% cases (8), whereby, involvement of fallopian tubes in adhesion process 
is typical (11,12). Thus, the topicality of searching for means for prevention of adhesions during 
any gynecological surgeries, as well as for prevention of their relapse after adhesiolysis is 
unmistakable. Despite multiple, presently offered means and recommendations for prevention of 
post-surgical adhesions, no reliable and efficient means have been found, and the result of using 
the administered drugs is fairly doubtful, because in the clinical practice there are no methods of 
objective control for post-surgical adhesions, evaluation of their efficacy is performed by indirect 
signs (13,14,15). JSC Pharmasyntez has developed a new drug Seroguard, solution (hereafter 
Seroguard or the test drug), mechanism of action of which is related to suppression of p38- 
mitogen-activated protein kinase activity (p38 MAPK). Role of these intracellular regulators in 
inflammatory processes is well known, their participation in pathogenesis of such inflammatory 
diseases as rheumatoid arthritis, Crohn’s disease, psoriasis, bronchial asthma, is described, search 
for the drugs suppressing p38 MAPK is going on (16). As inflammation underlies the adhesions, 
suppression of p38 MAPK in the abdominal cavity may reduce activity of adhesive process. This 
assumption is based on the results of several pre-clinical studies. Thus, Ward et al. in the study of 
rats showed that suppression of MAP KAP kinase II (MK2) which is activated by p38 MAPK 
causes decrease of inflammation and intra-abdominal adhesion severity (17). Katada et al. in the 
study of mice showed that in case of injured caecum, a p38 MAPK activity is increased, and 
administration of p38-MAPK inhibitor prevents formation of adhesions (18). The pre-clinical 
studies of the drug Seroguard also demonstrated high antiadhesive activity with no significant 
toxicity. Development of a new anti-adhesive drug Seroguard for clinical use is actual, justified 
by pathogenetic reasons and promising results of pre-clinical studies. In a double-blind placebo- 
controlled Phase I clinical study, a tolerability of the drug Seroguard was evaluated in patients 
after laparoscopic cholecystectomy (19). Seroguard was administered into abdominal cavity of 
patients at the end of the surgery at the dose of 2.4 mL/kg. Comparison to similar volume of 
placebo (0.9% sodium chloride) showed that incidence of adverse reactions in the both groups was 
comparable.
In the studies of the drug Adept® (Innoventica plc), maximally close to the test drug (20) by 
mechanism of action, a primary endpoint was used. It was determined as a decrease in number of 
adhesions during second look diagnostic laparoscopy by 3 or more (in patients with 10 or less 
adhesions at the baseline) or by 30% and more (in patients with >10 adhesions at the baseline), 
which is an adequate reflection of an expected mechanism of the drug action and allows to justify 
sample size required for performance of the study. Meanwhile, performance of second look 
laparoscopy in conditions of a similar study in the Russian Federation is ethically unacceptable, 
due to which using MRI is supposed for evaluation of the given endpoint. As per the publication 
data of Ghonge et al. (21), MRI data of the study sufficiently correlate with laparoscopic picture 
(including both pre-surgical and post-surgical studies with second look laparoscopies). The 
exclusion are the thinnest adhesions that may not be seen by MRI, which may be compensated by 
using high-field MRI. This allows to use MRI investigation as an analogue of second look 
laparoscopy while maintaining required accuracy of evaluating the primary endpoint.
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Presently, considering safety of the drug Seroguard when administered into abdominal cavity 
proved in the Phase I clinical study, it is planned to perform a Phase II clinical study, in which it 
is supposed to evaluate safety and efficacy of Seroguard for prevention of adhesions in the pelvis 
after laparoscopy adhesiolysis due to tubo-peritoneal infertility caused by pelvic adhesions.
2.1 
Name and description of the study drugs
The test original drug Seroguard, solution manufactured by JSC Pharmasyntez, is a drug for 
administration into serous cavities, containing conjugate of hydrochloride 4-[4-(4-fluorophenyl)- 
2-[4-methylsulfinyl)phenyl]-1H-imidazol-5-pyridine with poly-1-vinylimidazole as an active 
ingredient. The following is information as per the draft instruction for medical use.
Structural formula
Figure 1 -  Structural formula of the active ingredient of the drug Seroguard, solution
Pharmacotherapeutic group: Selective immunosuppressants
ATC code: L04AA
Pharmacodynamics
The drug doesn’t exert systemic influence on organs and systems of the body. It exerts local action. 
It is known that in case of injured serous membrane, in particular, in case of peritoneal trauma, a 
hyperexpression of a set of genes is observed. They are responsible for synthesis of biologically 
active substances (interleukins, integrines, growth factors, signaling cascades), which launch 
inflammatory process and process of reparation. Hyperexpression of genes responsible for 
synthesis of collagen is observed from Day 3 to Day 14, maximum on Day 3. A set of gene co­
expressions changed during reparative process in response to abdominal alteration is known.
Administration of Seroguard significantly modifies response of cells to alteration causing 
significant decrease in anti-inflammatory cytokine gene expression by Week 2 of the process, a 
sharp decrease of Csf3 colony-stimulating factor activation, interruption of second wave of
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activation of growth factor expression, suppression of a set of genes (Egf, Pdgfa, Tgfa). Activity 
of Wisp1 gene happens which codes main chain of WISP signaling pathway, maintaining 
proliferative activity of fibroblasts and activation of Col5a3 collagen gene is significantly 
decreased.
Experimental studies demonstrated that during administration of Seroguard, solution, cell response 
is significantly changed in the site of abdomen injury from the point of view of gene activity coding 
proteins of focal adhesion. Main fixed shifts are an earlier activation of these gene transcription 
(starting from Day 1 of the process in comparison to Day 3 in control), after which an activity is 
sharply decreased and is left less than in control group up to the end of follow-up. Decreased 
expression of membrane proteins of adhesion and related proteins of cytoskeleton, probably, 
interferes with interaction of cells with each other and with interstitial matrix in time corresponding 
to conversion of fibrin adhesions into fibrous adhesions.
p38 (P, у, 5 subunits), p44 and JNK3 kinases similar by 3-dimensional structural organization act 
as main biological targets in the mechanism of Seroguard action, which allows to consider MAP 
kinase inhibition to be main in the mechanism of action of the drug.
Pharmacokinetics
After intravenous administration to rats at the dose of 6.15 mg/kg, peak of concentration is 
observed at about 15 minutes after administration and is 38.89±2.50 pg/mL.
Half-life is 4.25 ±0.07 h.
Mean retention time is about 5.9 hours.
Volume of distribution is about 1300 mL/kg.
After intraperitoneal administration to rats at the dose of 6.15 mg/kg, the drug in blood plasma is 
not observed by HPLC method, which evidences absence of its significant absorption after by the 
given route of administration.
Indications
Prevention of adhesions 
Contraindications
Allergy to the drug components.
Intra-abdominal administration — purulent process in the abdominal cavity and the pelvis. 
Gynecological surgery — purulent process in the abdominal cavity and the pelvis.
Intrapericardial administration — presence of infectional pericarditis.
Intra-articular administration — presence of infected wounds, abrasions in the joint; joint 
infection; venous or lymphatic stasis from the side of injured joint.
Not tested in pregnant patients, patients under 18, patients with hepatic or renal failure.
Studies in animals did not show any toxic activity or negative effect on reproductive function, 
fertility and teratogenic effect by Seroguard.
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Posology and method of administration
Administered into serous cavity by method of single irrigation (by syringe, without injuring 
abdominal mesothelium) in aseptic conditions before completion of surgery. Re-administration is 
not recommended.
Before administration, aspirate all remaining fluids (blood, exudate, solutions administered 
intraoperatively).
Before use, heat the solution until body temperature.
Doses for adults:
For abdominal cavity surgery, the drug is administered at the dose of 2.4 mL/kg body weight into 
abdominal cavity.
For gynecological surgery, the drug is administered into abdominopelvic cavity at the dose of 1.5 
to 2.4 mL/kg providing post-surgical position preventing discharge of the drug from the pelvic 
cavity.
For surgeries related to pericardium dissection, the drug is administered intrapericardially at the 
dose of 0.05 mL x left ventricular stroke output.
For administration into joint cavity during arthroscopy - up to 2 mL depending on the volume of 
joint.
The drug is intended only for administration into serous cavity, intravenous administration is 
unacceptable. Do not mix with other drugs. Do not use as a vehicle of other drugs as antibiotics, 
chemotherapeutic agents, etc.
Side effect
In the Phase I clinical study, general incidence of side effects on administration of the drug 
Seroguard was similar to those during administration of the placebo. During the study, the 
following side effects possibly related to administration of the drug were found: hyperthermia (1.8 
%), pain in infraclavicular region (0.9 %), increased WBC count in blood (0.9 %).
Overdose
No information on overdose of the drug Seroguard is available.
2.2 
Results of pre-clinical and clinical studies significant for the given 
study
2.2.1 
Pre-clinical studies
Experimental studies of safety of Seroguard, solution were performed. They were aimed at 
evaluating acute and chronic toxicity, irritant properties, allergenicity, immunotoxicity, 
reproductive toxicity, mutagenicity and risk of carcinogenic action.
The test drug was proved to be low toxic, to have a high therapeutic index and safe after long-term 
(180 days) daily intraperitoneal administration to endotherm animals (rodents and dogs). Solution
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of the drug does not exert irritant action at the site of administration and is apyrogenic. It was 
shown that the drug does not have specific types of toxicity.
The performed studies showed that administration of Seroguard during modelling aseptic and 
purulent peritonitis had a marked therapeutic action and contributed to prevention of adhesions.
After intravenous administration to rats at the dose of 6.15 mg/kg, peak concentration is observed 
about at 15 minutes after administration and is 38.89±2.50 pg/mL. Half-life is 4.25±0.07 h. 
Average retention time is about 5.9 hours. Distribution volume is about 1300 mL/kg. After 
intraperitoneal administration to rats at the dose of 6.15 mg/kg, the drug is not observed in blood 
plasma which evidences absence of its significant absorption during the given route of 
administration.
According to hazard classification of drug products for clinical use, Seroguard, solution is referred 
to class III of low-toxic (low-hazard) drugs.
2.2.2 
Clinical studies
Seroguard, solution is a new original drug that has passed pre-clinical studies, Phase I clinical 
study was also performed (19). Multi-center double-blind placebo-controlled study included 
patients of both genders at the age from 18 to 75 years having indications for planned laparoscopic 
cholecystectomy. Treatment group (Seroguard) included 24 patients, and placebo group (0.9% 
sodium chloride) - 23 patients. Seroguard, solution 0.41 g/L, JSC Pharmasyntez, Russia or its 
respective placebo were administered into abdominal cavity at the end of laparoscopic 
cholecystectomy at the dose of 2.4 mL/kg. Incidence, nature and severity of adverse reactions 
(including clinically significant abnormalities of physical examination, vital signs, instrumental 
investigations, clinical laboratory parameters) were evaluated. 206 adverse reactions (AR) were 
recorded in the study: 110 (53,4%) -  in the group of treatment with Seroguard and 96 (46.6%) -  
in the placebo group. 14 cases of adverse reactions (6.8%) were moderate and one was severe, 
remaining adverse reactions were mild. 194 (94.2%) ARs were doubtfully related to administration 
of the drug, 8 (3,9%) -  conditionally related, and 4 ARs (1,9%) in the treatment group were 
evaluated as possibly related to the drug administration. 196 of 206 ARs (95.2%) completed by 
recovery of patient, in the remaining 10 cases (4.9%), a significant amelioration was observed. 4 
serious ARs were also recorded in three patients of both groups in the study.
No statistically significant changes, except for level of eosinophils and lymphocytes in the placebo 
group, were recorded in most of complete blood count and blood chemistry parameters. A 
statistically significant elevation (p = 0.0297) was noted in the level of eosinophils in the placebo 
group by Visit 11 (Day 28), however, it was not clinically significant. Similarly, elevation in 
lymphocytes (p = 0,0148) was observed by Visit 11 (Day 28), which was not clinically significant.
The performed analysis of coagulogram data did not reveal statistically significant differences in 
any parameter between the Visits (p > 0.05). Analysis did not also show any statistically significant 
variations in vital signs (p > 0.05).
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Thus, a good tolerability (comparable to that of placebo) of the drug Seroguard, solution 0.41 g/L, 
JSC Pharmasyntez, Russia was proved after administration into abdominal cavity at the end of 
laparoscopic cholecystectomy at the dose of 2.4 mL/kg in the Phase I study.
More detailed information on results of pre-clinical studies is provided in the Investigator’s 
Brochure.
2.3 
Known and potential risks and benefit for the study subjects
2.3.1 Risks and inconveniences related to participation in the study
ARs related to administration of the test drug and characteristic for the group of p38 MAPK 
inhibitors may be observed as well as AR not previously noted (known ARs during treatment with 
p38 MAPK inhibitors are provided in section 2.2.2.) may be noted during this study. Safety profile 
of p38 MAPK inhibitors is satisfactory even during systemic use, and considering the absence of 
Seroguard absorption from the abdominal cavity according to pre-clinical data, it is possible to 
calculate good tolerability of the drug. Based on results of the Phase I clinical study, safety profile 
of the drug Seroguard was comparable to that of placebo. Thus, AR incidence in the group of 
treatment with the test drug is expected not to exceed the similar parameter in the placebo-control 
group (risk related to the underlying disease which is an indication for surgery, risk of surgery and 
anesthesia).
Blood sampling for clinical laboratory investigations (see section 4.2.3.5) may be accompanied by 
mild pain which is fleeting and/or ecchymoses may be formed at the site of needle injection. A 
thrombus may be formed in vein or infectious complication may be developed significantly rarer. 
Dizziness and/or fatigue may be observed during and soon after blood sampling.
Electrocardiographic examination (see section 4.2.3.6) is a painless examination, however rash or 
irritation may develop on patient’s skin at the sites of gel application and using sticky electrodes 
for ECG.
Ultrasound investigation (see section 4.2.3.6) -  In the present study, USI of the abdominal cavity 
is performed by transabdominal access and USI of the pelvis - by transvaginal access. The latter 
may be accompanied by mild painful sensations.
Hysterosalpingography. Rare complications of performing HSG include development of acute or 
chronic endometritis (in cases when bacteria along with contrast agent get from vagina into the 
uterine cavity), as well as allergy to contrast agent (contrast contains iodine, that’s why presence 
of allergy to iodine should be specified in all women before HSG). Exceedingly rare complication 
of HSG is injury of fallopian tubes and/or uterine. In addition, during HSG a woman receives a 
small dose of X-ray irradiation (control of maximum individual effective irration dose is required).
