Clinical trial NCT04067492
Conditions: Gout Attack
Keywords: hyperuricemia acute arthritis gouty arthritis gout
Sponsor: R-Pharm
Start date: 2018-03-26; Completion date: 2020-05-12
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary goal of the study was to evaluate the parameters of efficacy, pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of RPH-104 in adult patients with acute gout attack.

Detailed description:
The study consisted of two periods:

Period 1. In Study Period 1, eligible patients were enrolled in a group of 22 patients and randomized to receive either RPH-104 4 mg or Voltaren® (diclofenac) in the 15:7 ratio (15 RPH-104: 7 Voltaren® (diclofenac)). In order to prevent damage to the gastric and duodenal mucosa caused by Voltaren® (diclofenac), all patients receiving Voltaren® (diclofenac) had to simultaneously take Ortanol® (omeprazole) 20 mg, orally (1 capsule) daily before breakfast throughout the course of Voltaren® (diclofenac) treatment

Period 2. Upon completion of the enrollment of 22 patients, Study Period 2 started. In Period 2, newly enrolled patients were randomly assigned to one of 5 treatment groups: RPH-104 20 mg, 40 mg, 80 mg and 160 mg and active control (Voltaren® (diclofenac)). It was planned to include 14 patients in the RPH-104 groups in Period 2, and 7 patients in the Voltaren® (diclofenac) group.

The enrollment of patients in Period 1 and Period 2 was sequential. There was no pause between the enrollment of patients in Period 1 and Period 2. The study design included screening (24 hours), 11 visits to the study site, and a phone call at the end of the 60-day follow-up period.

Total number of patients which were planned to be enrolled for the study: 85 (15 patients in the group of treatment with RPH-104 4 mg and 14 patients in the each of the other treatment groups). Due to the low patient recruitment rate in the study and the negative impact of the COVID-19 pandemic on the recruitment, at the decision of the sponsor, an interim analysis of the data of 47 patients included in the study as of November 2020 was carried out in order to assess the feasibility of continuing recruitment and further conducting the study.

Patients who did not tolerate pain were allowed to receive a rescue medication, triamcinolone acetonide 40 mg intramuscularly, to intensify therapy 2 hours after the test product was administered. If the attack recurred after the use of the rescue medication, treatment was carried out in accordance with the standard practice of the hospital.

The primary efficacy endpoints were evaluated 72 hours after the end of administration of the test drug. The secondary efficacy endpoints were evaluated for 45 days of the treatment period and follow-up. The safety parameters were evaluated for 60 days of the treatment period and follow-up. Total duration of the study for a volunteer was not more than 70 days.

Arms: arm 1: Subjects randomized to receive RPH-104, 4 mg, subcutaneous single-dose injection. In order to administer RPH-104 at the dose of 4 mg, 0.1 mL of RPH-104 solution is injected. arm 2: Subjects randomized to receive RPH-104, 20 mg, subcutaneous single-dose injection. In order to administer RPH-104 at the dose of 20 mg, 0.5 mL of RPH-104 solution is injected. arm 3: Subjects randomized to receive RPH-104, 40 mg, subcutaneous single-dose injection. In order to administer RPH-104 at the dose of 40 mg, 1 mL of RPH-104 solution is injected. arm 4: Subjects randomized to receive RPH-104, 80 mg, subcutaneous single-dose injection. In order to administer RPH-104 at the dose of 80 mg, 2 mL (whole vial) of RPH-104 solution is injected. arm 5: Subjects randomized to receive RPH-104, 160 mg, two subcutaneous injections of 80 mg administered at different injection sites. (1 vial of 2mL solution per each site) arm 6: Subjects randomized to receive Voltaren® (diclofenac) orally with water at the dose 50 mg thrice daily for 3 days (150 mg total daily dose), then 25 mg thrice daily for 9 days (75 mg total daily dose)
Interventions: intervention 1: RPH - 104 intervention 2: Voltaren®
Intervention descriptions: intervention 1: solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial intervention 2: Enteric-coated tablets, 25 mg and 50 mg

Protocol documents:
Prot_SAP_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
Investigational product 
provided by the Sponsor: 
RPH-104/L04018 
Study Sponsor 
Legal address 
R-Pharm International LLC 
123154, Russian Federation, Moscow, 19 Berzarina St., bld. 1, 
floor 1, office V, room 9 
Phone: +7 (495) 956-79-37 
Study Protocol Code: 
CL04018054 
Study title: 
An Open-label, Single-dose, Active-controlled Randomized Phase 
IIa Clinical Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of RPH-104 (L04018) 
Administered at Different Doses to Patients With Acute Gout 
Attack 
Study phase: 
IIa 
Protocol version: 
7.0 
Study Protocol Date: 
November 19, 2020 
 
 
CONFIDENTIALITY STATEMENT 
The present document contains commercial information that is inviolable or confidential, and 
may not be disclosed unless required by law. In any case, persons who come into possession of 
this information should be notified that this information is inviolable or confidential and should 
not be disclosed further. These disclosure limitations will be equally applied to all subsequent 
information submitted to you if it is marked as inviolable or confidential. 


R-Pharm International LLC 
CL04018054 Clinical Study Protocol 
RPH-104 
Version 7.0 of November 19, 2020 
 
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SIGNATURE PAGE 1 (STUDY SPONSOR) 
 
By signing this statement, the person signing this document approves the study protocol, version 
7.0 of November 19, 2020, and confirms that it has been created in accordance with the Ethical 
Principles of the Declaration of Helsinki, current edition of the ICH GCP E6 Good Clinical 
Practice Guidelines and applicable legislations. According to the Power of Attorney No. 25 dated 
May 14, 2018 issued by R-Pharm International LLC: 
 
Signature: 
Mikhail Yuryevich Samsonov, Cand. Med. Sci. 
Date:  
 
 


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SIGNATURE PAGE 2 (PRINCIPAL INVESTIGATOR) 
By signing this page, the Investigator approves the Study Protocol, version 7.0 of November 19, 
2020, and assumes an obligation to conduct the study at his/her study site in accordance with all 
requirements of the Protocol, including all the data confidentiality requirements, as well as the 
ethical principles of the Declaration of Helsinki, ICH GCP E6 Good Clinical Practice guidelines, 
and local regulatory requirements. 
Healthcare institution/study site 
address: 
Signature: 
Full name and position: 
Date: 
 
 


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CONTACT INFORMATION 
Study Sponsor: R-PHARM INTERNATIONAL LLC 
The study is conducted by R-Pharm JSC. 
NAME 
Position 
Contact information 
Mikhail Yuryevich 
Samsonov 
Director, Medical Department, R-
Pharm JSC 
Phone: +7 (985) 997-39-02 
e-mail: samsonov@rpharm.ru 
Sergey Alexandrovich 
Grishin 
Head of the Group of Scientific 
Business Support, Head of the Drug 
Safety Department, R-Pharm JSC 
Phone: +7 (963) 683-05-71 
e-mail: sa.grishin@rpharm.ru 
Margarita Leonidovna 
Shchedrova 
Scientific Adviser, R-Pharm JSC 
Phone: +7 (965) 765-14-39 
e-mail: schedrova@rpharm.ru 
Anastasia Valentinovna 
Alexandrova 
Head of the Department for Quality 
Assurance and Quality Control, R-
Farm JSC 
Phone: +7 (926) 098 26 10 
e-mail: av.aleksandrova@rpharm.ru 
Konstantin 
Alexandrovich Katkov 
Project manager, R-Pharm JSC 
Phone: +7 (968) 363-41-23 
e-mail: katkov@rpharm.ru 
 
Emergency Contact Information 
For medical advice in an emergency, please contact the on-duty medical expert Sergey Grishin: 
Emergency Contact Number: 
+7 (963) 683-05-71 
 
When reporting serious adverse events, one must be guided by the procedures described in 
Section 12.5. Investigators should inform the Sponsor of the development of serious adverse 
events within 24 hours of receipt of relevant information. The completed SAE notification form 
must be sent to the following number/ email address: 
Contact information for SAE reporting 
(24-hour) 
Fax: +7 (495) 956-79-38 
Safety@Rpharm.ru 
 
 


