Clinical trial NCT04463251
Conditions: Acute ST Segment Elevation Myocardial Infarction
Keywords: STEMI Myocardial infarction Cardiovascular diseases CVD Coronary heart disease CHD
Sponsor: R-Pharm Overseas, Inc.
Start date: 2020-12-07; Completion date: 2022-10-10
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of the study was to evaluate the effect of single administration of RPH-104 at 80 mg and 160 mg on parameters of systemic inflammation and outcomes of the disease in subjects with ST-segment elevation myocardial infarction (STEMI)

Detailed description:
After signing the informed consent form, the investigator assessed the subject's eligibility for the study. The following procedures were performed during the screening: collection of medical history, recording previous and concomitant therapy, demographic data, recording 12-lead ECG findings on which STEMI diagnosis was based, recording date and time of STEMI symptom development, recording date, time and results of coronary angiography (CAG) at admission to the study site, measurement of blood neutrophil count, vital signs, physical examination including measurement of body weight (if hospital bed is available), blood sampling for hematology, biochemistry, determination of concentration of hsCRP and brain natriuretic peptide (BNP; N-terminal (NT)-pro hormone brain natriuretic peptide (NT-pro-BNP)), for females with retained reproductive potential - pregnancy test (test strips).

The subjects meeting selection criteria were randomized to one of the three groups (in 1:1:1 ratio) for single subcutaneous administration of RPH-104 80 mg, RPH-104 160 mg or placebo.

Screening, randomization and administration of the study products were made on the same (first) study day.

Further 4-week (28-day) clinical follow-up and additional 6- and 12-month clinical follow-up period were performed.

The end of clinical part of the study was the date of the last visit of the last subject within additional 12-month clinical follow-up.

The maximum number of screened patients was planned to be 146 subjects, 102 subjects were randomized, 34 subjects per group.

Arms: arm 1: subjects received subcutaneous single injection of 2 mL (80 mg) of RPH-104 and 2 mL of placebo on different administration sites arm 2: subjects received subcutaneous single injection of 2 mL (80 mg) of RPH-104 and 2 mL of (80 mg) of RPH-104 on different administration sites arm 3: subjects received subcutaneous single injection of 2 mL of placebo and 2 mL of placebo on different administration sites
Interventions: intervention 1: RPH-104 80 mg intervention 2: Placebo
Intervention descriptions: intervention 1: solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL transparent glass vial intervention 2: Normal Saline (0.9% Sodium Chloride solution for Injection), 2 mL in the 4-mL transparent glass vial

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Protocol CL04018075  
 
version 4.0 final dated October 02, 2021 
CONFIDENTIAL 
Translation dated 27-Oct-2021 
based on Russian Version 4.0 dated 02-Oct-2021 
Page 1 of 98 
CLINICAL STUDY PROTOCOL 
 
International, double blind, randomized, placebo-controlled study to evaluate the effect on 
parameters of systemic inflammation and disease outcomes and safety of RPH-104 in 
subjects with acute ST-elevation myocardial infarction. 
 Study ID 
CL04018075 
Protocol version 
4.0 final  
Protocol date 
October 02, 2021 
Test product: 
RPH-104 
solution for subcutaneous injections 
40 mg/mL 
Study phase 
2a  
Study sponsor 
R-Pharm International, LLC in the Russian 
Federation 
Address: Berzarina St., 19, bldg 1, floor 1, room V, 
office 9, Moscow, 123154 
Phone: ++7 (495) 956-79-37 
 
R-Pharm Overseas, Inc. in the USA 
Address: 505 Coast Blvd, South Suite 102.  
La Jolla, CA 92037 
Telephone: (858) 900-2656 
Person authorized by Sponsor to sign Protocol and 
Protocol amendments 
Samsonov 
Mikhail 
Yuryevich,  
candidate of medical sciences 
Medical Department Director, R-Pharm, JSC 
Address: Leninskiy pr., 111, bldg. 1, Moscow 
Telephone: +7 (495) 956-79-37 
  
CONFIDENTIALITY STATEMENT 
The document contains commercial information which is inviolable or confidential and may not be 
disclosed unless such disclosure is ordered by laws. In any case the persons to which the information was 
disclosed should be aware that the information is inviolable or confidential and may not be further disclosed. 
These limitations to disclosure will be equally applicable to all further information provided to you which 
is marked as inviolable or confidential. 
  
 
 


 
 
Protocol CL04018075  
 
version 4.0 final dated October 02, 2021 
CONFIDENTIAL 
Translation dated 27-Oct-2021 
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Table of contents 
Table of contents ............................................................................................................................. 2 
Sponsor's signature .......................................................................................................................... 6 
Signature of Principal Investigator .................................................................................................. 7 
Document history ............................................................................................................................ 8 
Ethical approval ............................................................................................................................. 16 
Contact information ....................................................................................................................... 17 
Abbreviations ................................................................................................................................ 19 
1. 
Protocol summary .................................................................................................................. 21 
2. 
Study rationale ....................................................................................................................... 29 
2.1. 
Introduction ..................................................................................................................... 29 
2.2. 
Cumulative presentation of the results of nonclinical and clinical studies relevant 
for this study .............................................................................................................................. 30 
2.3. 
Brief summary of known and potential risks and benefits for the study subjects .......... 34 
2.4. 
Description and justification of method of administration, dose, dosing regimen 
and therapy duration .................................................................................................................. 36 
2.5. 
Legal framework ............................................................................................................. 36 
2.6. 
Description of study population ...................................................................................... 37 
3. 
Study purpose and objectives ................................................................................................ 37 
3.1. 
Study purpose ................................................................................................................. 37 
3.2. 
Study objectives .............................................................................................................. 37 
4. 
Study design .......................................................................................................................... 38 
4.1. 
Principal and additional study parameters ...................................................................... 38 
4.2. 
Description of the study design, design flow chart, description of the study 
procedures and stages ................................................................................................................ 39 
4.2.1. 
Discussion of study design ...................................................................................... 39 
4.2.2. 
Discussion of the study design including selection of control groups .................... 40 
4.3. 
The scheduled duration of participation in the study, description of sequence and 
duration of all study stages including follow-up period ............................................................ 40 
4.3.1. 
Screening ................................................................................................................. 41 
4.3.2. 
Treatment period...................................................................................................... 41 
4.3.3. 
Follow-up periods .................................................................................................... 41 
4.3.4. 
Description of visits ................................................................................................. 41 
4.4. 
Description of procedures and assessments .................................................................... 44 
4.4.1. 
Demographic and other baseline assessments ......................................................... 44 
4.4.2. 
Past medical history ................................................................................................. 44 
4.4.3. 
Information on the underlying disease .................................................................... 44 
4.4.4. 
Pregnancy test .......................................................................................................... 45 


 
 
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4.4.5. 
Efficacy assessment procedures .............................................................................. 45 
4.4.6. 
Safety cohort ............................................................................................................ 45 
4.5. 
Subjectivity minimization measures ............................................................................... 45 
4.5.1. 
Randomization ......................................................................................................... 45 
4.5.2. 
Blinding ................................................................................................................... 46 
4.6. 
Storage of randomization/identification codes and their unblinding .............................. 46 
4.7. 
List of data recorded directly in CRF ............................................................................. 46 
5. 
Selection and exclusion of the study subjects ....................................................................... 47 
5.1. 
Inclusion criteria ............................................................................................................. 47 
5.2. 
Non-inclusion criteria ..................................................................................................... 47 
5.3. 
Deviations from inclusion/exclusion criteria .................................................................. 48 
5.4. 
Study termination or suspension, early withdrawal criteria ........................................... 48 
5.4.1. 
Study termination criteria. ....................................................................................... 48 
5.4.2. 
Early withdrawal criteria ......................................................................................... 49 
5.4.3. 
The list of data by early withdrawn subjects and terms of their collection ............. 49 
5.4.4. 
Replacement of withdrawn subjects and accounting of their data .......................... 49 
5.4.5. 
Follow-up of withdrawn subjects ............................................................................ 50 
6. 
Treatment of the study subjects ............................................................................................. 50 
6.1. 
Study products ................................................................................................................ 50 
6.1.1. 
Description of the study products ............................................................................ 50 
6.1.2. 
Study product dosing scheme in treatment groups .................................................. 51 
6.1.3. 
Administration of the study product ........................................................................ 51 
6.1.4. 
Treatment compliance ............................................................................................. 52 
6.1.5. 
Overdose management ............................................................................................ 52 
6.2. 
Allowed and forbidden concomitant therapy .................................................................. 52 
6.2.1. 
Allowed concomitant therapy. ................................................................................. 52 
6.2.2. 
Forbidden concomitant therapy. .............................................................................. 54 
6.2.3. 
Use of the medicinal products not allowed or not provided for by the Protocol ..... 54 
6.3. 
Accounting of the study products ................................................................................... 54 
6.4. 
Control of compliance .................................................................................................... 55 
7. 
Efficacy evaluation ................................................................................................................ 55 
7.1. 
List of efficacy parameters.............................................................................................. 55 
7.2. 
Methods and terms of evaluation, reporting and analysis of efficacy parameters .......... 56 
8. 
Safety evaluation ................................................................................................................... 56 
8.1. 
List of safety parameters ................................................................................................. 56 
8.2. 
Methods and terms of evaluation, registration and analysis of safety parameters.......... 57 
8.2.1. 
General provisions ................................................................................................... 57 


 
 
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8.2.2. 
Adverse event determination ................................................................................... 58 
8.2.3. 
Adverse events of interest ....................................................................................... 58 
8.2.4. 
Reporting about adverse events ............................................................................... 59 
8.2.5. 
Definition of a serious adverse event ...................................................................... 59 
8.2.6. 
Serious adverse event reporting ............................................................................... 60 
8.2.7. 
Definition of unexpected adverse events ................................................................. 60 
8.2.8. 
Submission of reports on suspected unexpected adverse reactions (SUSAR) ........ 60 
8.2.9. 
Adverse event severity assessment .......................................................................... 60 
8.2.10. 
Adverse event outcome evaluation ...................................................................... 61 
8.2.11. 
Relationship between an adverse event and study drugs ..................................... 61 
8.2.12. 
Follow-up of adverse events ................................................................................ 62 
8.2.13. 
Pregnancy ............................................................................................................. 62 
8.2.14. 
Other safety reports .............................................................................................. 62 
9. 
Statistics ................................................................................................................................. 63 
9.1. 
General provisions .......................................................................................................... 63 
9.2. 
Selection of data for the analysis .................................................................................... 63 
9.3. 
Statistical methods .......................................................................................................... 63 
9.3.1. 
Subjects disposition ................................................................................................. 63 
9.3.2. 
Demographic and other baseline characteristics ..................................................... 63 
9.3.3. 
Efficacy analysis ...................................................................................................... 63 
9.3.4. 
Safety analysis ......................................................................................................... 65 
9.4. 
Sample size justification ................................................................................................. 65 
9.5. 
Applied level of significance .......................................................................................... 66 
9.6. 
Reporting deviations from the initial analysis plan ........................................................ 66 
9.7. 
Interim analysis ............................................................................................................... 66 
9.8. 
Independent study clinical outcome assessment committee ........................................... 66 
10. 
Quality control and quality assurance ................................................................................ 67 
10.1. General quality assurance information ........................................................................... 67 
10.2. Quality assurance ............................................................................................................ 67 
10.3. Selection of the study sites .............................................................................................. 67 
10.4. Protocol compliance by the investigator ......................................................................... 67 
10.5. Protocol deviations ......................................................................................................... 68 
10.6. Investigator's responsibility for Protocol violation ......................................................... 68 
10.7. Study monitoring ............................................................................................................ 68 
10.8. Sponsor's audit ................................................................................................................ 70 
10.9. Study termination ............................................................................................................ 70 
11. 
Ethics .................................................................................................................................. 70 


 
 
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11.1. Ethics aspects of the study .............................................................................................. 70 
11.2. Local Ethics Committee / Institutional Review Board ................................................... 71 
11.3. Confidentiality of the study subjects .............................................................................. 71 
11.4 Informed Consent .............................................................................................................. 71 
12. 
Data handling and record keeping ...................................................................................... 72 
12.1. Direct access to source data / documentation ................................................................. 72 
12.2. Record keeping in the study site ..................................................................................... 73 
12.3. Data collection ................................................................................................................ 73 
12.4. Database management and quality control ..................................................................... 73 
12.5. Data confidentiality ......................................................................................................... 74 
12.6. Document archiving ........................................................................................................ 74 
13. 
Financing and insurance ..................................................................................................... 74 
14. 
Protocol amendments ......................................................................................................... 74 
15. 
Study report and publications ............................................................................................. 75 
16. 
References .......................................................................................................................... 75 
17. 
Appendix 1. 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials .... 79 
 
  


 
 
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Sponsor's signature 
 
Protocol CL04018075 
version 4.0 dated October 02, 2021. 
International, double blind, randomized, placebo-controlled study to evaluate the effect on 
parameters of systemic inflammation and disease outcomes and safety of RPH-104 in 
subjects with acute ST-elevation myocardial infarction. 
 
This clinical study Protocol version 4.0 dated October 02, 2021 has been critically reviewed and 
approved by the Sponsor’s relevant Protocol Review Committee. The information contained in 
this Protocol is consistent with the current assessment of the risk and benefit of the test product. 
The clinical study will be conducted in accordance with the moral, ethical and scientific principles 
set forth in the Declaration of Helsinki, the Guideline of the International Conference on 
Harmonization (ICH GCP E6, current edition), the requirements set forth in the Code of Federal 
Regulations section 21 (21 CFR) parts 50, 54, 56 and 312, and in accordance with the applicable 
local regulatory requirements of the Russian Federation (RF), Eurasian Economic Union (EAEU) 
and the United States of America (USA). The investigator will receive detailed information about 
any significant or new data, including adverse effects, associated with the use of the test product. 
I approve this Protocol, including its appendices.  
 
 
Name and position  
Signature  
Date 
 
 
 
 
 
 
 


 
 
Protocol CL04018075  
 
version 4.0 final dated October 02, 2021 
CONFIDENTIAL 
Translation dated 27-Oct-2021 
based on Russian Version 4.0 dated 02-Oct-2021 
Page 7 of 98 
Signature of Principal Investigator 
 
Protocol CL04018075 
version 4.0 dated October 02, 2021. 
International, double blind, randomized, placebo-controlled study to evaluate the effect on 
parameters of systemic inflammation and disease outcomes and safety of RPH-104 in 
subjects with acute ST-elevation myocardial infarction. 
 
I have been warned that the information contained in this Protocol and all other information related 
to RPH-104, is the Sponsor's confidential and private information, and, except when required by 
federal, state or local laws or regulations, cannot be disclosed to third parties without the prior 
written permission of the Sponsor. 
I have read the Protocol, including all appendices, and agree that it contains all the necessary 
information for me and my staff to conduct this study as described. I will conduct the study as 
described in this document, in accordance with the moral, ethical and scientific principles 
described in the Declaration of Helsinki, the rules set forth in the International Conference on 
Harmonization Good Clinical Practice Guideline (ICH GCP E6, current edition), the requirements 
set forth in the Code of Federal Regulations section 21 (21 CFR) parts 50, 54, 56 and 312, and in 
accordance with the applicable local regulations of the RF, EAEU and the USA, and I will make 
reasonable efforts to complete the study at the scheduled time. I will provide all study staff under 
my control with copies of the Protocol and copies of any amendments, and I will provide access 
to all information provided by the Sponsor or designated authorized person. I will discuss the 
materials with the study team members to make sure they are fully informed about RPH-104 and 
the study. 
 
Signature of Principal Investigator: 
  
Full name in printed letters 
 
 
Name of facility 
 
 
 
 
Signature 
 
Date 
 


 
 
Protocol CL04018075  
 
version 4.0 final dated October 02, 2021 
CONFIDENTIAL 
Translation dated 27-Oct-2021 
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 Document history 
 
Protocol version and date  
List of changes 
Protocol version 1.0 dated 
December 26, 2019 
Not applicable – original version 
Protocol version 2.0 dated June 
18, 020 with incorporated 
Amendment 1 
Sponsor’s signature page: text changed. 
Signature of Principal Investigator page: text changed  
Inclusion criteria:  
3. STEMI diagnosis defined as chest pain or its equivalent 
with debut no more than 12 hours before randomization 
(instead of 24 hours). 
4. PCI with stenting was performed within no more than 12 
hours after onset of chest pain or its equivalent before 
randomization (instead of 24 hours). 
Exclusion criteria:  
6. the phrase “and/or unstable hemodynamics” was added  
Complications of acute myocardial infarction in the form of 
acute left ventricular failure and cardiogenic shock defined as 
stable blood pressure decrease (SBP<90 mm Hg) associated 
with signs of hypoperfusion as well as cases when inotropic 
and/or mechanical support is required to maintain SBP; 
and/or unstable hemodynamics.  
8. the phrase “IL-1 and other biological drugs” was added  
Recent (less than 5 half-life periods) or current administration 
of agents with an immunosuppressant mechanism of action, 
including, but not limited to, high doses of glucocorticoids (> 
1 mg/kg of methylprednisolone equivalent), TNFα blockers, 
IL-1 and other biological drugs, cyclosporine and other 
immunosuppressants. NSAIDs are allowed. 
9. – a new criterion was added  
Immunization with live vaccines within 90 days prior to the 
study product administration. 
Sections 4.5.1 and 4.6 were supplemented with clarifying 
information about the screening and randomization numbers. 
Section 8.2.1 General provisions 
The following text was added: “The unblinded medical 
monitor will receive and evaluate all adverse event reports on 
a regular basis during the study.”  
Section 10.5. Protocol deviations  


 
 
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The following text was added: “For the USA only. By signing 
a copy of the FDA 1572 form or other country-specific 
regulatory forms, the Principal Investigator confirms that 
he/she has received a copy of the Investigator's Brochure for 
RPH-104 and assures the Sponsor that he/she will comply 
with the Protocol and provisions included in the FDA 1572 
form or other country-specific regulatory forms. No changes 
to this Protocol may be made without the written consent of 
the Sponsor.” 
The following sections were added: 
11.1 Ethics aspects of the study 
11.2 Local Ethics Committee / Institutional Review Board  
14. Protocol amendments  
15. Study report and publications  
Clarifying information was added to Sections 11.3 
“Confidentiality of the study subjects” and 12.5 
“Document archiving.” 
Protocol version 3.0 dated 
October 
29, 
2020, 
with 
incorporated Amendment 2 
Table 1. Schedule of visits and procedures  
Added visit interval of ± 3 days for Day 14 and Day 28. 
Hereinafter, where applicable. 
The name of the “measurement of height” procedure was 
changed to “Height registration” - in the table and further in 
the text, where applicable. 
Added blood sampling procedure for clinical and biochemical 
blood tests on Day 14. Hereinafter, where applicable. 
The footnotes regarding the following were added: 
conducting the Day 3 visit procedures ahead of schedule (on 
Day 2) for patients discharged on Day 2, performing the 
administration of the study product within 3 hours of 
randomization, possible performing of Echo-CG within 24 
hours of randomization on Day1, height measurement at Visit 
3: “It is permissible to record any value obtained during the 
hospitalization, when it was possible to measure the patient's 
height”. Hereinafter, where applicable. 
ESR was removed from the complete blood count parameters. 
Hereinafter, where applicable. 
LDH "isoforms" were removed from the blood chemistry 
parameters.  
Section 2.1. Introduction 
The description of anakinra studies has been supplemented 
with a reference to a literature source describing the current 
study, Abbate A. et al., 2020. 


 
 
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Section 2.2. Cumulative presentation of the results of 
nonclinical and clinical studies relevant for this study 
Information on current and planned clinical trials of RPH-104 
was updated, currently available data on the safety and 
efficacy of the drug were added. 
Section 2.3. Brief summary of known and potential risks 
and benefits for study subjects 
The list of expected adverse events was adjusted based on the 
known safety profile of drugs belonging to the IL-1 inhibitor 
class. 
Section 2.4. Description and justification of method of 
administration, dose, dosing regimen and therapy 
duration 
Information from dose-ranging studies of rilonacept (a drug 
with a similar mechanism of action) was added. 
Section 3.2. Study objectives 
Objective 5 was corrected: “including but not limited to” was 
added to the determined echocardiographic parameters, “and 
the right ventricle” was removed - in this section and further 
in the text, where applicable. 
Section 4.2.1. Discussion of study design 
A clarification was added: "During the first 10 weeks, not 
more than 3 patients per week will be included in the study". 
Section 4.3.3. Follow-up periods 
The text was added: “If the patient's visit to the study site is 
administratively limited due to the current epidemiological 
situation associated with the SARS-CoV-2 coronavirus, the 
procedures of Visit 3 (Day 14±3) and Visit 4 (Day 28±3) can 
be carried out at the patient's home, if the patient agrees, by 
authorized employees of the study site team. At the same 
time, if possible, all efficacy and safety assessment 
procedures planned for a particular visit are carried out. The 
conduct of visits outside the study site must be agreed with 
the Sponsor in each case". 
Section 4.3.4.1. Visit 1 (Day 1) 
 “If available” was added for weight measurement on a 
hospital bed. 
Section 5.1. Inclusion criteria  
Criterion # 3 was adjusted:removed "starting no more than 12 
hours before randomization". 
Criterion # 4 has been revised to add "randomization within 
12 hours after PCI (ie, no more than 24 hours from the onset 
of chest pain to randomization)". 


 
 
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Section 5.2. Exclusion criteria:  
Criterion # 3 has been adjusted: AHA/ACC class C-D, NYHA 
FC III-IV have been clarified, removed "due to heart defects". 
Criterion # 4 has been adjusted: "decompensated" is replaced 
by "heavy valvular", added "according to the investigator’s 
assessment". 
Added criterion # 5: "Pre–existance of left ventricular 
dysfunction (ejection fraction <40%)".  
Criterion # 8 (7) regarding the use of immunosuppressive 
drugs was adjusted. 
Section 6.1.1.2. Placebo 
Added information about additional manufacturer and release 
form. 
Section 6.2.1. Allowed concomitant therapy 
Clarification was made on the collection of concomitant 
therapy data: "within 5 half-lives of the drug or 30 days 
(whichever is longer)". 
Section 6.2.2. Forbidden concomitant therapy: The list of 
prohibited drugs was adjusted. 
Section 6.3. Study drugs accounting 
Added information on the storage of placebo (manufactured 
by the Hospira incorporated, USA) at a temperature of +20 - 
+ 25 °С. 
Section 7.1. List of efficacy endpoints 
Secondary Endpoint 5: “including but not limited to” was 
added to the determined echocardiographic parameters, “and 
the right ventricle” was removed - in this section and 
hereinafter where applicable. 
Section 7.2. Methods and terms of evaluation, reporting 
and analysis of efficacy parameters 
It was clarified that echocardiography measurements would 
be carried out in accordance with the internal document on the 
interpretation 
of 
echocardiography 
findings. 
The 
echocardiography parameters were specified. 
Section 8.2.1.2. Laboratory examination 
Clarification was made: "At Visit 1 determination of the 
absolute neutrophil count is performed in the local laboratory 
of the site to assess the inclusion/exclusion criteria." 
The blood chemistry parameters were adjusted: “LDH” was 
added. 
Section 8.2.3. Adverse events of interest: updated. 


 
 
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Section 8.2.10. AE outcome: the definition of the 
"Aggravation" outcome was removed. 
Section 10.7. Study monitoring  
Text was added: “Remote monitoring may be used for these 
purposes, if necessary (for example, if administrative or 
sanitary and epidemiological restrictions are imposed in 
connection with the current epidemic situation associated 
with the SARS-CoV-2 coronavirus)”; “Remote monitoring, if 
necessary, will be carried out using the appropriate module of 
the electronic data acquisition system. The investigator will 
upload anonymized copies of the source documents of 
patients to this module for verification of the source data, as 
well as copies of other documents required for remote 
verification by the monitor. These documents will be 
temporarily stored in the data collection system, in the remote 
monitoring section. Upon completion of the scheduled check 
and resolution of all issues, copies of all documents will be 
removed from the system by the responsible data manager. " 
Section 12.3. Data confidentiality  
Text was added: “In case of remote monitoring, the 
investigator will provide the monitor with anonymized copies 
of the source documents of patients for verification of the 
source data. These source documents will be temporarily 
stored in the data collection system, in the remote data 
verification section. Upon completion of data verification and 
resolution of all issues regarding this data, the uploaded 
copies of source documents will be deleted from the system 
by the responsible data manager. Data circulation during 
remote monitoring will be carried out in accordance with the 
regulatory requirements of the country participating in the 
study." 
Section Appendix 1: Definition of “stroke and transient 
ischemic attack” and Definition of “interventional cardiology 
procedures” were added.  
Protocol version 4.0 of October 
02, 2021 with an incorporated 
amendment 3 
Section 2.2 Cumulative presentation of the results of 
nonclinical and clinical studies relevant for this study 
Information about ongoing and planned clinical studies or 
RPH-104 has been updated; new available safety and 
efficacys data have been added. 
Section 2.3 Brief summary of known and potential risks 
and benefits for the study subjects and section 2.4 
Description and justification of method of administration, 
dose, dosing regimen and therapy duration 
Information regarding risk assessment for the study 
participants and justification of the selected dose based on the 


 
 
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currently available safety and effectiveness data has been 
clarified. 
Section 3.2 Study objectives 
The wording of the objective No.5 has been adjusted: a 
clarification “including, but not limited to, left ventricular 
(LV) dimensions, LVMMI, systolic and diastolic function” 
has been deleted. 
Section 4.1 Principal and additional study parameters 
(Table 2. Study endpoints) 
The wording “including, but not limited to, left ventricular 
(LV) dimensions, LVMMI, systolic and diastolic function” 
has been deleted from the description of the respective 
objective and the study endpoint. 
The endpoint: “Rate of fatal outcomes (cardiac and non-
cardiac), hospitalizations (due to HF and other cardiac reasons 
not associated with HF or due to non-cardiac reasons) during 
12-month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]” 
has been changed to:  
“Incidence of fatal outcomes (cardiac and non-cardiac) during 
12-month follow-up period [Visit 1 Day 1 – Visit 6 Day 
365]”; 
“Incidence of hospitalizations due to HF or other cardiac 
reasons not associated with HF, or due to non-cardiac reasons 
during 12-month follow-up period [Visit 1 Day 1 – Visit 6 
Day 365]”. 
The endpoint: “Frequency of new cases of HF (defined as 
hospitalization due to HF or necessity in a new loop diuretic 
administration intravenously or oral dose doubling in the 
relevant clinical facilities) during 12-month follow-up period 
[Visit 1 Day 1 – Visit 6 Day 365]” 
has been changed to:  
“Incidence of new cases of HF (defined as hospitalization due 
to HF or new onset of HF) during 12-month follow-up period 
[Visit 1 Day 1 – Visit 6 Day 365].” 
Two additional secondary effectiveness endpoints have been 
introduced:  
Incidence of “fatal outcome (due to any reason) or 
hospitalization due to HF or new onset of HF” during 12-
month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]; 
Incidence of “fatal outcome (due to any reason) or 
hospitalization due to HF” during 12-month follow-up period 
[Visit 1 Day 1 – Visit 6 Day 365]. 