Study 
procedures 
performed 
under 
the 
protocol, 
including 
blood 
sampling 
and 
electrocardiographic investigation, are routine in general clinical practice. Frequency of their 
performance does not make any significant additional load for female patient.
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In order to minimize risks, the study will include female patients meeting inclusion criteria (section 
5.1) and not having non-inclusion criteria (section 5.2). All the study subjects before signing 
informed consent to participate in the given study will be informed on possible risks and 
discomfort as well as on necessity to inform the Medical Investigator on health problems, if any. 
Medical Investigator will perform close monitoring of the study participants during the study. If 
necessary (for example, development of ARs), Medical Investigator will take required measures 
to perform respective investigations and/or administration of the therapy required.
2.3.2 
Possible benefit related to participation in the study
In the study, no money compensation is planned for female patients, however, they will have 
possibility to take adequate treatment and investigation under the protocol. Decreased incidence, 
prevalence and severity of adhesions in abdominal cavity as a result of administration of the study 
drug, i.e. reduced risk of developing post-surgical complications related to adhesive process, which 
increases chances of becoming pregnancy and/or reduces probability of pelvic adhesions, is 
possible (but not obligatory) during the study.
Throughout the study, female subjects of the study will be under close control of employees of 
healthcare institution participating in conducting the study.
Considering the above, as well as pre-clinical data on safety of the drug Seroguard, the results of 
the Phase I clinical study and clinical data on administration of p38 MAPK inhibitors, risk/benefit 
ratio in the present study may be considered to be acceptable for patients who will participate in 
it.
2.4 
Description and justification of route of administration, dosages, 
dosage regimen and therapy course
The test drug Seroguard is administered once into serous cavity in aseptic conditions before 
completion of surgery. Repeated administrations are not recommended. The drug is ready for 
administration. Before administration, aspirate all the remaining liquids from serous cavity (blood, 
exudates, solutions administered intraoperatively). Before use, heat the drug to body temperature. 
After an adequate sanitation of the abdominal cavity with warm normal saline in the quantity of 
100 mL, the drug Seroguard, solution in the concentration of 0.41 g/L is administered through 
trocar with the help of a metal tube 25 cm long with inner diameter of 4 mm with a silicone nozzle 
5 cm long, which is tightly connected to Janet syringe containing an anti-adhesion 
solution/placebo.
The study drug shall be applied onto the operated surface in the quantity of 2.4 mL/kg body weight 
or 1.5 mL/kg body weight by means of forced pressing the plunger of the syringe.
In order to create the maximum afflux of anti-adhesion agent into the pelvis, all the patients should 
be recommended to practice active behavior (getting up and walking) in the end of the first day 
after the surgery and supine position with the head kept up by the bed head elevation during rest.
At the post-operative period, for all the groups patient management is performed in accordance 
with the established standards.
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The drug is intended only for administration into serous cavity, intravenous administration is 
unacceptable. Do not mix with other drugs. Do not use as a vehicle of other drugs as antibiotics, 
chemotherapeutic agents, etc.
Selection of dosage is based on principle of Seroguard action -  the drug acts at the site of its 
administration. Seroguard should cover the surface of abdomen in order to form an efficient liquid 
barrier which causes launch of apoptosis of activated fibroblasts, interrupting development of 
adhesive process at the site of abdomen injury.
In the studies by diZerega (22,23), area of abdomen and volume of liquid required for its complete 
coverage were determined. For a human being, a maximum weight coefficient is approximately
2.4 mL/kg (that is, for patient with weight of 80 kg, 80*2.4=192 mL minimum). Thickness of 
boundary layer, in which reaction to injury is developed, which causes adhesions, and in which it 
is necessary to block activity of kinase cascade, is about h=0.3 mm based on morphometry data. 
Thus, the volume of boundary layer is equal to multiplication of thickness of boundary layer by 
area of abdomen surface (V=S*h). Activity of cascades in cells of deeper layers is unfavorable to 
be suppressed, because of ongoing process of surgical wound healing.
For gradually released active component of IC50 value related to MAPK p38 fibroblasts, IC50 = 
300 nM, M=413.9 g (IC50=413.9*300*10-9=0.00012417 g/L = 0.12417 mg/L) (24).
Area of abdomen (approximately equal to body surface) of a person with weight of 80 kg and 
height of 180 cm is about 2 m2 Volume of boundary layer is 2*0.0003 = 0.0006 m3= 0.6 dm3 (the 
drug will be distributed at this volume).
Based on T1/2 coding RNA for MAPK (25) for 3-day exposure (based on absence of active 
absorption of conjugate in abdominal cavity):
0.12417 mg/L * 0.6 L * 24 = 1.79 mg
Considering additional 10 % (200 mL of liquid is administered), a dose administered should be
1.79*1.1=1.997 mg. Thus, for a person with weight of 80 kg and height of 180 cm, a quantity of 
the conjugate administered should contain about 2 mg of the drug, and the volume should be about 
200 mL, which is 2.4 mL/kg. Efficacy and safety of the dose 1.5 mL/kg will be also evaluated in 
the study considering that the drug will exert its action not on the whole surface of the abdomen, 
but mainly in the pelvis.
Maximum dose administered to rats in the toxicological study is 30 mL/kg intravenously and 
intraperitoneally, meanwhile neither death of animals, nor abnormal general condition or behavior 
of animals were noted. In the study in dogs, the maximum administered dose of Seroguard was 12 
mL/kg intraperitoneally, whereby no abnormal functioning of organs and systems of animals was 
observed. After recalculation for human being (26), both dosages exceed the above doses for the 
Phase II study for at least twice.
Sodium chloride, solution for infusion 0.9% (CJSC EAST-PHARM, Russia) was selected as the 
placebo). Selection of the drug is based on requirements to placebo in the given study:
• 
The drug may be used for irrigation of the abdominal cavity during the surgery;
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• 
The drug does not exert effect on the body of patient after selected route of administration 
in the dosage selected.
Sodium chloride solution is widely used in abdominal surgery as placebo (27,28,29,30), it does 
not also exert significant pharmacological action and may not influence on parameters of safety of 
patients, that’s why its use as a placebo is justified.
2.5 
Normative-regulatory base for conducting the clinical study
The present document is a protocol of a clinical study which is planned to be conducted as per the 
principles of Declaration of Helsinki of the World Health Association (adopted by 18th WMA 
General Assembly, Helsinki, June 1964, amended by 64th General Assembly, Fortaleza, October, 
2013), tripartite guideline for Good Clinical Practice (ICH GCP) and is regulated by acting 
legislation of the Russian Federation (RF):
• Federal Law dated 12.04.2010 No 61-ФЗ “On drug circulation” as amended.
• Federal Law dated 27.07.2006 No 152-ФЗ “On personal data” as amended.
• RF national standard GOST Р52379-2005 “Good Clinical Practice”.
• 
RF government decree No 714 dated 13.09.2010 (as amended by the RF government decree 
dated 18.05.2011 No 393, dated 04.09.2012 No 882) “On the approval of model rules of 
mandatory health and safety insurance for patients participating in a clinical drug study”.
• Order of RF Ministry of Healthcare dated 29th of November, 2012 No 986н “On approval 
of regulation on ethics board”
• 
Order of RF Ministry of Healthcare dated 01.04.2016 N 200н “On approval of Good 
Clinical Practice requirements”.
2.6 
Description of the study population
The study population will be hospitalized patients with confirmed diagnosis of pelvic adhesions. 
The study will include female patients aged from 18 to 45 years after signing informed consent. 
Patients meeting inclusion criteria, without non-inclusion criteria (sections 5.1 and 5.2), passed all 
the screening procedures, will be included into the study and randomized into one of the study 
groups
3 
Purposes and objectives of the study
3.1 
Purpose
The present study is aimed at evaluating efficacy of the drug Seroguard, solution, used for 
prevention of pelvic adhesions.
Main purposes of the study:
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Comparison of efficacy of the drug Seroguard, solution, administered in the volume of 1.5 mL/kg 
or 2.4 mL/kg and placebo (0.9% sodium chloride) in the volume of 1.5 mL/kg or 2.4 mL/kg by 
presence, severity and prevalence of adhesions during laparoscopic treatment of pelvic adhesions.
Study of safety profile of the drug Seroguard, solution administered in the volume of 1.5 mL/kg 
or 2.4 mL/kg, in comparison to placebo (0.9% sodium chloride) in the volume of 1.5 mL/kg or
2.4 mL/kg during laparoscopic treatment of pelvic adhesions.
3.2 
Study objectives
1. To determine change in number of pelvic adhesions based on MRI data in post-surgical 
period in comparison to data of pre-surgical MRI data
2. To determine change in thickness of pelvic adhesions based on MRI data in post-surgical
period in comparison to data of pre-surgical MRI data
3. To determine frequency of limited displaceability of pelvic organs in post-surgical period
(based on results of transvaginal ultrasound investigation).
4. To determine frequency of hyperechoic linear lesions in post-surgical period based on 
results of transvaginal ultrasound investigation.
5. To determine changes in frequency of detecting limited displaceability in comparison to 
baseline (absolute change and in % of baseline value).
6. To determine changes in frequency of detecting hyperechoic linear lesions based on 
repeated transvaginal ultrasound investigation in comparison to baseline.
7. To determine frequency of detecting complete absence of USI -  signs of adhesion process 
in pelvis in post-surgical period (defined as absence of limited displaceability of pelvic 
organs and absence of hyperechoic linear lesions)
8. To determine number of adhesions during surgery.
9. To determine number of dense adhesions during surgery.
10. To determine percentage of female patients with any adverse reactions.
11. To determine percentage of female patients with any serious adverse reactions.
12. To determine percentage of female patients with adverse reactions, relation of which to 
use of the test drug or the placebo is “definite”, “probable” or “possible”.
13. To determine percentage of female patients with serious adverse reactions, relation of 
which to use of the test drug or the placebo is “definite”, “probable” or “possible”.
14. To determine percentage of female patients with mild adverse reactions.
15. To determine percentage of female patients with moderate adverse reactions.
16. To determine percentage of female patients with severe adverse reactions.
17. To determine percentage of female patients with clinically significant changes in results 
of physical examination.
18. To determine percentage of patients with clinically significant changes in vital signs.
19. To determine percentage of female patients with clinically significant changes in 
electrocardiogram (ECG).
20. To determine percentage of female patients with clinically significant laboratory 
parameters.
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4 
Design of the study
4.1 
Primary and secondary endpoints evaluated in the study
Primary endpoints evaluated in the study will be efficacy and safety parameters after single 
administration of the test drug or the placebo.
Primary endpoint: achieving clinical efficacy determined as:
Frequency of reducing number of adhesions after repeated MRI by 3 or more (in female patients 
with 10 and less adhesions at the baseline) or by 30% and more (in patients with >10 adhesions at 
the baseline)) in comparison to baseline MRI data
Secondary efficacy endpoints:
1. Change in thickness of pelvic adhesions by repeated MRI in comparison to baseline MRI 
data
2. Frequency of limited displaceability of pelvic organs in post-surgical period (based on 
results of transvaginal ultrasound investigation) on Day 30±4 after the surgery
3. Frequency of hyperechoic linear lesions in post-surgical period based on results of 
transvaginal ultrasound investigation
4. Change in frequency of detecting limited displaceability in comparison to baseline 
(absolute change and in % of baseline value)
5. Changes in frequency of detecting hyperechoic linear lesions based on repeated 
transvaginal ultrasound investigation in comparison to baseline
6. Frequency of detecting complete absence of USI -  signs of adhesion process in the pelvis 
in post-surgical period (defined as absence of limited displaceability of pelvic organs and 
absence of hyperechoic linear lesions)
Safety parameters:
• 
Vital signs (body temperature, BP, HR, RR)
• 
Laboratory p aram eters:
Blood chemistry -  total protein, glucose, ALT, AST, total bilirubin, alkaline phosphatase, 
amylase, creatinine
Complete blood count -  RBC count, WBC count, platelet count, hemoglobin, hematocrit, 
WBC differential, ESR
Coagulogram -  coagulation time, international normalized ratio (INR), thrombin time, 
activated partial thromboplastin time (APTT)
Urinalysis -  color, transparency, pH, specific gravity, protein, glucose, WBC, RBC, bacteria, 
casts, salts
• 
ECG data -  heart rate [HR], PR, QRS, QT intervals and calculated QTc interval.
• 
USI data
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• 
Incidence of adverse reactions
• 
Incidence of serious adverse reactions
• 
Incidence of unexpected adverse reactions
• 
Incidence of adverse and serious adverse reactions caused termination/withdrawal from the 
study.
4.2 
Description of the study design, graphical scheme of the study design, 
procedures and stages of the study
4.2.1 
Description of the study design
A multicenter randomized double-blind placebo-controlled clinical study of efficacy and selection 
of dose of the drug Seroguard, solution (JSC Pharmasyntez, Russia) used for prevention of pelvic 
adhesions will be performed.
After successful completion of screening procedures, a female patient will undergo a planned 
laparoscopic surgery. Randomization of female patients into groups will be performed on the day 
of surgery using an online IWRS system (Interactive Web Response System). The test drug or the 
placebo are used at the final stage of the surgery. A female patient is planned to be under control 
in the hospital for 6 days after completion of the surgery. On Day 7 of the study, a female patient 
may be discharged from the hospital, if there are no any contraindications, in this case a follow- 
up of a female patient is performed on outpatient basis. Follow-up lasts for 4 weeks, up to Day 28 
of the study. Then a complete evaluation of treatment efficacy after repeated MRI-investigation of 
the abdominal cavity and the pelvis is performed.