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Study sites 
The study will involve up to 19 sites in the Russian Federation. 
No. 
Principal 
Investigator (full 
name) 
Site Name: 
Address: legal address, 
postal address 
Telephone 
1 
Ivan 
Gennadievich 
Gordeev 
State Budgetary Health Care Institution of 
the city of Moscow, O.M. Filatov Municipal 
Clinical Hospital No. 15, Moscow Healthcare 
Department 
Russia, 111539, Moscow, 
Veshnyakovskaya, St. 23 
+7 (495) 918 72 84 
2 
Olga 
Borisovna 
Ershova 
State Autonomous Healthcare Institution of 
the Yaroslavl Region N.V. Solovyev Clinical 
Emergency Hospital 
Russia, 150003, Yaroslavl, 
Zagorodnyy sad St., 11 
+7 (4852) 73 71 03, 
+7 (4852) 73 55 15 
3 
Elena Vladimirovna 
Zonova 
Private 
Healthcare 
Institution 
Railway 
Clinical Hospital at Novosibirsk-Glavny 
Railway Station of the Open Joint Stock 
Company Russian Railways 
Russia, 630003, 
Novosibirsk, Vladimirovsky 
Spusk, 2a 
+7 (383) 201 37 50 
4 
Marianna 
Semenovna Petrova 
St. Petersburg State Budgetary Healthcare 
Institution 
Municipal 
Clinical 
Rheumatological Hospital No. 25 
Russia, 190068, St. 
Petersburg, Bolshaya 
Podyacheskaya St., 30, lit. A 
+7 (812) 310 99 24 
5 
Andrey Eduardovich 
Pikhlak 
Federal State Budgetary Institution of Higher 
Education A.I. Evdokimov Moscow State 
Medical 
University 
of 
Medicine 
and 
Dentistry of the Ministry of Health of the 
Russian 
Federation 
At: 
Moscow City State Autonomous Healthcare 
Institution Moscow Scientific and Practical 
Center 
for 
Medical 
Rehabilitation, 
Restorative and Sports Medicine, Moscow 
Healthcare Department, Branch No. 3 
Legal address of the 
principal institution: 
Russia, 127473, Moscow, 
Delegatskaya St., 20, bldg. 1 
Legal address of the 
clinical site: 
Russia, 105120, Moscow, 
Zemlyanoy Val St., 53 
Actual address of the 
clinical site: 
Russia, 111674, Moscow, 2-
ya Volskaya St., 19, bldg. 3 
+7 (495) 410 51 73 
6 
Svetlana 
Anatolyevna 
Polyakova 
LLC Medical Center Maximum Zdorovya 
Russia, 650056, Kemerovo, 
Khimikov Ave., 8 
+7 (384) 254 91 44 
7 
Marina Leonidovna 
Stanislav 
Federal State Budgetary Scientific Institution 
V.A. 
Nasonova 
Research 
Institute 
of 
Rheumatology 
Russia, 115522, Moscow, 
Kashirskoe shosse, 34a 
+7 (499) 614 44 88 
8 
Elena 
Anatolyevna 
Smolyarchuk 
Federal State Autonomous Higher Education 
Institution “I.M. Sechenov First Moscow 
State Medical University” under the Ministry 
of 
Health 
of 
the 
Russian 
Federation 
(Sechenov University) 
Russia, 119991, Moscow, 
Trubetskaya St., 8, bldg. 2 
+7 (495) 915 15 78 
+7 (499) 245 04 68 
9 
Evgenia 
Isaakovna 
Schmidt 
Moscow 
City 
State 
Budgetary 
Health 
Institution N.I. Pirogov Municipal Clinical 
Hospital 
No. 
1, 
Moscow 
Healthcare 
Department (N.I. Pirogov City Clinical 
Hospital No. 1) 
Russia, 119049, Moscow, 
Leninsky Prospekt, 8 
+7 (495) 536 92 33 
10 Natalya Evgenievna Vladimir Region State Budgetary Institution Russia, 600023, Vladimir, 


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No. 
Principal 
Investigator (full 
name) 
Site Name: 
Address: legal address, 
postal address 
Telephone 
Nikulenkova 
of Healthcare Regional Clinical Hospital 
Sudogodskoe shosse, 41 
+7 (4922) 40 71 36 
11 
Marina 
Zinovievna 
Kanevskaya 
Moscow 
City 
State 
Budgetary 
Health 
Institution A.K. Yeramishantsev Municipal 
Clinical 
Hospital, 
Moscow 
Healthcare 
Department 
Russia, 129327, Moscow, 
Lenskaya St., 15 
+7 (495) 471 15 70 
12 
Svetlana 
Borisovna 
Erofeeva 
State Budgetary Healthcare Institution of 
Moscow Region Krasnogorsk Municipal 
Hospital No. 1 
Russia, 143408, Moscow 
Region, Krasnogorsk, 
Karbysheva St., 4 
+ 7 (495) 563 13 31 
13 
Olga 
Mikhailovna 
Lesnyak 
Limited Liability Company Astarta 
Russia, 199226, St. 
Petersburg, Nakhimova St., 
11, lit. A, room 49H, part of 
room 38H 
+7 (812) 337 23 03 
14 
Natalia 
Georgievna 
Poteshkina 
State Budgetary Health Care Institution of 
the city of Moscow, Municipal Clinical 
Hospital 
No. 
52, 
Moscow 
Healthcare 
Department 
Russia, 123182, Moscow, 
Pekhotnaya St., 3 
Phone: +7 (910) 442 22 16 
15 
Anton 
Sergeevich 
Povzun 
State Budgetary Institution I.I. Dzhanelidze 
St. 
Petersburg 
Research 
Institute 
for 
Emergency Medicine   
Russia, 192242, St. 
Petersburg, Budapestskaya 
St., 3 
Phone: +7(812) 709 61 57 
16 
Valentina 
Nikolaevna 
Sorotskaya 
State Healthcare Institution Tula Regional 
Clinical Dermatovenerologic Dispensary 
Russia, 300053, Tula, 1-y 
proezd M. Raskovoy, 1-A 
Phone: +7(4872) 48 66 21 
17 
Olga 
Viktorovna 
Bugrova 
Federal 
State 
Budgetary 
Educational 
Institution of Higher Education Orenburg 
State Medical University, Ministry of Health 
of the Russian Federation 
Russia, 460000, Orenburg, 
Sovetskaya St., 6 
Phone: +7(3532) 76 58 42 
18 
Galina 
Vasilievna 
Shestakova 
State Budgetary Health Care Institution of 
the Nizhny Novgorod Region City Clinical 
Hospital No. 13 of the Avtozavodsky 
District, Nizhny Novgorod 
Russia, 603018, Nizhny 
Novgorod, Patriotov St., 51 
Phone: +7 (831) 255 67 71 
19 
Konstantin 
Anatolyevich 
Zakharov 
Limited Liability Company Research Center 
Eco-Safety 
Russia, 196143, St. 
Petersburg, Yuriya Gagarina 
Ave., 65 
Phone: +7(812) 500 52 03 
 
Central laboratories 
1) Central Laboratory for the evaluation of pharmacokinetics, anti-drug antibodies 
and cytokines 
Laboratory of Immunochemistry 
Covance Laboratories Limited 
Immunochemistry Department 
Otley Road Harrogate North Yorkshire HG3 1PY. United Kingdom 
Contact person: Natalie Hayles 
phone: +44 (0)1423 635660 


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fax: +44 1423 569595 
e-mail:Natalie.Hayles@covance.com 
2) Central Laboratory for assessment of other samples 
CJSC Unimed Laboratories 
119049, Moscow, Chetverty Dobryninsky per., 4 
Phone: +7495931 99 76 
fax: +7495768 10 34 
www.unimedlab.ru 
Contact person: prof. Saprygin D.B. 
Program Manager 
Phone: +7 495 773 88 46 
е-mail: saprygin@unimedlab.ru 
 
 


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LIST OF ABBREVIATIONS 
ANCOVA 
Analysis of covariance 
AUC(0-∞) 
Area under the concentration of active substance–time curve in the time interval 
from zero (before taking the drug) to infinity 
AUC(0-t) 
Area under the concentration of active substance–time curve in the time interval 
from zero (before taking the drug) to the last detected concentration of the drug 
Cmax 
Maximum concentration of the active substance 
CTCAE 
Common Terminology Criteria for Adverse Events 
GCP 
Good Clinical Practice 
HAQ 
Health assessment questionnaire 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
LLoQ 
Lower limit of quantification 
LOCF 
Last observation carried forward 
T½ 
Half-life related to the terminal phase of the PK curve 
tmax 
Time to maximum concentration of the active substance 
SUSAR 
Suspected unexpected serious adverse reaction 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
APTT 
Activated partial thromboplastin time 
VAS 
Visual Analogue Scale 
ULN 
Upper Limit of Normal 
HIV 
Human Immunodeficiency Virus 
WHO 
World Health Organization 
GGT 
Gamma-glutamyl transpeptidase 
IL 
Interleukin 
BMI 
Body mass index 
CRF 
Case Report Form 
LDH 
Lactate dehydrogenase 
HDL 
High-density lipoproteins 
LDL 
Low-density lipoproteins 
INR 
International normalized ratio 
INN 
International nonproprietary name 
ADR 
Adverse Drug Reaction 
NSAID 
Nonsteroidal anti-inflammatory drug 
AE 
Adverse event 
SAE 
Serious adverse event 
ESR 
Erythrocyte sedimentation rate 
(hs) CRP 
(high-sensitivity) C-reactive protein 
PK 
Pharmacokinetics 
TNF 
Tumor necrosis factor 
HCG 
Human chorionic gonadotropin 