 
 
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Similar changes have been introduced into section 7.1 List of 
efficacy parameters, section 9.3.3.2 Analysis of secondary 
endpoints. 
Section 4.4.3 Information on the underlying disease 
Data that should be recorded at the screening have been 
clarified. 
Section 5.2 Exclusion criteria 
A clarification has been added to the criterion No.17: “If, in 
the Investigator’s opinion, administration of a non-live 
COVID-19 (SARS-CoV-2) vaccine increases the risk for the 
patient related to his/her participation in the study, the 
Investigator can make a decision not to include this patient 
into the study.” 
Section 6.2.2 Forbidden concomitant therapy 
The list of prohibited immunosuppressive agents has been 
clarified. 
Section 7.2 Methods and terms of evaluation, reporting 
and analysis of efficacy parameters 
 
A clarification has been added regarding the recording 
hospitalization as an outcome: “Hospitalization due to HF 
will also include cases of prolongation of current 
hospitalization for the treatment of ST segment elevation MI 
if HF has developed within 24 hours following hospital 
admission”. 
Sections 9.3.3.2 Analysis of secondary endpoints and 
9.3.3.3 Analysis of exploratory endpoints have been 
corrected 
Section 9.4 Sample size rationale 
The description of the planned number of included 
participants has been corrected. 
Section 9.7 Interim analysis 
The procedure of the interim statistical analysis has been 
corrected. 
The Protocol Summary has been updated in accordance 
with the changes introduced in mentioned sections. 
Other changes have been introduced to avoid contradictions 
in the Protocol, namely: 
Section 4.2.1 Discussion of study design – the missing 
procedures have been added to the description of the 
screening period; 
Section 4.3.1 Screening – the text related to the diagnosis 
required for the inclusion in the study has been corrected; 


 
 
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Section 4.4.2 Past medical history – a clarification has been 
added regarding the period of menopause – “if applicable”; 
Section 6.1.3 Administration of the study product – a 
clarification has been added that the study product 
administration will be performed by “unblinded” qualified 
study site personnel; 
Section 8.1 List of safety parameters – a phrase “during the 
study” has been added to the safety endpoints; 
Section 9 Statistics – the section has been corrected. 
Section 11.4 Informed consent – a phrase has been added: 
“If a patient agrees to participate in the study, he/she has to 
sign and date the Informed Consent Form for participation in 
the study in two copies”. 
The rest of the changes have been introduced in order to 
avoid technical errors in the Protocol. 
 


 
 
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Ethical approval  
 
Prior to the implementation of this version of the Protocol with the incorporated Amendment 3, it 
must be reviewed and approved by the regulatory healthcare authorities and the Independent Ethics 
Committee (IEC). Signed and dated evidence that the Protocol and other necessary documents 
have been approved by the IEC must be provided to the Sponsor or its representative before these 
documents become effective. 
 
 
 
 


 
 
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Contact information 
 
Names and addresses of clinical and other medical and/or technical services and/or 
institutions involved in the study: 
Name of organization 
Study role 
Organization address 
R-Pharm, JSC 
Study facility in the RF 
Legal address: Berzarina St., 
19/1, Moscow, 123154 
Postal address: Leninskiy pr., 
111/1, Moscow, 119421, 
Russia 
K-Research, LLC 
Study facility in the RF 
Marshala Koneva prospekt, 
29, office 43, Smolensk, 
214019, Russia  
Cromos Pharma LLC 
Study facility in the USA 
148 Canyonview Dr, 
Longview, WA 98632, USA 
DM 365, LLC 
Access to database, 
its setting, adaptation, 
modification, validation, 
testing, maintenance 
Vsevoloda Vishnevskogo St., 
12, lit. A, Saint-Petersburg, 
197022, Russia 
Keystat, LLC 
Statistical analysis of data 
20-ya Liniya 
Krasnoarmeyskoy Slobody, 
3, Smolensk, 214000, Russia. 
Tel.: +7 (915) 644-47-13 
  
Contact information of investigators responsible for performance of the study and study 
sites: 
The list of the study sites involved in this clinical study (name, address and phone of each study 
site) and contact information of principal investigators responsible for the study performance are 
presented in an individual List of study sites and principal investigators.  
 


 
 
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CONTACT INFORMATION FOR EMERGENCY CASES 
To obtain medical consultation in emergency cases, contact the Study Medical Monitor – a 
scientific adviser of R-Pharm, JSC, Daria Bukhanova 
Phone number for emergency cases: 
+7 (495) 956-79-37 
E-mail: bukhanova@rpharm.ru 
When reporting serious adverse events the procedures described in section 8.2.6 should be 
followed.  
 
 


 
 
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Abbreviations 
 
AE 
Adverse event 
AHA/ACC 
The American Heart Association / The American College of Cardiology 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
BNP 
Brain natriuretic peptide 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CAG 
Coronary angiography 
Cmax 
Peak blood product concentration 
CFR 
Code of Federal Regulations 
CHD 
Coronary heart disease 
CI 
Confidence interval 
CPK 
Creatinine phosphokinase 
CPK-MB 
Creatine phosphokinase cardiac specific isoenzyme 
(e)CRF 
(electronic) Case Report Form 
CRO 
Contract research organization 
(hs)CRP 
(high-sensitive) С-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVD 
Cardiovascular diseases 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
EAEU 
Eurasian Economic Union 
ECG 
Electrocardiogram 
Echo-CG 
Echocardiography 
EF 
Ejection fraction 
EU 
European Union 
FAS 
Full Analysis Set 
Fc 
Fragment crystallizable 
FC 
Functional class 
FL 
Federal law 
GCP 
Good Clinical Practice 
GDP 
Gross domestic product 
GGT 
Gamma-glutamyltranspeptidase 
HF 
Heart failure 
HR 
Heart rate 
IC50 
50% inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
The International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 


 
 
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IgG1  
Immunoglobulin type G1 
IL-1 
Interleukin-1 
IL-1R(1) 
Interleukin-1 receptor 
IL-1RA 
Interleukin-1 receptor antagonist 
IL-1RAcP 
Interleukin-1 receptor accessory protein 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ISOAC 
Independent study outcome assessment committee  
IV 
Intravenous 
IWRS 
Interactive Web Response System 
kDa 
Kilo Dalton 
LBBB 
Left bundle branch block 
LDH 
Lactate dehydrogenase 
LEC 
Local ethics committee 
LV 
Left ventricle 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MMRM 
Mixed effect Model Repeat Measurement 
MRC5 
Non-transformed human lung fibroblast cell line 
NOAEL 
No observed adverse effect level 
NSAID 
Nonsteroidal anti-inflammatory drugs 
NT-pro-BNP 
N-terminal (NT)-pro hormone brain natriuretic peptide 
NYHA 
New York Heart Association 
OATP1B1 
Organic-anion-transporting polypeptide 1B1 
PCI 
Percutaneous coronary intervention 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
RF 
Russian Federation 
RR 
Respiration rate 
SAA 
Serum amyloid A 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
subcutaneously 
SOP 
Standard Operating Procedure 
STEMI 
Acute ST-segment elevation MI 
SUSAR 
Suspected Unexpected Serious Adverse Drug Reaction 
Tmax 
Time to peak blood product concentration 
TMF 
Trial Master File 
TNF 
Tumour necrosis factor 
USA 
United States of America 
WHO 
World Health Organization 
 
 
 


 
 
Protocol CL04018075  
 
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1. Protocol summary 
 
Clinical study title 
International, double blind, randomized, placebo-controlled study to 
evaluate the effect on parameters of systemic inflammation and 
disease outcomes and safety of RPH-104 in subjects with acute ST-
elevation myocardial infarction. 
Study ID  
CL04018075 
Clinical study phase 
2a 
Protocol date and version 
4.0. dated October 02, 2021 final 
Study type 
interventional 
Test product 
RPH-104, solution for subcutaneous injections, 40 mg/mL. 
Reference product 
placebo 
Study purpose 
Evaluate the effect of single administration of RPH-104 at 80 mg 
and 160 mg on parameters of systemic inflammation and outcomes 
of the disease in subjects with ST-segment elevation myocardial 
infarction (STEMI). 
Study objectives 
1. Evaluate the effect of single administration of RPH-104 
at 80 mg and 160 mg compared to placebo on hsCRP level 
reduction within 14 days in subjects with STEMI. 
2. Evaluate the effect of single administration of RPH-104 
at 80 mg and 160 mg compared to placebo on hsCRP level 
reduction within 28 days in subjects with STEMI. 
3. Evaluate the effect of single administration of RPH-104 
at 80 mg and 160 mg compared to placebo on 
cardiovascular and other clinical outcomes within 12 
months in subjects with STEMI. 
4. Evaluate the effect of single administration of RPH-104 
at 80 mg and 160 mg compared to placebo on changes in 
levels of HF biomarkers (BNP and NT-pro-BNP) within 
12 months in subjects with STEMI. 
5. Evaluate the effect of single administration of RPH-104 
at 80 mg and 160 mg compared to placebo on parameters 
of cardiac remodeling (changes in structural and 
functional echocardiographic parameters) within 12 
months in subjects with STEMI. 
6. Evaluate safety and tolerability of single administration of 
RPH-104 at 80 mg and 160 mg compared to placebo in 
subjects with STEMI during the study. 
Exploratory objective: 
Evaluate interaction between STEMI outcomes and peculiarities of 
coronary bed lesion based on baseline CAG results.  


 
 
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Study design 
International, multicenter, phase 2a, double-blind, randomized, 
placebo-controlled clinical study comparing single administration of 
RPH-104 80 mg, RPH-104 160 mg and placebo (1:1:1) 
After signing the informed consent form, the investigator will assess 
the subject's eligibility for the study. The following procedures will 
be performed during the screening: collection of medical history, 
recording previous and concomitant therapy, demographic data, 
recording 12-lead ECG findings on which STEMI diagnosis was 
based, recording date and time of STEMI symptom development, 
recording date, time and results of CAG at admission to the study 
site, measurement of blood neutrophil count, vital signs, physical 
examination including measurement of body weight (if hospital bed 
is available), blood sampling for hematology, biochemistry, 
determination of concentration of hsCRP and brain natriuretic 
peptide (BNP; NT-pro-BNP), for females with retained reproductive 
potential – pregnancy test (test strips).  
The subjects meeting selection criteria will be randomized to one of 
the three groups for single subcutaneous administration of RPH-104 
80 mg, RPH-104 160 mg or placebo. 
Therefore, screening, randomization and administration of the study 
products will be made on the same (first) study day.  
Further 4-week (28-day) clinical follow-up and additional 6- and 12-
month clinical follow-up period will be performed.  
The end of clinical part of the study will be the date of the last visit 
of the last subject within additional 12-month clinical follow-up.  
An overview of the study design is provided in Figure 1. 
Scheduled number of subjects 
The maximum number of screened patients will be 146 subjects, 102 
subjects will be randomized, 34 subjects per group. 
Study population 
Male and female subjects aged from 18 years old (inclusive) 
hospitalized with STEMI to the study sites of the RF and the USA. 
Inclusion criteria 
The subjects eligible for the study should meet all of the following 
criteria: 
1. Subjects of either gender aged from 18 years old inclusive. 
2. Subjects who gave voluntary written informed consent to 
participate in the study and to follow all Protocol procedures. 
3. STEMI diagnosis defined as chest pain or its equivalent with ECG 
findings evidencing ST elevation (>1 mm) in two or more 
consecutive leads or acute left bunch branch block according the 
investigator's judgement. 
4. PCI with stenting was performed within no more than 12 hours 
after onset of chest pain or its equivalent and randomization was 
performed in no more than 12 hours after PCI (overall within 24 
hours of onset of chest pain or equivalent). 
5. Consent of female subjects with childbearing potential defined as 
all female subjects with physiological potential to conceive, to use 


 
 
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highly effective contraceptive methods throughout the study starting 
from screening (signing Informed Consent Form) and negative 
pregnancy test. 
Highly effective contraceptive methods include combination of two 
of the following methods (a+b or a+c or b+c): 
a) oral, injection or implanted hormonal contraceptives; in case 
of oral contraceptives, the female subjects should administer 
the same product for at least 3 months prior to the study 
therapy; 
b) intrauterine device or contraceptive system; 
c) barrier methods: condom or occlusive cap (diaphragm or 
cervical 
cap/vaginal 
fornix 
cap) 
with 
spermicidal 
foam/gel/film/cream/vaginal suppository 
6. Ability and willingness of the subject, according to the reasonable 
investigator's judgment, to attend the study site at all scheduled 
visits, undergo the study procedures and follow the Protocol 
requirements including subcutaneous injections by qualified site 
personnel.  
Non-inclusion criteria 
The subjects meeting any of exclusion criteria should not be 
enrolled: 
1. Hypersensitivity to test product (RPH-104) and/or its 
ingredients/excipients. 
2. Pregnancy and breastfeeding. 
3. Verified chronic HF (AHA/ACC C-D class, NYHA FC III-IV).  
4. Pre-existing severe valvular heart disease according to the 
investigator’s assessment. 
5. Pre-existing LV dysfunction (EF<40%). 
6. History of STEMI. 
7. Complications of acute MI in the form of acute left ventricular 
failure and cardiogenic shock defined as stable blood pressure 
decrease (SBP<90 mm Hg) associated with signs of 
hypoperfusion as well as cases when inotropic and/or 
mechanical support is required to maintain SBP; and/or unstable 
hemodynamics.  
8. Active infections (acute or chronic); active tuberculosis. 
9. Recent (less than 5 half-life periods) or current administration of 
colchicine, as well as agents with an immunosuppressant 
mechanism of action, including, but not limited to: 
glucocorticoids at doses of > 1 mg/kg of methylprednisolone 
equivalent, TNFα blockers, IL-1 and other biological drugs, 
cyclosporine and other immunosuppressants. NSAIDs are 
allowed.  
10. Immunization with live vaccines within 90 days prior to the 
study product administration. 


 
 
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11. Chronic systemic autoimmune or autoinflammatory diseases.  
12. Suspected necessity in cardiosurgery. 
13. Oncology (or diagnosis of oncology within the last 5 years). 
14. History of organ transplantation or necessity in transplantation 
at the screening initiation or scheduled transplantation during the 
study.  
15. Neutropenia (absolute neutrophil count <1800/mm3). 
16. Participation in another clinical study within the previous 
3 months prior to Screening visit. 
17. Other medical (including mental) conditions or abnormal 
laboratory findings which may increase the risk for the subject 
associated with the study participation or administration of the 
study products or which may affect interpretation of the study 
results and, according to the investigator, render the subject 
ineligible for the study.* 
18. The subjects working at the study site or subjects working for 
Sponsor directly involved in this clinical study. 
* If, in the Investigator’s opinion, administration of a non-live 
COVID-19 (SARS-CoV-2) vaccine increases the risk for the patient 
related to his/her participation in the study, the Investigator can 
make a decision not to include this patient into the study. 
Test product. Posology and 
method of administration 
Trade name: not assigned. 
International nonproprietary name: goflikicept 
Product in-house code: RPH-104 
Dosage form: solution for subcutaneous injections 
Strength: 40 mg/mL 
Doses: 80 mg and 160 mg 
Dosing frequency: single 
Route of administration: subcutaneous  
Duration of treatment: single dose 
Reference product.  
Posology 
and 
method 
of 
administration 
Placebo 
Trade name: not applicable 
International nonproprietary name: not applicable 
Dosage form: solution for subcutaneous injections 
Strength: not applicable 
Dosing frequency: single 
Route of administration: subcutaneous 
Duration of treatment: single dose 


 
 
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Study product dosing scheme in 
treatment groups 
To provide double blind design the study, the study products will be 
administered as follows:  
 
in RPH-104 80 mg group, the subjects will receive 2 mL 
(80 mg) of RPH-104 and 2 mL of placebo on different 
administration sites; 
 
in RPH-104 160 mg group, the subjects will receive 2 mL 
(80 mg) of RPH-104 and 2 mL of (80 mg) of RPH-104 on 
different administration sites; 
 
in placebo group, the subjects will receive 2 mL of placebo 
and 2 mL of placebo on different administration sites.  
Concomitant therapy 
During the study, the following medicinal products will be forbidden 
in the terms specified: 
 
biological medicinal drugs (except for RPH-104) including 
but not limited to: tocilizumab, rituximab, TNFα inhibitors 
[Visit 1 Day 1 - Visit 4 Day 28]. 
 
immunosuppressants [Visit 1 Day 1 – Visit 4 Day 28] 
including but not limited to:  
o corticosteroids 
at 
doses 
of 
>1 
mg/kg 
of 
methylprednisolone equivalent orally as well as 
systemic, except for IV ones for acute allergic 
reactions; 
o cyclosporine A, methotrexate, etc. 
 
colchicine [Visit 1 Day 1 – Visit 4 Day 28]; 
 
anakinra, canakinumab, rilonacept [Visit 1 Day 1 – Visit 6 
Month 12]. 
 
immunization with live vaccines within 90 days prior to or 
after the study product administration.  
 
any experimental products.  
NSAIDs are not forbidden.  
Study duration 
The study will consist of 1 day of the study product administration, 
4-week follow-up period and 6- and 12-month clinical follow-up 
periods.  
Scheduled recruitment duration: 9 months. 
Scheduled clinical part duration: 1 year 10 months. 
Scheduled period for study result report preparation: 3 months. 
Efficacy evaluation 
Primary endpoint: 
1. hsCRP area under curve (AUC) from Day 1 (baseline) until 
Day 14 [Visit 1 Day 1 – Visit 3 Day 14]. 
Secondary endpoints: 
1. hsCRP area under curve (AUC) from Day 1 (baseline) until 
Day 28 [Visit 1 Day 1 – Visit 4 Day 28]. 


 
 
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2. BNP area under curve (AUC) from Day 1 (baseline) until 
Day 28 [Visit 1 Day 1 – Visit 4 Day 28]. 
3. NT-pro-BNP area under curve (AUC) from Day 1 (baseline) 
until Day 28 [Visit 1 Day 1 – Visit 4 Day 28]. 
4. Incidence of fatal outcomes (cardiac and non-cardiac) during 12-
month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 
5. Incidence of hospitalizations due to HF or other cardiac reasons 
not associated with HF, or due to non-cardiac reasons during 12-
month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 
6. Incidence of new cases of HF (defined as hospitalization due to 
HF or new onset of HF) during 12-month follow-up period [Visit 
1 Day 1 – Visit 6 Day 365]. 
7. Incidence of “fatal outcome (due to any reason) or 
hospitalization due to HF or new onset of HF” during 12-month 
follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 
8. Incidence of “fatal outcome (due to any reason) or 
hospitalization due to HF” during 12-month follow-up period 
[Visit 1 Day 1 – Visit 6 Day 365]. 
9.  Changes in levels of BNP andNT-pro-BNP during 12-month 
follow-up period compared to baseline [Visit 1 Day 1 – Visit 6 
Day 365]. 
10. Changes in structural and functional echocardiographic 
parameters after 12 months compared to baseline [Visit 1 Day 1 
– Visit 6 Day 365]. 
Exploratory endpoints: 
1. Changes in concomitant therapy [Visit 1 Day 1 – Visit 6 
Day 365]. 
2. Interaction between STEMI outcomes and peculiarities of 
coronary bed lesion based on baseline CAG results [Visit 1 Day 
1 – Visit 6 Day 365]. 
Safety evaluation 
Safety endpoints: 
1. Frequency of AE/SAE during the study. 
2. Changes in physical examination (including body weight), vital 
signs during the study. 
Statistical analysis 
Statistical analysis will be performed in the following populations. 
Full Analysis Set (FAS): 
Full analysis set for efficacy analysis will include all randomized 
subjects, who received the study products and underwent at least one 
CRP measurement after administration of the study products. This 
set is the main population for efficacy analysis. 
Per Protocol Set (PPS): 
All FAS subjects without relevant Protocol deviations affecting 
assessment of the primary efficacy parameter. Such major Protocol 
deviations will be defined before database lock in a blinded data 


 
 
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review. This set is supplementary population for efficacy 
assessment.  
Safety Population: 
All randomized subjects, who received the study products. 
General considerations: 
Detailed description of statistical data analysis including last 
observation carried forward will be presented in statistical analysis 
plan (SAP). SAP development will be finalized until the study 
database lock. Any deviations from analysis planned in SAP should 
be justified in the report on study results.  
Any data will be generalized using descriptive statistics: number of 
the subjects, mean value, minimum and maximum, median and 
quartiles for continuous variables, frequency of observations with 
percentages - for qualitative variables. 
After the last subject completes 28-day follow-up period, an analysis 
of hsCRP, BNP and NT-pro-BNP will be performed for 14 and 28 
days of the study. The analysis results may be used to define the 
strategy for further RPH-104 development. 
At this stage the primary efficacy analysis will be performed. This 
analysis will be performed only once and will not be repeated during 
the final analysis stage. Sensitivity analysis cannot be done during 
the interim stage and will be performed during the final analysis 
stage. 
Secondary efficacy variables (AUC from day 1 to day 28) will be 
derived and analysed for parameters hsCRP, BNP and NT-pro-BNP 
at the interim analysis stage. This analysis will be performed only 
once and will not be repeated during the final analysis stage. 
After the completion of the study, a final statistical data analysis will 
be conducted, and the final study report will be prepared. 
 


 
 
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Table 1. Schedule of visits and procedures 
Time point/Study procedures 
Day 
1 
Day 
31 
Day 
14±3 
Day 28±3  
/Early 
withdrawal 
visit (from 
Day 1 till Day 
28) 
Month 62 
±2 weeks 
Month 12 
±2 weeks 
/Early 
withdrawal 
visit (from 
Day 29 till 
Day 365) 
Visit 
1 
2 
3 
4 
5 
6 
Informed consent 
Х 
 
 
 
 
 
Evaluation 
of 
inclusion/exclusion 
criteria 
Х 
 
 
 
 
 
Medical history 
Х 
 
 
 
 
 
Recording previous therapy 
Х 
 
 
 
 
 
Demographic data 
Х 
 
 
 
 
 
Recording 12-lead ECG results3 
Х 
 
 
 
 
 
Recording CAG findings4 
Х 
 
 
 
 
 
Randomization 
Х 
 
 
 
 
 
Administration of the study product5 
Х 
 
 
 
 
 
Urine pregnancy test for females with 
childbearing potential (test strips) 
Х 
 
 
 
 
 
Hematology6 
Х 
 
 
 
 
 
Efficacy evaluation 
Blood 
sampling 
for 
measuring 
hsCRP, BNP, NT-pro-BNP 
Х 
Х 
Х 
Х 
 
Х7 
Outcome registration 
 
Х 
Х 
Х 
Х 
Х 
Echo-CG 
Х8 
 
 
Х 
 
Х 
Safety evaluation 
Vital signs (BP, HR, RR, body 
temperature) 
Х 
Х 
Х 
Х 
 
Х 
Physical examination  
Х 
Х 
Х 
Х 
 
Х 
Body weight measurement 
Х9 
Х10 
X 
Х 
 
Х 
Height registration  
 
 
Х11 
 
 
 
Blood sampling for hematology and12 
biochemistry13 
Х 
 
X 
Х 
 
 
AE/SAE recording 
Х 
Х 
Х 
Х 
Х 
Х 
Recording concomitant therapy 
Х 
Х 
Х 
Х 
Х 
Х 
                                            
1For patients discharged on Day 2, the procedures of the Day 3 visit can be carried out ahead of schedule (on Day 2). 
2The visit might be conducted in the form of a telephone conversation with the patient. 
3Recording 12-lead ECG results on which STEMI diagnosis was based. 
4Recording CAG results performed at admission to the study. 
5Must be performed within 3 hours of randomization. 
6Hematology: determination of absolute neutrophil count in local laboratory of the site. 
7BNP and NT-pro-BNP will be determined. 
8On Day 1, Echo-CG can be performed within 24 hours of randomization. 
9Body weight is measured using hospital bed on Day 1; if not available, on Day 3. 
10Body weight measurement (for subjects who did not undergo measurement on Day 1). 
11It is permissible to record any value obtained during the hospitalization, when it was possible to measure the patient's 
height. 
12Hematology: hemoglobin, erythrocyte count, leukocyte count, leukogram with obligatory measurement of absolute 
neutrophil count, platelet count. 
13Biochemistry: hepatic chemistry values (AST, ALT, GGT, AP, LDH, total bilirubin, direct bilirubin, indirect bilirubin), 
renal chemistry values (serum creatinine, serum urea / urea nitrogen [BUN]), serum electrolytes (sodium, potassium, 
chlorides), CPK, CPK-МВ. 