Study procedures aimed at evaluating safety and efficacy of the test drug and the placebo will be 
identical in all the groups:
1) Placebo group, 1.5 mL/kg -  up to 30 screened female patients which corresponds to 26 
randomizations and 24 completed cases
2) Placebo group, 2.4 mL/kg -  up to 30 screened female patients which corresponds to 26 
randomizations and 24 completed cases
3) Seroguard group, 1.5 mL/kg -  up to 30 screened female patients which corresponds to 26 
randomizations and 24 completed cases
4) Seroguard group, 2.4 mL/kg -  up to 30 screened female patients which corresponds to 26 
randomizations and 24 completed cases
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4.2.2 
Graphical scheme of the study design
V
Scre en in g
N
• Visit 0 (from 1 to 15 days before use of the study 
drugs)
A d m in istratio n  of 
Se ro gu ard  or th e  
placebo
\
• Visit 1 (Day 0) - laparoscopy and administration 
of the test drug / placebo
Fo llo w -u p
>
• Visit 2 (Day 6±1) - interim safety assessment
Fo llo w -u p
N
• Visit 3 (Day 30±4) - evaluation of efficacy and 
safety of treatment
Fo llo w -u p
Figure 2 -  Graphical scheme of the study
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4.2.3 
Description of the study procedures 
Table 1 -  Schedule of the study procedures_____
Procedures
Screening
Surgery
Follow-up
Unscheduled visit1
Withdrawal visit
Visit 0
Visit 1
Visit 2
Visit 3
Day from 
-15 to -1
Day 0
Day 6±1
Day 30±4
Informed consent
+
Evaluation of inclusion, non-inclusion criteria
+
+
Evaluation of withdrawal criteria
+
+
Collection of medical and pharmacotherapeutic analysis
+
Collection of demographic and anthropometric data
+
Physical examination
+
+
+
+
+
+
Evaluation of local status
+
+
+
+
+2
M easurement of vital signs3
+
+
+
+
+
+
HIV, RW, HBV and HCV blood test
+
Pregnancy test
+
+
+
Randomization
+
Complete blood count
+
+
+
+
+
Blood chemistry
+
+
+
+
+
Coagulogram
+
+
+
Urinalysis
+
+
+
+
+
M RI of abdominal cavity and pelvic organs
+
+
+
USI of abdominal cavity
+
+
+
USI of pelvic organs
+
+
+
Gynecological examination and colposcopy
+
Cytological examination (Pap-smears)
+
Smear microscopy
+
Hys terosalpingography4
+
12-lead ECG
+
+
+
+
+
Evaluation of concomitant therapy
+
+
+
+
+
Administration of the test drug/placebo
+
Detection of ARs
+
+
+
+
+
+
1 Any additional study procedure may be performed in case of indications, at the discretion of the Principal Investigator.
2 If applicable
3 Blood pressure, heart rate at the radial artery, respiration rate, body temperature will be measured.
4 Performed at the discretion of a doctor for women included into the study with diagnosis “infertility”.
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4.2.3.1 
Collection of demographic data and history, anthropometry
During screening visit after signing informed consent, the following data will be collected from 
all the patients:
• 
Race, age (birth date).
• 
Body weight (kg), height (cm), BMI (kg/m2).
• 
Detailed medical history, including:
• 
previous surgeries and traumas;
• 
previous diseases
• 
allergy history;
• 
drugs used within the previous 30 days or 5 half-lives (which is longer) before visit 
of screening and used concomitantly, as well as herbal drugs and additives.
• Collection of gynecological anamnesis:
o Beginning of menses and their nature; 
o Date of beginning of the last menses;
o Presence/absence of previous pregnancies, their course and outcome;
Female patients signing informed consent should also provide consent to comply with efficient 
contraception throughout the study. Effective methods of contraception are use of one of the 
following methods (considering inclusion/non-inclusion criteria for the present study):
• 
Complete abstinence.
• 
Double barrier method: condom or occlusive cap (diaphragm or cervical/valt cap) plus 
spermicide (foam/gel/film/creme/suppository).
Women are obliged to comply with an adequate method of contraception throughout the whole 
study period.
4.2.3.2 
Physical examination
Physical examination will be performed at all the visits in order to reveal normal or changed 
physical data of patients, that were before administration of the study drug, as well as to reveal 
possible changes during and after its use. Acceptable terms of investigation performance are 
specified in section 4.2.4.
Physical examination includes:
• 
general condition of female patient;
• 
condition of skin;
• 
musculoskeletal system;
• 
lymphatic nodes;
• 
thyroid;
• 
upper respiratory tract and lungs;
• 
heart, blood vessels;
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• 
abdominal cavity organs, kidneys;
• 
psycho-neurological status.
4.2.3.3 
Evaluation of vital signs
Evaluation of vital signs will be performed at each visit. Acceptable terms of performance are 
specified in section 4.2.4. Evaluation includes:
• 
measurement of axillary temperature;
• 
measurement of systolic and diastolic blood pressure (BP);
• 
count of heart rate per 1 minute;
• 
count of respiration rate (RR) per 1 minute.
Measurements are performed in seated or semirecumbent position after 5 minutes of rest on one 
and the same hand (for measurement of BP and heart rate) and, if possible, by one and the same 
specialist of a clinical site during participation of a particular female patient in the study.
4.2.3.4 
Evaluation of local status (condition of postsurgical wounds)
To be evaluated:
• 
Palpatory tenderness
• 
Hyperemia
• 
Edema
• 
Presence of discharge
4.2.3.5 
Laboratory investigations
Scheduled blood and urine tests will be performed at screening (after signing informed consent) 
(Visit 0) and during visits 2 and 3, as well as in case of unscheduled visit and withdrawal visit. 
The following laboratory parameters will be determined/evaluated for the given studies:
• 
Blood chemistry -  total protein, glucose, ALT, AST, total bilirubin, alkaline phosphatase, 
amylase, creatinine.
• 
Complete blood count -  RBC, WBC, platelet count, hemoglobin, hematocrit, WBC 
differential, ESR.
• 
Coagulogram -  coagulation time, international normalized ratio (INR), thrombin time, 
activated partial thromboplastin time (APTT) -  performed only at visits 0, 3 and at 
withdrawal visit.
• 
Complete urinalysis with sediment microscopy - color, transparency, pH, specific gravity, 
protein, glucose, WBC, RBC, bacteria, casts, salts.
• 
HIV, RW, HBV and HCV blood tests -  only at screening.
Clinical laboratory investigations will be performed by local laboratory of a clinical site according 
to the standards of a respective site (including methods of biological sample collection and 
performance of laboratory investigations). Medical Investigator will obtain the study results,
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review, evaluate clinical significance of each parameter deviation from normal values (used in the 
local laboratory), put date and signature and store as a primary documentation. Samples of blood 
and urine for laboratory investigations are taken in fasting conditions, i.e. within 10 hours before 
sampling, a female patient of the study should not eat and drink anything, except for water.
Pregnancy test will be performed at screening (Visit 0) and at Visit 3, as well as at withdrawal 
visit, in a clinical site using strip-test (lateral flow immunoassay of beta-chorionic gonadotropin in 
urine).
Cytological examination (Pap-smear) and microscopic (bacterioscopic examination) 
examination of smears stained by Gram’s method. Smears for microscopy are taken from 
cervical canal, vagina and urinary tract. Smear is taken by spatula which does not injure mucosa 
of the specified organs and collect discharge in their lumen. Before collection of smears, 
gynecologist introduces a gynecological speculum into vagina. A material taken is applied on a 
glass slide and is sent to laboratory.
4.2.3.6 
Instrumental studies
Electrocardiography
Acceptable terms of ECG performance are specified in section 4.2.4.
Standard 12-lead ECG (with measurement of heart rate [HR], PR, QRS, QT intervals and 
calculation of QTc) will be performed in prone position after 5 minutes of rest. Recording rhythm 
in the respective leads should contain evaluable data of at least three cardiac cycles. All the changes 
in ECG should be subjected to evaluation by a primary care physician.
If any changes in ECG, Medical Investigator should evaluate their clinical significance. If 
clinically significant deviations at screening, Medical Investigator should evaluate possibility of 
inclusion of patient into the present study, at Visit 2 and 3 or in case of unscheduled visit or 
withdrawal visit -  to evaluate conformity to AR criteria (see section 8.2).
Ultrasound investigation of abdominal cavity and retroperitoneum
It is performed twice at Visits 0 and 2 as well as at withdrawal visit of the study as per the unique 
method presented in the separate guideline.
Performance of pelvic USI
Pelvic USI is performed at Visits 0 and 3 as well as at withdrawal visit of the study as per the 
unique method presented in the separate guideline, using transvaginal probe. Video recording of 
the performed investigation is required! Disc with the study results is attached to the primary 
documentation.
Performance of MRI of abdominal cavity and pelvis
The study is performed under fasting conditions (a female patient should starve before the 
investigation for at least 4 hours). 0.5 -  1.0 hours before the investigation, a female patient should
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void the bladder and colon. Before the investigation, features of abdominal cavity and pelvic MRI 
performance will be explained to a female patient in detail.
MRI of the abdominal cavity and the pelvis is performed at Visits 0 and 3, as well as at withdrawal 
visit as per the protocol of MRI investigation which will be provided in a separate guideline along 
with evaluation of adhesion severity according to the following method defined by the Sponsor:
Prevalence in abdominal cavity:
1. absence of adhesions;
2. one floor (up to 3 segments of one level);
3. two floors;
4. total adhesive process.
Prevalence in pelvic cavity:
1. Absence;
2. One region (right lateral space, left lateral space, pouch of Douglas or vesicouterine pouch);
3. Two regions;
4. Subtotal adhesive process in the pelvis (3 regions);
5. Total adhesive process in the pelvis.
Maximum severity of adhesions:
1. Thin (filmy or filiform);
2. Severe;
3. Severe with impaired passage through organs involved into the process (narrowing of the 
intestines for more than ^  of the lumen or hydrosalpinx).
Score of assurance evaluation is given for every adhesion in its presence:
absolute assurance, that the adhesion is present -  4;
adhesion is, probably, present -  3;
adhesion is, possibly, present -  2;
difficult to determine whether adhesion is present or absent -  1.
Pelvic adhesion index is determined:
PAI (pelvic adhesions index) = (A+B)*Ccp,
Determine as per the Tables A and B:
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A -  Prevalence of pelvic adhesive process
B -  Maximum severity of adhesions
Absence
0
Absence
0
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One region (right lateral space, left lateral 
space, pouch of Douglas or vesicouterine 
pouch)
1
Thin (filmy or filiform)
1
2 regions
2
Severe
2
Subtotal adhesive process in the pelvis (3 
regions)
3
Severe with 
impaired passage 
through organs involved into the 
process
3
Total adhesive process in the pelvis
4
Сср value is an arithmetic mean of assurance evaluation score during description of each detected 
adhesion.
Record of MRI-investigation results in DICOM-format will be sent to the study Sponsor for 
centralized evaluation in independent laboratory. Meanwhile, information on female patient by 
whom it could be identified, including therapy group, will remain blinded.
Hysterosalpingography
Hysterosalpingography is performed at Visit 0 at the discretion of a doctor only for female patients 
included into the study with diagnosis of infertility. May not be performed in case of 
hysterosalpingography results obtained on Day 7-10 of menstrual cycle at least 6 months before 
visit 0.
Water-soluble contrast agents are most commonly used for hysterosalpingography (50, 70% 
solutions of Cardiotrast, 60, 76% solutions of Triombtrastum, 60, 70% solutions of Urotrast, 76% 
solution of Verografin, etc.). Performed using radiotransparent urological examination chair by 
digital radiography equipment which permits to decrease radiation dose for patient. She is put on 
the edge of a table in a position comfortable for vaginal procedures. After treatment of vulva with 
disinfectant, a bimanual pelvic examination is performed. Spoon-shaped vaginal speculum is 
introduced into vagina. Its walls are wiped by dry cotton ball, and then by cotton ball moistened 
with alcohol. Anterior lip of cervix uteri is caught by bullet forceps, without piercing cervical canal 
mucosa reach with receptors.
Schultz cannula consisting of a tube 30-35 cm length is used for hysterosalpingography. Its internal 
diameter is 1.5-2.0 mm. One end of tube is connected to 10 or 20-gramm syringe. A cone-shaped 
tip is fixed on the other end; it is introduced into cervical canal in order to close external orifice of 
the uterus. There is a “rider” with a screw on the tube, on which ends of bullet forceps are fixed 
so as to firmly retain the tip in the cervix. Cannula is filled with contrast agent heated up to the 
body temperature. After ensuring in tightly closed external orifice by introducing a small quantity 
of contrast agent into uterine cavity a speculum is removed, and the woman is placed on the table 
so as to permit a central roentgen ray to pass through the upper edge of the uterus. In order to 
protect a doctor from roentgen radiation along with X-ray protection apron, fixed on radiography 
equipment for urological investigations, a mobile lead screen protecting the body and legs of a 
doctor is used. 2-3 mL of contrast agent are used for obtaining a first image in order to get a uterine 
cavity three-dimensional image. After treatment and examination of the first image, 3-4 more mL 
of contrast agent are added and the second image is obtained. In this case tighter filling of uterine 
cavity is obtained, and the contrast agent gets into tubes and abdominal cavity. After examination
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of a second image, a third image is obtained, if needed. 10-20 
mL of contrast agent are usually
used for the whole procedure. During hysterosalpingography using radiography equipment with
electro-optical converter on a TV screen, gradual filling of uterine cavity and tubes, movement of 
contrast agent into abdominal cavity may be seen, images are made while filling uterine cavity and 
tubes. On the day of procedure, it is required to shave pubic hair, and if no stool, perform cleansing 
enema. Before the procedure, void the bladder. After the procedure, patients should have rest on a 
couch for 40-60 min.
Gynecological examination
Gynecological examination of vulva, vagina and cervix is performed at Visit 0 as per the medical- 
economical standard (the study using speculum and bimanual examination) with obligatory 
recording of the following parameters:
• 
color of vaginal and cervical mucosa;
• 
presence or absence of abnormal changes (scars, polyps, erosions);
• 
form of cervix (conical, cylindrical, deformed);
• 
form of exterior mouth of the uterus (round, slit-like);
• 
nature of discharge 
Colposcopy
Colposcopy represents a diagnostic examination of vaginal orifice, vaginal walls and portio 
vaginalis using colposcope (lightening device and binocular with 40-fold magnification). Before 
the procedure, a woman should abstain from sex, vaginal douche, use of vaginal tablets and other 
topical drugs several days before the visit to a doctor. On the day of the procedure, a woman should 
wash her genitals with warm water and soap. There are not restrictions on the day of menstrual 
cycle.
Procedure of colposcopy is the following -  after a careful introduction of speculum, examine 
cervix and remove mucus. When introducing speculum and wiping cervix with cotton wool ball, 
try not to traumatize mucosa, otherwise it will be impossible to evaluate epithelium changes 
correctly. After introduction, a colposcope is fixed at the distance of 20-25 cm from the surface 
examined. Beam of light is directed on the cervix and, looking through the colposcope, ocular 
lenses are fixed so as to obtain a clear image of mucosa vaginal part of cervix, vaginal walls or 
vulva. Cervix is examined clockwise or by zones.