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RPH-104 
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ALP 
Alkaline phosphatase 
ECG 
Electrocardiogram 
 
 


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TABLE OF CONTENTS 
CONTACT INFORMATION ......................................................................................................... 4 
LIST OF ABBREVIATIONS ......................................................................................................... 8 
TABLE OF CONTENTS .............................................................................................................. 10 
2 
PROTOCOL SYNOPSIS .................................................................................................... 14 
3 
STUDY FLOW CHART ..................................................................................................... 18 
4 
STUDY RATIONALE AND GOAL................................................................................... 24 
4.1 
General information about the disease ............................................................................ 24 
4.2 
Description of investigational products and concomitant therapy .................................. 25 
4.2.1 Treatment with RPH-104 (investigational product provided by the sponsor) ............ 25 
4.2.2 Voltaren® (diclofenac) – reference product ................................................................ 25 
4.2.3 Ortanol® (omeprazole) – concomitant medication ..................................................... 26 
4.2.4 Triamcinolone acetonide (rescue medication) ............................................................ 27 
4.3 
Preclinical and clinical trial results essential for this study ............................................. 28 
4.3.1 Preclinical studies ....................................................................................................... 28 
4.3.2 Clinical pharmacology trials ....................................................................................... 28 
4.3.3 Adverse events during RPH-104 therapy ................................................................... 29 
4.4 
Concise description of known risks and potential benefits associated with the use of the 
investigational product .................................................................................................... 32 
4.5 
Justification for the sample size ...................................................................................... 32 
4.6 
Justification for the method of administration, dosing, dosing regimen, and treatment 
course............................................................................................................................... 32 
4.7 
Conformity of the principles of this study to international, regional, and other standards
 ......................................................................................................................................... 33 
5 
STUDY GOAL AND OBJECTIVES .................................................................................. 34 
5.1 
Study goal ........................................................................................................................ 34 
5.2 
Study objectives .............................................................................................................. 34 
6 
STUDY DESIGN................................................................................................................. 34 
6.1 
Primary and secondary endpoints.................................................................................... 34 
6.1.1 Primary efficacy variable ............................................................................................ 34 
6.1.2 Other efficacy variables .............................................................................................. 34 
6.1.3 Pharmacokinetic variables .......................................................................................... 35 
6.1.4 Pharmacodynamic variables ....................................................................................... 35 
6.1.5 Safety variables ........................................................................................................... 35 
6.1.6 Immunogenicity assessment ....................................................................................... 35 
6.2 
Study design and study design flowchart ........................................................................ 35 
6.3 
Subjectivity minimization measures ............................................................................... 37 
6.3.1 Randomization ............................................................................................................ 37 
6.3.2 Blinding ...................................................................................................................... 38 
7 
SELECTION OF THE PATIENT POPULATION ............................................................. 38 
7.1 
Principal diagnosis .......................................................................................................... 38 
7.2 
Inclusion criteria .............................................................................................................. 38 
7.3 
Exclusion criteria ............................................................................................................. 39 
8 
WITHDRAWAL FROM THE STUDY AND PREMATURE TERMINATION OF THE 
STUDY ................................................................................................................................ 40 
8.1 
Early withdrawal from the study ..................................................................................... 41 
8.2 
Premature termination of the study at an individual study site and premature termination 
of the study in general ..................................................................................................... 41 
9 
PATIENT TREATMENT .................................................................................................... 42 
9.1 
Description of investigational products and concomitant therapy .................................. 42 


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9.2 
Packaging and labelling................................................................................................... 43 
9.3 
Storage conditions ........................................................................................................... 43 
9.4 
Accounting and destruction of investigational products and concomitant therapy ......... 44 
9.5 
Dose, method of administration, dosing regimen, and duration of therapy .................... 44 
9.5.1 Use of the investigational product RPH-104 .............................................................. 44 
9.5.2 Voltaren® (diclofenac) intake ..................................................................................... 45 
9.5.3 Duration of treatment .................................................................................................. 45 
9.6 
Overdose with the sponsor’s investigational product...................................................... 46 
9.7 
Compliance assessment ................................................................................................... 46 
9.8 
Previous and concomitant therapies ................................................................................ 46 
9.8.1 Orthanol® (omeprazole) .............................................................................................. 46 
9.8.2 Rescue therapy for a gout attack ................................................................................. 46 
9.8.3 Recording information on prior and concomitant therapy ......................................... 47 
9.8.4 Allowed concomitant therapy ..................................................................................... 47 
9.8.5 Prohibited concomitant therapy .................................................................................. 47 
9.9 
Contraception during the study ....................................................................................... 48 
10 
CLINICAL EVALUATION PLAN AND STUDY VISITS ............................................... 48 
10.1 Pre-screening ................................................................................................................... 48 
10.2 Screening and treatment period ....................................................................................... 49 
10.3 Follow-up visit for early patient withdrawal from the study ........................................... 58 
10.4 Assessment of efficacy parameters before using the rescue medication......................... 59 
10.5 Unscheduled visits ........................................................................................................... 59 
11 
DESCRIPTION OF THE VARIABLES AND ASSESSMENT METHODS ..................... 59 
11.1 Baseline characteristics ................................................................................................... 59 
11.1.1 
Information on the primary disease ..................................................................... 59 
11.1.2 
Demographic data ................................................................................................ 59 
11.1.3 
Measurement of body weight and height ............................................................. 59 
11.1.4 
Collection of medical history data and information on concomitant diseases..... 60 
11.1.5 
Evaluation of creatinine, complete blood count parameters, chest X-ray ........... 60 
11.1.6 
Diagnosis of infections (HIV, hepatitis B, hepatitis C) ....................................... 60 
11.1.7 
Diagnosis of tuberculosis ..................................................................................... 61 
11.1.8 
Serum Pregnancy Test ......................................................................................... 61 
11.2 Evaluation of pharmacokinetics and anti-drug antibodies .............................................. 61 
11.2.1 
Analytical method ................................................................................................ 62 
11.3 Assessment of pharmacodynamics .................................................................................. 62 
11.4 Efficacy assessment ......................................................................................................... 62 
11.4.1 
Measurement of pain intensity in the assessed joint ............................................ 62 
11.4.2 
Patient global assessment of efficacy .................................................................. 62 
11.4.3 
Assessment of the degree of swelling, tenderness, and erythema in the assessed 
joint by physician ........................................................................................................ 63 
11.4.4 
Assessment of the degree of movement restriction in the assessed joint by 
physician ..................................................................................................................... 63 
11.4.5 
Assessment of the amount of the rescue medication used by the patient ............ 63 
11.4.6 
Health assessment questionnaire (HAQ) assessment .......................................... 64 
11.5 Safety and tolerability assessment ................................................................................... 64 
11.5.1 
Adverse event assessment .................................................................................... 64 
11.5.2 
Assessment of injection site reactions ................................................................. 64 
11.5.3 
Physical examination ........................................................................................... 64 
11.5.4 
Assessment of vital signs ..................................................................................... 64 
11.5.5 
Electrocardiography ............................................................................................. 64 
11.5.6 
Laboratory blood tests ......................................................................................... 65 