 
 
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2. Study rationale 
2.1. Introduction 
The term "myocardial infarction” (MI) is used when there is verified myocardial lesion (defined 
as increased cardiac troponin level by at least one value exceeding 99th percentile of normal 
reference value) and myocardial necrosis in clinical situations suggesting myocardial ischemia. To 
ensure urgent selection of treatment approach including reperfusion therapy, MI is diagnosed in 
cases of anginal pain or its equivalents with ST elevation in at least 2 or more consequent leads or 
acute left bundle branch block (LBBB) and defined as ST-segment elevation MI (STEMI) (Ibanez 
B. et al, 2017).  
Coronary heart disease (CHD) is the leading cause of mortality globally (1.8 million deaths 
annually) and is 20% of all fatal outcomes in Europe despite relevant variations between the 
countries (Ibanez B. et al, 2017).  
Epidemiological data in the RF are disparate. According to the available assessments, in Russia 
economic losses from all cardiovascular diseases (CVD) in 2016 was 2.7 trillion rubles being 
equivalent to 3.2% of GDP. In the structure of losses among all circulatory diseases, CHD rates 
the first, financial burden in Russia is more than 1 trillion rubles (Kontsevaya A.V. et al, 2018).  
One of the most relevant forms of CHD characterized by high mortality is MI. Globally more than 
15 million of new onset MI cases are reported annually (Garganeyeva А.А. et al, 2015; WHO, 
2017). MI aggravates prognosis significantly: according to European register, mortality among the 
subjects with STEMI during hospitalization varies from 4% to 12%, 6-month mortality may 
exceed 12%, 12-month mortality is approximately 10% and may reach 20% within 5 years (Ibanez 
B. et al, 2017). At that, unfavourable prognosis is still relevant for surviving post-MI subjects 
(Berger C.J., 1992; VNOK Work Group, 2007; Minzdrav, 2016).  
According to some authors, the urgency of MI epidemiological situation is determined by its 
frequency among the population aged > 60 years old both by morbidity and mortality parameters 
and by hospital and pre-hospital lethality (Okrugin S.А., 2018). 
The main therapeutic measures are directed at myocardial reperfusion as soon as possible with 
recanalization by percutaneous coronary intervention (PCI) (Ibanez B. et al, 2017).  
Despite significant progress in MI therapy, more than 20% surviving subjects develop HF (HF) 
within 90 days (Gjesing A. et al., 2014).  
According to Russian epidemiological studies (EPOHA-CHF, EPOHA-Hospital-CHF and 
EPOHA-Decompensation-CHF), prevalence of chronic HF in the RF increased from 4.9% (1998) 
to 10.2% (2014) within 16 years. At that, the number of subjects with chronic HF functional class 
(FC) II-IV increased significantly due to increased age of the subjects as well as increased weight 
of etiological CHD causes (69.7% in 2014) and previous MI (15.3% in 2014). Overall mortality is 
6% annually (Fomin I.V., 2016).  
STEMI is associated with intensive inflammatory response promoting further lesion and predicting 
increased mortality or HF risk (Frangogiannis N.G., 2008; Velagaleti R.S. et al., 2008; 
Vanhaverbeke M. et al., 2018).  
Interleukin-1 (IL-1) is the key mediator of local and systemic inflammatory response to injury. 
Nonclinical studies demonstrated that IL-1 inhibition improves infarction healing and prevents the 
development of HF (Abbate A. et al., 2006).  
The studies indicated that concentration of high-sensitive С-reactive protein (hsCRP), the marker 
of inflammatory response and surrogate marker of IL-1 activity, in subjects with acute coronary 


 
 
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syndrome/MI, independently correlated with the risk of unfavourable cardiovascular outcomes 
(including HF) (Ridker P. et al., 2005; Scirica B.M., 2009; Vanhaverbeke M. et al., 2018). 
Individual studies also demonstrated that, where the signs of persistent inflammation (increased 
hsCRP level) and hemodynamic stress (an increase in a proBNP level) are observed, the subjects 
are under the highest risk of HF (Scirica B.M., 2009; Vanhaverbeke M. et al., 2018).  
Currently evaluation of medicinal products blocking activity of IL-1 (anakinra, rilonacept, 
canakinumab) is performed to improve outcomes in subjects with acute coronary syndrome/MI 
(Buckley L.F. and Abbate A., 2018).  
Randomized double-blind placebo-controlled study of canakinumab (CANTOS) enrolled 
10061 subjects with MI and hsCRP level of ≥ 2 mg/L. The subjects received 50 mg, 150 mg or 
300 mg of canakinumab or placebo subcutaneously every 3 months. It was demonstrated that,after 
a single administration of the product, the subjects reaching reduced hsCRP below 2 mg/L showed 
reduced frequency of major adverse cardiovascular events by 25% and mortality by 31% compared 
to the subjects not reaching hsCRP reduction. Similar results were demonstrated for other 
outcomes (including hospitalization due to unstable angina requiring unscheduled 
revascularization (Ridker P.M. et al., 2017; Ridker P.M. et al., 2018). 
Three pilot clinical studies of anakinra for STEMI were carried out: VCU‐ART, VCU – ART2 
and VCU‐ART3 (Abbate A. et al., 2010; Abbate A., 2013, Abbate A. et al., 2020; Van Tassell 
B.W. et al., 2018). In total, these pilot studies enrolled 140 subjects with STEMI receiving 
reperfusion therapy who were randomized (within 12 hours post coronary angiography) for daily 
anakinra therapy for 14 days. Anakinra, a recombinant human IL-1 receptor antagonist (IL-1RA), 
was tolerated well and reduced serum hsCRP level. Anakinra-treated subjects showed tendency 
for more favourable left ventricular (LV) remodelling and lower frequency of HF in the mid-term 
and long run.  
RPH-104 belongs to the class of target agents affecting IL-1. It is a hybrid protein selectively 
binding and inactivating IL-1β. Nonclinical studies show that RPH-104 is being developed for the 
treatment of human subjects with diseases associated with increased activity of IL-1β.  
To date, the clinical study of drug use in treatment of acute gout attacks has been completed, and 
the studies of potential benefits of the drug for the treatment of Familial Mediterranean fever, 
idiopathic recurrent pericarditis are ongoing.  
Given similar mechanism of action of RPH-104 and anakinra, RPH-104 is expected to reduce 
intensity of inflammatory response at myocardial lesion in subjects with STEMI and, therefore, to 
reduce hsCRP level and improve short-term and long-term outcomes.  
2.2. Cumulative presentation of the results of nonclinical and clinical studies 
relevant for this study 
RPH-104 is a hybrid protein with a molecular weight of the non-glycosylated form of 
126.8 kilodalton (kDA) selectively binding and inactivating IL-1β. Two active parts of the molecule 
are responsible for RPH-104 binding with IL-1β: an extracellular portion of human IL-1 receptor 
type 1 (IL-1R1), type 1 and a portion of human IL-1 receptor accessory protein (IL-1RAcP) that is 
an IL-1 co-receptor. 
Structurally, RPH-104 molecule contains two polypeptide chains: the first one consists of 
extracellular part of IL-1 receptor (amino acids from 18 to 333 of human IL-1R1) and mutant Fc-
fragment of human immunoglobulin G1 (IgG1); the second one consists of the part of IL-1RAcP 
(amino acids from 21 to 358 of human IL-1RAcP) and mutant Fc-fragment of human IgG1. Each of 
the extracellular parts of the molecule also contains 7 covalently bound glycans, and each of Fc-


 
 
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fragments carries one glycan.  
RPH-104 is a highly active inhibitor of IL-1β-mediated signal pathway. 
Investigation of inhibitory effect of RPH-104 on IL-1β-mediated secretion of IL-6 cell line of non-
transformed human lung fibroblasts (MRC5) demonstrated that 50% inhibitory concentration of 
RPH-104 (IC50) is about 0.4 ng/mL (2.0 pmol/L). 
The amino acid sequence of the extracellular domain of IL-1 receptor in the RPH-104 molecule 
subunit is 94.7% identical to the amino acid sequence of IL-1 receptor of cynomolgus monkeys and 
only 64% identical to the IL-1R1 sequence of rodents. In addition, RPH-104 has comparable cross-
reactivity in tissues of humans and cynomolgus monkeys. Therefore, cynomolgus monkeys are a 
suitable biological species for nonclinical studies of RPH-104 in vivo. 
RPH-104 shows linear pharmacokinetics (PK) in animals and humans. After a single subcutaneous 
administration to cynomolgus monkeys, RPH-104 bioavailability is 52-85% without signs of 
accumulation. After repeated administration to cynomolgus monkeys, plasma concentration and 
half-life tended to decrease by 20-80% compared to single dose values due to production of anti-
product antibodies. Apparent gender-related differences in the product PK are lacking. 
RPH-104 toxicity has been studied in mice and monkeys. Clinical symptoms and abnormal 
laboratory values during 4-week study of the product were mild and reversible in most animals by 
the end of recovery period. No cases of product-related animal mortality were reported in this study. 
In a 26-week RPH-104 repeated dose nonclinical study on cynomolgus monkeys, cases of serious 
toxicity requiring early euthanasia were reported. The cases recorded were considered as related to 
immunosuppressive mechanism of action of RPH-104 as an IL-1β antagonist. Immunosuppression 
on the background of long-term administration of high doses of RPH-104 is due to inhibition of IL-
1β and meets the purpose of RPH-104 administration for the treatment of autoinflammatory diseases. 
The medicinal product has immunogenic properties in monkeys. 
The results of repeated dose toxicity studies with weekly subcutaneous 4-week administration 
suggest that RPH-104 no adverse effect level (NOAEL) in mice and monkeys was 100 mg/kg. 
Mathematic modeling studies demonstrated that the minimum effective dose of RPH-104 required 
to achieve the desired plasma level of free IL-1β was 1 mg upon once weekly dosing. Maximum 
tolerated dose (MTD) for humans is 6.4 mg/kg which is equivalent to 384 mg based on a 60 kg body 
weight. 
Nonclinical studies on the model of acute MI were not performed.  
Given its mechanism of action, RPH-104 is designed for investigation and use in humans for the 
treatment of autoinflammatory diseases associated with increased activity of IL-1β. 
In 2018, the first clinical study (phase 1) of RPH-104 was completed. The study aimed at evaluating 
the tolerability, safety, pharmacokinetics, pharmacodynamics and immunogenicity of the drug 
(RPH104FIH01/CL04018045) in healthy volunteers. The study results demonstrated that RPH-104 
at doses from 4 to 160 mg inclusive with a single subcutaneous injection are tolerated well by the 
volunteers of either gender. No serious adverse events (SAEs) or any other adverse events (AEs) 
resulting in early withdrawal have been reported. All adverse events (70 in total) in all dose groups 
were mild and resolved completely without any complications. Headache was the only AE with 
tendency for higher frequency in RPH-104 group compared to placebo. 
The results of investigation of RPH-104 PK after a single administration presented in analysis of this 
clinical study demonstrated linear and dose-dependent increase in Cmax and AUC(0-t) values. In 
general, median Tmax was 96 hours (4 days), however the median was 120 hours (5 days) in 40 and 
160 mg groups. Half-life was similar in all dose groups and was equivalent to 235-249 hours (10 


 
 
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days). 
The results of pharmacodynamic (PD) study presented in the RPH104FIH01/CL04018045 study 
report demonstrated that administration of the product at 4 to 160 mg did not cause any significant 
changes in IL-1α or IL-1β levels in healthy volunteers. The changes in the level of CRP were 
regarded as normal fluctuations. Volunteers receiving RPH-104 showed increased IL-1RA levels 
due to the time post dosing starting from 20 mg dose which was not observed in placebo group. This 
trend towards an increase in the IL-1RA levels over time after the product administration was noted 
at all dose levels. Such increase in IL-1RA level is considered as an additional benefit, potentially 
capable of increasing RPH-104 efficacy without increasing the drug-related safety risks. 
Nevertheless, this requires confirmation in further studies. The volunteers in the study did not show 
any relevant product-related changes in IL-6 levels associated. During the study, there were no signs 
of the effect of RPH-104 on S100 A8 levels. 
No antibodies to RPH-104 were detected in the blood samples of healthy volunteers collected during 
the study. 
In 2020, an international multicenter randomized double-blind adaptive placebo-controlled single-
dose study to evaluate the efficacy and safety of olokizumab (IL-6 inhibitor) and RPH-104 in patients 
with severe COVID-19 (SARS-CoV-2) infection conducted in RF was completed (CL04041078). 
The analysis of primary efficacy endpoint (response to treatment) showed no significant differences 
between the treatment groups. 
During the study of RPH-104 administration, 128 AEs were reported in 61 (49.6%) patients in the 
RPH-104 group and 111 AEs in 48 (38.7%) patients in the placebo group. The most common AEs 
belonged to the systemic organ class of “Investigations” (ALT increased, AST increased, GGT 
increased): 29 (23.6%) patients in the RH-104 group and 23 (18.5%) patients in the placebo group. 
Less common AEs belonged to the SOC of “Infections and infestations” (e.g. acute sinusitis, 
bacterial bronchitis, COVID-19, C.difficile-induced pseudomembranous colitis, otitis media, 
otosalpingitis, pneumonia, pseudomembranous colitis, sepsis, septic shock, urinary tract infection, 
fungal urinary tract infection, viral sepsis – none of events were reported in more than 5% in each 
treatment group). 
At least one SAE was reported in 12.2% of patients in the RPH-104 group and 6.5% of patients in 
the placebo group. The majority of SAEs belonged to the SOC “Infections and infestations” (i.e. 
sepsis, septic shock, COVID-19, viral sepsis). SAEs that led to death were reported in 11.4% and 
4.8% of patients in the RPH-104 and placebo groups, respectively. Only one SAE that resulted in 
death in the RPH-104 group was considered related to the study drug (i.e. a case of septic shock). 
RPH-104 was generally well-tolerated by patients. No new safety signals related to the use of 
RPH-104 were identified. It should be noted that no cases of death have been reported in any other 
ongoing studies of RPH-104 so far. 
In 2021, an open-label randomized phase 2a clinical study assessing the safety, tolerability, 
pharmacokinetics and pharmacodynamics of RPH-104 at various doses in subjects with an acute 
gout episode in the RF (CL04018054) was completed. In this study, the subjects received RPH-104 
at single subcutaneous doses of 4 mg, 20 mg, 40 mg, 80 mg, or 160 mg, control subjects received 
diclofenac orally for 12 days.  
The most pronounced decrease in the joint pain severity 72 hours after the start of the study treatment 
(primary endpoint) was observed in the RPH-104 20 mg, 80 mg and 160 mg dose groups, as well as 
the diclofenac group. In all groups, the use of the study treatment resulted in decreased severity of 
swelling and pain in the affected joint, elimination of erythema and improvement of the patients’ 
performance status. The results of analysis of changes in the health assessment parameters (using 
the HAQ) indicated clinically significant improvement of the patients’ performance status while on 


 
 
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the study treatment in the 20 mg, 40 mg, 160 mg dose groups, and the diclofenac group.  
The analysis of PK parameters in this study demonstrated a tendency to increased Cmax and AUC 
with the drug dose increased, except for the 20 mg dose group, which demonstrated higher mean 
values of these parameters, similar to those observed in the 80 mg dose group. High interindividual 
variability of Tmax was observed. The half-life in the dose groups was about 10 days. 
RPH-104 dosing in patients with acute gout attacks resulted in decreased concentrations of the main 
inflammatory markers – hsCRP and serum amyloid A (SAA). hsCRP and SAA levels tended to 
show more significant decrease in the RPH-104 80 mg and 160 mg dose groups; the 80 mg dose 
group also demonstrated a statistically significant superiority in respect of hsCRP level increase 
compared to the diclofenac group.  
The study demonstrated a favorable safety profile of the drug. AEs related to the use of RPH-104 
included: in the 40 mg dose group – injection site hemorrhage, gouty arthritis; in the 80 mg group – 
drug-induced liver injury; in the 160 mg group - leukocytosis, sinus tachycardia, injection site 
erythema, injection site itching, cholesterol level increased, creatinine level increased, triglyceride 
level increased, blood urea level increased, lymphocyte count increased, creatinine clearance 
decreased, neutrophil count and percentage decreased, arthralgia, joint swelling, pain in extremities, 
allergic dermatitis. Injection site reactions were observed only in three patients treated with RPH-
104: two patients in the 4 mg dose group (swelling, hemorrhage) and one patient in the 160 mg dose 
group (injection site erythema and itching).  
Two serious adverse events (SAEs) were reported in patients receiving the test product and one SAE 
in the active control group; there were no deaths. 
A 47-year-old male patient with acute gouty arthritis treated with RPH-104 SC 80 mg developed 
highly active drug-induced hepatitis on a background of fatty liver (Medical Dictionary for 
Regulatory Activities [MedDRA] preferred term: drug-induced liver injury). The investigator 
regarded this event as probably related to the study drug and acknowledged the possible role of 
existing liver disease. However, taking into account the normalization of liver enzyme levels within 
a few days after the onset of symptoms, along with a persisting noticeable increase in pancreatic 
enzyme levels (which is typical for pancreatitis of biliary origin), the patient's history of chronic 
pancreatitis, chronic cholecystitis, deformity of the duodenum (which could predispose to the 
development of acute pancreatitis or exacerbation of chronic pancreatitis), the Sponsor classified this 
event as unrelated to the study drug and regarded the detected disorders as more typical for 
pancreatitis than hepatitis.  
Another patient (male, 66 years old), who received once subcutaneous injection of RPH-104 80 mg 
for an acute attack of gout, had a positive test for Mycobacterium tuberculosis complex and was 
diagnosed with pulmonary fibrosis. According to the Investigator’s assessment, the study drug was 
not related to these events. The Sponsor assessed both events as unrelated to the use of RPH-104: 
a blood sample was taken 4 days after the RPH-104 administration, which makes the relationship 
of a positive result of the test for tuberculosis and the administration of the study drug biologically 
and chronologically implausible; the connection of pulmonary fibrosis with the use of PH-104 is 
chronologically impossible, since pulmonary fibrosis could not develop in such a short period.  
In general, the available data on the safety of RPH-104 do not indicate that there is a significant 
risk to the safety of the study participants.  
Based on the results of the efficacy assessment in the CL04041078 study, it was concluded that 
RPH-104 does not contribute to improving the clinical status (with respect to respiratory system 
function) or mortality rates in patients with severe COVID-19, however, the potential benefit in 
relation to other clinical outcomes requires study in further clinical studies. The results of the 
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160 mg for the treatment of acute gout attack, and are also promising with regard to the doses of 
80-160 mg in terms of treatment of diseases associated with increased IL-1 activity. To date, no 
data are available on the efficacy of RPH-104 in humans with other disorders. 
The efficacy and safety of the use of RPH-104 is also being studied in an ongoing double-blind 
randomized placebo-controlled phase 2/3 clinical trial in patients with idiopathic recurrent 
pericarditis (CL04018068) in the RF, during which patients receive the investigational product 
according to the following regimen: the first injection at a "loading" dose of 160 mg, then – at a 
dose of 80 mg – at Week 1 and 2 after the first injection, and then at a dose of 80 mg once every 2 
weeks. Three SAEs have been reported in this study: community-acquired pneumonia associated 
with coronavirus infection (RPH-104/placebo), exacerbation of idiopathic recurrent pericarditis 
(RPH-104), and bacterial community-acquired pneumonia (RPH-104). The case of bacterial 
community-acquired pneumonia was regarded by both the Investigator and the Sponsor as 
associated with RPH-104 due to the known effect of IL-1 inhibitors on the risk of infections’ 
development. These events were not included in the current safety analysis. In addition, patients 
are being recruited to an international multicenter double-blind placebo-controlled randomized 
clinical trial of the efficacy and safety of RPH-104 used to prevent recurrent seizures in adult 
patients with Familial Mediterranean fever with colchicine resistance or colchicine intolerance 
(CL04018065), for which a subsequent long-term open-label extension study is planned 
(CL04018071). 
A Phase 2, double-blind, placebo-controlled, randomized trial evaluating the efficacy and safety of 
RPH-104 in patients with Schnitzler syndrome is also planned to be conducted (CL04018066), and 
so is a double-blind randomized placebo-controlled phase 3 study to evaluate efficacy and safety of 
RPH-104 in adult-onset Still’s disease (CL04018093).  
In view of the mechanism of action, RPH-104 is expected to be a highly effective, safe drug for 
reducing the inflammatory response to myocardial injury in STEMI patients and for improving short- 
and long-term outcomes. 
Detailed data on the results of nonclinical and clinical studies of RPH-104 are provided in the 
Investigator's Brochure.  
2.3. Brief summary of known and potential risks and benefits for the study 
subjects 
RPH-104 study program currently includes the data from nonclinical studies and phase 1 clinical 
study on healthy volunteers, as well as a randomized double-blind placebo-controlled study of the 
use of RPH-104 in patients with severe COVID-19 (SARS-CoV-2 infection), and an open-label 
randomized phase 2a clinical study in patients with gout. Phase 1 study showed that RPH-104 
administration to healthy volunteers at doses from 4 mg to 160 mg inclusive were tolerated well 
by male and female volunteers after a single subcutaneous administration. There were no SAEs or 
AEs leading to withdrawal from the study. The only AE with a tendency towards a higher 
incidence in the RPH-104 group versus placebo group was headache. No antibodies to RPH-104 
were detected in blood samples of healthy volunteers during the study. No new safety signals have 
been identified during the studies of RPH-104 in patients with COVID-19 or gout. 
Based on the known safety profile of drugs in this class (IL-1 inhibitors), the following adverse 
reactions should be carefully monitored during their use: 
 Any infections (including serious infections), including but not limited to: upper 
respiratory tract infections, pneumonia, urinary tract infection, gastroenteritis, 
tuberculosis, opportunistic infections, sepsis; 
 Decreased neutrophil count; 


 
 
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 Decreased platelet count; 
 Drug-induced liver injury, any liver enzyme increase; 
 Elevation of blood lipid; 
 Development of malignant neoplasms; 
 Ineffective vaccination or generalized vaccine-associated infection; 
 Macrophage activation syndrome; 
 Development of anaphylactic and anaphylactoid reactions. These reactions can manifest 
as acute infusion reactions, allergic reactions, or delayed-type hypersensitivity reactions. 
To detect AEs and take timely medical measures, all subjects will undergo regular examinations 
including vital signs, physical examination, laboratory tests and evaluation of the product 
administration site.  
In addition, to assure safety of the subjects involved in the study, selection criteria stipulate 
ineligibility of the subjects in which the study product may increase the risk of AEs such as 
infections or reduced blood neutrophil count.  
Since the RPH-104 is a protein product, it may cause anaphylactic and anaphylactoid reactions 
when administered. These reactions may manifest as acute infusion reactions, allergic reactions or 
delayed-type hypersensitivity reactions. Therefore, administration of RPH-104 will be performed 
at the study sites provided with medicinal products and equipment designed for the treatment of 
anaphylactic and anaphylactoid reactions.  
Based on the information available from the results of nonclinical studies and from RPH-104 
administration to healthy volunteers, patients with COVID-19 and gout, single subcutaneous 
administration to the subjects with acute STEMI at 80 mg or 160 mg is not expected to cause 
severe or serious AEs. 
Placebo administration is not associated with additional risks for the study subjects with STEMI 
as the Protocol does not define any additional or treatment-limiting conditions. The subjects who, 
based on their status, will await for cardiosurgery will not be enrolled in this study.  
Physical methods of examination to be performed in this study are routine methods (weight and 
height measurement, evaluation of vital signs – blood pressure [BP], heart rate [HR], respiratory 
rate [RR], body temperature], physical examination) and do not pose any additional risk for the 
subjects during their participation in the study. 
Echocardiography (Echo-CG) is a routine examination method for the subjects with STEMI and 
does not pose additional burden and/or risks for the subjects participating in the study.  
According to the Protocol, laboratory examination requires blood sampling, therefore there is low 
risk of infection which may be ruled out by qualified performance of the procedure by experienced 
personnel of the study sites involved in this study. 
By means of examination and monitoring, the subjects will obtain reliable information on their 
health status within the examinations. 
In addition, based on the results of the studies of the products with similar mechanism of action in 
the same population, improved STEMI outcome may be expected: more favourable LV 
remodeling and lower rate of HF in the mid-term and long run.  
Therefore, benefit from the study for the patients is expected to outweigh the risk and overall risk-
benefit ratio is favorable. 


 
 
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2.4. Description and justification of method of administration, dose, dosing 
regimen and therapy duration 
The study product will be administered as a single subcutaneous dose of 80 mg (2 mL) or 160 mg 
(overall volume 4 mL: 2 mL in different administration sites).  
Placebo will be used as a single subcutaneous injection at 2 mL or 4 mL (2 mL in different 
administration sites).  
Nonclinical dose-ranging studies were not performed on relevant animal models.  
In the studies of anakinra, an agent with similar mechanism of action, the product was administered 
once daily for 14 days in subjects with STEMI. Given that RPH-104 half-life is 250 hours, single 
administration is supposed to provide inhibition of IL-1 with reduced hsCRP level. 
According to study data for rilonacept, a drug with a similar mechanism of action, a single dose of 
320 mg of rilonacept is well tolerated, and a dose of 160 mg weekly has proven its therapeutic 
efficacy in patients with diseases in which IL-1 plays a leading pathogenic role (Hashkes P.J. et 
al., 2012; Hoffman H.M. et al., 2008; Krause K. et al., 2012). RPH-104 contains active fragments 
similar to rilonacept, while the molecular weight of the former is 2 times less, therefore the same 
dose of RPH-104 can provide a molar ratio 2 times higher than that of rilonacept. In addition, 
according to the results of phase 1 study (RPH104FIH01/CL04018045) in healthy volunteers doses 
of 80 and 160 mg provide higher blood concentrations of the drug with a similar safety profile 
compared to lower doses. 
In addition, in an open-label phase 2a study in patients with gout, there was a tendency to a more 
pronounced decrease in hsCRP in the dose groups RPH-104 80 mg and 160 mg. A comparative 
intergroup analysis (RPH-104 at doses of 4 mg, 20 mg, 40 mg, 80 mg and 160 mg versus 
diclofenac) revealed a statistically significant superiority compared to the diclofenac group in 
reducing the hsCRP from the baseline level for the 80 mg dose group at certain time points after 
administration of the study drug. 
Dose selection (80 mg or 160 mg) for further phases of clinical studies will be based on the results 
of analysis of data from this study in terms of risk-benefit ratio for two doses of RPH-104.  
The results of phase 1 study demonstrated that single subcutaneous administration of RPH-104 at 
doses from 4 mg to 160 mg was tolerated well by healthy volunteers. These results, as well as the 
results of the use of RPH-104 in patients with COVID-19 or gout (during which no new safety 
signals were identified) suggest that in the present clinical study RPH-104 at 80 mg or 160 mg will 
be tolerated well by the subjects with acute STEMI.  
2.5. Legal framework 
This clinical study will be carried out in accordance with the present Protocol, Good Clinical 
Practice guidelines adopted at the International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH GCP E6 in the current 
version), ethical principles outlined in Helsinki Declaration of World Medical Association 
(Fortaleza, 2013), European Union Directive 2001/20/ЕС and requirements of laws of the RF, 
EAEU and USA: 
 Federal Law dated 21.11.2011 No. 323-FL (current version) "On fundamental healthcare 
principles in the RF"; 
 Good Clinical Practice. GOST R 52397-2005 (app. by Decree of Federal Agency on 
Technical Regulation and Metrology dated 27.09.2005 No. 232-st); 


 
 
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 Federal Law dated April 12, 2010 No. 61-FL (current version) "On medicinal products 
circulation"; 
 Decree of the RF Government dated 13.09.2010 No. 714 “On approval of standard 
regulations for obligatory insurance of life and health of the subject involved in clinical 
studies of medicinal product” (according to amendments made by Decree of the RF 
Government dated May 18, 2011 No. 393); 
 Decree of the RF Ministry of Health dated April 01, 2016 No. 200n "On approval of Good 
Clinical Practice"; 
 Resolution of the Council of the Eurasian Economic Commission dated November 3, 
2016 No. 79 "Regulations of Good Clinical Practice of Eurasian Economic Union"; 
 Title 21 of the Code of Federal Regulations; 
 other applicable regulations.  
2.6. Description of study population 
The study is supposed to enroll male and female subjects aged from 18 years old (inclusive) 
hospitalized with STEMI to the study sites of the RF and USA. Given that STEMI is a common 
condition and is a critical issue among the subjects of higher age groups, the study did not 
determine upper age limit.  
Selection criteria for this study were carefully developed to assure safety of the subjects and 
authenticity of the study results. 
3. Study purpose and objectives 
3.1. Study purpose 
Evaluate the effect of single administration of RPH-104 at 80 mg and 160 mg on parameters of 
systemic inflammation and outcomes of the disease in subjects with STEMI. 
3.2. Study objectives 
1. Evaluate the effect of single administration of RPH-104 at 80 mg and 160 mg compared to 
placebo on hsCRP level reduction within 14 days in subjects with STEMI. 
2. Evaluate the effect of single administration of RPH-104 at 80 mg and 160 mg compared to 
placebo on hsCRP level reduction within 28 days in subjects with STEMI. 
3. Evaluate the effect of single administration of RPH-104 at 80 mg and 160 mg compared to 
placebo on cardiovascular and other clinical outcomes within 12 months in subjects with STEMI. 
4. Evaluate the effect of single administration of RPH-104 at 80 mg and 160 mg compared to 
placebo on changes in levels of HF biomarkers (BNP and NT-pro-BNP) within 12 months in 
subjects with STEMI. 
5. Evaluate the effect of single administration of RPH-104 at 80 mg and 160 mg compared to 
placebo on parameters of cardiac remodeling (changes in structural and functional 
echocardiographic parameters) within 12 months in subjects with STEMI. 
6. Evaluate safety and tolerability of single administration of RPH-104 at 80 mg and 160 mg 
compared to placebo in subjects with STEMI during the study. 
Exploratory objective:  
Evaluate interaction between STEMI outcomes and peculiarities of coronary bed lesion based on 
baseline coronary angiography (CAG) results.  