Then, 3% acetic acid is applied on uterine cervix, under its effect, mucosa is removed, and 
epithelium cells become whitish-grey. Acetic acid solution starts to act 30-60 seconds after 
application of mucosa and lasts for 3-4 minutes. Then 2% Lugol’s aqueous solution is applied, 
after that a healthy mature stratified squamous epithelium of uterine cervix is colored into dark- 
brown color (positive Shiller’s test). All the abnormal sites of tissue after exposure of Lugol’s 
solution are not colored or colored into slightly-yellowish.
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4.2.4 
Description of periods and visits of the study
4.2.4.1 
Screening period
Visit 0 (from Day -15 to -1 of the study)
The following will be performed at the visit:
• 
Obtaining informed consent (see section 12.2). All the screening procedures will be 
performed only after obtaining informed consent.
• 
Collection of history, demographic and anthropometric data, gynecologic history (see 
section 4.2.3.1).
• 
Collection of information on previous therapy (see section 4.2.3.1).
• Physical examination (see section 4.2.3.2).
• Evaluation of vital signs (see section 4.2.3.3).
• Laboratory investigations: 
complete blood 
count, blood chemistry, 
urinalysis,
coagulogram, pregnancy test, HIV, HBV, HCV and RW blood test (see section 4.2.3.5).
• ECG (see section 4.2.3.6).
• 
USI of the abdominal cavity, pelvis (see section 4.2.3.6).
• MRI of the abdominal cavity and the pelvis (see section 4.2.3.6).
• Gynecological examination and colposcopy (see section 4.2.3.6).
• 
Cytological examination (PAP-smears) (see section 4.2.3.5).
• 
Microscopic (bacterioscopic examination) examination of the smear stained by Gram’s 
method (see section 4.2.3.5).
• Hysterosalpingography (see section 4.2.3.6).
• 
Evaluation of inclusion/non-inclusion criteria compliance (see section 5).
• Evaluation of AR (see section 8).
4.2.4.2 
Therapy period 
Visit 1 (Day 0)
Before the surgery:
• Physical examination (see section 4.2.3.2).
• Evaluation of vital signs (see section 4.2.3.3).
• 
Actualization of the information on concomitant therapy.
• 
Actualization of the information on concomitant diseases.
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• 
Re-evaluation of inclusion/non-inclusion criteria (see section 5).
• 
Randomization (see section 4.3.1).
• 
Surgical intervention using the test drug or the placebo 
After the surgery:
• 
Physical examination (see section 4.2.3.2).
• Evaluation of vital signs (see section 4.2.3.3).
• Evaluation of local status (condition of postsurgical wounds). (see section 4.2.3.4)
• Evaluation of AR (see section 8).
Visit 2 Interim safety assessment (Day 6±1)
• 
Physical examination (see section 4.2.3.2).
• Evaluation of vital signs (see section 4.2.3.3).
• Evaluation of local status (condition of postsurgical wounds). (see section 4.2.3.4) .
• Evaluation of withdrawal criteria (see section 5.3)
• 
Laboratory investigations: complete blood count, blood chemistry, urinalysis (see section
4.2.3.5).
• 
USI of the abdominal cavity (see section 4.2.3.6).
• 
ECG (see section 4.2.3.6).
• Actualization of the information on concomitant therapy.
• Actualization of the information on concomitant diseases.
• Evaluation of AR (see section 8).
Visit 3 (30±4) Evaluation of safety and efficacy
• 
Physical examination (see section 4.2.3.2).
• Evaluation of vital signs (see section 4.2.3.3).
• Evaluation of local status (condition of postsurgical wounds).
• 
Laboratory investigations: complete blood count, blood chemistry, coagulogram, 
urinalysis, pregnancy test (see section 4.2.3.5).
• 
USI of pelvic organs (transvaginal) (see section 4.2.3.6).
• 
MRI of the abdominal cavity and the pelvis (see section 4.2.3.6).
• 
ECG (see section 4.2.3.6)
• 
Actualization of the information on concomitant therapy.
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• 
Actualization of the information on concomitant diseases.
• 
Evaluation of AR (see section 8).
4.2.4.3 
Unscheduled visit
Unscheduled visit may be performed at the discretion of the Investigator in case of ARs for 
performance of the required investigations. During each unscheduled visit regardless of its reason, 
the Investigator performs the following procedures and completes respective pages of CRF 
(Additional/Unscheduled visit):
• 
Physical examination (see section 4.2.3.2).
• 
Evaluation of vital signs (see section 4.2.3.3).
• 
Evaluation of local status (condition of postsurgical wounds).
• 
Evaluation of withdrawal criteria (see section 5.3)
• 
Laboratory investigations: complete blood count, blood chemistry, urinalysis (see section
4.2.3.5).
• 
ECG (see section 4.2.3.6).
• 
Actualization of the information on concomitant therapy.
• 
Evaluation of AR (see section 8).
If any indications, any study procedure may be performed additionally (see section 4.2.3). 
Respective pages of CRF are completed in this case.
4.2.4.4 
Withdrawal visit
Medical aid is performed as per the standards accepted in the specific healthcare institution in case 
of withdrawal of patient from the study. Visit of withdrawal from the study will be similar to 
completion Visit 3 by contents.
• 
Physical examination (see section 4.2.3.2).
• 
Evaluation of vital signs (see section 4.2.3.3).
• 
Evaluation of local status (condition of postsurgical wounds) (see section 4.2.3.4) .
• 
Evaluation of AR (see section 8).
• 
USI of pelvic organs (transvaginal) (see section 4.2.3.6).
• 
MRI of the abdominal cavity and the pelvis (see section 4.2.3.6).
• 
USI of the abdominal cavity (see section 4.2.3.6).
• 
Laboratory investigations: complete blood count, blood chemistry, coagulogram, 
urinalysis, pregnancy test (see section 4.2.3.5).
• 
ECG (see section 4.2.3.6).
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If a female patient is withdrawn from the study before discharge from the hospital, withdrawal 
visit is performed on the same day. If a female patient is withdrawn from the study already after 
discharge from the hospital, the visit should be performed within 5 days after it became known on 
withdrawal of a female patient. If a hospitalized patient refuses to pass the visit procedures, it may 
be limited by collection of information on AR. If an ambulatory patient refuses to come to a 
withdrawal visit, a phone contact (in exceptional cases) is accepted.
A follow-up will be performed for patients withdrawn from the study voluntarily and with ARs. 
The follow-up will last until recovery of the study patient condition, until stabilization or 
establishing chronic AR.
4.3 
Measures aimed at minimization of subjectivity
4.3.1 Randomization procedure
After signing informed consent for participation in the present study by female patient, 
confirmation of inclusion criteria presence and non-inclusion criteria absence, all the study 
subjects will be distributed into groups of treatment by method of centralized block randomization 
in 1:1:1:1 ratio, without stratification by center using online IWRS system (Interactive Web 
Response System). Randomization ID of patient will be assigned to a female patient as per the 
order of access to IWRS system. Whereby randomization IDs corresponding to administration of 
the test drug or the placebo will be randomly assigned to the equal number of patients.
1. Placebo group, 1.5 mL/kg -  up to 30 screened female patients which corresponds to 26 
randomizations and 24 completed cases
2. Placebo group, 2.4 mL/kg -  up to 30 screened female patients which corresponds to 26 
randomizations and 24 completed cases
3. Seroguard group, 1.5 mL/kg -  up to 30 screened female patients which corresponds to 26 
randomizations and 24 completed cases
4. Seroguard group, 2.4 mL/kg -  up to 30 screened female patients which corresponds to 26 
randomizations and 24 completed cases
A block generation of randomization sequence will be used for generation of randomization list. 
Randomization list will be generated in statistics software using random number generator at the 
stage of preparation for the study
Only randomization ID of the study female patient will be recorded in CRF without specifying the 
drug administered.
The Investigators will pass an online training on using IWRS system.
Register of screened and randomized female patients will be performed for all the sites. Form of 
register is provided in the Study Site File. Completion of the form should be performed by the 
Investigator on a regular basis with entering all the required data.
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In order to identify a female patient in case of insurance cases, each of them will be assigned an 
individual identification code composed as per the below scheme:
• 
No of approval to conduct the clinical study;
• 
Date of issue of approval in the format DD.MM.YYYY;
• 
Serial No of a healthcare institution specified in the approval;
• 
Female patient initials (initial letters of surname and first names of a female patient);
• 
Birth date of a female patient in the format DD.MM.YYYY;
• 
Female patient’s unique number (may consist of numeric and (or) alphabetic symbols).
No of 
approval to 
conduct the 
clinical study
Date of issue of approval 
(DD.MM.YYYY)
Serial No of 
healthcare 
institution 
specified in 
the approval
Female 
patient 
initials 
(initial 
letters of 
surname and 
first names 
of female 
patient)
Birth date of female patient 
(DD.MM.YYYY)
Female patient’s unique number 
(may consist of numeric and (or) 
alphabetic symbols)
4.3.2 
Blinding procedure
The present study is planned as a double blind placebo controlled study. Neither Medical 
Investigator, nor female patient will have access to the code of treatment administration which is 
aimed at maximum objectification of the primary endpoint.
Blinding is performed in such a way that in case of required disclosure of randomization code of 
an individual subject of the study, unblinding of randomization code is excluded, in general (i.e. 
randomization code does not contain indications for treatment group).
In order to provide a double blind design of the study, an unblinded pharmacist of the 
Sponsor/CRO should be in the study team, who will provide calculation of volume of the drug 
administered (mL) to each concrete female patient according to the therapy group and data on 
female patient body weight.
The drug is delivered to a site as prepared by unblinded pharmacist of the Sponsor/CRO. 
Administration of the drug to a female patient is made by a phone call to an unblinded pharmacist 
of the Sponsor / CRO before the surgery aimed at administration of the drug to a female patient 
corresponding to randomization ID. Unblinded pharmacist of the Sponsor / CRO may not inform 
a site representative or other blinded project team members on a treatment group (except for cases 
when unblinding is required for making decisions on the further strategy of a female patient 
maintenance). Unblinding fact as well as reasons for inquiry of information unblinding should be 
recorded in the primary documentation of a female patient in detail.
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4.4 
Description of the drugs used in the study -  description of the dosage 
form, packing and labeling
4.4.1 
Dosage form, composition and clinical-pharmacological characteristics 
Trade name: Seroguard
International non-proprietary name of the drug -  not determined
Chemical name: conjugate of hydrochloride 4-[4-(4-fluorophenyl)-2-[4-methylsulfinyl)phenyl]- 
1H-imidazol-5-pyridine with poly-1-vinylimidazole.
Dosage form: Solution for intracavitary administration.
Composition per 1 mL of solution.
Active ingredients: 
Quantity
Hydrochloride 
4-[4-(4-fluorophenyl)-2-[4-methylsulfinyl)phenyl]-1H- 
0.01 mg
imidazol-5-pyridine (functional imidazolinium salt)
Poly-1-vinylimidazole 
0.4 mg
Active ingredient:
conjugate of hydrochloride 4-[4-(4-fluorophenyl)-2-[4-methylsulfinyl)phenyl]-1H-imidazol-5- 
pyridine with poly-1-vinylimidazole - 0.41 mg/mL.
Description
Transparent colorless liquid.
Pharmacotherapeutic group:
ATC code: L04AA 
Pharmacological properties 
Pharmacodynamics
The drug doesn’t exert systemic influence on organs and systems of the body. It exerts local action. 
It is known that in case of injured serous membrane, in particular, in case of peritoneal trauma, a 
hyperexpression of a set of genes is observed. They are responsible for synthesis of biologically 
active substances (interleukins, integrines, growth factors, signaling cascades), which launch 
inflammatory process and process of reparation. Hyperexpression of genes responsible for 
synthesis of collagen is observed from Day 3 to Day 14, maximum on Day 3. A set of gene co­
expressions changed during reparative process in response to abdominal alteration is known.
Excipient:
Water for injection
up to 1 mL
Theoretical osmolality
0.073 mOsm/L
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Administration of Seroguard significantly modifies response of cells to alteration causing 
significant decrease in anti-inflammatory cytokine gene expression by Week 2 of the process, a 
sharp decrease of Csf3 colony-stimulating factor activation, interruption of second wave of 
activation of growth factor expression, suppression of a set of genes (Egf, Pdgfa, Tgfa). Decreased 
activity of Wisp1 gene happens which codes main chain of WISP signaling pathway, maintaining 
proliferative activity of fibroblasts, and decreases activation of Col5a3 collagen gene is 
significantly decreased.
Experimental studies demonstrated that during administration of Seroguard, solution, cell response 
is significantly changed in the site of abdomen injury from the point of view of gene activity coding 
proteins of focal adhesion. Main fixed shifts are an earlier activation of these gene transcription 
(starting from Day 1 of the process in comparison to Day 3 in control), after which an activity is 
sharply decreased and is left less than in control group up to the end of follow-up. Decreased 
expression of membrane proteins of adhesion and related proteins of cytoskeleton, probably, 
interferes with interaction of cells with each other and with interstitial matrix in time corresponding 
to conversion of fibrin adhesions into fibrous adhesions.
p38 (P, у, 5 subunits), p44 and JNK3 kinases similar by 3-dimensional structural organization act 
as main biological targets in the mechanism of Seroguard action, which allows to consider MAP 
kinase inhibition to be main in the mechanism of action of the drug.
Pharmacokinetics
After intravenous administration to rats at the dose of 6.15 mg/kg, peak of concentration is 
observed at about 15 minutes after administration and is 38.89±2.50 |ig/mL.
Half-life is 4.25 ±0.07 h.
Mean retention time is about 5.9 hours.
Volume of distribution is about 1300 mL/kg.
After intraperitoneal administration to rats at the dose of 6.15 mg/kg, the 
not observed, which evidences absence of its significant absorption 
administration.
Indications
Prevention of adhesions
Contraindications
Allergy to the drug components.
Intra-abdominal administration — purulent process in the abdominal cavity and the pelvis. 
Gynecological surgery — purulent process in the abdominal cavity and the pelvis.
Intrapericardial administration — presence of infectional pericarditis.
Intra-articular administration — presence of infected wounds, abrasions in the joint; joint 
infection; venous or lymphatic stasis from the side of injured joint.