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11.5.7 
Urinalysis ............................................................................................................. 66 
12 
ADVERSE EVENTS ........................................................................................................... 67 
12.1 Adverse event recording .................................................................................................. 67 
12.2 Causality assessment between the adverse event and the use of the investigational 
product ............................................................................................................................. 68 
12.3 Adverse event severity .................................................................................................... 69 
12.4 Serious adverse events (SAEs) ........................................................................................ 69 
12.5 SAE reporting procedure ................................................................................................. 69 
12.6 Investigator’s responsibilities related to reporting of serious adverse events ................. 70 
12.7 Pregnancy ........................................................................................................................ 70 
12.8 Actions in emergency situations...................................................................................... 71 
12.9 Follow-up of adverse events............................................................................................ 71 
13 
DATA ANALYSIS AND STATISTICAL ANALYSES .................................................... 71 
13.1 General provisions ........................................................................................................... 71 
13.1.1 
Analysis populations ............................................................................................ 71 
13.1.2 
Sample size .......................................................................................................... 72 
13.1.3 
Planned number of subjects in each site .............................................................. 72 
13.1.4 
Applicable level of significance........................................................................... 72 
13.1.5 
Study termination criteria .................................................................................... 72 
13.1.6 
Missing data ......................................................................................................... 72 
13.1.7 
Deviations from the statistical analysis plan ........................................................ 72 
13.1.8 
Demographics, information concerning the primary disease, and other baseline 
parameters ................................................................................................................... 73 
13.1.9 
Concomitant therapy ............................................................................................ 73 
13.2 Pharmacokinetic analysis ................................................................................................ 73 
13.3 Analysis of anti-drug antibody levels .............................................................................. 74 
13.4 Pharmacodynamic analysis ............................................................................................. 74 
13.5 Efficacy analysis.............................................................................................................. 74 
13.5.1 
Efficacy endpoints ............................................................................................... 74 
13.5.2 
Analysis of the primary efficacy endpoint ........................................................... 75 
13.5.3 
Analysis of other efficacy endpoints ................................................................... 75 
13.6 Safety data analysis ......................................................................................................... 76 
13.6.1 
Adverse events ..................................................................................................... 76 
13.6.2 
Vital signs ............................................................................................................ 76 
13.6.3 
Electrocardiography ............................................................................................. 76 
13.6.4 
Laboratory tests .................................................................................................... 76 
13.6.5 
Concomitant therapy ............................................................................................ 76 
13.7 Interim data analysis ........................................................................................................ 77 
14 
DATA HANDLING, DOCUMENTATION MANAGEMENT AND STORAGE ............ 77 
14.1 Source documents............................................................................................................ 77 
14.2 Archiving of study documentation at the study site ........................................................ 77 
15 
STUDY MONITORING AND QUALITY ASSURANCE ................................................ 79 
15.1 Study monitoring ............................................................................................................. 79 
15.2 Study quality assurance ................................................................................................... 79 
16 
ETHICAL ASPECTS OF THE STUDY ............................................................................. 79 
16.1 General provisions ........................................................................................................... 79 
16.2 Informed Consent Form for participation in the study, consent to transfer and 
management of personal data, and consent to disclosure of confidential health 
information ...................................................................................................................... 80 
16.3 Confidentiality and identification of study subjects ........................................................ 80 
16.4 Ethics Committee / Local Ethics Committee .................................................................. 80 


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17 
FUNDING AND INSURANCE .......................................................................................... 80 
18 
PUBLICATION ................................................................................................................... 80 
REFERENCES .............................................................................................................................. 81 
APPENDIX 1. 
Tuberculosis risk assessment questionnaire ................................................. 83 
APPENDIX 2. 
Assessment of the degree of swelling, tenderness, erythema and movement 
restriction in the assessed joint ............................................................................................. 84 
 
LIST OF FIGURES 
Figure 6.1 
Flow diagram of the study design............................................................................ 37 
Figure 9.1 
Areas of the anterior abdominal wall where RPH-104 should be administered. .... 45 
 
LIST OF TABLES 
Table 3.1 Schedule of the study procedures ............................................................................... 18 
Table 4.1 
Pharmacokinetic parameters of RPH-104 after a single subcutaneous injection in 
healthy volunteers ................................................................................................................ 28 
Table 4.2 Adverse events reported in a phase 1 study of RPH-104 in healthy volunteers ......... 30 
Table 6.1 Number of patients by treatment groups .................................................................... 36 
Table 9.1 Injected volume of RPH-104 to patients .................................................................... 45 
 
 


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2 
PROTOCOL SYNOPSIS 
Sponsor Name: 
R-Pharm International LLC 
 
 
Investigational medicinal product provided by the 
Sponsor: 
RPH-104/L04018 
Name of the active ingredient: 
RPH-104/L04018 
Study title: 
An Open-label, Single-dose, Active-controlled Randomized Phase IIa Clinical 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of RPH-104 (L04018) Administered at Different Doses to 
Patients With Acute Gout Attack 
Study sites: 
Approximately 19 sites in the Russian Federation 
Clinical study phase: 
IIa 
Study goal and 
objectives: 
Study goal: 
To evaluate the efficacy, pharmacokinetics, pharmacodynamics, safety and 
tolerability of RPH-104 following a single injection in adult patients with an 
acute gout attack. 
Objectives: 
 
To investigate the efficacy of RPH-104 in the treatment of an acute 
gout attack following a single subcutaneous injection at doses of 4, 20, 
40, 80 and 160 mg; 
 
To investigate the pharmacokinetics of RPH-104 following its single 
subcutaneous injection; 
 
To investigate the effect of RPH-104 following its single subcutaneous 
injection on concentrations of high-sensitivity C-reactive protein (hs-
CRP), serum amyloid protein, blood cytokines (IL-1α, IL-1β, IL-1RA, 
IL-6, IL-8, TNF-α); 
 
To investigate the safety parameters of RPH-104 in adult patients with 
an acute gout attack. 
Study methods: 
A multicenter, randomized, parallel group, single-dose, phase IIa, open-label 
study of the sponsor's investigational product to evaluate its efficacy, 
pharmacokinetics, pharmacodynamics, and safety. 
It is planned to enroll patients in two periods: in the first period, it is planned to 
randomize 7 patients for treatment with the reference product Voltaren® 
(diclofenac) and 15 patients for treatment with RPH-104 4 mg; in the second 
period, it is planned to randomize 7 patients into the reference product 
Voltaren® (diclofenac) group and 56 patients into the RPH-104 groups at doses 
of 20 mg, 40 mg, 80 mg and 160 mg, 14 patients in each group. 
Number of patients: 
 
Number of patients 
participating in the 
study enrollment 
procedures: 
up to 135 
Patients treated with 
investigational product 
therapy: 
85 
In each treatment treatment with RPH-104: 15 patients – 4 mg, 14 patients – doses of 20 mg, 40 


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Translation of Protocol final version 7.0 dated November 19, 2020 into English dated February 26, 2022 
Sponsor Name: 
R-Pharm International LLC 
 
 
Investigational medicinal product provided by the 
Sponsor: 
RPH-104/L04018 
Name of the active ingredient: 
RPH-104/L04018 
group: mg, 80 mg, 160 mg 
therapy with Voltaren® (diclofenac): 14 patients 
Primary diagnosis: 
Acute gout attack 
Main eligibility 
criteria: 
Male and female patients aged 18 to 80 years with an acute gout attack that 
occurred within not more than 120 hours (5 days) before randomization, with 
at least one painful joint at screening with pain intensity of 50 mm and more 
on a 100 mm visual analogue scale (VAS) for pain intensity assessment. 
Investigational product 
provided by the 
Sponsor: 
RPH-104, solution for subcutaneous injection, 40 mg/ml 
Doses: 4, 20, 40, 80, 160 mg 
Route of 
administration: 
For doses 4, 20, 40, 80 mg – subcutaneously, once. A 160 mg dose is divided 
into two injections, 80 mg each at different injection sites. 
Reference product: 
Voltaren® (diclofenac), enteric-coated tablets 
Doses: 50 mg and 25 mg 
Route of 
administration: 
Orally, 50 mg 3 times a day for 3 days, then 25 mg 3 times a day for 9 days 
(total 12 days). 
Rescue therapy: Patients who do not tolerate pain receive the rescue medication 2 hours after 
the first use of the investigational product to intensify therapy. The rescue 
medication is triamcinolone 40 mg intramuscularly. If an attack recurs after the 
use of the rescue medication, treatment is carried out in accordance with the 
standard practice of the hospital. 
Concomitant therapy: In order to prevent damage to the gastric and duodenal mucosa caused by 
Voltaren® (diclofenac), all patients receiving Voltaren® (diclofenac) will 
simultaneously take Ortanol® (omeprazole) as follows: 20 mg, orally daily 
before breakfast throughout the course of Voltaren® (diclofenac) treatment. On 
the first day of therapy in the study, it is possible to take it regardless of meals 
and at a later time. 
Method of administration of Ortanol® (omeprazole): orally, with a sufficient 
amount of liquid. 
Duration of treatment: Treatment with RPH-104: single dose (a 160 mg dose is divided into two 
injections, 80 mg each at different injection sites. 
therapy with Voltaren® (diclofenac): 12 days 
Evaluation criteria: 
 
Primary efficacy 
variable 
Change in pain intensity in the assessed joint at 72 hours after start of the 
investigational product therapy compared to baseline, as measured on the 
visual analogue scale (VAS). 
Other efficacy 
variables: 
 
Change in pain intensity in the assessed joint at 15, 30, 45 minutes, 1, 
1.5, 2, 4, 8, 24, 48, 72 hours, on days 5, 6, 10, 15, 18, 22, 29 and 45 
after start of the investigational product therapy compared to baseline 
(as measured on VAS). 
 