 
 
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4. Study design 
4.1. Principal and additional study parameters 
Table 2. Study endpoints 
Objectives 
Endpoints 
Evaluate the effect of single administration of RPH-
104 at 80 mg and 160 mg compared to placebo on 
hsCRP level reduction within 14 days in subjects with 
STEMI. 
hsCRP area under curve (AUC) from Day 1 
(baseline) until Day 14 [Visit 1 Day 1 – Visit 3 Day 
14]. 
Evaluate the effect of single administration of RPH-
104 at 80 mg and 160 mg compared to placebo on 
hsCRP level reduction within 28 days in subjects with 
STEMI. 
hsCRP area under curve (AUC) from Day 1 
(baseline) until Day 28 [Visit 1 Day 1 – Visit 4 Day 
28]. 
Evaluate the effect of single administration of RPH-
104 at 80 mg and 160 mg compared to placebo on 
cardiovascular and other clinical outcomes within 12 
months in subjects with STEMI. 
Incidence of fatal outcomes (cardiac and non-
cardiac) during 12-month follow-up period [Visit 1 
Day 1 – Visit 6 Day 365]. 
Incidence of hospitalizations due to HF or other 
cardiac reasons not associated with HF, or due to 
non-cardiac reasonsduring 12-month follow-up 
period [Visit 1 Day 1 – Visit 6 Day 365]. 
Incidence of new cases of HF (defined as 
hospitalization due to HF or new onset of HF) 
during 12-month follow-up period [Visit 1 Day 1 – 
Visit 6 Day 365]. 
Incidence of “fatal outcome (due to any reason) or 
hospitalization due to HF or new onset of HF” 
during 12-month follow-up period [Visit 1 Day 1 – 
Visit 6 Day 365]. 
Incidence of “fatal outcome (due to any reason) or 
hospitalization due to HF” during 12-month 
follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 
Exploratory endpoint: 
Changes in concomitant therapy [Visit 1 Day 1 – 
Visit 6 Day 365]. 
Evaluate the effect of single administration of RPH-
104 at 80 mg and 160 mg compared to placebo on 
changes in levels of HF biomarkers (BNP and NT-pro-
BNP) within 12 months in subjects with STEMI. 
BNP area under curve (AUC) from Day 1 
(baseline) until Day 28 [Visit 1 Day 1 – Visit 4 Day 
28]. 
NT-pro-BNP area under curve (AUC) from Day 1 
(baseline) until Day 28 [Visit 1 Day 1 – Visit 4 Day 
28]. 
Changes in levels of BNP and NT-pro-BNP during 
12-month follow-up period compared to baseline 
[Visit 1 Day 1 – Visit 6 Day 365]. 


 
 
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Evaluate the effect of single administration of RPH-
104 at 80 mg and 160 mg compared to placebo on 
parameters of cardiac remodeling (changes in 
structural 
and 
functional 
echocardiographic 
parameters) and others within 12 months in subjects 
with STEMI. 
Changes 
in 
structural 
and 
functional 
echocardiographic parameters after 12 months 
compared to baseline [Visit 1 Day 1 – Visit 6 Day 
365]. 
Evaluate 
safety 
and 
tolerability 
of 
single 
administration of RPH-104 at 80 mg and 160 mg 
compared to placebo in subjects with STEMI during 
the study. 
Frequency of AE/SAE during the study. 
Changes in physical examination (including body 
weight), vital signs during the study. 
Exploratory objective: 
Evaluate interaction between STEMI outcomes and 
peculiarities of coronary bed lesion based on baseline 
CAG results. 
Exploratory endpoint: 
Interaction 
between 
STEMI 
outcomes 
and 
peculiarities of coronary bed lesion based on 
baseline CAG results [Visit 1 Day 1 – Visit 6 Day 
365]. 
See detailed description in Section 7 and Section 8. 
4.2. Description of the study design, design flow chart, description of the 
study procedures and stages 
4.2.1. Description of the study design 
International, multicenter, phase 2a, double-blind, randomized, placebo-controlled clinical study 
comparing single administration of RPH-104 80 mg, RPH-104 160 mg and placebo (1:1:1) in 
subjects with STEMI at the study sites of the RF and USA. 
After the signing informed consent form (ICF), the investigator will assess the subject's eligibility 
for the study. The following procedures will be performed during the screening: collection of 
medical history, recording previous and concomitant therapy, demographic data, recording 12-
lead electrocardiography (ECG) findings on which STEMI diagnosis was based, recording date 
and time of STEMI symptom development, recording date, time and results of CAG at admission 
to the study site, measurement of blood neutrophil count, vital signs assessment, physical 
examination (including weight measurement if a functional bed is available), blood collection for 
hematology, biochemistry, determination of concentration of hsCRP and brain natriuretic peptide 
(BNP; NT-pro-BNP), for females with retained reproductive potential – pregnancy test (test 
strips).  
During the first 10 weeks, not more than 3 patients per week will be included in the study. 
The subjects meeting selection will be randomized to one of the three groups for single 
subcutaneous administration of RPH-104 80 mg, RPH-104 160 mg or placebo. 
Therefore, screening, randomization and administration of the study products will be made on the 
same (first) study day.  
Further 4-week (28-day) clinical follow-up and additional 6- and 12-month clinical follow-up 
period will be performed.  
The end of clinical part of the study will be the date of the last visit of the last subject within 
additional 12-month clinical follow-up.  
An overview of the study design is provided in Figure 1. 


 
 
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Figure 1. Study design flow chart 
4.2.2. Discussion of the study design including selection of control groups 
The design chosen was multicenter, double blind, randomized, placebo-controlled clinical study 
comparing single administration of RPH-104 80 mg, RPH-104 160 mg and placebo (1:1:1) in 
subjects with acute STEMI.  
Randomized, double-blind, controlled studies are currently a golden standard of the clinical study 
design as they minimize risk of bias upon distribution to treatment groups and outcome evaluation.  
Selection of two doses of test product and placebo as a reference product will allow to obtain 
reliable data concerning safety and efficacy of lower and higher doses of the product compared to 
placebo.  
Selection of a surrogate endpoint - area under concentration - time curve (AUC) for hsCRP from 
Day 1 (baseline) till Day 14 – as a primary efficacy criterion is determined by necessity to confirm 
the study concept that administration of RPH-104 reduces concentration of hsCRP, a surrogate 
marker of IL-1 activity and predictor of adverse cardiovascular outcomes (Ridker P. et al., 2005; 
Scirica B.M., 2009; Abbate A. et al., 2010; Abbate A., 2013; Ridker P.M. et al., 2017; 
Vanhaverbeke M. et al., 2018; Ridker P.M. et al., 2018; Van Tassell B.W. et al., 2018).  
At that, direct cardiovascular and other clinical outcomes were chosen as secondary endpoints in 
accordance with international definitions of cardiovascular outcomes for clinical studies 
(Hicks K.A.et al., 2018) allowing to evaluate direct product effects on the disease outcomes.  
In addition, structural and functional cardiac parameters (based on the Echo-CG findings) allowing 
to consider remodelling and concentration of brain natriuretic peptide (BNP, NT-pro-BNP), a 
surrogate marker of HF will be evaluated.  
Therefore the selected study design and endpoints will suggest reasonability of RPH-104 
administration in subjects with acute STEMI and further development of the product for this 
indication based on the study results.  
4.3. The scheduled duration of participation in the study, description of 
sequence and duration of all study stages including follow-up period 
Study duration shall be determined for each subject by duration of each study period. Scheduled 
study duration for each subject will be no more than 12 months. 
RPH-104 
80 мг
(n=34)
наблюдение
RPH-104 
160 мг
(n=34)
наблюдение
Плацебо 
(n=34)
наблюдение
ИМпST 
(n=102) 
День 1 
месяц 12 
follow-up 
follow-up 
follow-up 
Day 1 
month 12 
Placebo 
(n=34) 
RPH-104 
80 mg 
(n=34) 
RPH-104 
160 mg 
(n=34) 
STEMI 
(n=102) 


 
 
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4.3.1. Screening 
The screening will be made on Day 1. The screening is intended to obtain written informed consent 
of the subject to participate in the study and examine the subject's eligibility for the study. Informed 
consent will only be obtained after full explanation of the study essence and procedures to each 
subject and before any of the procedures or assessments are performed. Obtaining informed 
consent is detailed in Section 11.4.  
The subjects should have diagnosis of acute STEMI defined as chest pain or its equivalent with 
ECG findings evidencing ST elevation (>1 mm) in two or more consecutive leads or acute LBBB 
according the investigator's judgement. At that, the time from the symptom debut until PCI with 
stenting should be no more than 12 hours after debut of chest pain or its equivalent, and 
randomization should be conducted within 12 hours after the PCI (i.e. the period of time from the 
onset of chest pain to the randomization should be not more than 24 hours).  
4.3.2. Treatment period 
The day of treatment initiation will coincide with the day of screening, treatment period will 
include single administration of the study products.  
4.3.3. Follow-up periods 
Follow-up period after administration of the study products will last for 4 weeks and will include 
follow-up after administration of the study product (Day 1), Visit 2 (Day 3), Visit 3 (Day 14±3) 
and Visit 4 (Day 28±3). The following will be performed during this period: the subject's condition 
monitoring, laboratory and instrumental examination.  
Additional clinical follow-up will last for 12 months after the study product administration and 
will include Visit 5 (Month 6±2 weeks) and Visit 6 (Month 12±2 weeks). During this period, the 
subject's condition will be monitored and laboratory and instrumental examination will be 
performed.  
If the patient's visit to the study site is administratively limited due to the current epidemiological 
situation associated with the SARS-CoV-2 coronavirus, the procedures of Visit 3 (Day 14±3) and 
Visit 4 (Day 28±3) can be carried out at the patient's home, if the patient agrees, by authorized 
employees of the study site team. At the same time, if possible, all efficacy and safety assessment 
procedures planned for a particular visit are carried out. The conduct of visits outside the study 
site must be agreed with the Sponsor and the patient in each case, which must be documented. 
4.3.4. Description of visits 
Periodicity of the procedures and assessments is also provided in Schedule of visits and procedures 
(see Table 1).  
4.3.4.1. 
Visit 1 (Day 1) 
Visit 1 (Day 1) includes screening, randomization and administration of the study products.  
Before any study-related procedures are performed, the study nature and study-related potential 
risks should be explained to all study subjects and they should provide their informed consent. 
After informed consent is obtained, the following procedures will be carried out:  
 collection of medical history; 
 recording previous and concomitant therapy; 
 collection of demographic data; 
 recording 12-lead ECG results on which STEMI diagnosis was based 


 
 
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 recording CAG results; 
 evaluation of vital signs (BP, HR, RR, body temperature); 
 physical examination; 
 body weight measurement (using hospital bed, if available); 
 determination of absolute neutrophil count (in local laboratory); 
 urine pregnancy test for females with childbearing potential (test strips); 
 blood collection for hematology and blood chemistry, determination of hsCRP, BNP and 
NT-pro-BNP; 
 Echo-CG (this procedure is permitted to be done within 24 hours from the moment of 
randomization); 
 evaluation of inclusion/exclusion criteria. 
After the above-mentioned procedures if the subject meets selection criteria, the following 
procedures will be carried out: 
 randomization; 
 administration of the study product (must be done within 3 hours after the randomization); 
 recording AE and SAE; 
 recording concomitant therapy.  
4.3.4.2. 
Visit 2 (Day 3) 
The following procedures will be carried out at the visit: 
 blood sampling for measuring hsCRP, BNP and NT-pro-BNP; 
 outcome registration; 
 evaluation of vital signs (BP, HR, RR, body temperature); 
 body weight measurement (for subjects who did not undergo measurement on Day 1); 
 physical examination; 
 recording AE and SAE; 
 recording concomitant therapy.  
For patients discharged on Day 2, the procedures of the Day 3 visit can be carried out ahead of 
schedule (on Day 2). 
4.3.4.3. 
Visit 3 (Day 14±3) 
The following procedures will be carried out at the visit: 
 blood sampling for hematology and biochemistry, for measuring hsCRP, BNP and NT-
pro-BNP; 
 outcome registration; 
 evaluation of vital signs (BP, HR, RR, body temperature); 
 body weight measurement; 
 height registration (it is permissible to record any value obtained during the hospitalization, 
when it was possible to measure the patient's height); 
 physical examination; 
 recording AE and SAE; 
 recording concomitant therapy.  
4.3.4.4. 
Visit 4 (Day 28±3) 
The following procedures will be carried out at the visit: 


 
 
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 blood collection for hematology and biochemistry, determination of hsCRP, BNP and NT-
pro-BNP; 
 outcome registration; 
 evaluation of vital signs (BP, HR, RR, body temperature); 
 physical examination; 
 body weight measurement; 
 Echo-CG; 
 recording AE and SAE; 
 recording concomitant therapy.  
4.3.4.5. 
Visit 5 (Month 6±2 weeks) 
The visit may be made by phone. The following procedures will be performed at the visit: 
 outcome registration;  
 recording AE and SAE; 
 recording concomitant therapy.  
4.3.4.6. 
Visit 6 (Month 12±2 weeks) 
The following procedures will be performed at the visit:  
 blood sampling for measuring BNP and NT-pro-BNP; 
 outcome registration;  
 evaluation of vital signs (BP, HR, RR, body temperature); 
 physical examination; 
 body weight measurement; 
 Echo-CG; 
 recording AE and SAE; 
 recording concomitant therapy.  
By the end of all visit procedures, the study will be considered as completed for the subject. 
4.3.4.7. 
Unscheduled visits 
The subjects may consult Investigator and make an unscheduled visit at any time in case they have 
adverse events or if, according to investigators, their condition requires medical intervention. 
Investigator shall record the data into source medical documentation and the electronic Case 
Report Form (eCRF) (Unscheduled visit page). The following information should be added on an 
obligatory basis: visit date, visit reason, examination findings and data of additional investigations. 
If an AE was the reason of the visit or if an AE was revealed at unscheduled visit, recording of 
such AE shall be made using regular scheme (see Section 8). 
After an unscheduled visit, the next visit shall be made according to the pre-established plan per 
Protocol. 
4.3.4.8. 
Early withdrawal visits 
In case of early withdrawal at the follow-up period post dosing (Visit 1 Day 1 – Visit 4 Day 28), 
an early withdrawal visit is advised including Visit 4 (Day 28±3) procedures: 
 blood collection for hematology and biochemistry, determination of hsCRP, BNP and NT-
pro-BNP; 
 outcome registration; 


 
 
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 evaluation of vital signs (BP, HR, RR, body temperature); 
 physical examination; 
 body weight measurement; 
 Echo-CG; 
 recording AE and SAE; 
 recording concomitant therapy.  
In case of early withdrawal during additional clinical follow-up period (Day 29 – Visit 6 
Month 12), an early withdrawal visit is advised including Visit 6 (Month 12±2 weeks) procedures: 
 blood sampling for measuring BNP and NT-pro-BNP; 
 outcome registration;  
 evaluation of vital signs (BP, HR, RR, body temperature); 
 physical examination; 
 body weight measurement; 
 Echo-CG; 
 recording AE and SAE; 
 recording concomitant therapy.  
4.4. Description of procedures and assessments 
Periodicity of the procedures and assessments is also provided in Schedule of visits and procedures 
(see Table 1).  
4.4.1. Demographic and other baseline assessments 
At the screening (Day 1, baseline), the following data will be recorded: 
 date of birth; 
 sex; 
 race. 
4.4.2. Past medical history 
At the screening (Day 1, baseline), the data on previous and concomitant diseases, surgeries and 
injuries will be collected. The following data will be recorded for female subjects: contraception 
method, menopause terms (if applicable) or causes for which she is considered infertile (see also 
Section 6.2.1.2.). The resulting data will be recorded in source medical documentation and in 
eCRF in section "Previous Diseases" and "Comorbidities".  
4.4.3. Information on the underlying disease 
At the screening (Day 1, baseline), the following data will be recorded: 
 date and time of manifestations of ST-segment elevation myocardial infarction with which 
the patient is included in the study; 
 results of 12-lead ECG based on which STEMI diagnosis was made (specifying the leads 
with elevated ST and extent of elevation in mm); 
 date and time of CAG (specifying relevant findings based on its results), the fact of 
performing a PCI with stenting;  
 history of MI (specifying the date) if any; 
 diagnosis of chronic HF (specifying the date of diagnosis) if any. 
The data obtained will be recorded in source medical documentation and eCRF. 


 
 
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4.4.4. Pregnancy test 
Urine pregnancy test will be performed by female subjects with retained childbearing potential at 
the screening (Day 1, baseline) using test strips. The data obtained will be recorded in source 
medical documentation and eCRF.  
4.4.5. Efficacy assessment procedures 
Efficacy assessment procedures will include: 
 determination of hsCRP concentration; 
 determination of concentration of HF biomarkers (BNP and NT-pro-BNP); 
 echo-CG; 
 outcome registration. 
Description of procedures is provided in Section 7.2. 
4.4.6. Safety cohort 
Safety assessment procedures will include: 
 evaluation of vital signs (BP, HR, RR and body temperature), 
 physical examination (with obligatory assessment of injection site); 
 hematology; 
 biochemistry; 
 AE/SAE recording. 
Description of procedures is provided in Section 8.2.1. 
4.5. Subjectivity minimization measures 
4.5.1. Randomization 
The subjects will be randomized in 1:1:1 ratio without stratification into one of treatment groups 
- RPH-104 80 mg, RPH-104 160 mg or placebo based on randomization scheme prepared using 
the relevant software by the responsible study statistician. Distribution will be made using block, 
non-adaptive, centralized randomization using Interactive Web Response System (IWRS).  
At Visit 1 after eligibility of the patient is confirmed by the authorized blinded investigator, the 
unblinded investigator will perform randomization using the IWRS and obtain information about 
the patient's randomization number and assigned therapy group.  
Detailed information on IWRS system will be presented in an individual IWRS manual kept in 
Trial Master File (TMF) and in each Investigator Site File (ISF). 
The unblinded researcher will keep a register linking the screening and randomization numbers of 
study participants and therapy groups. Access to these registers for blinded employees will be 
limited. 
Study participant randomization number may not be changed during the study. Distribution of the 
subject to a treatment group may not be changed during the study.  
If the subject decides to refuse to participate or withdraw from the study for any reason, his/her 
randomization number may not be re-used.  
Randomization scheme and identification of each subject will be added to the study report. 


 
 
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4.5.2. Blinding 
The study will be double-blind, i.e. neither the physician (investigator) performing examination 
and follow-up, nor the subject will be aware of the treatment group to which the subject has been 
assigned and of the product administered. To assure double blind design, unblinded investigator's 
team and unblinded monitor will be involved. Detailed description of operational peculiarities will 
be presented in an individual Guidelines on medicinal product handling.  
Given that administration of RPH-104 at 160 mg is only possible by two 80 mg injections (2 mL) 
at different sites and appearance of the finished forms of test product and placebo may differ, the 
following dosing regimen will be used to assure double blind design:  
 in RPH-104 80 mg group, the subjects will receive 2 mL (80 mg) of RPH-104 and 2 mL 
of placebo on different administration sites; 
 in RPH-104 160 mg group, the subjects will receive 2 mL (80 mg) of RPH-104 and 2 mL 
of (80 mg) of RPH-104 on different administration sites; 
 in placebo group, the subjects will receive 2 mL of placebo and 2 mL of placebo on 
different administration sites.  
Unblinded investigators will be aware of the treatment group from IWRS and perform 
administration of the study products. 
Additional conditions limiting the subject's visual control will be enforced upon the study product 
administration. 
Monitoring of this process on Sponsor's behalf will be made by unblinded monitor.  
4.6. Storage of randomization/identification codes and their unblinding 
The investigator should ensure confidentiality of the subjects. CRFs and other documents should 
only identify the subjects by their identification codes rather than by their names or surnames. In 
this study, the screening number is the patient’s identification code. The screening number is 
assigned by the IWRS system after the patient has signed the ICF. 
The blinded investigator must enter the patient’s screening number in the source documentation 
and keep a separate screening and randomization log. The patient’s screening number cannot be 
changed during the study. 
The investigator should keep a special identification log/list of numbers, surnames, addresses and 
phones and numbers of medical documentation (if available).  
Unblinding of the identification code of the subject is only possible with his consent verified in 
writing and/or for the sake of his life and health. 
Until the end of the study, randomization plan will be kept by the responsible study statistician. 
Unblinded staff of the center should ensure that a clinical study participant receives the therapy 
matching the therapy group assigned by the IWRS system. 
Unblinding randomization codes and treatment groups may be performed as agreed with Sponsor 
in case of urgency and/or SAEs. Treatment group unblinding will be performed by the unblinded 
investigator using the IWRS and the subject’s identification number, according to the procedure 
described in an individual IWRS guideline.  
4.7. List of data recorded directly in CRF 
Electronic case report form (eCRF) shall be filled for each subject participating in the study 
including basic study-related data. 


 
 
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All the information added to eCRF should comply with the one in source documents (medical 
treatment record, clinical record, laboratory test reports, Protocols and extracts from other 
examinations). 
No data to be entered in eCRF without reflecting the same information in source documentation 
will be stipulated by the current study. All study-related data will be first recorded in source 
documentation and then in eCRF. 
5. Selection and exclusion of the study subjects 
5.1. Inclusion criteria 
The subjects eligible for the study should meet all of the following criteria: 
1. Subjects of either gender aged from 18 years old inclusive. 
2. Subjects who gave voluntary written informed consent to participate in the study and 
to follow all Protocol procedures. 
3. STEMI diagnosis defined as chest pain or its equivalent with ECG findings evidencing 
ST elevation (>1 mm) in two or more consecutive leads or LBBB according the 
investigator's judgement. 
4. PCI with stenting was performed within no more than 12 hours after onset of chest pain 
or its equivalent and randomization was performed in no more than 12 hours after PCI 
(overall within 24 hours of onset of chest pain or equivalent). 
5. Consent of female subjects with childbearing potential defined as all female subjects 
with physiological potential to conceive, to use highly effective contraceptive methods 
throughout the study starting from screening (signing informed consent) and negative 
pregnancy test. 
Highly effective contraceptive methods include combination of two of the 
following methods (a+b or a+c or b+c): 
a) oral, injection or implanted hormonal contraceptives; in case of oral 
contraceptives, the female subjects should administer the same product for 
at least 3 months prior to the study therapy; 
b) intrauterine device or contraceptive system; 
c) barrier methods: condom or occlusive cap (diaphragm or cervical 
cap/vaginal fornix cap) with spermicidal foam/gel/film/cream/vaginal 
suppository. 
6. Ability and willingness of the subject, according to the reasonable investigator's 
judgment, to attend the study site at all scheduled visits, undergo the study procedures and 
follow the Protocol requirements including subcutaneous injections by qualified site 
personnel.  
5.2. Non-inclusion criteria 
The subjects meeting any of exclusion criteria should not be enrolled: 
1. Hypersensitivity to test product (RPH-104) and/or its ingredients/excipients.  
2. Pregnancy and breastfeeding. 
3. Verified chronic HF (AHA/ACC C-D class, NYHA FC III-IV).  
4. Pre-existing severe valvular heart disease according to the investigator’s assessment. 
5. Pre-existing LV dysfunction (EF<40%). 
6. History of STEMI. 