Not tested in pregnant patients, patients under 18, patients with hepatic or renal failure.
drug in blood plasma is 
by the given route of
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Studies in animals did not show any toxic activity or negative effect on reproductive function and 
fertility by Seroguard.
Posology and method of administration
Administered into serous cavity by method of single irrigation (from syringe, without injuring 
abdominal mesothelium) in aseptic conditions before completion of surgery. Re-administration is 
not recommended.
Before administration, aspirate all remaining fluids (blood, exudate, solutions administered 
intraoperatively).
Before use, heat the solution to body temperature.
Doses for adults:
For abdominal cavity surgery, the drug is administered at the dose of 2.4 mL/kg body weight into 
abdominal cavity.
For gynecological surgery, the drug is administered into abdominopelvic cavity at the dose of 1.5 
to 2.4 mL/kg providing post-surgical position preventing discharge of the drug from the pelvic 
cavity.
For surgeries related to pericardium dissection, the drug is administered intrapericardially at the 
dose of 0.05 mL x left ventricular stroke output.
For administration into joint cavity during arthroscopy - up to 2 mL depending on the volume of 
joint.
The drug is intended only for administration into serous cavity, intravenous administration is 
unacceptable. Do not mix with other drugs. Do not use as a vehicle of other drugs as antibiotics, 
chemotherapeutic agents, etc.
Side effect
In the Phase I clinical study, general incidence of side effects on administration of the drug 
Seroguard was similar to those during administration of the placebo. During the study, the 
following side effects possibly related to administration of the drug were found: hyperthermia (1.8 
%), pain in infraclavicular region (0.9 %), increased WBC count in blood (0.9 %).
Overdose
No information on overdose of the drug Seroguard is available.
4.4.2 
Packing and labeling
Primary packing: 50 mL, 100 mL, 150 mL, 200 mL, 230 mL, 250 mL into type I-III USP dark 
glass vials. Vials are sealed with butylrubber stopper, crimped with aluminum cap.
Secondary packing: 1 vial along with package insert into consumer’s carton pack.
Labeling of the study drugs
Labeling should provide security of the study subject, possibility of tracking and identification of 
the drug and the study and it should contribute to correct use of the drug in the study.
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The following information should be provided on the label of the test drug/placebo:
• 
dosage form, route of administration, number of dosage units;
• 
code for identification of contents;
• 
number (code) of the study, information on the Investigator, Visit No;
• 
identification No (ID) of female patient of the clinical study -  entered in the study site after 
access to IWRS system and before delivery of the drug for surgery performance;
• 
signature: “For clinical studies”;
• 
storage conditions;
• 
period of use with specifying month and year so as to avoid any confusion (data until which 
the drug should be used, expiry date or retest date may be specified);
Symbols and pictograms may be used in order to clarify the above information. An additional 
information, warning and/or package insert may be provided.
Name, address and phone number of the Sponsor, contract research organization or the 
Investigator contractually employed (main contact to obtain information on the drug, the clinical 
studies and for urgent decodification) will be specified on a card which will be kept by a female 
patient throughout the clinical study.
If it is necessary to change the date of using the drug, it’s necessary to apply an additional label on 
the pack. On an additional label, there should be a new date until which the drug should be used 
as well as Batch No should be specified again. An additional label may be applied on a previous 
date of use, but it should not cover an initial Batch No which is related to quality control. This 
procedure may be performed at the manufacturing site which has a right to do it. If necessary, this 
may be performed in the study institution by pharmacist performed clinical studies or under his/her 
control, as well as by other medical staff as per the requirements of the acting legislation. If it is 
impossible, the procedure may be performed by a person who has passed respective training. The 
procedure should be performed as per the GMP requirements according to the special and standard 
methods and, if required, by the contract; the procedure should be controlled by a second person. 
An additional labelling should be thoroughly documented both in clinical study documents and in 
Batch protocols.
4.4.3 
Storage conditions
Store in the original manufacturer’s container at the temperature from 2 to 8°С.
Keep out of reach of children.
Shelf life: 18 months. Do not use after an expiry date specified on pack.
4.4.4 
Principles of the study drug dosing
The test drug or the placebo are administered into abdominal cavity at the end of the surgery at the 
dose of 1.5 mL/kg or 2.4 mL/kg according to the draft package insert. Justification of the dose is 
provided in section 2.4.
4.4.5 
Additional therapy methods
• 
Immediate mobilization
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• 
During post-surgical period for all the groups, management of patients is as per the accepted 
standards
4.5 
Expected duration of participation of female patients in the study
Screening period (up to 15 days before the surgery)
Treatment period (Day 0)
Interim safety evaluation (Day 6±1)
Evaluation of treatment efficacy (Day 30±4 days)
Considering the given periods, the minimum duration of the study for female patient is 28 days, 
and the maximum duration is 50 days.
4.6 
Description of “termination rules” or “withdrawal criteria” for 
separate subjects or the study, in general.
Withdrawal criteria for separate subjects of the study are described in section 5.3.
According to the Article 40 of the FL No 61-ФЗ “On drug circulation” dated 12.04.2010 as 
amended and the requirements of the Good Clinical Practice of the Russian Federation, approved 
by the order of the Ministry of Health of the RF dated 19.06.2003 No 266, a clinical study may be 
discontinued or terminated, if in the process of its performance, hazard to life, health of patients is 
revealed. In case of revealed hazard to life, health of a female patient of the clinical study, 
investigators are obliged to inform on this a head of healthcare institution or organization that 
obtained permission of authorized federal agency for conducting the clinical study of the drug. 
Decision on discontinuation of the clinical study of the medical drug is made by a head of the 
healthcare institution and (or) the Sponsor of the study (or CRO)1, decision on termination of such 
a study is made by an authorized federal agency based on written report by the head of medical 
organization or organization of the study Sponsor (or CRO).
Report on completion, discontinuation or termination of the clinical study of the medical drug is 
sent to an authorized federal agency as per the form established by it within five working days 
from the date of such completion, discontinuation or termination of the clinical study.
The Investigator must immediately inform the study subjects on discontinuation or termination of 
the study, provide them adequate medical care and follow-up. Upon termination of the study the 
Investigator must assure that interests of the study subjects are adequately protected.
1 Organization obtained permission from an authorized federal agency for organization of the clinical study of the 
medical drug.
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The Investigator and (or) healthcare institution should immediately inform the Sponsor of the 
study (or CRO) on termination or discontinuation of the study with detailed explanation of reasons 
in the written form.
If the study Sponsor (or CRO) discontinues or terminated the study, the Investigator should 
immediately inform the administration of the healthcare institution on this.
The Investigator and (or) healthcare institution should immediately inform Ethics Committee on 
discontinuation or termination of the study with detailed explanation of reasons in the written form.
If Ethics Committee finally or temporarily recalls decision on the study performance, the 
Investigator should inform the administration of the healthcare institution on this.
The Investigator and (or) healthcare institution should immediately inform an organization- 
developer on final or temporary recall of decision for performance of the clinical study with 
detailed written explanation of reasons.
The clinical study may be discontinued or terminated, if an authorized federal agency provides a 
conclusion on performance of the clinical study with violation of Good Clinical Practice 
requirements based on results of checking activity of one or several healthcare institutions 
performing clinical studies of the drug.
The study performance in a separate clinical site may be terminated, if the Sponsor or its 
representatives, Investigator, regulatory bodies or LEC of a clinical site consider it to be necessary 
for any reason.
4.7 
Procedures for accounting the study drugs
4.7.1 Preparation and distribution of the study drugs
Quantity of the study drugs (Seroguard and placebo) will be sufficient for the whole therapy 
period. Every participating clinical site should use the study drugs only for the purposes under the 
present clinical study in strict compliance with the study protocol.
The Sponsor or its representative will provide all clinical sites with special forms of accounting 
receipt, distribution and return of the study drugs for facilitation of physical inventory procedure.
An employee of a clinical site responsible for circulation of the study drugs should maintain a log 
for accounting the study drugs. Date when the drugs were received in the clinical site, distribution 
among female patients and return of unused drugs are recorded in the log. Account of the study 
drug number should be documented throughout the study.
In case of unreasonable delay in the study performance, an authorized employee of the site 
responsible for circulation of the drugs in the study should confirm that their shelf life is not over.
Compliance with the dosage regimen of the study drugs will be provided by the nature of the study 
-  the drugs will be administered to patients in the hospital.
The Medical Investigator is responsible for the study drugs:
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• 
to be used only for the female patients of the present study;
• 
to be kept locked up and in a safe place having access only for employees taking part in the
study before administration to a female patient of the study;
• 
to be strictly accounted, and the account of the drugs is documented with indication of the
ID of a study subject who used the drug.
4.7.2 
Supplies, disposal, accounting the study drugs
The study drugs packed and labeled according to the current requirements (see section 4.4.2) will 
be provided by the Sponsor in the amount sufficient for performance of the whole study. A clinical 
site receives the study drugs from the study Sponsor as per the acceptance certificate.
The Investigator should keep records in the Log for accounting the study drugs reflecting number 
of used and unused drug in order. An authorized representative of the Sponsor regularly checks 
how the Investigator uses the drugs by counting their number.
After completion of the study, an employee of a clinical site responsible for circulation of the test 
drug and the placebo should provide the Sponsor or the study monitor with the originals of 
completed forms of receipt, distribution and return of the study drugs. Upon completion of the 
study, it is necessary to perform count of the drugs and to provide a written explanation in case of 
any non-conformances. Packs of the used drugs and the unused drugs should be returned to the 
Sponsor. Return is performed as per the acceptance certificate.
The Sponsor confirms a final report on accounting the drugs, one original of which is placed into 
the Investigator file.
The Sponsor is responsible for disposal of the unused and/or returned drug products for the study. 
It is not accepted to dispose drug products for the clinical studies without permission from the 
Sponsor. In case of drug disposal, the Sponsor should be provided a certificate of destruction with 
date or another document on disposal. Batch Nos and/or patient IDs (or possibility of their tracking 
should be provided), and number of the drugs disposed should be specified in these documents.
4.8 
Storage of randomization codes
See also section 4.3.1
The Principal Investigator will be provided an envelope with information for decoding the group 
of patient by randomization ID. The Principal Investigator will be responsible for storage of 
envelope with decoding information so as to provide confidentiality and integrity of information, 
but with preserved possibility of access, if it is necessary to disclose randomization ID. Upon 
completion of the study, the Principal Investigator must return the envelope to the Sponsor despite 
the fact whether it was opened or not.
In case of unintentional unblinding of female patient or staff of the clinical site, the Sponsor should 
be informed immediately.
In cases when unblinding of the treatment group and the drug administered is required to provide 
safety of the study subject (for example, in case of AR development), unblinding should be
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performed after approval and consent of the Sponsor’s medical expert. If it is technically 
impossible, and unblinding is required by vital indications, the medical expert of the Sponsor 
should be informed on the given fact as soon as possible.
Unblinding of randomization ID, in general, will be performed upon completion of the study and 
database shutdown.
4.9 
List of data recorded directly in the CRF and considered as primary
All the data will be initially entered into primary documentation (medical history or medical 
record) of female patient, and only then they will be transferred into CRF of the study patient.
5 
Selection and exclusion of the study subjects 
5.1 
Inclusion criteria
1. Female patients aged from 18 to 45 years with confirmed diagnosis of pelvic adhesions 
with indications for surgery (laparoscopic adhesiolysis)
2. Voluntarily and personally signed and dated Form of Informed Consent to participate in 
the study
3. Female patients with pelvic adhesions confirmed by gynecological examination and USI
5.2 
Non-inclusion criteria
1. Female patients having contraindications to operative treatment (including acute or 
exacerbated chronical adnexal inflammatory process)
2. Body mass index 30.0 kg/m2 and more
3. Known hypersensitivity to components of the test drug (Seroguard)
4. Pregnancy, lactation or planning for pregnancy during the clinical study
5. Refusal to use effective contraception methods throughout the study
6. Positive HIV, RW, HBV or HCV test results.
7. Alcohol abuse, drug addiction, and toxicomania (except for smoking)
8. Category III and higher by physical status classification of the American Society of 
Anesthesiologists (ASA).
9. Purulent process in the abdominal cavity
10. Disseminated endometriosis
11. Elevated WBC count in complete blood count exceeding 10*109/L
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12. Necessity of using any other drugs during the surgery (except for 0.02% chlorhexidine 
aqueous solution throughout the surgery, as well as the test drug or the placebo (0.9% 
sodium chloride) in the end of surgery) administered intraperitoneally
13. Concomitant diseases that may require conversion of the surgical intervention by other 
indications
14. Type I or II diabetes mellitus
15. Deep vein thrombosis and/or PATE at screening or in the history
16. Renal impairment (reduced glomerular filtration rate below 60 mL/min/1.73 m2 evaluated 
by the CKD-EPI equation)
17. Liver disorders determined as more than 2-fold elevation of the upper limit of normal of 
one of the following enzymes: ALT, AST, GGTP, AP, or more than 2-fold elevation of 
total bilirubin level
18. Myocardial infarction within 6 months before screening
19. Any concomitant diseases accompanied by heart failure.
20. Clinically significant changes in ECG (in Investigator’s opinion).
21. Any concomitant diseases accompanied by respiratory failure
22. Any oncology disease within 3 years before enrollment into the study.
23. Systemic inflammatory diseases.
24. Diseases associated with chronic hemorrhages
25. Blood diseases (anemias of any origin, hemoglobinopathies, inherited and acquired 
coagulopathies, hemostasis disorders, thrombocytopenias, and thrombocytopathias, any 
hemoblastoses)
26. Any other disease, that, in the Investigator’s opinion, may distort the study results or 
present an additional threat to well-being of a female patient after administration of the 
study drug
27. Administration of anticoagulants, antiaggregants (except for acetylsalicylic acid at the dose 
of less than 325 mg/day) at the moment of inclusion into the study or planning to do so 
during the study.
28. Administration of drugs with pronounced hemato-, hepato-, or nephrotoxic action, drugs 
of biological origin
29. Necessity of administration of cytostatics, systemic glucocorticosteroids and other 
immunosuppressive agents in the period of participation in the study.