Proportion of patients who rated the response to the investigational 
product therapy as "Excellent" or "Good" at 15, 30, 45 minutes, 1, 1.5 


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Translation of Protocol final version 7.0 dated November 19, 2020 into English dated February 26, 2022 
Sponsor Name: 
R-Pharm International LLC 
 
 
Investigational medicinal product provided by the 
Sponsor: 
RPH-104/L04018 
Name of the active ingredient: 
RPH-104/L04018 
hours, 2, 4, 8, 24, 48, 72 hours, on days 5, 6, 10 15, 18, 22, 29, and 45 
after initiation of the investigational product therapy; 
 
Change in the degree of swelling, tenderness, erythema in the assessed 
joint at 24, 48, 72 hours, on days 5, 6, 10, 15, 18, 22, 29 and 45 after 
start of the investigational product therapy compared to baseline; 
 
Change in movement restriction in the assessed joint at 24, 48, 72 
hours, on days 5, 6, 10, 15, 18, 22, 29 and 45 after start of the 
investigational product therapy compared to baseline; 
 
Time to 50% reduction in pain intensity in the assessed joint relative to 
the baseline level according to the VAS; 
 
Time to use of the rescue medication; 
 
The proportion of patients who received the rescue medication within 
72 hours of starting the investigational product therapy and over the 
entire treatment period; 
 
Changes in the health assessment questionnaire (HAQ) scores 15, 29, 
and 45 days after start of the investigational product therapy compared 
to baseline. 
Pharmacokinetic 
variables: 
Blood samples for pharmacokinetic assessment will be collected from patients 
who have received RPH-104 at the following times: before RPH-104 
administration, at 2, 8, 24, 48, 72, 96, 120, 216, 336, 408, 504, 672, 1056 hours 
after the investigational product administration. 
Pharmacokinetic parameters of subcutaneous RPH-104: AUC0-t, AUC0-∞, 
Cmax, tmax, t1/2, Kel. 
Immunogenicity 
vairables: 
Blood samples for immunogenicity assessment will be collected from patients 
treated with RPH-104 at the following time points: before administration of 
RPH-104, on Day 15, Day 45. Anti-RPH-104 antibody concentrations will be 
assessed. 
Pharmacokinetic 
variables: 
 
Change in serum hs-CRP levels at 24, 72 hours, 5, 6, 15, 29 and 45 
days after start of the investigational product therapy compared to 
baseline. 
 
Change in serum amyloid protein A levels at 24, 72 hours, 5, 6, 15, 29 
and 45 days after start of the investigational product therapy compared 
to baseline. 
 
Change in serum cytokine (IL-1α, IL-1β, IL-1RA, IL-6, IL-8, TNF-α) 
levels at 24, 72 hours, 5, 6, 15, 29 and 45 days after start of the 
investigational product therapy compared to baseline. 
Safety variables: Adverse events, laboratory results, vital signs, physical examination findings, 
ECG findings. 
Statistical methods: 
Data analysis 
Descriptive statistics of continuous variables will be presented using means, 


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Translation of Protocol final version 7.0 dated November 19, 2020 into English dated February 26, 2022 
Sponsor Name: 
R-Pharm International LLC 
 
 
Investigational medicinal product provided by the 
Sponsor: 
RPH-104/L04018 
Name of the active ingredient: 
RPH-104/L04018 
median, 25th and 75th percentiles, standard deviation, minimum, maximum, 
number of observations available. Categorical data will be presented as 
absolute and relative values for each category. Time to event parameters will 
be plotted using Kaplan-Meier curves. 
Efficacy analysis 
The primary efficacy variable will be analyzed by analysis of covariance using 
baseline and treatment group as covariates. Other continuous efficacy variables 
will be analyzed using repeated measures ANOVA. Efficacy variables 
representing time to event will be compared using a log rank test. 
The pharmacokinetic, pharmacodynamic and immunogenicity parameters of 
RPH-104, as well as safety of the therapy with the investigational products will 
be assessed using descriptive statistics methods. 
Interim data analysis 
Due to the low patient recruitment rate in the study and the adverse impact of 
the COVID-19 pandemic on the recruitment, at the decision of the sponsor, an 
interim analysis of the data of 47 patients included in the study as of November 
2020 will be carried out in order to assess the feasibility of continuing 
recruitment and further conducting the study. All patients whose data will be 
included in the interim analysis completed their participation in the study; 
follow-up is not required in the study. The interim analysis will include the 
efficacy, safety, pharmacokinetics and pharmacodynamics data available and 
verified at the time of analysis. No changes in the declared statistical methods 
in connection with the interim analysis are planned. The dose dependence of 
the pharmacokinetics and pharmacodynamics of the investigational product, as 
well as the main efficacy measures (reduction in pain intensity) will be studied 
using descriptive statistics, a confidence interval approach, and graphical 
methods. The safety analysis will be carried out using descriptive statistics 
methods. Formal testing of hypotheses is not planned in the study. In view of 
the exploratory nature of the study, no corrections for multiple comparisons are 
planned. 
Sample size justification 
Fourteen (14) patients per group will allow constructing 95% confidence 
intervals around the mean change in pain intensity on a visual analogue scale 
at 72 hours after the start of the investigational product use in each group with 
an accuracy of 30 mm change in pain intensity. 
In addition, this sample size will allow establishing statistically significant 
differences between the groups in pairwise comparisons, without control for 
type I error for multiple comparisons, taking into account the type I error α = 
5%, if the difference between the compared groups is ≥ 20 mm. The sample 
size was calculated assuming a standard deviation of 26 mm for change in pain 
intensity at 72 hours. 


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3 
STUDY FLOW CHART 
Table 3.1 
Schedule of the study procedures 
 
Прескрининг1 
Day 1 
D2 D3 D4 D5 D6 
D10 
D15 
D18 
D22 
D29 
D45 
D60 BRM FUV 
Procedure/time (hours)  
 
Screening2 0 
2 
4 
8 24 48 72 96 120 216 ± 1 
day 
336 ± 1 
day 
408 ± 1 
day 
504 ± 1 
day 
672 ± 1 
day 
1056 ± 1 
day 
± 7 
days 
 
 
Time window for evaluation 
of PK, PD, overall pain 
intensity in the assessed joint, 
and patient global assessment 
of efficacy 
 
 
 
±10 
minutes 
±2 
hours 
±3 hours 
 
 
 
 
 
Visit (V); Telephone call (Т) 
V 
В27 
 
 
 
 
V 
V 
V 
V 
V 
В3 
V 
В3 
В3 
V 
V 
T  
 
Handing over the patient 
information sheet with 
information about the study to 
the patient, informing the patient 
about the study procedures and 
possible participation 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signing of the Informed Consent 
Form 
Х1 
Х4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history collection 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis risk assessment 
questionnaire 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recording concomitant/previous 
therapy24 
 
Х 
X Throughout the study 
Х 
Collection of demographics5 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy and pharmacodynamic assessment 
 
Pain intensity in the assessed 
joint6 
 
Х7 
Х8 Х Х29 Х Х 
Х 
Х 
Х 
Х 
Х26 
Х 
Х26 
Х26 
Х 
Х 
 
Х25  
Patient global assessment of 
efficacy6 
 
 
Х8 Х Х29 Х Х 
Х 
Х 
Х 
Х 
Х26 
Х 
Х26 
Х26 
Х 
Х 
 
Х25  
Health assessment questionnaire 
(HAQ) 6 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of the degree of 
swelling, tenderness, erythema 
 
Х 
 
 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 


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Прескрининг1 
Day 1 
D2 D3 D4 D5 D6 
D10 
D15 
D18 
D22 
D29 
D45 
D60 BRM FUV 
Procedure/time (hours)  
 
Screening2 0 
2 
4 
8 24 48 72 96 120 216 ± 1 
day 
336 ± 1 
day 
408 ± 1 
day 
504 ± 1 
day 
672 ± 1 
day 
1056 ± 1 
day 
± 7 
days 
 
 
Time window for evaluation 
of PK, PD, overall pain 
intensity in the assessed joint, 
and patient global assessment 
of efficacy 
 
 
 
±10 
minutes 
±2 
hours 
±3 hours 
 
 
 
 
 
and movement restriction in the 
assessed joint by physician9 
High-sensitivity (hs) CRP10 
 
Х 
 
 
 
 
Х 
 
Х 
Х 
Х 
 
Х 
 
 
Х 
Х 
 
 
 
Serum amyloid protein A10 
 
Х 
 
 
 
 
Х 
 
Х 
Х 
Х 
 
Х 
 
 
Х 
Х 
 
 
 
Cytokines (IL-1α, IL-1β, IL-
1RA, IL-6, IL-8, TNF-α) 10 
 
Х 
 
 
 
 
Х 
 
Х 
Х 
Х 
 
Х 
 
 
Х 
Х 
 
 
 
Recording the timing of rescue 
therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Х25 
 
Diagnosis of infections: HIV, 
HBsAg, HCV Ab 10,11 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis of tuberculosis (T-
SPOT.TB) 10 
 