 
 
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7. Complications of acute MI in the form of acute left ventricular failure and cardiogenic 
shock defined as stable blood pressure decrease (SBP<90 mm Hg) associated with 
signs of hypoperfusion as well as cases when inotropic and/or mechanical support is 
required to maintain SBP; and/or unstable hemodynamics.  
8. Active infections (acute or chronic); active tuberculosis. 
9. Recent (less than 5 half-life periods) or current administration of colchicine, as well as 
agents with an immunosuppressant mechanism of action, including, but not limited to: 
glucocorticoids at doses of > 1 mg/kg of methylprednisolone equivalent, tumor necrosis 
factor-alfa (TNFα) blockers, IL-1 and other biological drugs, cyclosporine and other 
immunosuppressants. The use of non-steroidal anti-inflammatory drugs (NSAIDs) are 
allowed. 
10. Immunization with live vaccines within 90 days prior to the study product 
administration. 
11. Chronic systemic autoimmune or autoinflammatory diseases. 
12. Suspected necessity in cardiosurgery. 
13. Oncology (or diagnosis of oncology within the last 5 years). 
14. History of organ transplantation or necessity in transplantation at the screening 
initiation or scheduled transplantation during the study. 
15. Neutropenia (absolute neutrophil count <1800/mm3). 
16. Participation in another clinical study within the previous 3 months prior to Screening 
visit. 
17. Other medical (including mental) conditions or abnormal laboratory findings which 
may increase the risk for the subject associated with the study participation or 
administration of the study products or which may affect interpretation of the study 
results and, according to the investigator, render the subject ineligible for the study. * 
18. The subjects working at the study site or subjects working for Sponsor directly involved 
in this clinical study. 
*If, in the Investigator’s opinion, administration of a non-live COVID-19 (SARS-CoV-2) vaccine 
increases the risk for the patient related to his/her participation in the study, the Investigator can 
make a decision not to include this patient into the study. 
Presence of neutropenia for evaluation of exclusion criteria will be performed based on 
hematology performed at the study site local laboratory.  
5.3. Deviations from inclusion/exclusion criteria 
No deviations from the inclusion/exclusion criteria are permitted. The investigator can call the 
study’s medical monitor to discuss eligibility for any study participant. 
5.4. Study termination or suspension, early withdrawal criteria 
5.4.1. Study termination criteria.  
Sponsor and principal investigator will have the right to terminate or suspend the study at any time 
for the reasons including (but not limited to) safety issues, ethical issues or major Protocol 
violations, lack of achievement of the study purposes or for other reasons.  
Particularly, the study will be terminated early or suspended in the following cases: 
 at Sponsor's initiative; 
a) upon receipt of new toxicological or pharmacological data or data concerning SAEs 
requiring revision of earlier evaluation of risk-benefit ratio for participation in the 
study; 


 
 
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b) frequency of AEs and/or their severity do not allow to continue the study; 
c) other reasons including administrative ones; 
 at investigator's initiative: frequency of AEs and/or their severity unacceptably increases 
the risk for the study subjects. 
 at the decision of regulatory authorities.  
At that, Sponsor shall notify Investigator or management of medical facility on early 
discontinuation/suspension of the study in writing.  
If the study will be terminated/suspended for safety reasons, Sponsor shall immediately report this 
to the investigators as well as to regulatory authorities and ethics committees.  
Where the investigator terminates the study before its termination at the study site, he/she should 
notify Sponsor immediately and provide the reasons. 
Regulatory authorities or ethics committees will be entitled to terminate the study for the reasons 
including (but not limited to) safety issues according to the current local regulatory requirements. 
5.4.2. Early withdrawal criteria 
The subject may withdraw the study at any time before its termination (Visit 6). The investigator 
may also decide to withdraw a subject at his/her own discretion.  
The reasons for study withdrawal will be reflected in source medical documents and eCRF and 
may include the following: 
1. Recall of informed consent to participate in the study. 
2. Serious or intolerable AE requiring withdrawal from the study at the investigator's 
discretion. 
3. Investigator's decision that continuation of the study participation contradicts the subject's 
interests. 
4. Investigator's decision if the subject does not follow the study procedures and/or Protocol.  
5. Protocol deviation which, according to the investigator, requires early subject withdrawal 
from the study (e.g. necessity or performance of additional therapy forbidden by the 
Protocol). In this case, decision on the subject withdrawal will be agreed with Sponsor.  
6. Study termination by Sponsor. 
7. Study termination by regulatory authorities. 
8. Pregnancy of the subject. 
9. Death of the subject. 
5.4.3. The list of data by early withdrawn subjects and terms of their collection 
In case of early withdrawal, justification of such decision and its reason should be specified in 
source medical documents and eCRF.  
Where a subject recalls his/her informed consent, the investigator should try to learn the cause of 
such a decision. 
In case of early withdrawal at the follow-up period post dosing (Visit 1 Day 1 – Visit 4 Day 28) 
an early withdrawal visit is advised including Visit 4 procedures. 
In case of early withdrawal during additional clinical follow-up period (Day 29 – Visit 6 Month 12) 
an early withdrawal visit is advised including Visit 6 procedures. 
5.4.4. Replacement of withdrawn subjects and accounting of their data 
The subjects withdrawn will not be replaced.  


 
 
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The data of the subjects withdrawn before randomization will be taken into account in the study 
report in subject disposition analysis only. The data from the subjects withdrawn post 
randomization will be taken into account in the final analysis in the relevant set (see Section 9).  
5.4.5. Follow-up of withdrawn subjects 
Follow-up of the subjects withdrawn due to a SAE will be performed until its resolution or 
stabilization. 
The subjects withdrawn for other reasons will not be followed.  
6. Treatment of the study subjects 
6.1. Study products 
6.1.1. Description of the study products 
6.1.1.1. 
Test product 
Trade name: not assigned 
International nonproprietary name: goflikicept 
Product in-house code: RPH-104 
Dosage form: solution for subcutaneous injections 
Strength: 40 mg/mL 
Doses: 80 mg and 160 mg 
Dosing frequency: single 
Route of administration: subcutaneous  
Duration of treatment: single dose 
Composition:  
Component 
Content in 1 mL 
Relative content 
Active ingredient 
RPH-104 
40 (± 4) mg 
- 
Composition of buffer solution 
sucrose 
60 mg 
6% 
polyethylene glycol (PEG) 3350 
30 mg 
3% 
sodium chloride 
2.92 mg 
50 mmol/L 
L-histidine 
3.1 mg 
20 mmol/L 
рН 6.5 
 
 
Presentation: 4 mL transparent glass vials with rubber stopper, aluminum crimp cap and red lid. 1 
vial contains 2 mL of study product solution 40 mg/mL. 
Shelf life: 24 months. The expected maximum shelf life of the medicinal product is 3 years on the 
basis of the existing stability program.  
Storage conditions: Protected from light at +2 to +8ºС.  
Manufacturer: Branch of R-Pharm, JSC "Yaroslavl Plant of Finished Dosage Forms", 
Gromova St., 15, Yaroslavl, 150061 


 
 
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6.1.1.2. 
Placebo 
Trade name: not applicable 
International nonproprietary name: not applicable 
Dosage form: solution for subcutaneous injections 
Strength: not applicable 
Dosing frequency: single 
Route of administration: subcutaneous 
Duration of treatment: single dose 
Composition:  
Component 
Content in 1 mL 
Relative content 
Sodium chloride 
9 mg 
0.9% 
water for injection 
up to 1 mL 
99.1% 
Presentation: 4 mL transparent glass vials with a rubber stopper, aluminum crimp cap and red lid. 
1 vial contains 2 mL of 0.9% sodium chloride solution (manufactured by JSC "R-Pharm", Russia) 
/ plastic ampoules, 10 ml, 1 ampoule contains 10 ml of sodium chloride solution 10 ml 
(manufactured by the Hospira inc., USA). 
Shelf life: 3 years.  
Storage conditions: Protected from light at +2 to +8ºС (manufactured by JSC R-Farm Russia) / at 
temperatures from +20 to + 25 ° С (manufactured by Hospira inc., USA).  
Manufacturer: Branch of R-Pharm, JSC "Yaroslavl Plant of Finished Dosage Forms", 
Gromova St., 15, Yaroslavl, 150061 / Hospira incorparated, Lake Forest, USA. 
6.1.1.3. 
Packing and labelling 
Test product and placebo will be prepared and provided by Sponsor. Sponsor will provide the 
study sites with test product and placebo. Sponsor will be responsible for manufacturing, package 
and labelling of the products for the clinical study in accordance with the applicable local 
regulatory requirements.  
6.1.2. Study product dosing scheme in treatment groups 
To provide double blind study design, the study products will be administered as follows:  
 in RPH-104 80 mg group, the subjects will receive 2 mL (80 mg) of RPH-104 and 2 mL 
of placebo on different administration sites; 
 in RPH-104 160 mg group, the subjects will receive 2 mL (80 mg) of RPH-104 and 2 mL 
of (80 mg) of RPH-104 on different administration sites; 
 in placebo group, the subjects will receive 2 mL of placebo and 2 mL of placebo on 
different administration sites. 
6.1.3. Administration of the study product 
Preparation of the study products will be made by unblinded study site personnel.  
The study products will be administered by unblinded qualified study site personnel.  


 
 
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RPH-104/placebo will be administered subcutaneously at anterior abdominal wall at one of the 
areas shown in Figure 2. Each injection will be made to different sites with relevant records in 
eCRF. 
 
Figure 2. Anterior abdominal wall sites for the study product administration 
6.1.4. Treatment compliance 
Given that administration of the study products will be performed by the study site personnel, 
evaluation of dosing regimen compliance is not planned.  
6.1.5. Overdose management 
No cases of RPH-104 overdose have been reported. The treatment of overdose cases is 
symptomatic.  
6.2. Allowed and forbidden concomitant therapy 
6.2.1. Allowed concomitant therapy. 
6.2.1.1. 
General provisions 
If concomitant pathology is not an exclusion criterion, the treatment of concomitant pathology 
during the study should be carried out according to the regular scheme. At that, concomitant 
therapy should not be forbidden by the Protocol (see section 6.2.2). 
Concurrent/ongoing treatment with any cytochrome P450 substrate (see Table 3) with a narrow 
therapeutic index should be clinically monitored to ensure therapeutic effect is maintained; doses 
of the cytochrome P450 substrate may need to be adjusted as the enzyme may be normalized with 
co-administration with RPH-104.  
Table 3. Examples of drugs that are Р450 substrates 
 
Highly sensitive substrates 
Moderately sensitive substrates 
CYP1A2 
alosetron, caffeine, duloxetine, melatonin, 
ramelteon, tasimelteon, tizanidine 
clozapine, 
pirfenidone, 
ramosetron, 
theophylline 
CYP2B6 
bupropion1 
efavirenz 1 
CYP2C8 
repaglinide2 
montelukast, pioglitazone, rosiglitazone 
 
 
 


 
 
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Highly sensitive substrates 
Moderately sensitive substrates 
CYP2C9 
celecoxib3 
glimepiride, 
phenytoin, 
tolbutamide, 
warfarin 
CYP2C19 
S-mephenytoin, omeprazole 
diazepam, 
lansoprazole4, 
rabeprazole, 
voriconazole 
CYP2D6 
atomoxetine, 
desipramine, 
dextromethorphan, eliglustat5, nebivolol, 
nortriptyline, perphenazine, tolterodine, R-
venlafaxine 
encainide, 
imipramine, 
metoprolol, 
propafenone, 
propranolol, 
tramadol, 
trimipramine, S-venlafaxine 
CYP3A 
alfentanil, avanafil, buspirone, conivaptan, 
darifenacin, 
darunavir6, 
ebastine, 
everolimus, 
ibrutinib, 
lomitapide, 
lovastatin7, 
midazolam, 
naloxegol, 
nisoldipine, 
saquinavir6, 
simvastatin7, 
sirolimus, tacrolimus, tipranavir6, triazolam, 
vardenafil 
alprazolam, 
aprepitant, 
atorvastatin3, 
colchicine, eliglustat5, pimozide, rilpivirin, 
rivaroxaban, tadalafil 
budesonide, 
dasatinib, 
dronedarone, 
eletriptan, 
eplerenone, 
felodipine, 
indinavir6, 
lurasidone, 
maraviroc, 
quetiapine, sildenafil, ticagrelor, tolvaptan 
 
1 
Listed based on an in vivo induction study and the observed effect might be partly attributable to induction 
of other pathway(s). 
2 
OATP1B1 substrate. 
3 
Listed based on pharmacogenetic studies. 
4 
S-lansoprazole is a sensitive substrate in CYP2C19 extensive metabolizer subjects. 
5 
Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A. 
6 
Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. 
7 
Acid form is an OATP1B1 substrate. 
Abbreviations: CYP: cytochrome P450;OATP1B1: organic anion transporting polypeptide 1B1. 
Source: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers#table3-1; accessed 30 Dec 2019. 
Information on concomitant medicinal products (trade name, composition, dose or dose 
adjustment, indications, dosing frequency, method of administration, treatment initiation, 
treatment discontinuation) taken by the subject for 5 half-lives of the drug or 30 days (whichever 
is longer) prior to enrollment and during the study should be recorded in the relevant section of 
eCRF including screening visit. All subsequent changes in concomitant therapy during the study 
should also be reflected in eCRF. 
6.2.1.2. 
Contraception 
Throughout the clinical study female subjects with childbearing potential should use highly 
effective contraceptive methods including combination of two of the following methods (a+b or 
a+c or b+c): 
a) oral, injection or implanted hormonal contraceptives; in case of oral contraceptives, the 
female subjects should administer the same product for at least 3 months prior to the study 
therapy; 
b) intrauterine device or contraceptive system; 


 
 
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c) barrier methods: condom or occlusive cap (diaphragm or cervical cap/vaginal fornix cap) 
with spermicidal foam/gel/film/cream/vaginal suppository 
The study may enroll females not using highly effective methods of contraception if they are 
diagnosed as sterile for the following reasons:  
 history of hysterectomy, bilateral ovariectomy, bilateral tubal ligation;  
 menopause (physiological amenorrhea with lack of menses within at least 2 years); 
Prior to the study, female subjects of childbearing potential should be informed on the importance 
of contraception during the study and potential risk factors in case of unwanted pregnancy. 
Subjects should sign ICF specifying this information. Pregnancy test will be performed by female 
subjects with childbearing potential. 
6.2.2. Forbidden concomitant therapy 
During the study, the following medicinal products will be forbidden in the terms specified: 
 biological (except for RPH-104) including but not limited to: tocilizumab, rituximab, 
TNFα inhibitors [Visit 1 Day 1 - Visit 4 Day 28]; 
 immunosuppressants [Visit 1 Day 1 – Visit 4 Day 28] including but not limited to:  
o corticosteroids at doses of >1 mg/kg of methylprednisolone equivalent orally as 
well as systemic, except for intravenous (i.v.) ones for acute allergic reactions; 
o cyclosporine A, methotrexate etc.; 
 colchicine [Visit 1 Day 1 – Visit 4 Day 28]; 
 anakinra, canakinumab, rilonacept [Visit 1 Day 1 – Visit 6 Month 12]; 
 immunization with live vaccines within 90 days prior to or after the study product 
administration; 
 any experimental products.  
NSAIDs are not forbidden. 
6.2.3. Use of the medicinal products not allowed or not provided for by the Protocol 
If a life- or health-threatening situation took place during the study and the subject required 
additional therapy with forbidden medicinal products or the medicinal products not specified in 
the Protocol, such medicinal products may be prescribed in this case. However, Study Sponsor 
should be notified on the Protocol deviation within 24 hours. In this case, the subject who received 
forbidden medicinal products or medicinal products not specified in the Protocol may be excluded 
from the study.  
6.3. Accounting of the study products 
The products for the study will be provided by Sponsor to the study initiator with Acceptance act 
and certificate of analysis. The product delivery from Sponsor should be accepted and processed 
by a responsible person (Investigator or authorized person). All study product accounting and 
storage procedures will be made using specially appointed unblinded members of the investigator's 
team. The products will be stored until their dispensing in a dry, protected from light place: in the 
fridge (suitable for medicinal product storage) at temperature from +2 to +8°С for RPH-104 and 
placebo manufactured by JSC R-Pharm, and at a temperature from +20 to + 25 ° С - for placebo 
produced by Hospira inc., USA. The products will be stored in specially equipped limited access 
premises.  
The study organizer will provide the study products to the study site in the amount sufficient for 
the study. 


 
 
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Control, accounting and storage of the products in clinical center shall be made by the qualified 
person authorized by the principal investigator according to the internal regulations of the clinical 
center and Sponsor's instructions.  
Unblinded investigators should assure the product storage in safe conditions preventing from loss, 
theft and impaired environmental conditions (temperature) outlined in Guidelines on medicinal 
product handling and Investigator's Brochure.  
Administration of the study products will always be made at the study site by the appointed 
unblinded study team member.  
More detailed information on acceptance, storage, accounting and administration to the study 
subjects is provided in Guidelines on medicinal product handling for investigators.  
Study product accounting, storage and issue will also be monitored by unblinded monitor on behalf 
of Sponsor.  
6.4. Control of compliance 
Monitoring of compliance with all the study procedures will be made by the Principal Investigator.  
7. Efficacy evaluation 
7.1. List of efficacy parameters 
Primary endpoint 
1. hsCRP area under curve (AUC) from Day 1 (baseline) until Day 14 [Visit 1 Day 1 – Visit 
3 Day 14].  
Secondary endpoints 
1. hsCRP area under curve (AUC) from Day 1 baseline) until Day 28 [Visit 1 Day 1 – Visit 
4 Day 28]. 
2. BNP area under curve (AUC) from Day 1 (baseline) until Day 28 [Visit 1 Day 1 – Visit 4 
Day 28]. 
3. NT-pro-BNP area under curve (AUC) from Day 1 (baseline) until Day 28 [Visit 1 Day 1 – 
Visit 4 Day 28]. 
4. Incidence of fatal outcomes (cardiac and non-cardiac) during 12-month follow-up period 
[Visit 1 Day 1 – Visit 6 Day 365]. 
5. Incidence of hospitalizations due to HF or other cardiac reasons not associated with HF, or 
due to non-cardiac reasons during 12-month follow-up period [Visit 1 Day 1 – Visit 6 Day 
365]. 
6. Incidence of new cases of HF (defined as hospitalization due to HF or new onset of HF) 
during 12-month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 
7. Incidence of “fatal outcome (due to any reason) or hospitalization due to HF or new onset 
of HF” Frequency of fatal outcomes for any cause OR hospitalization for HF OR the 
development of HF in the outpatient settingsduring 12-month follow-up period [Visit 1 
Day 1 – Visit 6 Day 365]. 
8. Incidence of “fatal outcome (due to any reason) or hospitalization due to HF” during 12-
month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 


 
 
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9. 9. Changes in levels of BNP and NT-pro-BNP during 12-month follow-up period 
compared to baseline [Visit 1 Day 1 – Visit 6 Day 365]. 
10. Changes in structural and functional echocardiographic parameters after 12 months 
compared to baseline [Visit 1 Day 1 – Visit 6 Day 365]. 
Exploratory endpoints 
1. Changes in concomitant therapy [Visit 1 Day 1 – Visit 6 Day 365]. 
2. Interaction between STEMI outcomes and peculiarities of coronary bed lesion based on 
baseline CAG results [Visit 1 Day 1 – Visit 6 Day 365].  
7.2. Methods and terms of evaluation, reporting and analysis of efficacy 
parameters 
Periodicity of the procedures and assessments is also provided in Schedule of visits and procedures 
(see Table 1). 
Blood sampling to determine concentration of hsCRP and level of brain natriuretic peptide (BNP, 
NT-pro-BNP) will be made at Visit 1 Day 1 (at baseline), Visit 2 (Day 3), Visit 3 (Day 14±3) and 
Visit 4 (Day 28±3) of the study. In addition, blood sampling to determine level of brain natriuretic 
peptide (BNP, NT-pro-BNP) will be made at Visit 6 (Month 12±2 weeks) of the study. 
Concentration of hsCRP and level of brain natriuretic peptide (BNP, NT-pro-BNP) will be 
determined in central laboratory.  
Throughout the clinical study, the investigator will follow the subjects to evaluate and record 
cardiovascular and other outcomes (fatal outcomes, hospitalizations1, new HF) based on the 
current clinical recommendations and terminological criteria "2017 Cardiovascular and 
Stroke Endpoint Definitions for Clinical Trials" (Hicks K.A.et al., 2018) (see Attachment 1).  
Echo-CG will be carried out at Visit 1 (Day 1) (this procedure is permitted to be done within 24 
hours from the moment of randomization), Visit 4 (Day 28±3) and Visit 6 (Month 12±2 weeks) 
by qualified personnel of the study site using relevant diagnostic equipment. Measurements will 
be carried out in accordance with the internal document on the interpretation of echo-CG findings. 
Echo-CG parameters assessed during the study are described in detail in the Statistical Analysis 
Plan. Given than Echo-CG is an operator-dependent technique, assessment and recording echo-
CG results will be centralized.  
The following information will be collected upon dose change, dosing scheme modification or 
product discontinuation in concomitant therapy: date of change, description of change 
(discontinuation, dose escalation, dose reduction, switch to another product of another group), 
cause of changes (improved condition, aggravated condition, adverse events/adverse reactions 
associated with the study product).  
8. Safety evaluation 
8.1. List of safety parameters 
Safety endpoints: 
1. Incidence of AE/SAE during the study. 
2. Changes in physical examination (including body weight), vital signs during the study. 
                                            
1Hospitalization due to HF will also include cases of prolongation of current hospitalization for the treatment of ST 
segment elevation MI if HF has developed within 24 hours following hospital admission 


 
 
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8.2. Methods and terms of evaluation, registration and analysis of safety 
parameters 
8.2.1. General provisions 
Safety assessment will include monitoring all recording all AEs and SAEs according to MedDRA 
and Common Terminology Criteria for Adverse Events (CTCAE v.5.0.).  
The unblinded medical monitor will receive and evaluate all AE reports on a regular basis during 
the study. 
Monitoring will include physical examination including vital signs, hematology, serum chemistry 
as outlined in Schedule of visits and procedures (see Table 1).  
8.2.1.1. 
Physical examination 
Physical examination will be carried out at Visit 1 (Day 1), Visit 2 (Day 3), Visit 3 (Day 14±3), 
Visit 4 (Day 28±3) and Visit 6 (Month 12± 2 weeks) and will include the assessment of the 
following: general condition, injection site, condition of skin, musculoskeletal system, lymph 
nodes, thyroid gland, upper and lower respiratory tract, heart, vessels, abdominal organs, kidneys, 
psychoneurological status. Abnormal values reported at the screening visit will be recorded in 
eCRF section "Co-morbidities". At the following visits, "Adverse Events" section of eCRF will 
include only abnormal values/changes relative to screening physical examination values meeting 
AE definition.  
Weight measurement will be carried out at Visit 1 (Day 1) or Visit 2 (Day 3), Visit 3 (Day 14± 3), 
Visit 4 (Day 28±3) and Visit 6 (Month 12±2 weeks). Based on severity of the subject's condition, 
body weight will be measured in recumbent condition at Visit 1 Day 1 using hospital bed or, if not 
available, at Visit 2 (Day 3) in standing position using the relevant balance. At the remaining visits, 
measurement will be done in standing position using the relevant balance. 
Height measurement will be done in a standing position at Visit 3 (Day 14±3) or at any time during 
the hospitalization (it is permissible to record any value obtained during the hospitalization, when 
it is possible to measure the patient's height).  
Vital signs will be measured at Visit 1 (Day 1) or Visit 2 (Day 3), Visit 3 (Day 14±3), Visit 4 (Day 
28±3), Visit 6 (Month 12±2 weeks). Based on severity of the subject's condition, vital signs will 
be measured in recumbent position or sitting position after a 5-min rest. Systolic and diastolic BP 
will be measured on the same arm using the same device. HR will be measured on the apex of 
heart using phonendoscope. HR and RR will be measured for 1 min. Body temperature will be 
taken by the axillary route.  
8.2.1.2. 
Laboratory examination 
Hematology and biochemistry will be made at Visit 1 (Day 1) (baseline), at Visit 3 (Day 14±3) 
and Visit 4 (Day 28±3) in central laboratory. At Visit 1 determination of the absolute neutrophil 
count is performed in the local laboratory of the site to assess the inclusion/exclusion criteria. 
Hematology will include the following parameters: hemoglobin, erythrocyte count, leukocyte 
count, leukogram with obligatory measurement of absolute neutrophil count, platelet count. 
Biochemistry will include the following parameters: hepatic chemistry values (AST, ALT, GGT, 
AP, LDH, total bilirubin, direct bilirubin, indirect bilirubin), renal chemistry values (serum 
creatinine, serum urea/urea nitrogen [BUN]), serum electrolytes (sodium, potassium, chlorides), 
CPK, CPK-МВ.  


 
 
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Results of laboratory tests performed within 12 hours before randomization may be used for the 
study eligibility assessment. 
8.2.2. Adverse event determination 
An adverse event - AE - is any untoward medical event arising after administration of the study 
product regardless of causality. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
AEs include (but not limited to) the following: 
 Laboratory values outside normal range having clinical relevance.  
 Pre-existing findings at physical examination which aggravated compared to baseline and 
are considered clinically relevant.  
 Physical examination findings (including vital signs) considered clinically relevant.  
8.2.3. Adverse events of interest 
The following safety concerns have been identified as Adverse Events of Special Interest (AESIs) 
based on the safety data currently available for RPH-104 and IL-1 inhibitor biologics: 
 Infections (including serious infections), including tuberculosis and opportunistic 
infections 
 Confirmed cases of active tuberculosis should also be documented as SAEs; 
 Malignant neoplasms 
 The 
investigator 
will 
be 
asked 
to 
provide 
relevant 
medical 
information/documentation 
(i.e. 
the 
results 
of 
pathological/histological 
examination) for all cases of malignant neoplasms, regardless of their seriousness, 
as these cases are subject to entry into the safety database; 
 Increased blood lipids (i. e., hypercholesterolemia, increased blood cholesterol, increased 
blood triglycerides, hypertriglyceridemia, and increased LDL cholesterol); 
 Systemic reactions to drug administration and hypersensitivity reactions; 
 Neutropenia, thrombocytopenia, leukopenia; 
 Drug-induced liver injury, any liver enzyme increase; 
 Injection site reactions. 
All of the above events are subject to recording and analysis as AESIs. 
8.2.3.1. 
Emergency 
Given that in rare cases anaphylactic and anaphylactoid reactions are possible during the product 
administration, the study site should dispose of the relevant medicines and equipment for urgent 
medical assistance including antishock therapy. Development of such urgency and measures taken 
should be recorded on the relevant pages of eCRF.  


 
 
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8.2.4. Reporting about adverse events 
The investigator and study site personnel will be responsible for detection, relevant medical 
assistance, documentation and reporting of cases meeting AE and SAE definition. 
Information on AEs will be collected since signing ICF and until the study completion by the 
subject. SAEs will be recorded since signing ICF and for up to 30 days after the study product 
treatment discontinuation or until the last visit whichever is the latter. AEs recorded prior to the 
study product administration will be added to eCRF section "Medical history".  
The investigator should document all the AEs during the study in case histories and eCRFs.  
Adverse events will be recorded based on complaints reported by the subjects themselves, results 
of interviews between investigator and subject, results of physical examination and laboratory 
tests. The investigator should formulate his questions to the subject in the manner not provoking 
the subject to report unreliable information. 
AEs will be recorded in the relevant eCRF sections as well as in source medical documents of the 
subject.  
The following information should be specified when recording adverse events: 
 Subject identification number; 
 Nature of AE (preferably diagnosis rather than the list of symptoms); 
 Date of AE onset and resolution (and time if applicable); 
 Measures related to AE; 
 AE meeting SAE criteria; 
 AE severity; 
 AE meeting unexpected AE criteria; 
 Relationship between the AE and study product administration (according to the 
investigator); 
 Outcome of AE. 
8.2.5. Definition of a serious adverse event 
A serious adverse event - SAE - is defined as any untoward medical occurrence that:  
 Resulted in death; 
 Was life-threatening; 
 Resulted in permanent or pronounced incapacity or disability; 
 Required hospitalization or its prolongation; 
 Resulted in a birth defect/congenital abnormality in children of patients who had been 
treated with the drug. 
 Furthermore, serious adverse events include any event not meeting the criteria above 
though being a relevant medical event according to the investigator. 
Any other AEs not meeting these criteria will be rated as non-serious.  