30. Participation in another clinical study within 30 days before screening
31. Contraindications for performance of MRI (presence of implants or implanted electronic 
devices)
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32. Impossibility or inability to comply with the requirements of the protocol, including those 
for physical, psychic or social reasons, in Investigator’s opinion
5.3 
Withdrawal criteria
1. Withdrawal of informed consent by female patient
2. Female patient’s non-compliance with the rules of participation in the study.
3. Pregnancy occurrence.
4. Necessity of conversion during surgical intervention
5. Necessity of surgery during the period between adhesiolysis surgery and Visit 3
6. Other reasons occurring during the study and interfering with the study performance in 
accordance with the protocol.
7. Necessity of drain tube installation revealed during the surgery
5.3.1 
Early withdrawal
Patients willing to terminate their participation in the study (recall of informed consent) are 
withdrawn from the study. Each female patient has a right to terminate her participation in the 
study at any time without explaining the reasons.
After randomization and beginning of a clinical phase, the Medical Investigator may prematurely 
exclude a female patient from the study in case of:
• 
Female patient’s refusal to continue participation in the study.
• 
Occurrence of reasons/appearance of situations threatening safety of female patient found 
during the study (for example, hypersensitivity reactions, serious life-threatening adverse 
reactions related to the drug administration, pregnancy of female patient).
• 
Development of diseases in a female patient described in non-inclusion criteria, required 
administration of the drugs not permitted by the protocol.
• 
Appearance of another reasons during the study interfering with performance of the study 
according to the protocol.
Detection of reasons of withdrawal from the study in patients included into the study leads to their 
exclusion from the study at the stage of detection of these reasons. In any case of early termination 
by female patient/withdrawal of female patient from the study, the Medical Investigator should 
make a respective record in the CRF with obligatory indication of early termination or withdrawal 
from the study as well to inform the Sponsor’s representative.
5.3.2 
Collection of data on the study participants early terminated their participation 
in the study
All the cases of withdrawal of female patients from the study will be documented. The Investigator 
should specify date and reason of early withdrawal from the study in the primary documentation 
and the CRF in section for the study completion.
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If a patient terminates participation in the study voluntarily, the Investigator should try to find out 
the reason. If an early termination of a female patient is related to AR or serious adverse reaction 
(SAR), the Investigator should make every effort for collection of information on its outcome and 
to record it in the CRF, section on AR/SAR. If exclusion/withdrawal from the study was related 
to SAR, it is necessary to follow the procedure on notification of the Sponsor on SAR (see section 
8.3).
All ARs developed during the study in female patients withdrawn from the study, including ARs 
to the moment of terminating participation of female patient in the study will be analyzed and 
included into a final report on the study performance.
If withdrawal/exclusion from the study was after administration of the study drug to a female 
patient, her data collected before the moment of withdrawal/exclusion from the study will be 
analyzed during analysis of safety and, if possible, during analysis of efficacy. Approaches to 
analysis of data on the study participants early terminated their participation in the study are 
described in section 9.5.
5.3.3 
Substitution procedure
Female patients withdrawn before randomization will be substituted by new female patients (in 
the volume considered by the calculated number of female patients screened). Female patients 
withdrawn from the study after randomization and beginning of the therapy will not be replaced 
by new ones, and their data will be considered in the final analysis (see section 9.5).
5.3.4 
Follow-up of female patients early terminated the study
Follow-up of female patients withdrawn from the study is not planned intentionally. See also 
section 4.2.4.4.
If a female patient was withdrawn from the study due to the reason of AR/SAR, she is followed 
up due to resolution of the AR/SAR or until the Investigator considers it to be “chronic” or 
“stable”. The follow up of female patients of the study withdrawn from the study and, in the 
meantime, having ARs or having other parameters of safety, which could cause therapy 
termination, is described in section 8.4.
6 
Treatment of the study subjects 
6.1 
Dosage regimen of the test drug and the placebo
See section 4.4.4.
6.2 
Previous and concomitant therapy
Previous therapy is intake of the drugs or non-drug therapy by a female patient before the moment 
of inclusion into the study (an information on the drugs received by female patient within 30 days 
before Visit 0 is collected).
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Concomitant therapy is intake of the drugs or non-drug therapy by a female patient at the moment 
of her inclusion into the study and in the period of participation in the study.
Information on previous therapy will be collected and evaluated by Medical Investigator based on 
data of patient record/medical history and patient’s questionnaire (collection of medical history) 
during selection of candidates for participation in the study and during screening period (Visit 0).
Information on concomitant therapy will be collected and evaluated by Medical Investigator based 
on data of patient record/medical history and patient’s questionnaire of the study during the 
following periods:
• 
Administration of the test drug or the placebo (Visit 1);
• 
Follow-up visit (Visits 2-3).
Data on the drugs used for previous and concomitant therapy, dose, route and frequency of 
administration, dates of beginning and completion of the therapy, should be entered into primary 
documentation and into the CRF. Information on the test drug/placebo will be entered into a 
separate/specified for this section of the CRF.
6.2.1 
Permissible previous and concomitant therapy
Any previous therapy, except for described in section Ошибка! Источник ссылки не найден., 
is acceptable.
Female patients also may receive any drugs administered by a doctor and required for treatment 
of concomitant diseases/contraception, except for the drugs that may interfere with interpretation 
of new data obtained during the study (see section Ошибка! Источник ссылки не найден..). 
Decision on administration of the concomitant therapy drugs will be made by the Medical 
Investigator at his/her discretion and in case justified necessity of such an administration. 
Continuation of therapy with drugs not included into the list of forbidden therapy should be agreed 
before inclusion of patient into the study.
6.2.2 
Forbidden previous and concomitant therapy
• 
During the surgery, it is forbidden to use any drugs intraperitoneally, except for normal 
saline or 0.02% chlorhexidine bigluconate as well as the test drug and the respective 
placebo before suture of surgical wound.
• 
Systemic glucocorticosteroids, cytostatics and other immunosuppressors.
• 
Anticoagulants, antiaggregants (except for acetylsalicylic acid at the dose of less than 325
mg/day).
• 
Oral contraceptives (combined drugs, containing estrogen component and progestogen, or
progestogen only), used for at least 4 weeks/1 menstrual cycle before the first use and
4 weeks/1 menstrual cycle after the last use of the drugs compared.
• 
Injectable progestogen.
• 
Implants with progestogen.
• 
Vaginal ring containing estrogen and progestogen components.
• 
Transdermal system containing estrogen and progestogen components.
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• 
Copper-containing intrauterine system.
• 
Levonorgestrel-releasing intrauterine system.
If during the study, it becomes necessary or it is established that the drugs or therapy methods 
specified in the present section are used, a female patient should be withdrawn from the study.
Use of forbidden or not specified by the protocol drugs and therapy methods
In case of single and/or irregular administration of the drugs specified in the present section, 
decision on inclusion of patient into the study is made by the Medical Investigator.
If during the study, it becomes necessary or it is established that the drugs or therapy methods 
specified in the present section are used, a female patient should be withdrawn from the study.
6.3 
Methods of control for compliance with the procedures by the study 
subjects
6.3.1 
Measures to provide compliance
In the present clinical study, the test drug and its respective placebo will be administered into 
cavity of the pelvis at the final stage of the surgery by the Medical Investigator once at Visit 1. 
Due to this, control of patient compliance with treatment is not required.
In order to provide compliance with the visit schedule, a coordinator of the clinical site 
preliminarily, before the scheduled outpatient visit, reminds the study subject on date and time of 
visit (phone call, fax, e-mail, etc.). If it is impossible to contact with the study subject, a phone call 
is made to a relative or connected person of the study subject. Attempts to contact with the study 
subject, her relative or connected person are made thrice.
Regardless of contact type, the Investigator receives a confirmation on received reminder from the 
study subject, on which a record is made in the Log of phone calls.
If the study subject can not visit the study site at the next scheduled visit, a possible postpone of 
visit is discussed considering acceptable deviations.
6.3.2 
Evaluation of compliance
Not applicable. The drug is administered once, intraperitoneally by the staff of the clinical site.
7 
Efficacy evaluation
7.1 
List of efficacy parameters
Primary endpoint: achieving clinical efficacy determined as:
• 
Frequency of reducing number of adhesions after repeated MRI by 3 or more (in female 
patients with 10 and less adhesions at the baseline) or by 30% and more (in patients with 
>10 adhesions at the baseline)) in comparison to baseline MRI data
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Secondary efficacy endpoints:
1. Change in thickness of pelvic adhesions by repeated MRI in comparison to baseline MRI 
data
2. Frequency of limited displaceability of pelvic organs in post-surgical period (based on 
results of transvaginal ultrasound investigation) on Day 30±4 after surgery
3. Frequency of hyperechoic linear lesions in post-surgical period based on results of 
transvaginal ultrasound investigation
4. Change in frequency of detecting limited displaceability in comparison to baseline 
(absolute change and in % of baseline value)
5. Change in frequency of detecting hyperechoic linear lesions in comparison to baseline (4 
and less) based on repeated transvaginal ultrasound investigation
6. Frequency of detecting complete absence of USI -  signs of adhesion process in the pelvis 
in post-surgical period (defined as absence of limited displaceability of pelvic organs and 
absence of hyperechoic linear lesions)
7.2 
Methods and terms of evaluation, recording and analysis of efficacy 
parameters
Evaluation of efficacy of the study drugs Seroguard, solution 0.41 g/L (JSC Pharmasyntez, Russia)
and the Placebo will be performed for all the study subjects at Visit 3 based on considering
parameters specified in section 8.1
8 
Evaluation of safety
8.1 
List of safety parameters
• 
Vital signs (body temperature, BP, HR, RR)
• 
Laboratory investigations:
• 
Blood chemistry -  total protein, glucose, ALT, AST, total bilirubin, alkaline 
phosphatase, amylase, creatinine
• 
Complete blood count -  RBC, WBC, platelet count, hemoglobin, hematocrit, WBC 
differential, ESR
• 
Coagulogram -  coagulation time, international normalized ratio (INR), thrombin time, 
activated partial thromboplastin time (APTT)
• 
Urinalysis -  color, transparency, pH, specific gravity, protein, glucose, WBC, RBC, 
bacteria, casts, salts
• 
ECG data -  heart rate [HR], PR, QRS, QT intervals and calculated QTc interval
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• 
USI data
• 
Incidence of adverse reactions
• 
Incidence of serious adverse reactions
• 
Incidence of unexpected adverse reactions
• 
Incidence 
of 
adverse 
and 
serious 
adverse 
reactions 
caused 
treatment 
discontinuation/withdrawal from the study
8.2 
Methods and terms of evaluation, recording and analysis of safety 
parameters
Evaluation of safety of the study drugs Seroguard, solution 0.41 g/L (JSC Pharmasyntez, Russia) 
and the Placebo will be performed for all the study subjects at Visits 1-3, based on account of 
parameter, specified in section 8.1. Detection of adverse reactions (ARs) happens from the moment 
of signing informed consent to visit 3 inclusive. In addition, each study subject will be provided a 
phone number of the Investigator for contact in case of any problems with health. Clinical 
symptoms that will be developed after signing informed consent, but before use of the test drug or 
the placebo will be recorded as concomitant disease.
If the Investigator finds/receives information on AR, an unscheduled visit at the study site will be 
appointed in the nearest time (if required). At the moment of receiving information on AR, after 
analysis of AR and evaluation of risk for the study subject, the Investigator comes to a decision on 
delivery of required medical care. At the unscheduled visit, the Investigator makes decision on 
possibility of further participation of female patient in the study.
In case of indications, by the decision of the Medical Investigator or the physician, additional 
clinical and/or laboratory-instrumental investigations may be performed at unscheduled visits (see 
section 4.2.4.5).
The Investigator is responsible for notification of the Sponsor on any event considered as unusual, 
even if this event may be considered as unexpected benefit for the study subject.
Adverse reactions
AR means “any unintended and unfavorable reaction of the body which may be related to the drug 
administration” (Federal Law dated 12.04.2010 No 61-ФЗ “On drug circulation”).
AR severity grades
AR severity grade will be established as per the below classification:
• 
Grade 1: mild. 
Asymptomatic (detected at physical or laboratory-instrumental 
investigation) or with minimally pronounced symptoms, easily tolerable by a subject, 
causing minimum discomfort and not interfering with normal activity, not requiring special 
treatment;
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• 
Grade 2: moderate. Causing discomfort, limiting normal activity; requiring medical aid 
without invasive interventions (for example, applying a dressing);
• 
Grade 3: severe. Making normal activity impossible; disabling; requiring invasive 
intervention; requiring hospitalization; life-threatening; death.
Causal relation of AR to administration of the study drugs
Causal relation of AR to administration of the study drugs will be evaluated based on criteria of 
the World Health Organization (WHO):
• 
Definite. Clinical manifestations of AR, including laboratory abnormalities, observed 
during administration of the drugs, which may not be explained by presence of current 
diseases and influence of other factors and chemical compounds. Side reaction 
manifestation regress after the drug withdrawal and develop after re-administration.
• 
Probable. Clinical manifestations of AR, including laboratory abnormalities, related to 
time of the drug administration, which are unlikely related to concomitant diseases or other 
factors and which regress after the drug withdrawal. Response reaction to re-administration 
is unknown.
• 
Possible. Clinical manifestations of AR, including laboratory abnormalities, related to time 
of the drug administration, which may be explained by presence of concomitant diseases 
or administration of the other drugs and chemical compounds. Information on reaction to 
withdrawal of the drug is unclear.
• 
Unlikely. Clinical manifestations of AR, including laboratory abnormalities, which develop 
with no clear temporary relation to the drug administration; there are other factors (drugs, 
diseases, chemical substances), that may be a reason of their development.
• 
Conditional. Clinical manifestations of AR, including laboratory abnormalities, related to 
“side reactions”, that require obtaining additional data (for accurate estimate) or these 
obtained data are analyzed at present.
• 
Unclassified. Reports on suspected side reaction may not be evaluated, because the 
information is not sufficient or it is contradictory.
Serious adverse reaction or unexpected adverse reaction
Serious AR (SAR) is an adverse reaction of the body related to the administration of the drug that 
led to death, congenital anomaly or birth defects or life-threatening, requiring hospitalization or 
incapacitating and (or) disabling (Federal Law dated 12.04.2010 No 61-ФЗ “On drug circulation”).
In case of SAR development in the study subject, administration of the study drug is discontinued, 
the Medical Investigator completes the respective section of the CRF of the study subject and SAR 
Report Form.
If SAR develops, the Investigator (if required) must take actions to provide respective qualified 
medical assistance to the study subject, including performance of clinical and/or laboratory- 
instrumental investigations.
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In this case, follow up of the study subject should be continued before resolution/stabilization of 
the SAR observed.