Х22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for 
pharmacokinetic assessment 10, 12 
 
 
Х Х 
 
Х Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
Х 
Anti-drug antibodies 10, 12 
 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
Х 
 
 
Х 
Serum pregnancy test for women 
of childbearing potential 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Х 
 
 
Х 
Clinical laboratory tests13 
 
Х14 
 
 
 
 
 
 
 
Х 
 
 
Х 
 
 
 
Х 
 
 
Х 
Urinalysis with sediment 
microscopy (site laboratory)23 
 
Х 
 
 
 
 
 
 
 
Х 
 
 
Х 
 
 
 
Х 
 
 
Х 
Physical examination15 
 
Х 
 
 
 
 
 
 
 
 
 
 
Х 
 
 
 
Х 
 
 
Х 
Vital signs16 
 
Х 
 
 
 
 
Х 
 
Х 
Х 
Х 
 
Х 
 
Х 
Х 
Х 
 
 
Х 
Weighing 
 
 
 
 
 
 
 
 
 
Х 
 
 
Х 
 
 
 
Х 
 
 
Х 
12-lead ECG 
 
Х14 
 
 
 
 
 
 
 
Х 
 
 
 
 
 
 
Х 
 
 
Х 
Chest X-ray in 2 views 
 
Х14,17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event recording  
 
Х18 
Х Х 
Х 
Х Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
Х 


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Прескрининг1 
Day 1 
D2 D3 D4 D5 D6 
D10 
D15 
D18 
D22 
D29 
D45 
D60 BRM FUV 
Procedure/time (hours)  
 
Screening2 0 
2 
4 
8 24 48 72 96 120 216 ± 1 
day 
336 ± 1 
day 
408 ± 1 
day 
504 ± 1 
day 
672 ± 1 
day 
1056 ± 1 
day 
± 7 
days 
 
 
Time window for evaluation 
of PK, PD, overall pain 
intensity in the assessed joint, 
and patient global assessment 
of efficacy 
 
 
 
±10 
minutes 
±2 
hours 
±3 hours 
 
 
 
 
 
Eligibility assessment 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subcutaneous administration of 
RPH-10412 
 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of injection site 
reactions 12, 19 
 
 
Х19 Х 
Х 
Х Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 
First dosing Dispensing of 
Voltaren® (diclofenac) and 
Ortanol® (omeprazole) 20 
 
 
Х28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing 
of 
Voltaren® 
(diclofenac) 
and 
Ortanol® 
(omeprazole) 
for 
self-
administration 20 
 
 
Х28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Use 
of 
rescue 
medication 
Kenalog25 
 
 
 
Х 
 
 
 
Handing 
over 
the 
Patient 
Diary21,30 
 
 
Х 
 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 
 
Patient diary collection 
 
 
 
 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 
 
D – day, CRP – C-reactive protein, PK – Pharmacokinetics, PD – pharmacodynamics (in this study, these are hsCRP, serum amyloid protein A, cytokines), BRM – before the 
administration of rescue medication, FUV – follow-up visit for early discontinuation of the patient from study 
1. At pre-screening, the patient is informed about the study procedures, signs the informed consent to participate in the pre-screening, and is given the 
patient information sheet with informed consent form describing the main study for familiarization. 
2. Screening procedures must be performed within 24 hours and the patient is randomized during this time. If necessary (in exceptional cases), the screening 
period can be extended, while randomization had to be carried out no later than 120 hours (5 days) after the onset of an attack. 


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3. Visits to the study site on Study Days 10, 18 and 22 are required for patients receiving RPH-104; Patients receiving Voltaren® (diclofenac) do not have to 
come to the study site, but they must fill out the patient diary and patient questionnaires on these days (pain in the assessed joint, patient global 
assessment of efficacy). 
4. Informed consent to participate in the study must be obtained and the informed consent form for participation in the study be signed prior to starting any 
study procedure. 
5. This includes date of birth, sex, race, weight, height, body mass index, and information on alcohol consumption. 
6. The patient is given questionnaires at the visits to record pain intensity in the assessed joint on the visual analogue scale (VAS), patient global assessment 
of efficacy, and scores of the health assessment questionnaire. 
7. The VAS must be completed twice: the first time at the screening to assess the patient's eligibility and the second time before randomization to obtain a 
baseline value. Re-assessment of pain intensity in the assessed joint must be performed immediately (within 1 hour) before randomization. 
8. Assessment of pain intensity and global efficacy assessment must be performed prior to taking blood samples. It is necessary to hand over a questionnaire 
to the patient for assessment of pain intensity and global efficacy assessment after 15, 30, 45 minutes, (interval ± 5 min) 1 and 1.5 hours (interval ± 10 
min) after the use of the investigational products. 
9. The physician assesses the degree of swelling, tenderness, erythema and movement restriction in the assessed joint using the categorical scales specified 
in this protocol. 
10. hs-CRP, serum amyloid protein A, cytokines, HIV, HBsAg, HCV Ab, T-SPOT.TB tests, pharmacokinetics and anti-drug antibodies (including the test 
for neutralizing antibodies) are performed in central laboratories. 
11. For the diagnosis of infections (HIV, HBsAg, HCV Ab), blood serum samples will be sent to the central laboratory. In addition, rapid tests for the 
diagnosis of HIV, hepatitis B and C are performed at the screening. Rapid test results should be evaluated prior to patient randomization. Patients 
suspected of having HIV, hepatitis B or C on the basis of rapid test results should not be randomized. 
12. Administration of RPH-104, assessment of injection site reactions, blood sampling to assess the pharmacokinetics of the investigational product and anti-
drug antibodies will be performed only for patients randomized to receive RPH-104. 
13. These include: complete blood count (hemoglobin, hematocrit, erythrocytes, platelets, total WBC count with WBC differential in %, absolute neutrophil 
count), blood chemistry: sodium, potassium, chlorine, magnesium, calcium, phosphorus, bicarbonates, BUN (or urea), uric acid, total protein, albumin, 
glucose, creatinine with estimation of creatinine clearance using the Cockcroft-Gault formula, bilirubin (total and direct), AST, ALT, alkaline 
phosphatase, LDH, amylase, lipase, GGT, creatine kinase, MB-creatine kinase; blood lipids (cholesterol, triglycerides, LDL, HDL); coagulation tests 
(fibrinogen, INR, aPTT). Complete blood count and creatinine test at screening and on Study Days 5, 15, 45 and with early discontinuation of the patient 
from the study are performed at the local laboratory of the study site. Blood chemistry tests with blood lipids and coagulation tests are performed in the 
central laboratory. 
14. The results of ECG, chest x-ray in 2 views, creatinine level, absolute neutrophil count, leukocyte and platelet counts should be assessed prior to patient 
randomization. To be included in the study, the patient has to meet the study eligibility criteria based on these data. 


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15. Physical examination includes: assessment of overall health, skin (presence of rash or lesions), head, mouth, eyes, ears, throat, nose, lungs (auscultation), 
heart (auscultation for murmurs, gallop rhythm, pericardial friction rubs), lower extremities (peripheral edema, presence of varicose veins), abdomen 
(palpation and auscultation), nervous system (mental status, gait, reflexes, motor and sensory functions, coordination) and lymph nodes. 
16. This includes: body temperature, blood pressure, respiratory rate and heart rate in a sitting position after 5 minutes at rest. 
17. Chest X-ray in 2 views is performed at screening if the patient does not have results of chest X-ray in 2 views or fluorography of the chest in 2 views or 
chest CT performed within 3 months before the expected date of the first injection of the investigational product; 
18. Serious adverse events are recorded from the time of signing the informed consent to participate in the study. Other adverse events are recorded from the 
time of administration to the patient (the first intake by the patient) of the investigational product. 
19. In patients receiving RPH-104, the assessment of injection site reactions is carried out 15, 30, 45 minutes (interval ± 5 min) after administration and then 
in accordance with the table of study procedures. The physician assesses the presence of tenderness, redness, swelling, induration, hemorrhage and 
itching at the RPH-104 injection site. The patient is assessed for these reactions at each visit. They are recorded as adverse events. 
20. Voltaren® (diclofenac) and Ortanol® (omeprazole) are dispensed only for patients receiving Voltaren® (diclofenac). 
21. In the diaries, patients record information about the development of adverse events and changes in concomitant therapy (discontinuation or dose change) 
or use of new concomitant therapy. Patients receiving Voltaren® (diclofenac) are also given additional diaries to record information about the use of 
Voltaren® (diclofenac). The diaries are filled in by patients when they are outside the study site. 
22. Blood sampling for T-SPOT.TB test should be carried out either at screening, or during the time the patient is in the hospital. 
23. Urine analysis includes: color, transparency, specific gravity, pH level, glucose, protein, ketone bodies, bilirubin, urobilinogen, nitrites. Analysis of urine 
sediment includes: leukocyte count, erythrocyte count, epithelial cell count with cell type, and bacterial count. 
24. Information is collected about all previous therapy for the primary disease—gout, information about other prior therapy is collected for a period of 30 
days before the start of screening. 
25. Patients who do not tolerate pain receive the rescue medication after 2 hours and until Day 45 of the study after the first use of rescue medication 
Kenalog® (triamcinolone) to intensify therapy. If it is necessary to use the rescue medication, immediately before its use, an unscheduled assessment of 
pain severity using a visual analogue scale (VAS) and global assessment of efficacy is to be performed and the time of use of the rescue medication is to 
be registered. 
26. If patients receiving Voltaren® (diclofenac) miss visits on Day 10, 18 and 22, they record pain intensity in the assessed joint and the patient global 
assessment of efficacy at home. For this purpose, they are given patient questionnaires to take home at Visits on Days 6 (1 score) and 15 (2 scores). 
27. By the decision of the investigator, after the use of the investigational products, patients can be hospitalized and remain under observation in the hospital. 
All procedures in accordance with the visit schedule for these patients are carried out in a hospital setting. Patients who, in the investigator's opinion, are 
not eligible for hospitalization, are followed up for at least 3 hours after the investigational product administration, after which they can leave the study 
site and continue to participate in the study with all assessments performed on an outpatient basis. 