 
 
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8.2.6. Serious adverse event reporting 
To assure safety of the subjects in case of any SAE development after signing ICF and until the 
end of the study, regardless of suspected causes of SAE or association with the study product, SAE 
should be reported to Sponsor within 24 hours after the investigator became aware of the SAE.  
If a subject has a SAE considered to be related to the study product, a report thereof should be 
submitted even in case the study has been terminated already.  
Filling serious adverse event report form 
SAEs should be reported by filling out the SAE page in the eCRF within 24 hours from the time 
the investigator finds out about the SAE. In the event that access to the eCRF is temporarily 
impossible, the center has the opportunity to report the SAE by sending a scan of the hard copy of 
the serious adverse event report by email to 
Safety@Rpharm.ru 
or by fax: 
+7 (495) 956-79-38 
The investigator must notify the Local Ethics Committee (LEC)/Institutional Review Board (IRB) 
on the SAE according to LEC/IRB standard operation procedures.  
8.2.7. Definition of unexpected adverse events 
An unexpected AE in its nature or severity is inconsistent with the ones outlined in the current 
Investigator's Brochure.  
Any other AEs are considered to be expected.  
8.2.8. Submission of reports on suspected unexpected adverse reactions (SUSAR) 
The study sponsor should notify regulatory authorities on all suspected unexpected serious adverse 
reactions (SUSARs)within the terms specified by laws. In context of notification of regulatory 
authorities and investigators, the SUSARs will mean unexpected SAEs considered by the 
investigator and/or Sponsor as related to the study product.  
8.2.9. Adverse event severity assessment 
AE severity will be evaluated according to CTCAE v5.0 classification. If an AE is lacking in 
CTCAE classification, it will be classified based on the following grading:  
Grade 0:  
No AE 
Grade 1:  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living.2 
                                            
2 Limitation of age-appropriate self-care includes cooking, purchasing goods and clothes, using phone, money 
management, etc. 


 
 
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Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living.3  
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE.  
Severe AE is not necessarily serious by nature and SAE is not necessarily severe by definition.  
8.2.10. Adverse event outcome evaluation 
AE outcome will be determined as follows:  
Fatal: 
The subject died due to AE (death is an outcome, not an AE) 
Recovering/Resolving 
Reduced intensity of AE 
Not Recovered/ Not Resolved 
(Continuing) 
AE did not resolve, intensity unchanged 
Recovered/Resolved 
with 
Sequelae 
AE resolved but with a permanent defect.  
Recovered/Resolved 
AE resolved completely without sequelae 
Unknown: 
AE outcome is unknown as the subject did not attend the 
follow-up visit and attempts to obtain the follow-up 
information were useless (loss to follow-up) 
8.2.11. Relationship between an adverse event and study drugs 
The investigator will be responsible to assess causality between the AE and study product 
administration (related/unrelated). The investigator should use his knowledge on the subject, 
circumstances of the event and evaluation of any potential alternative causes to determine whether 
the AE is related to the study product or not. One of the following options should be chosen for 
relationship between AE and the study product: "related" or "unrelated". The following 
recommendations should be taken into account: 
 relationship between AE development and initiation of the study product 
administration; 
 AE changes over time after discontinuation of the study product; 
 known relationship between the study product or similar treatments; 
 risk factors increasing the risk of AE; 
 any non-treatment-related factors associated with the event frequency. 
The investigator should report relationship of every event with the study product based on the most 
probable relationship assessment, at that the study site personnel will be responsible to obtain any 
lacking data.  
                                            
3Limitation of self-care includes bathing, dressing and undressing, using the toilet, taking medications, but not 
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If relationship assessment changes over time due to new or modified information, it may be 
revised.  
8.2.12. Follow-up of adverse events 
All AEs should be monitored until their resolution or stabilization. 
8.2.13. Pregnancy 
Pregnancy per se is not an AE except for the cases when it is reasonable to suppose that 
administration of the study product reduced efficacy of contraceptive methods. Congenital 
abnormalities or birth defects in children of study subjects are considered to be SAEs. Elective 
abortions, abortions for medical reasons, with sequelae as well as any serious pregnancy 
complications (including spontaneous abortions) should be recorded as SAEs. Planned abortions 
without sequelae are not AEs. 
All pregnancy cases reported during the study (including pregnancies of female partners of the 
study subjects) should be duly recorded. Where pregnancy is confirmed, the investigator should 
notify Sponsor pharmacovigilance officer by submitting a pregnancy report. Pregnancy report 
should be filled by authorized employee of the study site within 24 hours after obtaining pregnancy 
information. A pregnancy should be reported by filling out the “Pregnancy” page in the eCRF 
within 24 hours by an authorized study site employee from the time the information about 
pregnancy becomes available. If access to the eCRF is temporarily impossible, the center has the 
opportunity to report the pregnancy by sending a scan of the hard copy of the Pregnancy Report 
Form by email to: 
Safety@Rpharm.ru 
or by fax: 
+7 (495) 956-79-38 
Further Sponsor should be provided with the information on the pregnancy outcome. Pregnancy 
of the study subjects and partners of male study subjects will be recorded since the study product 
administration until the last study-related procedure. 
Outcome of each pregnancy (spontaneous abortion, elective abortion or for medical reasons, 
normal delivery or delivery of a child with congenital abnormalities or birth defects) should be 
recorded even if the study subject withdrew from the study. Infant's health status should be 
monitored where possible until 6 weeks, 6 months and 1 year old.  
8.2.14. Other safety reports 
Investigators will submit to LEC/IRB reports on other treatment safety aspects subject to 
immediate notification if they affect risk-benefit ratio, related to the treatment or may require 
relevant changes in the treatment within the study or study methodology.  
In addition to urgent reports, Sponsor will annually prepare safety update reports on RPH-104 
containing all the new relevant safety information obtained during the reporting interval. Summary 
of these reports will be sent to the investigators for submission to LEC/IRB of medical institutions 
on an annual basis.  


 
 
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9. Statistics 
9.1. General provisions 
Detailed description of statistical data analysis including last observation carried forward will be 
presented in statistical analysis plan (SAP). SAP development will be finalized until the study 
database lock. Any deviations from analysis planned in SAP should be justified in the clinical 
study report.  
Any data will be generalized using descriptive statistics: number of the subjects, mean value, 
minimum and maximum, median and quartiles for continuous variables, frequency of observations 
with percentages - for qualitative variables.  
9.2. Selection of data for the analysis 
Statistical analysis will be conducted in the following study sets: 
Full analysis set (FAS) for the efficacy analysis 
Full analysis set (FAS) for efficacy analysis will include all randomized subjects who received the 
study products and underwent at least one hsCRP measurement after administration of the study 
products. This set is the main population for efficacy assessment. 
Per Protocol Set (PPS) 
ProtocolAll FAS subjects without important Protocol deviations affecting assessment of the 
primary efficacy parameter. Such Protocol deviations will be defined before breaking the blind in 
a blinded data review. This set is supplementary population for efficacy assessment. 
Safety set 
All randomized patients who have received the study drugs. 
9.3. Statistical methods  
9.3.1. Subjects disposition 
The study report will contain the number of subjects enrolled (signed the ICF), the number of 
subjects randomized, the number and proportion of the subjects who completed the study per 
Protocol, the number and proportion of the subjects who withdrew early after randomization 
specifying the reasons. The number of screening failures will also be added specifying the reasons.  
9.3.2. Demographic and other baseline characteristics 
Demographic and other baseline characteristics including age, gender, race, anthropometric 
characteristics, medical history (time from STEMI debut) and other ones will be presented 
descriptively by treatment groups for FAS population. All data concerning demographic and other 
baseline characteristics will also be presented as lists. Analysis of group comparability by 
demographic and other baseline characteristics will be done.  
9.3.3. Efficacy analysis 
9.3.3.1. 
Analysis of primary endpoint 
Primary endpoint is hsCRP area under curve (AUC) from Day 1 (baseline) until Day 14 [Visit 1 
Day 1 – Visit 3 Day 14]. 


 
 
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The following hypotheses will be tested for each RPH-104 dose level: 
Null hypothesis H0: difference between mean AUC1-14 days CRP in RPH-104 group and 
mean AUC1-14 days CRP in placebo group is equal to 0.  
Two-sided alternative hypothesis H1: difference between mean AUC1-14 days CRP in RPH-
104 group and mean AUC1-14 days CRP in placebo group is different from 0.  
Individual AUC1-14 days CRP values will be calculated using trapezoidal method. Mean AUC1-14 days 
CRP value will be compared between RPH-104 and placebo groups using analysis of variance 
ANOVA. Mean AUC values for RPH-104 80 mg, RPH-104 160 mg and placebo groups, 
differences in mean values and relevant two-sided 95% confidence intervals (CI) and well as р-
values will be presented.  
All hsCRP concentration values by study visits will also be presented as lists. 
9.3.3.2. 
Analysis of secondary endpoints 
 hsCRP area under curve (AUC) from Day 1 (baseline) until Day 28 [Visit 1 Day 1 – Visit 4 
Day 28]. 
 BNP area under curve (AUC) from Day 1 (baseline) until Day 28 [Visit 1 Day 1 – Visit 4 
Day 28]. 
 NT-pro-BNP area under curve (AUC) from Day 1 (baseline) until Day 28 [Visit 1 Day 1 – 
Visit 4 Day 28]. 
Analysis will be done similar to the analysis of the primary endpoint described above.  
 Incidence of fatal outcomes (cardiac and non-cardiac) during 12-month follow-up period 
[Visit 1 Day 1 – Visit 6 Day 365]. 
 Incidence of hospitalizations due to HF or other cardiac reasons not associated with HF, or 
due to non-cardiac reasons during 12-month follow-up period [Visit 1 Day 1 – Visit 6 Day 
365]. 
 Incidence of new cases of HF (defined as hospitalization due to HF or new onset of HF) 
during 12-month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 
 Incidence of “fatal outcome (due to any reason) or hospitalization due to HF or new onset 
of HF” during 12-month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 
 Incidence of “fatal outcome (due to any reason) or hospitalization due to HF” during 12-
month follow-up period [Visit 1 Day 1 – Visit 6 Day 365]. 
The number and proportions of subjects (of the number of FAS subjects and valid %) with fatal 
outcomes, subjects with hospitalizations and subjects with new cases of HF will be presented by 
treatment groups. Intergroup comparisons will be performed using exact Fisher's test.  
 Changes in levels of brain natriuretic peptide (BNP, NT-pro-BNP) during 12-month 
follow-up period compared to baseline [Visit 1 Day 1 – Visit 6 Day 365]. 
Changes in BNP, NT-pro-BNP levels will be presented by descriptive statistics by the study visits 
and treatment groups. Changes relative to baseline will be calculated for each visit.  
Comparison of changes between the treatment groups after the treatment initiation, as well as the 
comparison of mean changes in BNP, NT-pro-BNP levels by Visits will be performed using a 
basic linear mixed model with the inclusion of the baseline as a covariate and the therapy group as 
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- 
Changes in structural and functional echocardiographic parameters after 12 months from 
the baseline [Visit 1 Day 1 - Visit 6 Day 365]. 
The parameters will be analyzed similar to the analysis of changes in brain natriuretic peptide level 
described above. 
In case of significant deviations from the normal data distribution, data transformation 
(logarithmic or other) can be used. In case of using transformations, the relevant descriptive 
statistics will also include a geometric mean value. 
9.3.3.3. 
Analysis of exploratory endpoints 
- 
Changes in concomitant therapy [Visit 1 Day 1 – Visit 6 Day 365]. 
Number and proportion of subjects (of the number of FAS-subjects and valid %) with changes in 
the prescribed concomitant therapy with their causes will be presented by treatment groups.  
- 
Interaction between STEMI outcomes and peculiarities of coronary bed lesion based on 
baseline CAG results [Visit 1 Day 1 – Visit 6 Day 365]. 
Detailed description of assessment methods will be presented in the SAP.  
9.3.4. Safety analysis 
Safety analysis will be carried out on safety set.  
Scope of application will be presented specifying the following variables: the number of subjects 
receiving RPH-104 80 mg, the number of subjects receiving RPH-104 160 mg and the number of 
subjects receiving placebo.  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). The number 
and percentage of the subjects with AE/SAE, overall number and percentage of recorded AE/SAE, 
the number and percentage of AE/SAE resulting in early withdrawal will be presented by system 
organ class, preferred terms and treatment groups. The data will also be generalized by the number 
and percentage of AEs/SAEs with various categories of causality, expectedness and severity. All 
AEs will be additionally presented as listings. 
Quantitative safety laboratory parameters will be presented using descriptive statistics by visits 
and treatment groups. Changes relative to baseline and abnormal laboratory values will also be 
provided. The data on the number of subjects with abnormal laboratory values will be generalized 
for the whole study period, by visits and treatment groups. All laboratory findings will be presented 
as lists.  
Vital signs will be presented using descriptive statistics by visits and treatment groups. Changes 
relative to baseline will also be presented.  
9.4. Sample size justification 
Rationale for sample size will be based on testing the hypothesis of statistical superiority to 
compare hsCRP area under curve AUC between day 1 and day 14 (primary endpoint) between 
each RPH-104 group and placebo. Given exploratory nature of the study, adjustment of α-level 
due to multiple comparisons (two RPH-104 doses and placebo) will not be used.  
Assuming that the expected mean hsCRP AUC will be 350±250 mg/L for the subjects with STEMI 
in placebo group (according to the pilot study (Van Tassell B.W. et al., 2018) and standardized 
effect size (d Cohan) 0.80 for the lowest dose (conservative estimate based on (Van Tassell B.W. 
et al., 2018), 34 randomized subjects in each treatment group (1:1:1) (102 randomized subjects in 
total) will assure the study power > 90% (2-sided level α = 0.05) for comparison of lower dose 


 
 
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with placebo and study power > 95% to detect the expected further hsCRP AUC 50% reduction 
by 50% and increased effect of the higher RPH-104 dose compared to placebo.  
Given proportion of withdrawals and/or 20% statistical analysis (conservative estimate), the study 
power > 80% will be maintained for all comparisons.  
Given potential screening failures of up to 30%, the study will enroll not more than 146 subjects.  
9.5. Applied level of significance 
Probability of type I error (two-sided level of significance) is established at 5% level for all 
comparisons. Due to exploratory nature of the study, adjustments for multiple comparisons are not 
planned.  
9.6. Reporting deviations from the initial analysis plan 
Deviations from the planned statistical analysis will be agreed with Sponsor and reflected in the 
study report. 
9.7. Interim analysis 
After the last subject completes 28-day follow-up period, an interim analysis of hsCRP, BNP and 
NT-pro-BNP will be performed after 14 and 28 days of the study. Based on this analysis, decision 
on the study termination will not be taken. The analysis results may be used to define the strategy 
for further RPH-104 development.  
Population for performing an interim analysis – Full Analysis Set. 
During the interim analysis the primary efficacy analysis will be performed (see section 9.3.3.1). 
This analysis will be performed only once and will not be repeated during the final analysis stage. 
Sensitivity analysis can’t be done during the interim stage and will be performed during the final 
analysis stage. 
Secondary efficacy variables (AUC from day 1 to day 28) will be derived and analysed for 
parameters hsCRP, BNP and NT-pro-BNP at the interim analysis stage (see section 9.3.3.2). This 
analysis will be performed only once and will not be repeated during the final analysis stage. 
Values at visits (Day 1 – baseline, Days 3, 14 and 28) and changes from baseline (Days 3, 14 and 
28) will be described for hsCRP, BNP and NT-pro-BNP parameters using descriptive statistics 
upported with graphics. 
All individual subject’s data will be kept blinded for the Sponsor and all other staff involved into 
the data review except unblinded statistician. 
9.8. Independent study clinical outcome assessment committee 
An independent study outcome assessment committee (ISOAC) will be arranged to assure 
reliability and quality of data on assessment of cardiovascular and other Protocol-defined 
outcomes as efficacy parameters. The committee will include three independent cardiologists with 
the relevant qualification for outcome classification according to terminology criteria 2017 
Cardiovascular and Stroke Endpoint Definitions for Clinical Trials (Hicks K.A.et al., 2018) (see 
Attachment 1). Outcome classification will be blinded. ISOAC-defined outcome classification will 
be considered to be final for the purpose of the study result analysis. The committee shall convene 
in accordance with the approved work plan. The information on the composition, procedures and 
decisions of ISOAC will be included into the study report.  


 
 
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10. 
Quality control and quality assurance 
10.1. General quality assurance information 
Sponsor should establish relevant quality assurance and control system for the performance of this 
clinical study in accordance with the study Protocol, Good Clinical Practice and current regulations 
of the RF, EAEU and USA. 
The study procedures specified in the Protocol should be followed strictly by Investigator and 
investigator's team members. 
10.2. Quality assurance 
According to ICH GCP and regulatory requirements, Sponsor, third party on his behalf, regulatory 
authorities or Ethics committees may perform audits (inspections) to assure quality at any time 
throughout the study or after the study termination. The investigator should provide auditors with 
direct access to the study-related documents including source documents and allow his own and 
his personnel time to cooperate with the auditors when discussing audit and inspection results and 
other issues. 
10.3. Selection of the study sites 
Selection of the study sites will be approved by Sponsor prior to the study to assure availability of 
the necessary personnel and evaluation of feasibility of the study by this personnel according to 
Good Clinical Practice guidelines adopted at the International Conference on Harmonization (ICH 
GCP E6 in the current version), applicable regulations of the RF, EAEU and USA. 
10.4. Protocol compliance by the investigator 
Prior to the study, the investigator should be familiar with the Protocol conditions, accept them 
and perform the study in accordance with the Protocol, ICH GCP and other applicable regulations 
of the participating country. 
During the study, the Protocol deviations are not allowed except for the cases when it is necessary 
to prevent any direct risk for the subject. 
The investigator should have enough time for accurate performance and completion of the study 
within the time frames agreed by Sponsor and have sufficient number of qualified employees and 
adequate equipment required for the study performance per Protocol. 
Each co-investigator involved in the study should be familiar with the Protocol requirements and 
his obligations during the study. Delegation of any activities in the study to co-investigators will 
be documented by the principal investigator in writing in the relevant section of Investigator's Site 
File. 
Decision on early withdrawal of the subject in each study site should be agreed by Sponsor. 
If the decision to withdraw a subject was made by the Investigator, he should notify the Sponsor's 
representative by sending an email specifying the reason thereof. Within 48 hours excluding 
weekend and public holidays after the letter receipt, Sponsor will inform on his consent for the 
subject's withdrawal. If immediate withdrawal is required due to serious adverse events, the 
Investigator will notify Sponsor on SAE within 24 hours, however, without waiting for Sponsor's 
consent for the subject withdrawal. 
In case of loss of contact with the subject or modification of doses of the study product not 
stipulated by the Protocol, the Investigator should notify Sponsor within 24 hours after becoming 


 
 
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aware of the violation to obtain instructions on further management of the subjects and recording 
deviations from the Protocol in CRF/source documents. 
In case of violation of the above-mentioned agreement procedures or multiple Protocol deviations, 
temporary or final study termination in this study site will be considered.  
10.5. Protocol deviations 
Protocol deviation denotes any change, non-conformance or deviation from the study design or 
study Protocol procedures. 
Any deviation from the Protocol during the clinical study should be recorded and added into study-
related documents. 
For the USA only. By signing a copy of the FDA 1572 form or other country-specific regulatory 
forms, the Principal Investigator confirms that he/she has received a copy of the Investigator's 
Brochure for RPH-104 and assures the Sponsor that he/she will comply with the Protocol and 
provisions included in the FDA 1572 form or other country-specific regulatory forms. No changes 
to this Protocol may be made without the written consent of the Sponsor. 
10.6. Investigator's responsibility for Protocol violation 
Non-compliance with the Protocol, standard operating procedures (SOPs) and/or relevant 
regulations by the Investigator/study site personnel, contract research organization (CRO) or 
Sponsor's officers should result in immediate Sponsor's actions designed to assure their fulfillment. 
Where serious and/or recurrent cases of non-compliance with the relevant requirements by the 
Investigator/medical institution are identified during monitoring or audit, Sponsor should 
discontinue participation of the breaching party in the study. If participation of the 
Investigator/study site was terminated due to serious or recurrent cases of non-compliance, the 
Sponsor should notify the competent authorities thereof. 
10.7. Study monitoring 
The study will be monitored by blinded and unblinded monitors appointed by the Sponsor. The 
blinded monitor, as well as the blinded members of the study team, will not have access to any 
data that allows to determine the treatment group assigned by the IWRS to participants of the 
clinical study. The unblinded monitor will monitor the compliance of the study drug administration 
with the Protocol, as well as the accountability of the study drugs. 
Prior to the study at the initiation visit to the site or at the meeting of Investigators representative 
of Sponsor (monitor or clinical study manager) or CRO appointed by Sponsor will conduct training 
in the Protocol and CRF completion for the Investigators and site personnel. During the study the 
study site monitor will make regular visits to the site to check completeness of the subject 
documents, accuracy of the information in CRF, compliance with the Protocol and Good Clinical 
Practice requirements, course of subject recruitment, product storage, issue and product reporting 
as per requirements. Remote monitoring may be used for these purposes, if necessary (for example, 
if administrative or sanitary and epidemiological restrictions are imposed in connection with the 
current epidemic situation associated with the SARS-CoV-2 coronavirus). The key site members 
should attend any monitoring visits to cooperate with the monitor and solve the issues arising. 
Remote monitoring, if necessary, will be carried out using the appropriate module of the electronic 
data acquisition system. The investigator will upload anonymized copies of the source documents 
of patients to this module for verification of the source data, as well as copies of other documents 
required for remote verification by the monitor. These documents will be temporarily stored in the 


 
 
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data collection system, in the remote monitoring section. Upon completion of the scheduled check 
and resolution of all issues, copies of all documents will be removed from the system by the 
responsible data manager. 
Monitoring of clinical study shall be carried out by Sponsor or authorized organization (CRO) for: 
- 
assurance of protection of rights and health of the study subjects; 
- 
control of accuracy and reliability of data in CRFs with respect to the data in source 
documentation; 
- 
control of compliance of the investigator, members of Investigator's team with the 
approved Study Protocol, Amendments to the Protocol in the current version (if 
applicable), Good Clinical Practice and current regulations. 
Clinical study monitoring shall be performed according to the approved plan. Clinical study 
monitor/manager should assure proper performance and documentation of the study. Clinical study 
monitor/manager will be responsible for the following: 
 Check availability of the relevant Investigator's qualification and sufficient resources 
including laboratories, equipment and personnel throughout the study; 
 Performs control the study product (conditions and terms of storage, sufficient amount of 
the products in the study site, correct prescription of the study product, product 
accounting); 
 Check compliance of the approved Protocol and all amendments thereto by the Investigator 
(if applicable); 
 Control timely, i.e. prior to the subject initiation of the study, signing Patient Information 
Sheet and ICF; 
 Assure availability of the current version of the documents for the clinical study 
performance to the Investigator (Protocol, amendments thereto (if applicable), 
Investigator's Brochure, Patient Information Sheet and ICF); 
 Assure sufficient awareness of the investigator and investigator's team members 
concerning the study; 
 Monitor performance of the Investigator's and his team member's obligations according to 
the Protocol and other applicable agreements/contracts between Sponsor and 
Investigator/medical institution and independence of their roles (identification of 
delegation of Investigator's roles to unauthorized persons); 
 Monitor compliance of selection criteria by the Investigator; 
 Notifies Sponsor on the rate of subject recruitment into the study; 
 Monitors accuracy and completeness of data in CRF, source documents and other study-
related records by their reconciliation; 
 Informs the Investigator on any errors, omissions and illegible records in CRFs; 
 Controls observance of the terms of reporting adverse events determined by the Protocol; 
 Checks keeping the main documents by the investigator; 
 Notifies the Investigator on deviations from Protocol, SOPs, regulations and take necessary 
measures to prevent repetition of similar deviations. 
The Investigator should keep source documents containing the data on each subject, and records 
made at the visits (hospital or clinic medical documents) including demographic and medical 
information, laboratory test findings, electrocardiograms and any other tests or examinations. Any 
CRF information should originate from the source documents of the subject. Furthermore, the 
Investigator should keep the original ICF (the second copy of signed ICF will be issued to the 
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The Investigator should provide the monitor with access to all the subject's source documents for 
confirmation of compliance of source document data with CRF data. The Investigator should 
assure timely CRF filling prior to monitor or clinical study manager visit. 
To confirm compliance of the study with Helsinki Declaration, ICH GCP, regulatory requirements 
of the member states and study Protocol as well as identity, accuracy and completeness of data, 
the clinical study monitor/manager will check CRFs and other study-related documents by 
verifying the source data. 
By the end of the study, the Sponsor representative (clinical study monitor/manager) should make 
a visit to the site for Study termination visit. 
10.8. Sponsor's audit 
Sponsor's audit will be made separately and independently of the routine roles of monitoring and 
quality control of the clinical study. The audit purpose is to evaluate compliance of the study with 
the Protocol, SOPs and regulations. 
To perform audit, the Sponsor defines the persons not related to the clinical study. 
Sponsor should make sure that auditors are duly qualified to perform audit in the relevant manner. 
Auditor's qualification should be documented. 
Sponsor or authorized company will develop the audit plan and the study audit procedures 
according to which the audit will be performed. 
10.9. Study termination 
Sponsor may suspend or terminate the study for safety, ethical reasons, for the Protocol compliance 
issues or for any other reasons. In case of such necessity, Sponsor will take measures to notify the 
site in advance. If the study is suspended or terminated, Sponsor and investigator will be 
responsible to inform Ethics Committees and regulatory authorities in a timely manner. In such 
cases, Sponsor should receive all the study-related data and all unused study products should be 
returned to Sponsor. 
11. 
Ethics 
11.1. Ethics aspects of the study 
The study will be carried out in accordance with the ethical principles outlined in the Declaration 
of Helsinki of the World Medical Association, ICH GCP guideline and applicable regulations of 
the participating states. 
The final version of the Protocol including Patient Information Sheet and ICF will be submitted 
for approval to regulatory authorities of the participating states and to ethics committees (see 
section below) of the study sites prior to the study start. 
All subsequent amendments to the Protocol concerning not only administrative aspects should also 
be approved before their introduction in accordance with the procedure specified. 
Obtaining informed consent from the subjects will be made prior to any study-related procedures. 
Patient Information will contain all the data on the clinical study required for making a reasonable 
and independent decision. 
During the study all SAEs will be reported within 24 hours to the Sponsor who, based on analysis 
of the reports, may decide to suspend the study. The Ethics Committee will also be notified of 
SAEs, unexpected and related to the study product, according to the investigators. 