Unexpected adverse reaction
Unexpected AR (UAR) is an adverse reaction of the body which is related to administration of the 
drug at the doses recommended in the protocol of the clinical study, Investigator’ brochure, or to 
administration of the drug at the doses recommended in the package insert on its use for prevention, 
diagnostics, treatment of diseases or medical rehabilitation of patient, and nature, severity and 
outcome of which do not correspond to information on the drug, contained in the protocol of the 
clinical study, Investigator’s brochure or in package insert of the drug (Federal Law dated 
12.04.2010 No 61-ФЗ “On drug circulation”)
Pregnancy
See section 8.3.
Deviations in values of laboratory and instrumental investigation parameters
Deviations from the normal (values accepted in the respective clinical site) results of laboratory or 
instrumental investigations are considered as clinically significant and, respectively, as ARs, if 
they are:
• confirmed in repeated investigation;
• 
accompanied by clinical manifestations or symptoms;
• 
accompanied by withdrawal of a female patient from the study;
• confirm development of disease/manifestation of toxic properties of the study drug;
• require appointing unscheduled visits, additional diagnostic procedures and/or therapeutic 
measures;
AR outcome
AR outcome is indicated to the moment of time when it is documented as per the following 
categories:
• recovered/resolved (no signs of AR completely);
• 
recovering/resolving (regress of sign/symptom of AR, incomplete disappearance);
• recovered/resolved with sequelae;
• 
not recovered/not resolved (AR existing at the moment of documentation or at the moment 
of death of the study subject due to any reason or due to development of another AR);
• lethal outcome (death due to developed AR);
• no data (for example, if the study subject did not come for final examination or follow-up 
visit and cannot be contacted).
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8.3 
Requirements to reports, procedures for recording and reporting 
adverse reactions and intercurrent diseases
Adverse event recording
If any AR develops, the Investigator should complete the respective sections of the CRF of the 
study subject, evaluate feasibility of continuing the study by female patient (exclude the study 
subject or continue participation of female patient in the study). ARs will be recorded from the 
moment of the study drug administration and to completion of the final visit (Visit 3).
For each AR, the following information should be recorded in the primary medical documentation:
• 
AR nature as per the ICD-10 terminology system (International Classification of Diseases 
10th revision);
• 
severity grade (mild/ moderate/ severe AR);
• 
causal relation to administration of the test drug/reference drug (definite/ probable/ 
possible/ unlikely/ conditional/ unclassified);
• 
duration (start date and time / stop date and time);
• 
outcome (resolved/ resolving/ resolved with sequelae/ not resolved / lethal outcome/ no 
data);
• 
is AR serious.
Report on serious adverse reaction to the Sponsor
In case of SAR, it is necessary to record the fact of SAR development in the primary 
documentation and complete respective pages of the CRF of the study subject.
Information on SAR should be sent to the pharmacovigilance officer of JSC Pharmasyntez, 
Natalya Anatolyevna Dvoynikova within 24 hours:
• 
Phone: 8 (3952) 55-03-28;
• 
Fax: 8 (3952) 55-03-25;
• 
E-mail: n.dvoynikova@pharmasyntez.com.
A special form of serious adverse reaction is completed in this case (see section 17.1), original of 
which is sent to JSC Pharmasyntez to the following address: Rosa Luxemburg str., 184, Irkutsk 
664040, Russia.
Notification form should be sent, even if the Investigator has incomplete volume of information 
on SAR. However, after the primary report on SAR, the Investigator should always inform on 
evaluation of degree of SAR relation to the administration of the study drug (see section 8.2). The 
Investigator should receive confirmation that the information is delivered.
If provided by the current requirements, the Sponsor will send respective notifications on AR to 
appropriate healthcare authorities.
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Pregnancy during the study
Before the study beginning, female patients are instructed on effective methods of contraception 
used throughout the study. All the study subjects pass pregnancy test at Visit 0, 3 or at Withdrawal 
Visit (see section 4.2.3.5), they are also instructed on required obligatory notification of the 
Investigator at any time when pregnancy is suspected. In this case, during the next/unscheduled 
visit, a pregnancy test is repeated (using test-strip, see section 4.2.3.5) and, if required, a 
concentration of beta-chorionic gonadotropin in blood is determined, and examination by 
gynecologist is performed. If fact of pregnancy is confirmed, female patient discontinues her 
participation in the study (see section Ошибка! Источник ссылки не найден.).
8.4 
Method and duration of follow-up of the study subjects after adverse 
reactions
Information on all newly developed/continuing ARs is recorded at each next/unscheduled visit. In 
case of repeated report on continuing AR, it is necessary to complete a new template of AR Report 
Form with note of date of a primary report on continuing AR.
All ARs should be traced until their resolution or until the Investigator considers them as “chronic” 
or “stable” (AR outcomes in such cases are classified as resolving/resolved with sequelae/ not 
recovered). Information on this should be recorded in the primary documentation, CRF of a female 
patient and the final AR Report Form.
At the final visit (Visit 3), the Investigator instructs the study subject on necessity to report on any 
ARs subsequently which, in the opinion of a female patient or her physician may be related to the 
administration of the test drug/reference drug.
8.5 
Modification of the study drug dosage regimen
In the present study, modification of the study drug dosage regimen is not considered which is 
provided by the purposes and design of the present study.
9 
Statistics
9.1 
Description of statistical methods to be used, including terms of each 
planned interim analysis
Statistical analysis will be performed using a specialized software, selection of which will be 
performed at the stage of preparation of statistical analysis plan.
Continuous (quantitative) data will be presented using a number of observations, arithmetic mean, 
95 % confidence interval (CI) for the mean (unless otherwise specified), standard (mean square) 
deviation, median, interquartile range, minimum and maximum.
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Serial, categorical and qualitative data will be provided using absolute frequency (number of 
observations), relative frequencies (percent) and 95 % CI (unless otherwise specified).
Unless otherwise specified, in the plan of statistical analysis, statistical test will be bilateral with 
5% confidence level.
Anamnesis and ARs will be coded using MedDRA classificator.
This section briefly describes the planned analysis. A complete analysis will be described in the 
plan of statistical analysis.
9.1.1 
Demographic data, baseline data and follow-up data
Demographic characteristics, characteristics of baseline level and follow-up, such as anamnesis 
(classified according to MedDRA) and concomitant drugs will be described by treatment groups 
for ITT population and then for safety, if they are different (see section 9.7).
9.1.2 
Analysis of main efficacy parameters
Main efficacy parameter in the given study is achieving clinical efficacy of the drug defined as:
• 
Frequency of reducing number of adhesions after repeated MRI by 3 or more (in female 
patients with 10 and less adhesions at the baseline) or by 30% and more (in patients with 
>10 adhesions at the baseline)) in comparison to baseline MRI data
Considering that the given analysis will be performed in the confirmation form of superiority over 
placebo hypothesis (superiority testing), unilateral statistical criteria will be used, and the level of 
significance will be established at 5%. For differences between each dose of the drug Seroguard 
and the placebo, a bilateral 95% binominal accurate confidence interval will be calculated for 
percentage difference. Superiority will be confirmed, if the lower limit of the confidence interval 
will exceed 0.05 (5%).
9.1.3 
Analysis of secondary efficacy endpoints
For evaluation of the following additional efficacy parameters:
• 
Frequency of hyperechoic linear lesions in post-surgical period based on results of 
transvaginal ultrasound investigation
• 
Change in frequency of detecting limited displaceability in comparison to baseline 
(absolute change and in % of baseline value)
• 
Change in frequency of detecting hyperechoic linear lesions based on repeated transvaginal 
ultrasound investigation in comparison to baseline
• 
Frequency of detecting complete absence of USI -  signs of adhesion process in the pelvis 
in post-surgical period (defined as absence of limited displaceability of pelvic organs and 
absence of hyperechoic linear lesions)
Respective relative (%) and absolute (number of observations) frequencies as well as accurate 95% 
binominal CIs will be calculated for each group. For evaluation of difference between each dose
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of the drug Seroguard and the placebo, Fisher’s exact test will be used as well as accurate 95% CI 
will be calculated for differences in percentages between the groups.
9.1.4 
Safety analysis
Descriptive part of safety analysis by primary endpoint will include evaluation of frequencies and 
bilateral 95% CI for the following primary endpoint parameters:
• 
AR -  common frequency and frequency in separate groups (as per ICD-10)
• 
SAR - common frequency and frequency in separate groups (as per ICD-10)
• 
Frequency of clinically significant changes in results of physical examination -  in general, 
for the study and by visits
• 
Frequency of clinically significant changes in parameters of laboratory investigations -  in 
general, for the study and by visits
• 
Frequency of clinically significant changes in parameters of BP and heart rate -  in general, 
for the study and by visits
• 
Frequency of clinically significant changes in ECG parameters -  in general, for the study 
and by visits
Comparison of frequencies between main and control groups will be performed using Fisher’s 
exact test (bilateral variant).
Analysis of the specified safety parameters will be performed for ITT and safety population (if it 
is different from ITT).
9.2 
Planned number of the study subjects
In the studies of the drug Adept® (Innoventica plc), maximally close to the test drug by mechanism 
of action, a primary endpoint was used. It was determined as a decrease in number of adhesions 
during second look diagnostic laparoscopy by 3 or more (in patients with 10 or less adhesions at 
the baseline) or by 30% and more (in patients with >10 adhesions at the baseline)) is 45%.
Performance of second look laparoscopy under the present study is unacceptable from the ethical 
point of view, MRI will be used for evaluation of the primary end point. As per the publication 
(21), MRI data highly correlate with laparoscopy picture (both pre-surgical and post-surgical 
studies during repeated laparoscopies). The exclusions are the thinnest adhesions that may not be 
seen on MRI which may be compensated by use of high-field MRI. Hence, MRI allows to visualize 
adhesions qualitatively and quantitatively and to obtain data with the same degree of detalization 
as during laparoscopic investigation before and after the surgery.
Thus, calculation of sample size will be based on efficacy of similar drugs studied based on 
laparoscopic data, however, MRI control will be used in the study, first of all due to ethical 
considerations and due to strong correlation between MRI data and laparoscopy data.
Accordingly, as per the above studies of the drug Adept® (20), efficacy related to achieving the 
primary end point (clinical efficacy determined as a decrease in number of adhesions during 
second look diagnostic laparoscopy by 3 and more (in female patients with 10 or less adhesions at
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the baseline) or by 30% and more (in patients with > 10 adhesions at the baseline)) is 45%. In the 
control group (placebo) based on literature review and metha-analysis (31) achieving clinical 
efficacy is recorded in not more than 10% cases.
Using these baseline data, the following assumptions were introduced (as per the method specified 
in (32)):
• 
The study will be conducted as a superiority trial, i.e. at least one dosage of Seroguard must 
be more efficient than the placebo, whereby the superiority margin will be 5% and more 
(definition of endpoint and superiority margin from the main study of Adept® was used). 
Comparison with placebo will be performed for each dosage of the drug separately. 
Comparison of dosages by efficacy between them is not planned and will be a subject of 
investigation in the Phase III of clinical studies of the drug
• 
Expected rates of achieving the primary endpoint in the groups with different dosages will 
be considered initially equal
• 
First type error (a) = 5 % (0.05) for superiority hypothesis
• 
Second type error (P) = 20 % (0.2), that corresponds to 80 % power.
• 
Expected withdrawal from the study will make 15% at screening and 10% after 
randomization
Null and alternative hypotheses for the superiority testing stage are worded as follows:
1. Null hypothesis (H0) holds that the difference in the rate of the primary endpoint 
achievement for one of the dosages of the drug Seroguard and the placebo will not exceed 
5% in favor of the drug
Ho- P i - P o  ^ 0.05
2. Alternative hypothesis (Ha ) holds that the difference in the rate of the primary endpoint 
achievement of one of the dosages of the drug Seroguard and the placebo will exceed 5% 
in favor of the drug
HA: Pi - P o >  0.05
Where p0 and p1 are the rates of the primary endpoint achievement in the groups of the placebo 
and Seroguard (of any dosage), respectively.
For the purpose of calculation of the sample size in each group in this case, the formula is applied 
which is given in (33)
n = ( p i X (1 -  po ) + po x (1 -  po )) x ( i-a + 1-^)
\ P i - Po - S/
where
n is the size of one group;
z is the value of the normal distribution function with the given a and P levels;
8 is superiority margin - 5%;
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p 1 is the expected percentage in the active drug group (one of the dosages) -  45% 
p0 is the expected percentage in the placebo group -  5%
Applying the above data into this formula, we obtain the minimum number of patients in the 
placebo group without considering withdrawal: 24 completed cases which corresponds to 26 
randomizations and 30 screenings.
Thus, the total number to be enrolled in the study is:
1) Placebo group, 1.5 mL/kg -  up to 30 screened female patients that corresponds to 26 
randomizations and 24 completed cases
2) Placebo group, 2.4 mL/kg -  up to 30 screened female patients that corresponds to 26 
randomizations and 24 completed cases
3) Seroguard group, 1.5 mL/kg -  up to 30 screened female patients that corresponds to 26 
randomizations and 24 completed cases
4) Seroguard group, 2.4 mL/kg -  up to 30 screened female patients that corresponds to 26 
randomizations and 24 completed cases
Thus, total of 120 female patients are to be screened and at least 104 female patients are to be 
randomized for the study.
9.3 
A significance level used
In all the tests, a 5% significance level will be used, whereby a primary endpoint will be analyzed 
using unilateral test, and bilateral statistical tests will be used for analysis of secondary endpoints.
9.4 
Study termination criteria
Study termination criteria are described in section 4.6.
9.5 
Procedures for accounting absent, unevaluable and doubtful data
At monitoring visit in the clinical site, monitoring officers authorized by the Sponsor will perform 
analysis of CRFs of the study subjects to check for absence of the required data. In case of absence 
of data in CRF and presence of respective information in the primary documentation, questions to 
the Investigators and assignments for elimination of non-conformities will be sent.
When checking database of the study results, a statistician authorized by the Sponsor and the 
Principal Investigator will perform analysis with respect to doubtful, omitted and unevaluable data 
by results of which the questions to the Investigators will be sent.
When applicable, the Investigators will eliminate the revealed errors in the CRF and inform the 
Principal Investigator and authorized representatives of the Sponsor on it. If the errors found in 
data will be impossible to be corrected after completion of female patient participation in the study, 
during statistical analysis of data, an analysis of sensitivity of the resulting parameters to presence
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of doubtful data will be performed. Information on omitted, doubtful and unevaluable analysis of 
data will be provided in the final report on the clinical study.