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28. At the visit on Day 1, all patients in the Voltaren® (diclofenac) group are given the drug for dosing at the study site; patients who are hospitalized by the 
decision of the investigator are given the drug in a hospital setting before being discharged; subsequently, these patients are given the drug in an amount 
sufficient for self-administration at home in accordance with the study protocol. Patients who are not eligible for hospitalization receive the drug for self-
administration on Day 1 after the rest of the procedures and assessments. 
29. Patients receiving Voltaren® (diclofenac) on an outpatient basis are allowed to leave the study site 3 hours after taking the drug. In this case, they are 
given patient questionnaires (measurement of pain in the assessed joint, patient global assessment of efficacy) to fill at home 4 and 8 hours after taking 
the drug. 
30. New patient diaries are issued as needed. 


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4 
STUDY RATIONALE AND GOAL 
The present study is a phase IIa study. This study aims to evaluate the efficacy, 
pharmacokinetics, pharmacodynamics, safety and tolerability of RPH-104 following a single 
injection in adult patients with an acute gout attack. 
To clarify certain aspects of conducting a clinical trial, the following changes have been made to 
this protocol compared to the previous version 6.0 of June 6, 2019: 
 
An interim analysis of data from patients randomized as of November 2020 was included. 
Rationale for change: Due to the low rate of enrollment in the study (between March 2018 and 
November 2020, 47 patients [~55% of the planned sample size] were enrolled in the study) and 
the negative impact on enrollment of the COVID-19 pandemic, the sponsor decided to conduct 
an interim analysis of the data of 47 patients included in the study as of November 2020 in order 
to assess the feasibility of continuing the recruitment and further conducting the study. All 
patients whose data will be included in the interim analysis completed their participation in the 
study; follow-up is not required in the study. The interim analysis will include the efficacy, 
safety, pharmacokinetics and pharmacodynamics data available and verified at the time of 
analysis. An interim report based on the results of the analysis may become final. In case of early 
termination of the study, the sponsor will send respective notifications to the investigators and 
the regulatory authorities. 
4.1 
General information about the disease 
Gout is a metabolic disease characterized by the deposition of urate crystals in the form of 
sodium monourate or uric acid in different tissues of the body. 
An increase in the blood concentration of uric acid (hyperuricemia) underlies the development of 
gout. Increased blood concentrations lead to the formation of needle-shaped crystals of sodium 
salt of uric acid in the joints. Macrophages recognized and uptake these crystals, then they are 
attacked by neutrophils. The subsequent release of IL-1β provokes inflammation, vasodilation 
and attraction of immune cells to the focus [1]. 
Clinically, gout manifests by recurrent acute arthritis: a reddened, tender, hot, and swollen joint. 
Pain usually develops quickly, in less than 12 hours. The first metatarsophalangeal joint is 
affected in about half of patients. Gout can also lead to the development of gouty nodules (tophi) 
and kidney damage. The disease more frequently affects men. 
Gout treatment is based on alleviating acute attacks, management of hyperuricemia and 
prevention of flares. First-line therapy for acute attacks includes non-steroidal anti-inflammatory 
drugs, steroids and colchicine, as well as various methods of prevention of flares during periods 
of remission 2, 3, 4]. Despite the effectiveness of these methods, 69% of patients experience 
another gout attack within a year; furthermore, tolerability of these drugs is limited, especially in 
patients with concomitant hepatic, kidney, and heart disease, diabetes and hypertension. 
Therefore, in recent years, studies of drugs with an alternative mechanism of action were 
ongoing, in particular, of IL-1 inhibitors [5]. 
In this study, Voltaren® (diclofenac) was selected as a reference drug to alleviate a gout attack. 
The reason for choosing Voltaren® (diclofenac) was the presence of the indication ‘treatment of a 
gout attack’ in the Voltaren® (diclofenac) labeling, as well as in accordance with the National 
Rheumatology Guidelines [6] and due to the widespread use of Voltaren® (diclofenac) in clinical 
practice. 


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4.2 
Description of investigational products and concomitant therapy 
4.2.1 Treatment with RPH-104 (investigational product provided by the sponsor) 
RPH-104 is a hybrid protein that selectively binds IL-1β at femtomolar concentrations [7]. Two 
active fragments of the molecule are responsible for RPH-104 binding to IL-1β: an extracellular 
portion of human IL-1 receptor, type 1 and a portion of IL-1 receptor accessory protein (IL-1-
RAcP) that is an IL-1 co-receptor. 
Structurally, the RPH-104 molecule comprises two polypeptide chains: the first one consists of 
the extracellular portion of IL-1 receptor and a mutant Fc-fragment of human IgG1; the second 
one consists of the IL-1-RAcP portion and a mutant Fc-fragment of human IgG1. 
A tissue cross-reactivity study performed using tissue samples from humans and cynomolgus 
monkeys showed specific staining of the following structures of both types with the RPH-104–
biotin complex: cytoplasm and membrane of macrophages and histiocytes of lymph nodes, 
hepatic epithelium and Kupffer cells. Based on the study findings, it has been concluded that 
staining of human and cynomolgus monkeys tissues with the RPH-104–biotin complex is highly 
similar. 
The toxicity of RPH-104 has been studied following single and repeated dosing to cynomolgus 
monkeys. The study showed that a single subcutaneous injection of RPH-104 at doses of 5, 50, 
and 200 mg/kg and a single intravenous administration of RPH-104 at doses of 5 and 200 mg/kg 
were well tolerated by animals and did not cause adverse events. RPH-104 was also well 
tolerated by the animals following repeated subcutaneous injections to monkeys at doses of 5, 
50, and 100 mg/kg, once a week for 4 weeks. Based on the study findings, it was concluded that 
NOAEL for RPH-104 administered weekly for 4 weeks is 100 mg/kg. Anti-drug antibodies were 
detected in 68% of monkeys at the end of the administration period. The drug was not 
immunotoxic in monkeys. 
The first clinical study of RPH-104 aimed at investigation of the tolerability, safety, 
pharmacokinetics, pharmacodynamics and immunogenicity of single subcutaneous 4-, 20-, 40-, 
80- and 160-mg doses of RPH-104 in healthy volunteers was completed in 2018. The results of 
this clinical study showed that RPH-104 was well tolerated by healthy volunteers at all doses 
tested. A list of adverse events observed in subjects in this study is presented in Table 4.2. 
More detailed information about RPH-104 is contained in the current version of the 
Investigator's Brochure. 
4.2.2 Voltaren® (diclofenac) – reference product 
Voltaren® (diclofenac) is a non-steroidal anti-inflammatory drug (NSAID). Voltaren® 
(diclofenac) has pronounced anti-inflammatory, analgesic and antipyretic effects. The main 
mechanism of action of Voltaren® (diclofenac) is the inhibition of the synthesis of 
prostaglandins, which play an important role in the development of inflammation, pain and fever. 
Pharmacokinetics 
After oral administration of coated tablets, Voltaren® (diclofenac) is completely absorbed in the 
intestine. After a single dose of 50 mg of the drug, the maximum concentration in the blood is 
observed after 2 hours and is 1.5 μg/mL. If Voltaren® (diclofenac) tablets are taken during or 
after a meal, the rate of absorption may slow down, but the amount of absorbed Voltaren® 
(diclofenac) does not change. 
Diclofenac is 99.7% bound to plasma proteins, predominantly with albumin (99.4%). Voltaren® 
(diclofenac) enters the synovial fluid, where maximum concentrations are measured 2-4 hours 
later than in blood. Two hours after reaching the maximum concentration in the blood, the 