 
 
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The data identifying the subjects will be confidential and may only be disclosed in cases stipulated 
by law and on the decision of judicial authorities only. Study subjects will be insured according to 
local regulations.  
11.2. Local Ethics Committee / Institutional Review Board 
The study must be approved by an Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) formed according to the established procedure. Approval is required for the study 
Protocol, Protocol amendments, Patient Information Sheet with ICF, promotional materials. No 
study drugs will be sent to the site until the Sponsor or its representative receives a written 
permission from the IEC/IRB. The principal investigator or its designated person will provide the 
Sponsor or its representative with a copy of the approved Patient Information Sheet with ICF prior 
to the start of the study. 
The investigator, in collaboration with the Sponsor or designated person, will be responsible for 
informing the IEC/IRB of all changes during the study, including amendments to the Protocol, 
updates to the investigator’s brochures, IND safety reports (for the USA only), all unforeseen 
problems associated with risks for study participants, and termination of the study. The 
investigator will also be responsible for providing reports on the progress of the study to the 
IEC/IRB at regular intervals appropriate for the degree of risk to the participants involved, but at 
least once a year. Copies of all notifications and IEC/IRB approvals (if necessary) will be sent to 
the study monitor. 
Only for the USA. The requirements for approval of study documents by the institution, as set out 
in section 21 of the Code of Federal Regulations (21 CFR), part 56, will be followed. The Protocol, 
Patient Information Sheet with ICF, investigator’s brochure and other necessary documents must 
be approved by the Local Ethics Committee/Institutional Review Board (LEC/IRB) before the 
start of study enrollment. The sponsor or designated person must confirm that the LEC/IRB 
complies with the general standards regarding the composition, operation and responsibilities of 
the LEC/IRB as set forth in the ICH GCP Guideline, Sections 3.1 - 3.4, and 21 CFR, Part 56. 
11.3. Confidentiality of the study subjects 
The investigator will be responsible to observe confidentiality of the subjects, text of this Protocol 
and any other study materials and results. 
The investigator should ensure confidentiality of the subjects. CRFs and other documents provided 
to Sponsor should identify the subjects by their identification numbers and codes rather than by 
their names or surnames. 
The investigator should keep a special identification log of subjects' numbers, surnames, addresses 
and phones and numbers of case histories (if applicable). The investigator should observe strict 
confidentiality of the data not designed for submission to Sponsor. 
All the study materials belonging to Sponsor may not be submitted to third parties except for the 
cases stipulated by applicable laws. 
11.4 Informed Consent 
Before obtaining an informed consent, the investigator or an authorized person should provide the 
subject with the study-related information in the language and at the complexity level 
understandable to the subject both verbally and in writing.  
Prior to any study procedures are carried out, the subject should give his consent to participate in 
this study in writing by signing two copies of Informed Consent Form (ICF). The subject shall be 


 
 
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provided with Patient Information Leaflet with ICF reflecting complete, objective, authentic, 
adapted information on the study including the data on: 
 absolutely voluntary nature of the decision to participate in the study and ability to 
discontinue the study at any time without explanation of reasons; 
 purposes of the clinical study, its nature and all aspects; 
 therapy options during the study and the chances to be randomly assigned into one of the 
study groups; 
 study procedures; 
 expected risks and benefit of participation in the study, study-related discomfort; 
 subject's obligations during the clinical study; 
 alternative treatments in addition to the one stipulated by the Protocol, available procedures 
and treatment methods; 
 the number of subjects to be enrolled; 
 suggested duration of the subject's participation in the study; 
 presentation of additional information during the study; 
 procedure of medical assistance to the subject or reimbursement of expenses to such 
assistance in case of health damage of the subject during the study, terms of medical 
assistance; 
 insurance of the subject, insurance terms and any guarantees, provision of the insurance 
company address (if required by the local regulations); 
 confidentiality terms. 
The investigator will explain that the subject will be entitled to refuse to participate or recall their 
consent at any time without any consequences for their further therapy and without providing a 
reason. 
Each subject should be given an opportunity to discuss the study or its alternatives with the 
investigator. 
If a patient agrees to participate in the study, he/she has to sign and date the Informed Consent 
Form for participation in the study in two copies. 
Investigator shall also sign and date both copies of ICF thus evidencing that the consent has been 
obtained and the subject had an opportunity to ask questions and received full answers.  
The subject should have one dated original of the ICF. The second original copy should be added 
to the trial file by the investigator. When giving informed consent, the subject should provide a 
consent for direct access to his medical information for the study monitoring and audit and 
inspection by IEC/IRB and/or authorities. 
The study subject should be informed in a timely manner on new information which may affect 
his/her willingness to participate in the study. Transfer of this information will be documented in 
new version of Patient information leaflet with ICF which should be signed by the study subject 
and investigator in two copies specifying the date.  
12. 
Data handling and record keeping 
12.1. Direct access to source data / documentation 
Source data include the information contained in original medical records and their certified copies 
describing the results of clinical observations, examinations and other activities allowing 
reproducing the course of the clinical study and evaluating its quality. Source data are contained 
in source documentation (original or certified copies) and in electronic format. Source documents 


 
 
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include the original copies of documents related to the study, treatment, patient’s medical history 
and the description of the patient’s condition. For example, a medical record and discharge 
summaries with the results of laboratory tests are source documents. 
The investigator or the study site should not interfere with direct access to the source 
data/documents for the study-related monitoring, audit, ethical inspection and inspection by 
competent authorities.  
12.2. Record keeping in the study site 
All the study-related documents should be archived in the study site or central archive of the 
Institution. Thorough list of all ID data on the study subjects is required. 
According to ICH GCP, the requisite documents include: signed Protocol and all amendments 
thereto, copies of filled CRFs, signed ICFs of all the subjects, case histories and other source 
documents, approvals by ethics committees and regulatory authorities and all the correspondence 
with them including approved documents, product handling records, study correspondence and list 
of the subjects' surnames and addresses. This list is the key one in the documents to be stored by 
the investigator. 
Accurate and precise records of the study course are the responsibility of the investigator. Source 
documents will be maintained according to the regulatory requirements. Records in the source 
documents will be made at each examination of the subject. The relevant data will be transferred 
to eCRF within the terms specified in SOPs of CRO/Sponsor/Clinical site or other documents. 
If corrections in the source documents are required, the incorrect record should be deleted with a 
single horizontal line and the correct record will be written close to it specifying the date of 
correction, the correcting person's initials and signature. Any means deleting the previous record 
or making it illegible are not allowed. 
12.3. Data collection 
Electronic versions of CRF (eCRF) will be used in this study. Principal investigator will be 
responsible for completeness and accuracy of all the data in eCRF and timeliness of data entry and 
update. 
The monitor will be responsible to check eCRF for completeness and accuracy of records, 
instruction of the site personnel on necessity to make relevant corrections or additions. 
12.4. Database management and quality control 
In the studies using eCRFs the Sponsor (or appointed CRO) representatives will analyze the data 
entered by the site personnel for accuracy and completeness. In case of discrepancies or missing 
values, queries for data will be generated specifying the nature of the issue and required 
clarification. These queries will be forwarded to the study site. The appointed study site officer is 
required to provide responses to the queries and make any necessary amendments immediately. 
By the end of the study, any Protocol deviations will be determined. By the end of these actions 
and confirmation of database completeness and accuracy, it will be locked and prepared for data 
analysis. 
After database lock, the Investigator will receive a CD or paper version of subject data for 
archiving in the study site. 


 
 
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12.5. Data confidentiality 
Information about the study participants will be kept in compliance with confidentiality 
requirements. When processing it, applicable laws and regulations will be observed. 
In order to prevent unauthorized access to confidential information about the study participants, 
security elements are built into the data collection system for this study to encrypt all data when 
they are transmitted in both directions. Access to the system will be controlled using a sequence 
of individually assigned user identification codes and passwords, which will be provided only to 
authorized employees. 
In the case of remote monitoring, the investigator shall provide the monitor with depersonalized 
copies of the patients' source documents for verification of the source data. These source 
documents will be temporarily stored in the data collection system in the section for remote data 
verification. Upon completion of data verification and resolution of all questions regarding this 
data, the uploaded copies of the source documents will be deleted from the system by the 
responsible data manager. Data turnover during remote monitoring will be carried out in 
accordance with the regulatory requirements of the country where the study is being conducted. 
12.6. Document archiving 
The investigator must organize the retention of study documentation in the study site. The scope 
of documentation and its shelf life should comply with the requirements of the relevant regulatory 
authority, but should not be less than 2 years after receiving the first approval of the drug. In 
addition, the shelf life must meet the strictest applicable regulatory requirements. The investigator 
must take measures to prevent accidental or premature destruction of these documents. 
By signing the Protocol, the Investigator shall give his consent to comply with the document 
storage and archiving procedures. Source documentation and investigator's site file will be subject 
to storage including subject identification list and study-related correspondence. The study subject 
documents will be archived according to the Study site rules. 
The investigator should notify Sponsor on the place of storage of the relevant documents and 
contact Sponsor to obtain approval prior to destroying any of them. Investigator should take 
measures to prevent accidental or early destruction of these documents. 
Sponsor will be responsible for archiving Clinical Trial Master File. 
If Sponsor terminates clinical development of the study product, the Investigator and regulatory 
authorities will be notified thereof. 
13. 
Financing and insurance 
This clinical study will be financed by Sponsor.  
The subjects will not be compensated for participation in this study. 
During the study, the subjects will be insured as the study subjects according to the laws of the 
country participating in the study. 
If health damage occurred due to administration of the study product or medical procedure per 
study Protocol, the subject will receive free qualified medical care as appropriate. 
14. 
Protocol amendments 
Modifications of the Protocol can only be done by the Sponsor, except in cases where it is 
necessary to reduce the inevitable risk for the subjects of the study. A change in the Protocol in 
order to prevent obvious acute danger to subjects may be made without delay, provided that the 


 
 
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LEC is informed within 5 days. Any fixed change to the Protocol will be in the form of an 
amendment. A proposed Protocol amendment should be submitted to the LEC and investigators 
should wait for its approval before starting to apply it. The Sponsor will file Protocol amendments 
with the relevant regulatory authorities for approval. 
If, in the opinion of the IEC, investigators, or the Sponsor, a Protocol amendment significantly 
changes the design of the study, increases the potential risk for the study participants, or affects 
the inclusion of patients in the study, similar changes will need to be made to the current approved 
version of the ICF. In such cases, patients included in the study will need to sign a new approved 
version of the ICF. 
15. 
Study report and publications 
The investigator must understand that data obtained during the study can be used by the Sponsor 
or its agent for presentation to other investigators or governmental organizations. It should be 
understood that all data obtained during the study should be provided at the first request of the 
Sponsor. 
The representative of the Sponsor, as well as the representatives of authorized state institutions, 
should have access to any primary sources of documents; however, the anonymity of the study 
participants should be respected as a professional requirement. 
The Principal Investigator and his/her colleagues may subsequently publish additional results of 
this study in scientific journals or present them at scientific conferences, provided that the Sponsor 
is given the full opportunity to review any proposed abstract, manuscript or presentation of slides 
before they are submitted. This review is necessary to ensure that the Sponsor is aware of all oral 
or written representations of the data and does not imply any editorial revision or restriction of the 
contents of the presentation or use. The authorship of any publication will be agreed with all other 
investigators and the Sponsor. In accordance with the uniform requirements for manuscripts 
submitted to biomedical journals published by the International Committee of Medical Journal 
Editors, investigators whose contribution is solely in data collection will not be named individually 
as authors. Such investigators will rather be co-authored as the “RPH 104 Study Group” and will 
be indicated in a note. 
The investigator must not publish results of this study, including those obtained at his/her study 
site, without the consent of the Sponsor. Results obtained in a separate study site should not be 
published before publication of the general results of the study. 
The results of the study will be published to the extent and at the times established in accordance 
with the Sponsor's publication policy. 
16. 
References 
Abbate A. et al., 2006 
Abbate A, Bussani R, Amin MS, Vetrovec GW, Baldi A. Acute myocardial infarction and heart 
failure: role of apoptosis. Int J Biochem Cell Biol. 2006; 38: 1834–1840 
Abbate A. et al., 2010 
Abbate A., Kontos M.C., Grizzard J.D. et al. Interleukin-1 Blockade With Anakinra to Prevent 
Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth 
University Anakinra Remodeling Trial [VCU-ART] Pilot Study). American Journal of Cardiology 
2010; 105(10):1371 – 1377 


 
 
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Abbate A., 2013 
Abbate A., Kontos M.C., Grizzard J.D. et al. Effect of Interleukin-1 Blockade With Anakinra to 
Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (from the Virginia 
Commonwealth University Anakinra Remodeling Trial (2) [VCU-ART2] Pilot Study). Am J 
Cardiol 2013; 111(10): 1394-1400. 
Abbate A. et al., 2020 
Abbate A., Trankle C.R., Buckley L.F. et al. Interleukin‐1 Blockade Inhibits the Acute 
Inflammatory Response in Patients With ST‐Segment–Elevation Myocardial Infarction. Journal 
of the American Heart Association. 2020; 9(5). 
Bahit M.C. et al., 2018 
Bahit M.C., Kochar A., Granger C.B. Post-Myocardial infarction heart failure. J Am Coll Cardiol 
HF 2018 Mar; 6(3): 179-186.  
Berger C.J., 1992 
Berger C.J., Murabito L.M., Evans J.C., Anderson K.M., Levy D. Comparison of Q-wave and non-
Q-wave Myocardial Infarction in the Framingham Heart Study. JAMA 1992; 268 (12): 1545-1551 
Buckley L.F. and Abbate A., 2018 
Buckley L.F. and Abbate A. Interleukin-1 blockade in cardiovascular diseases: a clinical update. 
European Heart Journal 2018; 39:2063-2069. 
Frangogiannis NG., 2008 
Frangogiannis NG. The immune system and cardiac repair. Pharmacol Res. 2008;58(2):88–111. 
Gjesing A. et al., 2014 
Gjesing A., Gislason G.H., Køber L. et al. Nationwide trends in development of heart failure and 
mortality after first-time myocardial infaction 1997-2010: a Danish cohort study. Eur J Intern Med 
2014; 25(8): 731-738. 
Hashkes P.J. et al., 2012 
Hashkes P.J., Spalding S.J., Giannini E.H. et al. Rilonacept for colchicine-resistant or -intolerant 
familial Mediterranean fever: a randomized trial// Ann Intern Med. 2012 Oct 16;157(8):533-41. 
Hicks K.A.et al., 2018 
Hicks K.A., Mahaffey K.W., Mehran R., Nissen S. et al. 2017 Cardiovascular and Stroke Endpoint 
definitions for clinical trial. Circulation 2018; 137(9)% 961-972. 
Hoffman H.M. et al., 2008 
Hoffman H.M., Throne M.L., Amar N.J. et al. Efficacy and safety of rilonacept (interleukin-1 
Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential 
placebo-controlled studies// Arthritis Rheum. 2008 Aug;58(8):2443-52. 
Ibanez B. et al, 2017 
Ibanez B, James S, Agewall S, Antunes M.J., Bucciarelli-Ducci Ch, Bueno H, et al. ESC Scientific 
Document Group, 2017 ESC Guidelines for the management of acute myocardial infarction in 
patients presenting with ST-segment elevation: The Task Force for the management of acute 
myocardial infarction in patients presenting with ST-segment elevation of the European Society 
of Cardiology (ESC). European Heart Journal 2018 January; 39 (2):119–177 


 
 
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Krause K. et al., 2012 
Krause K, Weller K, Stefaniak R. et al. Efficacy and safety of the interleukin-1 antagonist 
rilonacept in Schnitzler syndrome: an open-label study// European journal of allergy and clinical 
immunology, Volume67, Issue7 July 2012 943-950. 
Lang R.M. et al., 2015 
Lang R.M., Badano L.P., Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations 
for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the 
American Society of Echocardiography and the European Association of Cardiovascular Imaging, 
European Heart Journal - Cardiovascular Imaging, 2015, March; 16(3): 233–271. 
Ridker P.M. et al., 2005 
Ridker P.M., Cannon C.P., Morrow D., Rifai N., Rose L.M., et al. C-Reactive protein and 
outcomes after statin therapy. N Engl J Med 2005; 352: 20-28. 
Ridker P.M. et al., 2017 
Ridker P.M., Everett B.M., Thuren T., MacFadyen J.G., Chang W.H. et al. CANTOS trial group. 
Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 
(12): 119-1131 
Ridker P.M. et al., 2018 
Ridker P.M., MacFadyen JG., Everett B.M., Libby P., Thuren T., Glynn RJ., CANTOS Trial 
Group. Relationship of C-reactive reduction to cardiovascular event reduction following treatment 
with canakinumab: a secondary analysis from the CANTOS randomized controlled trial. Lancet 
2018; 391(10118):319-328. 
Scirica B.M., 2009 
Scirica B.M., Cannon C.P., Sabatine M.S., Jarolim P. et al. Concentration of C-reative protein and 
B-type Natriuretic peptide 30 days after acute coronary syndromes independently predict 
hospitalization for heart failure and cardiovascular death. Clinical Chemistry 2009; 55 (2): 265-
273.  
Thygesen K. et al., 2018 
Thygesen K., Alpert J.S., Jaffe A.S., Chaitman B.R. et al. Fourth Definition of myocardial 
infarction (2018). J Am Coll Cardiol 2018; 72 (18): 2231-2264. 
Van Tassell B.W. et al., 2018 
Van Tassell BW, Lipinski MJ, Appleton D, et al. Rationale and design of the Virginia 
Commonwealth University-Anakinra Remodeling Trial-3 (VCU-ART3): A randomized, placebo-
controlled, double-blinded, multicenter study. Clin Cardiol. 2018;41(8):1004–1008.  
Vanhaverbeke M. et al., 2018 
Vanhaverbeke M., Veltman D., Pattyn N. et al. C-reactive protein during and after myocardial 
infarction in relation to cardiac injury and left ventricular function at follow-up. Clinical 
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Velagaleti RS, Pencina MJ, Murabito JM, et al. Long-term trends in the incidence of heart failure 
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WHO, 2017 
Cardiovascular diseases. WHO Information Bulletin. Access link: https://www.who.int/ru/news-
room/fact-sheets/detail/cardiovascular-diseases-(cvds) 
Garganeyeva А.А et al., 2015 
Garganeyeva А.А.,Okrugin S.А., Borel К.N. WHO Program "Register of acute myocardial 
infarction: possibilities and prospects in investigation and prediction of outcomes of socially 
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Kontsevaya А.V. et al., 2018 
Kontsevaya А.V., Drapkina О.М., Balanova Yu.А. et al. Economic losses from cardiovascular 
diseases in the Russian Federation in 2016 // Reasonable Pharmacotherapy in Cardiology 2018; 
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Mareyev V.Yu. et al, 2018 
Mareyev V.Yu., Fomin I.V., Ageyev F.Т., Begrambekova Yu.L.,Vasyuk Yu.А. et al. Clinical 
recommendations ОССН_РКО_РНМОТ. Cardiac failure: chronic (CHF) and acute 
decompensated (ADHF). Diagnosis, prevention and therapy. Cardiology. 2018; 58(6S): 8-158. 
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Okrugin S.А., 2018 
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Fomin I.V. Chronic heart failure in the RF: what we currently know and what we should do. 
Russian Cardiological Journal. 2016; 8(136): 7-13.  
 
 


 
 
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17. 
Appendix 1. 2017 Cardiovascular and Stroke Endpoint 
Definitions for Clinical Trials 
(translation of extracts from publication by Hicks K.A.et al., 2018) 
Definition of cardiovascular death 
 
Cardiovascular death includes death due to acute myocardial infarction (MI), sudden cardiac 
death, death from heart failure (HF), death from stroke, death from cardiovascular (CV) 
procedures, death from CV hemorrhage and other CV death. 
 
More specific classification of cardiovascular death (MI, sudden death, etc.) in outcome studies 
is not generally required. Furthermore, such classification is difficult as it refers to both principal 
cause (e.g. acute MI which may cause fatal arrhythmia or HF) and to death (sudden, arrhythmic; 
HF due to MI or aggravated HF) which are mostly overlapping. However, the following 
definitions may be used as necessary. 
  
1. Death due to acute myocardial infarction belongs to any cardiovascular death (e.g. 
arrhythmia, sudden death, HF, stroke, pulmonary embolism, peripheral artery disease) 
within 30 days after MI4 associated with direct consequences of MI including progressive 
HF and refractory arrhythmia. We noted that mechanisms of CV death may be currently 
under assessment, however, for convenience, if CV death occurs within 30 days post MI, it 
will be considered to be MI-related death. 
 
Acute MI should be confirmed by diagnostic criteria of acute MI where possible (see 
Definition of MI in publication by Hicks K.A.et al., 2018 and publication by Thygesen K. 
et al., 2018) or by the results of autopsy suggesting a previous MI or coronary artery 
thrombosis. 
 
Death due to MI therapy procedure (percutaneous coronary intervention (PCI), coronary 
artery bypass grafting (CABG) or treatment of MI-related complication should also be 
considered as death due to acute MI. 
 
Death due to coronary procedure for the treatment of myocardial ischemia (i.e. chronic stable 
angina) or death due to MI as a result of CV examination/procedure/surgery should be 
considered as death due to treatment of CV pathology. 
 
2. Sudden cardiac death means sudden death outside of 30-day period post acute MI. Sudden 
cardiac death includes the following scenarios: 
 
                                            
4 30-day period is voluntary 


 
 
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a. Death which was certified and occurred without development or aggravation of 
symptoms  
b. Death was certified within 60 min after development or aggravation of cardiac symptoms 
if the symptoms do not verify acute MI  
 
c. Death certified and caused by identified arrhythmia (e.g. recorded at electrocardiogram 
(ECG), recorded on the monitor or not certified but detected at inspection of implantable 
cardioverter defibrillator) 
 
d. Death after unsuccessful resuscitation at cardiac arrest (e.g. sudden cardiac death without 
response to implantable cardioverter defibrillator (ICD), electric activity arrest without 
pulse) 
 
e. Death after successful resuscitation at cardiac arrest without determination of specific 
cardiac or non-cardiac etiology  
 
f. Uncertified death of the subject who was seen alive and clinically stable within 24 hours 
before he/she was found dead, without any evidence of a specific non-cardiovascular 
cause of death (where appropriate, the information on the subject's clinical status should 
be provided) 
 
General provisions 
 
o If additional information does not suggest an alternative cause of death (e.g. other 
cardiovascular death), if the subject was seen alive within 24 hours before he/she was 
found dead, sudden cardiac death (2f criterion) should be recorded. For the subjects who 
were not seen alive within 24 hours before death, the cause of death should be recorded 
as undefined (e.g. the subject found dead in his/her bed if the family did not see him/her 
for more than 24 hours).  
 
3. Death from heart failure means death due to clinical aggravation of the symptoms and/or 
signs of HF regardless of etiology of HF (see Heart failure definition). HF death may have 
various etiologies including single or recurring MI, ischemic or non-ischemic 
cardiomyopathy, hypertension or heart valve disease. 
 
4. Death from stroke means death post stroke which is a direct consequence of stroke or its 
complication. Acute stroke should be verified using diagnostic stroke criteria where possible 
(see Appendix 8 of publication by Hicks K.A.et al., 2018).  
 
5. Death from cardiovascular procedures means death caused by direct complications of a 
cardiovascular procedure. 
 


 
 
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6. Death from cardiovascular hemorrhage means death associated with a hemorrhage 
including non-stroke intracranial hemorrhage (e.g. subdural hematoma) (see Appendix 8 to 
publication by Hicks K.A.et al., 2018), non-procedural or non-traumatic vessel rupture (e.g. 
aorta aneurysm) or hemorrhage causing cardiac tamponage. 
 
7. Other cardiovascular death refers to death from CV pathologies not included into the 
categories above where there is a certain known cause (e.g. pulmonary embolism or 
peripheral artery disease). 
 
 
Definition of non-cardiovascular death 
 
Non-cardiovascular death is any death with a specific cause which in its nature is not 
associated with a cardiovascular pathology as specified in Definition of cardiovascular death. 
Detailed recommendations on classification of non-CV causes of death are beyond this 
document. The required level of details and optimal classification will depend on the nature of 
the study population and expected number and type of non-CV deaths. Any specific expected 
safety issue should be added as an individual cause of death. Below is the recommended list of 
causes of non-CV death. 
 Pulmonary 
 Renal 
 Gastrointestinal 
 Hepatobiliary 
 Pancreatic 
 Infection (including sepsis) 
 Inflammatory (e.g. systemic inflammation response syndrome (SIRS)/Immune 
(including autoimmune) (may include environmental anaphylactic reaction (e.g. food 
allergy))  
 Bleeding other than CV hemorrhage or stroke (see Definition of cardiovascular death, 
Section 6 and Appendix 8 of publication by Hicks K.A.et al., 2018) 
 Procedure or surgery not associated with a CV pathology 
 Injury (including murder) 
 Suicide 
 Response to OTC product or overdose 
 Response to an OTC product or overdose (may include anaphylactic reaction) 
 Neurological (non-CV) (other than CV death due to ischemic stroke, hemorrhagic stroke 
or stroke for unknown cause or CV hemorrhage into central nervous system) 
 Malignant tumour (e.g. leukemia, lymphoma or another malignant tumour) 


 
 
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 Another non-CV cause (specify): _________________ 
 
 
Definition of uncertain cause of death 
 
Undefined cause of death refers to death not related to any of the CV or non-CV death 
categories above. Inability to classify the cause of death may be due to lack of information (e.g. 
the only available information is "the subject died") or due to deficit of additional information 
or data to determine the cause of death. Overall, most deaths should be classified as CV-related 
or non-CV-related, therefore this category of death is not encourage and should only be used in 
rare cases in well-designed clinical studies. 
 
General analytical approach to analysis of death causes consists in assumption that all 
unexpected cases belong to CV category (e.g. supposed CV death, particularly "other CV 
death"). Nevertheless, the relevant classification and analysis of undefined causes of death 
depend on the population, study intervention, follow-up period and disease course (assumption 
that CV death is unlikely, e.g. in subjects with advanced oncology, advanced pulmonary disease, 
long-lasting infection, etc.). The approach should be pre-defined and described in the Protocol 
and other study-related documents including determination of endpoint and/or statistical 
analysis plan. 
 
 
Definition of hospitalization due to unstable angina 
 
Unstable angina requiring hospitalization includes 
 
1. Ischemic discomfort (angina pectoris or equivalent symptoms) ≥ 10 minutes  
 at rest or 
 with increased intensity and frequent episodes associated with progressive reduction 
of physical exercise. 
 
AND 
 
2. Unscheduled hospitalization within 24 hours since the last symptom. Hospitalization is 
defined as admission to a hospital or intensive care unit with at least 24-hour stay (or change 
of calendar date if the time of hospitalization or time of discharge is lacking). 
 
AND 


 
 
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3. At least one of the below-mentioned: 
 
a. New change in ST or T-wave or their aggravation on ECG at rest (with no 
confounding factors including left bunch branch block or left ventricular 
hypertrophy) 
 
 Temporary ST elevation (< 20 min) 
New ST elevation at J-point on two adjacent electrodes with separation point:  
≥ 0.1 mV for all electrodes except for V2-V3 to which the following separation 
points are applicable: ≥ 0.2 mV for males aged ≥ 40 years old (≥ 0.25 mV for 
males aged < 40 years old) or ≥ 0.15 mV for females.  
 ST depression and modification of T-wave 
New horizontal or descending ST depression ≥ 0.05 mV on two adjacent 
electrodes and/or new inversion of T-wave ≥ 0.3 mV on two adjacent waves with 
marked R-wave or R/S > 1. 
 
b. Myocardial ischemia is definitely suspected by:  
 early positive physical exercise test, i.e. ST elevation or ST depression ≥ 2 mm 
up to 5 metabolic equivalents  
OR 
 stress-echocardiography (reversible wall movement deviation) OR 
 myocardial scintigraphy (reversible perfusion defect) OR 
 MRI (deficit of myocardial perfusion at pharmacological burden). 
  
 
and presumed association with the symptoms/signs of myocardial ischemia. 
 
c. Angiographic evidence of a new lesion site or aggravation a pre-existing site ≥ 70% 
(≥ 50% for left main site) and/or clot in epicardial coronary artery presumably 
responsible for myocardial ischemia symptoms/signs. 
 
d. Necessity in coronary revascularization (PCI or CABG) due to the site causing acute 
condition according to 3c criterion. This criterion will be met if revascularization 
was carried out during unscheduled hospitalization or after transfer to another facility 
without prior discharge. 
 