9.6 
Procedures of reporting on any deviations from the primary 
statistical plan
Decision on change in statistical plan reflected under the present protocol is made by the Sponsor.
All the changes in the primary statistical plan along with their justification are provided in the final 
report on the clinical study.
9.7 
Selection of the study subjects for the analysis
9.7.1 
Intent-to-treat population (ITT)
ITT set, also known as full analysis set, comprises all the randomized patients administered the 
study drug regardless of the degree of compliance with the protocol during the study. This set of 
data is main for the analysis; it will be used for evaluation of all the planned parameters.
9.7.2 
Per protocol population
All the planned parameters will be analyzed (in addition to analysis as per ITT) using set of data 
of the study subjects, selected by the per protocol principle (PP). The given population will not be 
analyzed, if it is more than 90% and less than 50% from ITT population. A subj ect will be excluded 
from PP set in the following cases:
• 
Significant violation of inclusion and non-inclusion criteria.
• 
Use of forbidden concomitant therapy.
• 
Any other significant violation of the protocol accepted as significantly violating main 
evaluation of efficacy in the specific subject of the study.
9.7.3 
Safety population
Safety set is identical to that of ITT. However, compared to the treatment administered, subjects 
are analyzed depending on the real treatment (in case when it is different from treatment which 
was administered by randomization). All the types of safety analysis will be based on using set of 
data for evaluation of safety.
All the decisions concerning determination of the databases analyzed will be summarizing the 
results of the database shutdown.
10 Direct access to primary data/documentation
Primary data is all the information which is contained in the original records and attested copies 
concerning the clinical data, observations and other activities within the study and which is 
necessary for reconstruction and evaluation of the study. The Investigator provides possibility of
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the study monitoring, audit (-s), inspection by Ethics Committee and regulatory bodies, represents 
a direct access to the primary data/records.
Primary data should be kept for the maximum period of time allowed by the local rules. For each 
included subject, the Investigator will specify a fact of participation in the present study in the 
primary records as well as will record at least the following information: individual identification 
code, personal data on female patients (full names, addresses), dates of the drug administration, 
vital signs, any ARs, dates of the study completion and main reasons of treatment discontinuation 
(if applicable).
The Investigator is responsible for provision of direct access to primary data and documentation 
for the study monitor of the Sponsor and/or its authorized representatives (CRO), auditor of 
competent authorities, representatives of an insurance company, ethics committees.
11 Quality control and quality assurance
11.1 Study monitoring
Regular visits of the study monitor by order of the Sponsor and according to Standard Operating 
Procedures (SOP) before beginning, during and after the study contribute to successful 
performance of the study and serve as a guarantee of accurate data collection, early detection of 
possible errors, documenting the process of the clinical study and provision of protecting the rights 
of the study subjects, conformity of the study performance to requirements of an international 
legislation and the legislation of the Russian Federation.
Routine monitoring of the study includes:
• 
Confirmation of adequate performance and documenting the process of obtaining informed 
consent as well as screening and inclusion of subjects into the study.
• 
Verification of data in CRF and primary medical documentation of the study subjects.
• 
Confirmation of documentation and early reporting the data on AR during the study.
• 
Confirmation of compliance with the requirements to performance of diagnostic and 
therapeutic procedures of the study protocol by the staff of the clinical site.
• 
Confirmation of documenting supplies, storage, distribution and disposal of the test 
drug/the placebo and the study materials.
• 
Confirmation of the competence of the study site staff, independent laboratory required for 
conducting the study.
• 
Confirmation of conformity of diagnostic and laboratory equipment to the requirements of 
safe and adequate use during the study.
• 
Confirmation of cooperation of the Investigator with local ethics committee on issues of
the study safety and entering amendments to the study protocol agreed with the Sponsor.
Provision of the study result quality control is performed by the Sponsor’s employees/Sponsor’s
authorized representative (for example, CRO), performing management of the study electronic
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database who reveal non-conformities, erroneously entered data and omitted data. In case of 
questions or required clarification, a special form is sent to the Investigator by e-mail/fax, its 
inquiry should be satisfied in written form within 7 days after its delivery.
According to the legislation requirements, the Sponsor or authorized governmental bodies have a 
right to perform check (audit) of equipment and material procurement of the study and the study 
documentation. The Investigator should provide access to documentation and all the required 
information to persons authorized to perform audit or inspection.
11.2 Amendments to the protocol, deviations and violations of the protocol
Signatures of Investigators on the approval page mean written confirmation of consent to perform 
the study as per the given protocol. During the clinical study, changes and additions may be entered 
into the study materials. Such changes and additions are considered as amendments.
Amendment to the protocol is a written description of changes or official clarification of the 
clinical study protocol text. Amendments may be essential and not essential. Any amendment to 
the protocol, before coming into force, should be adequately approved according to the in-house 
SOPs of the Sponsor company, then it should be approved by regulatory bodies, NEC and signed 
by the Investigator.
In the Decree of the Ministry of Health of the RF No 775 dated 31.08.2010 “On approval of review 
procedure of entering the required changes in the protocol of the clinical study of the drug for 
medical use”, a list of significant/insignificant amendments and the order of providing materials 
on them for inspection is determined.
Amendments to materials of the clinical study are significant, if they may influence on purposes, 
forms of organization, methodology of conducting, statistical methods of handling the results of 
the clinical study and measures to provide safety of female patients participating in it.
Amendments to materials of the clinical study are insignificant, if they do not influence on 
purposes, forms of organization, methodology of conducting, statistical methods of handling the 
results of the clinical study and measures to provide safety of female patients participating in it.
In case of required entering changes into the present protocol, the Sponsor of the study submits a 
message on required entering changes into the clinical study protocol to the MoH of the RF. Taking 
decision on entering changes or on refusal from entering changes is performed by the MoH of the 
RF after an inspection of the submitted updated materials. Amendments to the protocol should be 
kept along with initial revision of the protocol. Amendment No and effective date should be 
recorded on the title page of the protocol.
All the protocol deviations in the study should be recorded during monitoring of the clinical study 
and reported to the Sponsor company.
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12 Ethics 
12.1 General provisions
The present study will be conducted as per the World Medical Association Declaration of Helsinki 
“Ethical principles for medical research involving human subjects” dated 1964 as amended; 
National standard of the Russian Federation “Good Clinical Practice” GOST R52379-2005 dated 
25.09.2005, the Federal Law of the Russian Federation dated April, 12 2010 No 61-ФЗ “On drug 
circulation” (as amended), as well as regulatory documents of the International Conference on 
Harmonization - Good Clinical Practice (ICH GCP).
12.2 Procedure of obtaining informed consent
Written information and oral explanation of purposes, objectives and methods of conducting the 
study as well as of the expected benefit and possible risk related to participation in the study are 
provided to female patients before inclusion into the study. Besides, female patients should be 
informed on voluntary nature of participation in the study and on the fact that the subject has a 
right to refuse from participation in the study at any time, and that this refusal will not affect the 
quality of medical service provided to her. In case of the study discontinuation, a subject is not 
obliged to inform on the reasons, motivated her to discontinue participation in the study, however, 
the Investigator should try to clarify these reasons without disturbing the rights of the female 
patient. Consent of the female patient should be obtained before any study procedures.
Handling of data collected during the study is performed in compliance with confidentiality of 
subject’s data. The study subjects should be informed on purposes of planned computer handling 
of data and on conditions of publishing these data (for example, for presentation in medical 
conferences, in magazine articles and other open sources), provided only in summary, not allowing 
to make their identification.
Female patients should be notified that authorized representatives of health authorities and of the 
Sponsor will have access to their confidential medical information in order to perform monitoring, 
inspection and audit. However, a strict confidentiality of all the information allowing to identify a 
study subject and non-disclosure of such information should be guaranteed to subjects.
Informed consent form (patient information sheet) is to be completed in two copies, signed and 
dated by a female patient and Investigator by their own hands. The first copy of signed forms of 
Informed consent is kept by Investigator in Investigator’s file, a second copy is provided to the 
study subject.
12.3 Confidentiality and identification of the study subjects
Confidentiality of records allowing to identify the study subjects will be provided adhering to the 
rights to privacy and protection of confidentiality according to the regulatory requirements. 
Records identifying personality of patient will be confidential and may be disclosed only to the
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extent to which it is allowed by the legislation. In publication of the study results, confidentiality 
of the study subject data will be kept.
12.4 Enrollment of the study subjects from vulnerable and special groups
Inclusion/non-inclusion criteria consider participation in the study of fertile women, if they 
provide consent to use effective contraception methods throughout the study.
13 Data management and record keeping
In the clinical site, all the records and documents related to the clinical study kept in the 
Investigator’s File, including CRFs, informed consent forms, logs, registers of female patients as 
well as primary medical documentation of the study subjects are kept for 15 years after the study 
completion. The Sponsor of the study provides storage of all the materials of the clinical study 
throughout the life cycle of the study drug. Archival data may be stored as photocopies or on 
optical/electronic data storage devices. The Principal Investigator must immediately inform the 
Sponsor on facts of disposal, change of storage place of the clinical study archival materials.
After each planned visit by the study subjects and completion of CRF by the Investigator, 
verification of CRF and the primary documentation will be performed by authorized monitors of 
the Sponsor. If CRFs are completed accurately and precisely in accordance with the data of the 
primary documentation, the study monitor withdraws original pages of CRFs and sends them to 
the Sponsor, whereby copies of CRF pages are left in the site. If at the stage of evaluating data in 
CRF, a manager on control of data and/or biostatistician will have questions on data, all the 
clarifications and changes in CRF data will be documented by preparing forms of clarifying 
queries (data queries). Responses completed, signed and dated by the Investigator to clarifying 
queries are checked by the monitor and in case of recognizing the response as sufficient, originals 
of completed forms will be withdrawn from the site, whereby the copies of the completed forms 
of clarifying queries will be left in the site.
The Investigator must provide information confirming possible timely enrollment of the study 
subjects when complying with the criteria under the protocol.
The study must be performed according to the protocol, Sponsor’s Standard Operating Procedures. 
If necessary, entering changes in the protocol are agreed by the Investigator and the Sponsor and 
provided as an amendment to the protocol approved by ethics committee.
Completion of main documentation of the clinical study -  primary medical documentation and 
CRF -  is obligatory for all the subjects of the study.
The Investigator is responsible for complete and precise completion of CRF. All the data recorded 
in CRF should be reflected in the primary medical documentation of the study subject in print 
format or in written records made by the Investigator or other authorized person of the clinical site.
All planned data on participation of a female patient in the study are recorded in CRF according 
to the primary documentation. CRF should also contain data on completed participation by female
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patient in the study. CRF should be completed within 5 days after visit of the study subject in the 
clinical site. CRF should be completed in a legible handwriting with black ink. The mistakes made 
in the text should not be corrected over the record or erased slightly, or deleted using correction 
fluid. Instead of this, an error is crossed out with a straight line, a corrected text or digit is written 
above it as well as signature, date and initials of the Investigator. For all the omitted data, 
explanations in CRF should be provided, which will be realized by presence of a special tag field 
(“tick”), confirming omission of data. If required, on the page of comments in CRF with reference 
to respective page, explanations of data omission reasons will be provided. CRFs should be signed 
by Co-Investigator and Principal Investigator. The signatures confirm that the information 
contained in the CRF is true.
All the information on the study and the collected data are strictly confidential. The Investigator 
has a right to report information on the study to persons not directly participating in the study 
performance, only after permission of the Sponsor.
A final report consisting of statistical and clinical report is prepared after database shutdown and 
completion of statistical handling of the study results.
The final report is signed by the Principal Investigator of the clinical site, who confirms the results 
and inferences of the study by affixing a seal of his (her) institution.
14 Finance and insurance
Finance of the present study is performed by the Sponsor company through CRO. Before the study 
beginning, respective agreement will be concluded between CRO and each study site.
The Sponsor of the study provides insurance of life and health of female patients -  subjects of the 
clinical study. Female patients will be paid for damage in case of threatening to life or health due 
to administration of the test drug/placebo according to the current legislation.
15 Publications
15.1 General provision
Information contained in the present document is a property of the Sponsor and its presentation to 
third parties is permitted only after written approval of the Sponsor. A right to access to the given 
information is provided only to investigators and employees of the study site participating in the 
study, members of NEC and employees of healthcare authorities, authorized to control the clinical 
study. Information on the study in the volume required for making decision on providing consent 
for participation is provided to female patients who may participate in the present study.
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15.2 Issues of publication and use of the study results
The study Sponsor has exclusive rights for the present study results. No data of the present study 
may be presented or published without written approval of the Sponsor.
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16 Literature
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17 Annexures
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17.1 Serious adverse reaction report form
Site ID:
Protocol ID:
Principal Investigator/Coordinator:
Office phone No:
Information on patient:
ID: 
Randomization ID:
Gender: M / F Birth date: 
/ 
/
Previous participation in the clinical studies: yes / no
Information on the drug:
Name 
Dose
Route of administration
Date of administration: 
/ 
/
Time of administration: 
hour 
min
Brief description of adverse reaction:
Report: primary /  secondary
SAR start date and time:
Date: 
/ 
/
Time: 
hour 
min
SAR end date and time:
Date: 
/ 
/
Time: 
hour 
min
Is SAR unexpected:
Yes / No
Criteria of AR seriousness:
[ ] death
[ ] life-threatening
[ ] hospitalization or its prolongation 
[ ] persistent or significant disability/incapacity 
[ ] congenital anomaly/birth defect 
[ ] important from medical point of view
Causal relation of SAR to administration of the study drugs:
[ ] definite 
[ ] doubtful 
[ ] probable 
[ ] conditional 
[ ] possible 
[ ] unrelated 
[ ] unclassified
Severity
[ ] mild 
[ ] moderate 
[ ] severe
Actions taken
[ ] withdrawal of patient from the study 
[ ] hospitalization
[ ] drug or non-drug therapy for relief of SAR 
[ ] no 
[ ] other
SAR outcome:
[ ] recovered/resolved
[ ] recovering/resolving
[ ] recovered/resolved with sequelae
[ ] not recovered/not resolved
[ ] fatal
[ ] unknown
[ ] other
Additional information:
Signature of the Investigator:
Date:
Protocol ID SG-2/1215
Revision 3.2 dated 06.03.2017.
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