AND 
 


 
 
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4. Negative cardiac biomarkers and lack of MI evidence  
 
General provisions 
 
1. Escalation of pharmacotherapy at ischemia including intravenous administration of nitrates 
or elevation of β-adrenoblocker dose should be considered as supporting but not diagnosing 
unstable angina. However, typical treatment and hospitalization with pharmacotherapy 
escalation without any additional results outlined in category 3 are insufficient to verify 
classification of hospitalization due to unstable angina. 
 
2. If the subjects are admitted with suspected unstable angina and further testing reveals non-
cardiac or non-ischemic etiology, this event should not be recorded as hospitalization due to 
unstable angina. Potential ischemic events meeting MI criteria should not be considered as 
unstable angina. 
3. Scheduled hospitalization or repeated hospitalization for scheduled revascularization in 
subjects not meeting unstable angina criteria should not be considered as hospitalization due to 
unstable angina. For example, 
 
 Hospitalization of a subject with stable effort angina for coronary angiography and PCI 
based on positive outpatient stress test should not be considered as hospitalization due 
to unstable angina. 
 
 Repeated hospitalization of a subject meeting the criteria of unstable angina which has 
been stabilized, with further discharge and repeated hospitalization for revascularization 
is not a second hospitalization due to unstable angina. 
  
4. A subject undergoing elective catheterization after coronary artery disease is diagnosed and 
further undergoing coronary revascularization does not meet hospitalization criteria for unstable 
angina.  
 
 
Definition of heart failure 
 
Heart failure includes hospitalization due to heart failure and may include emergency 
outpatient visits. Hospitalization due to HF should be isolated from emergency visits. If 
emergency visits are included into HF endpoint, the number of emergency visits should be 
specified separately from hospitalizations. 
 
Hospitalization due to heart failure is an event meeting ALL the criteria below:  


 
 
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1) The subject is hospitalized with primary diagnosis of HF  
 
2) Hospitalization period is at least 24 hours (or change of calendar date if admission and 
discharge time are lacking) 
 
3) Upon admission the subject has new or aggravated pre-existing symptoms due to HF 
including at least ONE of the following:  
 
a. Dyspnea (exertional dyspnea, dyspnea at rest, orthopnea, paroxysmal nocturnal 
dyspnea) 
b. Decreased exercise tolerance 
c. Fatigue 
d. Other symptoms of decreased perfusion of the target organ or volume overload 
(should be specified or described in the Protocol) 
 
4) The subject has objective evidence of a new or aggravated pre-existing HF including at 
least TWO results of physical examination OR one result of physical examination and 
at least ONE laboratory test) including:  
 
a. Results of physical examination associated with heart failure including 
development of new or aggravation of pre-existing:  
 
i. Edema peripheral 
ii. Progressive bloating or ascites (without underlying liver disease) 
iii. Pulmonary rales/sounds 
iv. Increased jugular vein pressure and/or hepatojugular reflux 
v. Third heart sound gallop rhythm 
vi. Clinically relevant or rapid body weight gain presumably due to fluid 
retention 
 
b. Laboratory evidence of a new or aggravated pre-existing HF when obtained 
within 24 hours post admission including: 
 
i. Increased level of natriuretic peptide B (BNP)/N-terminal fragment BNP 
(NT-proBNP) correlates with heart failure decompensation (e.g. 
BNP > 500 pg/mL or NT-proBNP > 2000 pg/mL). Subjects with 
chronically increased natriuretic peptide level should have significant 
increase above baseline. 
 
ii. Radiological confirmation of pulmonary congestion 
 
iii. Non-invasive diagnostic evidence of clinically relevant increased left or 
right ventricular filling pressure or low cardiac output. E.g. 
echocardiographic criteria may include: septal or lateral E/e’> 15 or > 12, 
respectively; D-dominant nature of pulmonary venous inflow; plethoric 
inferior vena cava with minimum collapse at inspiration; or moderate 


 
 
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minute distance of left ventricular outflow tract (LVOT) (time-velocity 
integral [TVI])  
  
OR 
 
iv. Invasive diagnostic evidence with right cardiac catheterization 
demonstrating wedge pressure in pulmonary capillary (pulmonary artery 
occlusive pressure) ≥ 18 mm Hg, central venous pressure ≥ 12 mm Hg or 
cardiac index <2.2 L/min/m2 
 
Note: All results of diagnostic tests should be reported if any, even if they do 
not meet the criteria above as they provide important information to decide 
on these events.  
 
5) The subject receives at least ONE of HF treatments below: 
 
 
a. Significant intensification of oral diuretic therapy (e.g. doubling dose of a loop 
diuretic, initiation of supporting therapy with a loop diuretic, initiation of 
combined diuretic therapy)  
b. Initiation of intravenous administration of a diuretic (even at a single dose) or 
vasoactive product (e.g. inotropic, vasoconstrictive, vasodilating agents)  
c. Mechanic or surgical intervention including: 
i. Mechanical circulatory support (e.g. aortic balloon pump, ventricular 
assist device, extracorporeal membrane oxygenation, artificial heart) 
ii. Mechanic fluid elimination (e.g. ultrafiltration, hemofiltration, dialysis) 
  
General considerations (hospitalization due to HF) 
 
Combined diuretic therapy may include 1) thiazide diuretic (e.g. hydrochlorothiazide, 
metolazone, chlorothiazide) + loop diuretic; or 2) mineralocorticoid receptor antagonist 
(MCRA) (e.g. spironolactone or eplerenone) + loop diuretic. 
 
Emergency visit due to heart failure is an event meeting all the criteria below:  
 
1) The subject seeks urgent unscheduled assistance from a physician or in an intensive care 
unit with the primary HF diagnosis but does not meet criteria for HF hospitalization.  
2) The subject has all the signs and symptoms of HF hospitalization (i.e. 3),  
4) results of physical examination/laboratory tests evidencing new or aggravated pre-
existing HF as detailed above) 
3) The subject receives at least ONE of HF treatments below:  
 
a. Initiation of intravenous administration of a diuretic or vasoactive product (e.g. 
inotropic, vasoconstrictive, vasodilating agents)* 
 
b. Mechanic or surgical intervention including: 


 
 
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i. 
Mechanical circulatory support (e.g. aortic balloon pump, ventricular assist 
device, extracorporeal membrane oxygenation, artificial heart) 
ii. 
Mechanic fluid elimination (e.g. ultrafiltration, hemofiltration, dialysis) 
 
* Note that significant intensification of oral diuretic therapy is NOT sufficient to meet 
urgent HF visit criteria. 
 
 
General considerations (urgent HF visit) 
 
1. Clinical visits for scheduled therapy or procedures associated with HF (e.g. intravenous 
administration of diuretics, intravenous administration of vasoactive agents or mechanical 
fluid elimination) are NOT qualified as HF without hospitalization. 
  
 
Definition of Stroke and Transient Ischemic Attack 
 
Introduction 
 
These definitions of Stroke and Transient Ischemic Attack apply to a wide range of clinical 
trials. They are general, overarching, and widely applicable definitions combined with a specific 
clinical measurement of disability. They are flexible in their application and consistent with 
contemporary understanding of the pathophysiology of stroke. This approach enables clinical 
trials to assess the clinically relevant consequences of vascular brain injury for determining the 
safety or effectiveness of an intervention. 
 
The distinction between an Ischemic Stroke and a Transient Ischemic Attack is the presence of 
infarction. Persistence of symptoms is an acceptable indicator of acute infarction. Thus, duration 
of symptom persistence that will be used to distinguish between transient ischemia and acute 
infarction should be defined for any clinical trial in which it is used. 
 
In trials involving patients with stroke, evidence of vascular central nervous system injury 
without recognized neurological dysfunction may be observed. Examples include 
microhemorrhage, asymptomatic infarction, and asymptomatic hemorrhage. When encountered, 
the clinical relevance of these findings may be unclear. If appropriate for a given clinical trial, 
however, they should be precisely defined and categorized. 
 
Subdural hematomas are intracranial hemorrhagic events and not strokes. 
 
Transient Ischemic Attack 


 
 
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Transient ischemic attack (TIA) is defined as a transient episode of focal neurological 
dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. 
 
Stroke 
 
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by brain, 
spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. 
 
Classification: 
 
A. Ischemic Stroke 
 
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of central nervous system tissue. 
 
Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an 
ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke. 
 
B. Hemorrhagic Stroke 
 
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
 
C. Undetermined Stroke 
 
Undetermined stroke is defined as an acute episode of focal or global neurological 
dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a result 
of hemorrhage or infarction but with insufficient information to allow categorization as 
either ischemic or hemorrhagic. 
 
Stroke Disability 
 
Disability should be measured by a reliable and valid scale in all cases, typically at each visit 
and 90 days after the event. For example, the modified Rankin Scale may be used to address 
this requirement:  
 


 
 
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Scale Disability 
0 
No symptoms at all 
1 
No significant disability despite symptoms; able to carry out all usual duties and 
activities 
2 
Slight disability; unable to carry out all previous activities, but able to look after own 
affairs without assistance 
3 
Moderate disability; requiring some help, but able to walk without assistance 
4 
Moderately severe disability; unable to walk without assistance and unable to attend 
to own bodily needs without assistance 
5 
Severe disability; bedridden, incontinent and requiring constant nursing care and 
attention 
6 
Dead 
 
Interventional Cardiology Definitions 
 
A. Clinical Definitions 
 
1. Clinically-Driven Target Lesion Revascularization: Revascularization is clinically-
driven if the target lesion diameter stenosis is > 50% by quantitative coronary 
angiography (QCA) and the subject has clinical or functional ischemia which cannot be 
explained by another native coronary or bypass graft lesion. Clinical or functional 
ischemia includes any of the following: 
 
a. A history of angina pectoris, presumably related to the target vessel 
b. Objective signs of ischemia at rest (electrocardiographic changes) or during exercise 
test (or equivalent), presumably related to the target vessel 
c. Abnormal results of any invasive functional diagnostic test [e.g., coronary flow 
reserve (CFR) or fractional flow reserve (FFR)] 
 
Comment: Target lesion revascularization (TLR) of a > 70% diameter stenosis by QCA 
in the absence of the above signs or symptoms may be considered clinically-driven. 
 
Comment: In the absence of QCA data or if a < 50% stenosis is present, TLR may be 
considered clinically-driven by the Clinical Events Committee (CEC) if severe ischemic 
signs and symptoms attributed to the target lesion are present. 


 
 
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2. Non-Target Lesion and Non-Target Lesion Revascularization: A lesion for which 
revascularization is not attempted or one in which revascularization is performed using 
a non-study device, respectively. 
 
3. Non-Target Vessel and Non-Target Vessel Revascularization: A vessel for which 
revascularization is not attempted or one in which revascularization is performed using 
a non-study device, respectively. 
 
4. Percutaneous Coronary Intervention (PCI) Status: 
 
a. Elective: The procedure can be performed on an outpatient basis or during a 
subsequent hospitalization without significant risk of myocardial infarction (MI) or 
death. For stable in-patients, the procedure is being performed during this 
hospitalization for convenience and ease of scheduling and NOT because the 
patient's clinical situation demands the procedure prior to discharge.  
 
b. Urgent: The procedure should be performed on an inpatient basis and prior to 
discharge because of significant concerns that there is risk of myocardial ischemia, 
MI, and/or death. Patients who are outpatients or in the emergency department at the 
time that the cardiac catheterization is requested would warrant hospital admission 
based on their clinical presentation.  
 
c. Emergency: The procedure should be performed as soon as possible because of 
substantial concerns that ongoing myocardial ischemia and/or MI could lead to 
death. "As soon as possible" refers to a patient who is of sufficient acuity that one 
would cancel a scheduled case to perform this procedure immediately in the next 
available room during business hours, or one would activate the on-call team were 
this to occur during off-hours. 
 
d. Salvage: The procedure is a last resort. The patient is in cardiogenic shock when the 
PCI begins (i.e., the time at which the first guide wire or intracoronary device is 
introduced into a coronary artery or bypass graft for the purpose of mechanical 
revascularization) OR within the last ten minutes prior to the start of the case or 
during the diagnostic portion of the case, the patient has also received chest 
compressions or has been on unanticipated circulatory support (e.g., intra-aortic 
balloon pump, extracorporeal membrane oxygenation, or cardiopulmonary support). 
 
5. Percutaneous Coronary Intervention (PCI): Placement of an angioplasty guide wire, 
balloon, or other device (e.g., stent, atherectomy catheter, brachytherapy delivery device, 
or thrombectomy catheter) into a native coronary artery or coronary artery bypass graft 
for the purpose of mechanical coronary revascularization. In the assessment of the 
severity of coronary lesions with the use of intravascular ultrasound, coronary flow 


 
 
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reserve (CFR), or fractional flow reserve (FFR), insertion of a guide wire will NOT be 
considered PCI. 
 
6. Procedural Success: Achievement of < 30 % residual diameter stenosis of the target 
lesion assessed by visual inspection or QCA and no in-hospital major adverse cardiac 
events (MACE, a composite of death, MI, or repeat coronary revascularization of the 
target lesion). Ideally, the assessment of the residual stenosis at the end of the procedure 
should be performed by an angiographic core laboratory. 
 
Comment: For some device interventions (e.g., balloon angioplasty), achievement of  
< 50% diameter stenosis by visual inspection or QCA is an acceptable definition for 
procedural success. 
 
7. Target Lesion: Any lesion treated or attempted to be treated during the PCI with the 
study device. The target lesion includes the arterial segment treated with the study device 
(stent, in most cases) plus 5 mm proximal and 5 mm distal to the treatment site. 
 
8. Target Lesion Failure (TLF): The composite of ischemia-driven revascularization of 
the target lesion, MI related to the target vessel, or cardiac death related to the target 
vessel. If it cannot be determined with certainty whether the MI or death was related to 
the target vessel, it is considered a TLF. 
 
9. Target Lesion Revascularization (TLR): Any repeat percutaneous intervention of the 
target lesion (including 5 mm proximal and 5 mm distal to the target lesion) or surgical 
bypass of the target vessel performed for restenosis or other complication involving the 
target lesion. In the assessment of TLR, angiograms should be assessed by an 
angiographic core laboratory (if designated) and made available to the CEC for review 
upon request. 
 
10. Target Vessel: A major native coronary artery (e.g., left main coronary artery, left 
anterior descending coronary artery, left circumflex coronary artery, or right coronary 
artery) or bypass graft containing the target lesion. A native coronary artery target vessel 
includes the arterial segments upstream and downstream to the target lesion plus major 
side branches. 
 
11. Target Vessel Failure (TVF): The composite of ischemia-driven revascularization of 
the target vessel, MI related to the target vessel, or cardiac death related to the target 
vessel. If it cannot be determined with certainty whether the MI or death was related to 
the target vessel, it is considered a TVF. 
 
12. Target Vessel, Non-Target Lesion, and Target Vessel, Non-Target Lesion 
Revascularization: Any lesion or revascularization of a lesion in the target vessel other 
than the target lesion, respectively. 


 
 
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13. Target Vessel Revascularization (TVR): Any repeat percutaneous intervention or 
surgical bypass of any segment of the target vessel. In the assessment of TVR, 
angiograms should be assessed by an angiographic core laboratory (if designated) and 
made available to the CEC for review upon request. 
 
14. Vascular Complications:  
 Access site hematoma: Development of a new, localized collection of blood at a 
vascular access site sufficient to produce a palpable mass within 72 hours of a 
procedure. 
 Arteriovenous fistula: Development of a new, unintended communication between 
an artery and a vein occurring at a vascular access site within 72 hours of a procedure. 
 Peripheral ischemia: Development of new arterial insufficiency sufficient to 
produce clinical signs or symptoms of ischemia (pallor, pain, paresthesia) distal to a 
vascular access site within 72 hours of a procedure. 
 Peripheral nerve injury: Development of new sensory or motor loss of peripheral 
nerve function from external nerve compression (e.g., as a result of positioning 
during a procedure), or internal compression or direct nerve damage from the 
procedure, occurring within 72 hours of a procedure. 
 Pseudoaneurysm: Development of a new localized collection of blood with a 
persistent communication (neck) originating at a vascular access site and occurring 
within 72 hours of a procedure. 
 Retroperitoneal hemorrhage: Development of new bleeding into the 
retroperitoneal space originating at a vascular access site and occurring within 72  
hours of a procedure. 
 
B. Angiographic Definitions 
 
1. Abrupt Closure: New intra-procedural severely reduced flow (TIMI grade 0-1) within 
the target vessel that persists and requires intervention by stenting or other treatment, or 
results in MI or death. Abrupt closure requires an association with a vascular dissection, 
thrombus, or severe spasm at the treatment site or within the instrumented vessel. 
 
2. Coronary Lesions Treated  
 
Coronary Artery Segments 
Definition 
Right coronary artery ostium 
Origin of the right coronary artery, including 
the first 3 mm of the artery 
Proximal right coronary artery 
Proximal portion of the right coronary artery, 
from the ostium of the right coronary artery to 


 
 
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the origin of the first right ventricular branch 
(pRCA) 
Mid right coronary artery 
Middle portion of the right coronary artery, 
from the origin of the first right ventricular 
branch to the acute margin (mRCA) 
Distal right coronary artery 
Distal portion of the right coronary artery, 
from the acute margin to the origin of the 
posterior descending artery (dRCA) 
Right posterior descending artery 
In right dominant and mixed circulations, the 
vessel that runs in the posterior interventricular 
groove and supplies septal perforator branches 
(PDA) 
Posterolateral segmental artery 
In right dominant circulations, the distal 
continuation of the right coronary artery in the 
posterior atrioventricular groove after the 
origin of the right posterior descending artery 
(PLSA) 
First right posterolateral branch 
In right dominant circulations, the first 
posterolateral branch originating from the 
right posterior atrioventricular artery (RPL1) 
Second right posterolateral branch 
In right dominant circulations, the second 
posterolateral branch originating from the 
right posterior atrioventricular artery (RPL2) 
Third right posterolateral branch 
In right dominant circulations, the third 
posterolateral branch originating from the 
right posterior atrioventricular artery (RPL3) 
Posterior 
descending 
septal 
perforator 
Septal perforator vessel originating from the 
posterior descending artery 
Right ventricular branch 
Branch arising from the right coronary artery 
to supply the right ventricular wall (RV) 
Left main coronary artery ostium 
Origin of the left coronary artery, including the 
first 3 mm of the artery 
Left main coronary artery body 
Body of the left main coronary artery, from the 
ostium to the bifurcation (LM) 
Left main coronary artery bifurcation 
Distal end of the left main, including the 
terminal 3 mm through the bifurcation of the 
left main into the left anterior descending and 
left circumflex arteries 


 
 
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Left 
anterior 
descending 
artery 
ostium 
Origin of the left anterior descending coronary 
artery, including the first 3 mm of the artery 
Proximal left anterior descending 
artery 
Proximal portion of the left anterior descending 
coronary artery, from the ostium to the origin 
of the first septal (pLAD) 
Mid left anterior descending artery 
Middle portion of the left anterior descending 
coronary artery, from the origin of the first 
septal artery to the origin of the third septal 
artery (mLAD) 
Distal left anterior descending artery 
Distal portion of the left anterior descending 
coronary artery, from the origin of the third 
septal artery to the terminus (dLAD) 
First diagonal branch 
First of the three longest branches originating 
from the left anterior descending artery to 
supply the anterolateral wall of the left ventricle 
(D1) 
First diagonal lateral branch 
Branch of the first diagonal branch 
Second diagonal branch 
Second 
of 
the 
three 
longest 
branches 
originating from the left anterior descending 
artery to supply the anterolateral wall of the left 
ventricle (D2) 
Second diagonal lateral branch 
Branch of the second diagonal branch 
Third diagonal branch 
Third of the three longest branches originating 
from the left anterior descending artery to 
supply the anterolateral wall of the left ventricle 
(D3) 
Third diagonal lateral branch 
Branch of the third diagonal branch 
Anterior descending septal perforator 
Septal perforator vessel originating from the 
left anterior descending artery to supply the 
interventricular septum 
Left circumflex artery ostium 
Origin of the left circumflex coronary artery, 
including the first 3 mm of the artery 
Proximal left circumflex artery 
Proximal portion of the left circumflex 
coronary artery, from the ostium to the origin 
(or the nominal location of) the first marginal 
branch (pLCX) 
Mid left circumflex artery 
Middle portion of the left circumflex coronary 
artery, from the origins of (or nominal locations 


 
 
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of) the first marginal to the second marginal 
(mLCX) 
Distal left circumflex artery 
Distal portion of the left circumflex coronary 
artery, from the origin of (or the nominal 
location of) the second marginal to the terminus 
(in right dominant systems), or to the origin of 
the 1st left posterolateral in all other dominance 
systems (dLCX) 
First obtuse marginal branch 
First of the three longest branches originating 
from the left circumflex artery to supply the 
lateral wall of the left ventricle (OM1) 
First obtuse marginal lateral branch 
Branch of the first marginal branch 
Second obtuse marginal branch 
Second 
of 
the 
three 
longest 
branches 
originating from the left circumflex artery to 
supply the lateral wall of the left ventricle 
(OM2) 
Second 
obtuse 
marginal 
lateral 
branch 
Branch of the second marginal branch 
Third obtuse marginal branch 
Third of the three longest branches originating 
from the left circumflex artery to supply the 
lateral wall of the left ventricle (OM3) 
Third obtuse marginal lateral branch Branch of the third marginal branch 
Left atrioventricular artery 
In left dominant and mixed circulations, the 
distal continuation of the left circumflex 
coronary 
artery 
in 
the 
posterior 
atrioventricular groove 
Left posterior descending artery 
In left dominant circulations, the vessel that 
arises from the distal continuation of the left 
atrioventricular artery, travels in the posterior 
interventricular groove, and supplies septal 
perforator branches (LPDA) 
First left posterolateral branch 
In left dominant and mixed circulations, the 
first posterolateral branch originating from the 
posterior atrioventricular left circumflex artery 
(LPL1) 
Second left posterolateral branch 
In left dominant and mixed circulations, the 
second posterolateral branch originating from 
the posterior atrioventricular left circumflex 
artery (LPL2) 


 
 
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Third left posterolateral branch 
In left dominant and mixed circulations, the 
third posterolateral branch originating from 
the posterior atrioventricular left circumflex 
artery (LPL3) 
Ramus intermedius branch 
Branch vessel whose origin bisects the origins of 
the left anterior descending and circumflex 
arteries (RI) 
Ramus intermedius lateral branch 
Branch of the ramus intermedius branch 
 
3. Dissection: 
Based on the National Heart, Lung, and Blood Institute (NHLBI) Dissection 
Classification System: 
 Grade A: Minor radiolucencies within the lumen during contrast injection with no 
persistence after dye clearance 
 Grade B: Parallel tracts or double lumen separated by a radiolucent area during 
contrast injection with no persistence after dye clearance 
 Grade C: Extraluminal cap with persistence of contrast after dye clearance from the 
lumen 
 Grade D: Spiral luminal filling defect with delayed but complete distal flow 
 Grade E: New persistent filling defect with delayed antegrade flow 
 Grade F: Non-A-E types with total coronary occlusion and no distal antegrade flow 
 
Note: Grade E and F dissections may represent thrombus 
 
4. Late Loss: Minimum lumen diameter (MLD) assessed at follow-up angiography minus 
the MLD assessed immediately after the index procedure. MLDs are measured by QCA. 
 


 
 
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5. Minimum Lumen Diameter (MLD): The mean minimum lumen diameter (typically 
measured in-lesion, in-stent, and in-segment) derived from two orthogonal views by 
QCA. 
 
6. No Reflow: An acute reduction in coronary flow (TIMI grade 0-1) in the absence of 
dissection, thrombus, spasm, or high-grade residual stenosis at the original target lesion. 
 
7. Percent Diameter Stenosis (% DS): The value calculated as 100 x (1 – MLD/RVD) 
using the mean values determined by QCA from two orthogonal views (when possible).  
 
8. Reference Vessel Diameter (RVD): Defined as the average of normal segments within 
10 mm proximal and 10 mm distal to the target lesion from two orthogonal views using 
QCA.  
 
9. Restenosis: Re-narrowing of the vessel following the treatment of a prior stenosis 
 
 Binary restenosis: A diameter stenosis of > 50% at the previously treated lesion 
site, including the originally treated site plus the adjacent vascular segments 5 mm 
proximal and 5 mm distal to the site. 
 
 In-stent restenosis (ISR): A previously stented lesion with a > 50% diameter. 
stenosis. 
 
10. Thrombus (Angiographic): A discrete, mobile, intraluminal filling defect with defined 
borders with or without associated contrast staining. 
 
11. TIMI (Thrombolysis in Myocardial Infarction) Flow Grades:  
 
 Grade 0 (no perfusion): There is no antegrade flow beyond the point of occlusion.
 
 
 
 Grade 1 (penetration without perfusion): The contrast material passes beyond the 
area of obstruction but “hangs up” and fails to opacify the entire coronary bed distal 
to the obstruction for the duration of the cineangiographic filming sequence. 
 
 Grade 2 (partial perfusion): The contrast material passes across the obstruction and 
opacifies the coronary bed distal to the obstruction. However, the rate of entry of 
contrast material into the vessel distal to the obstruction or its rate of clearance from 
the distal bed (or both) is perceptibly slower than its entry into or clearance from 


 
 
Protocol CL04018075  
 
version 4.0 final dated October 02, 2021 
CONFIDENTIAL 
Translation dated 27-Oct-2021 
based on Russian Version 4.0 dated 02-Oct-2021 
Page 98 of 98 
comparable areas not perfused by the previously occluded vessel (e.g., the opposite 
coronary artery or the coronary bed proximal to the obstruction). 
 
 Grade 3 (complete perfusion): Antegrade flow into the bed distal to the obstruction 
occurs as promptly as antegrade flow into the bed proximal to the obstruction and 
clearance of contrast material from the involved bed is as rapid as from an 
uninvolved bed in the same vessel or the opposite artery. 
 
12. Vessels 
 Left main coronary artery (LMCA) 
 Left anterior descending artery (LAD) with septal and diagonal branches 
 Left circumflex artery (LCX) with obtuse marginal branches 
 Ramus intermedius artery 
 Right coronary artery (RCA) and any of its branches 
 Posterior descending artery 
 Saphenous vein bypass graft(s) 
 Arterial bypass graft(s): Right internal mammary graft, left internal mammary graft, 
radial artery graft, and gastroepiploic artery graft.