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concentration of Voltaren® (diclofenac) in the synovial fluid is higher than in the blood, and its 
values remain higher over a period of up to 12 hours. 
Voltaren® (diclofenac) is metabolized in the liver. About 60% of the administered dose of the 
drug is excreted in the urine as glucuronic conjugates of the unchanged active substance, as well 
as in the form of metabolites, most of which are glucuronic conjugates. Less than 1% of the dose 
taken is excreted unchanged. The rest of Voltaren® (diclofenac) is excreted in the form of 
metabolites via bile with feces. 
Pharmacokinetic properties in special populations 
After oral administration, there are no differences in absorption, metabolism and excretion of the 
drug associated with the age of patients. 
In patients with renal impairment, no accumulation of Voltaren® (diclofenac) was noted when 
used at usual doses. In patients with chronic hepatitis or compensated liver cirrhosis, 
pharmacokinetic properties of Voltaren® (diclofenac) are similar to those without liver disease. 
Indications 
 Inflammatory and degenerative diseases of the musculoskeletal system, including 
rheumatoid, 
juvenile, 
chronic 
arthritis; 
ankylosing 
spondylitis 
and 
other 
spondyloarthropathies; osteoarthritis; gouty arthritis; bursitis, tendovaginitis; 
 Spinal pain syndromes (lumbago, sciatica, ossalgia, neuralgia, myalgia, arthralgia, 
radiculitis); 
 Post-traumatic postoperative pain accompanied by inflammation (e.g. in dentistry and 
orthopedics); 
 Algodismenorrhea; 
 Pelvic inflammatory disease (including adnexitis); 
 Infectious and inflammatory diseases of ENT organs, accompanied with severe pain (as 
part of complex therapy): pharyngitis, tonsillitis, otitis media. 
For more information about Voltaren® (diclofenac), see the instructions for medical use. When 
evaluating the relationship of adverse events with Voltaren® (diclofenac), the investigator should 
take into account all information about Voltaren® (diclofenac) from the instructions for medical 
use. 
4.2.3 Ortanol® (omeprazole) – concomitant medication 
Ortanol® (omeprazole) is a proton pump inhibitor. In this study, this drug will be used in 
combination with Voltaren® (diclofenac) to prevent damage to the gastric and duodenal mucosa 
caused by the NSAID, Voltaren® (diclofenac). The indication and route of administration of 
Ortanol® (omeprazole) in this study correspond to the information in the instructions for medical 
use. 
Ortanol® (omeprazole) is contraindicated in the following conditions: hypersensitivity to 
Ortanol® (omeprazole) or other components of the drug; age under 4 years (or weight below 31 
kg) in the treatment of duodenal ulcers and under 2 years with a weight below 20 kg for the 
treatment of reflux esophagitis, symptomatic treatment of heartburn and acid regurgitation in 
gastroesophageal reflux disease; concomitant use with nelfinavir, erlotinib and posaconazole; 
rare hereditary forms of lactose intolerance, deficiency of lactase, sucrase/isomaltase or 
malabsorption of glucose/galactose. 
For more information about Ortanol® (omeprazole), see the instructions for medical use. 


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4.2.4 Triamcinolone acetonide (rescue medication) 
In this study, triamcinolone acetonide has been selected as a rescue medication to be 
administered in the form of intramuscular injection 40 mg. The rescue medication was selected 
on the basis of national recommendations for its use for the relief of an acute gout attack [6]. The 
intramuscular route of administration has been selected on the basis that the study will include, 
among other things, patients with a polyarticular form of gout who are indicated for systemic 
therapy. The dose for use was selected on the basis of the US instructions for medical use of 
triamcinolone acetonide, valid at the time of writing the protocol [14] and the experience with 
this drug in clinical trials to relieve an acute gout attack [10]. If triamcinolone acetonide is 
ineffective, the Investigator may select another drug for the patient in accordance with standard 
hospital practice. 
 


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4.3 
Preclinical and clinical trial results essential for this study 
This Study Protocol presents a brief description of the results of the most important studies. 
Detailed information on the results of preclinical and clinical studies of RPH-104 is contained in 
the latest version of the Investigator's Brochure. 
4.3.1 Preclinical studies 
Mechanism of action studies. 
In vitro studies have investigated the kinetics of binding of RPH-104 to human type 1 IL-1 
receptor ligands: IL-1α, IL-1β, and an interleukin 1 receptor antagonist (IL-1RA). The studies 
have shown that the mean dissociation constant for these ligands is 18 nM, 11.8 fM and 21.6 pM 
for IL-1α, IL-1β and IL-1RA, respectively. Thus, it has been found that the affinity of RPH-104 
to IL-1α, IL-1β and IL-1RA differs significantly. The affinity of RPH-104 for IL-1β is 
approximately 2000 times higher than the affinity of RPH-104 for IL-1RA and approximately 
1,000,000 higher than the affinity of RPH-104 for IL-1α. 
4.3.2 Clinical pharmacology trials 
Pharmacokinetics of RPH-104 in humans 
At the time of writing this protocol, data on the pharmacokinetics of RPH-104 were available for 
a single subcutaneous injection in healthy volunteers at doses of 4 and 20 mg. The results of 
evaluation of pharmacokinetic RPH-104 parameters from phase 1 studies in healthy volunteers 
are provided in Table 4.1 below. 
Table 4.1 
Pharmacokinetic parameters of RPH-104 after a single subcutaneous 
injection in healthy volunteers 
PK 
parameters/RP
H-104 dose 
4 mg 
(N=5) 
20 mg 
(N=5) 
40 mg 
(N=3) 
80 mg 
(N=5) 
160 mg 
(N=5) 
Cmax (ng/mL) 
198 ± 89.1 
1280 ± 402 
1650 ± 257 
5120 ± 1410 
10300 ± 4470 
AUC(0-t) 
(h*ng/mL) 
74500 ± 247
00 
430000 ± 9570
0 
661000 ± 1580
00 
1610000 ± 3170
00 
3390000 ± 14500
00 
AUC(0-∞) 
(h*ng/mL) 
87100 ± 283
00 
505000 ± 1050
00 
804000 ± 1960
00 
1850000 ± 3530
00 
3990000 ± 18100
00 
t1/2 (h) 
245 ± 9.50 
249 ± 6.08 
255 ± 43.1 
235 ± 22.8 
243 ± 40.4 
tmax (h) 
96 (94.4 – 
192) 
96 (48. – 96.2) 
120 (96 – 192) 
96 (72 – 120) 
120 (72 – 120) 
Note: data are presented as means ± standard deviation, except for tmax values, where the median is presented 
(minimum value – maximum value) 
As can be seen from the presented table, the maximum concentration of RPH-104 appears in the 
blood on average approximately 4-5 days after the subcutaneous administration of RPH-104. The 


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study results showed that RPH-104 at doses ranging from 4 to 160 mg has linear 
pharmacokinetics and its half-life is approximately equal to 10 days. 
4.3.3 Adverse events during RPH-104 therapy 
The study of single doses of RPH-104 in healthy volunteers was conducted as a randomized, 
double-blind, single-center study with a gradual increase in the dose of RPH-104 in each 
subsequent cohort. Each cohort included 7 volunteers who were randomized in a 5:2 ratio to 
receive a single pre-specified dose of RPH-104 or placebo. Volunteers were followed up for 60 
days, of which 3 days the volunteers spent in the hospital, 27 days the volunteers came for visits 
to the study site, and at the end of the follow-up period (day 60) they received a call to collect 
information on adverse events (AEs). 
In order to assess the safety of RPH-104 therapy, information on adverse events, vital signs, 
physical examination, clinical laboratory tests (complete blood count, blood chemistry tests, 
coagulation tests and urinalysis), ECG were evaluated in volunteers. The decision to include 
volunteers in each subsequent cohort was made by an independent data monitoring committee, 
based on an assessment of the therapy safety data and pharmacokinetic data in the previous 
cohort. A total of 35 healthy volunteers took part in the study [13]. 
A list of all reported adverse events is presented in Table 4.2 below. No serious adverse events 
were reported. A total of 70 adverse events were recorded. In the 4 mg and 20 mg dose groups, 
of 5 subjects treated with RPH-104, 3 subjects (60%) experienced gastrointestinal disturbances. 
In the 20 mg dosing group, AEs of nervous system disorders were reported with the same 
frequency (60%). In the 40 mg dosing group, the most commonly reported AEs were infections 
(40%). Five subjects (100%) who received RPH-104 80 mg and 3 subjects (60%) who received 
160 mg had headache. All reported AEs in all dosing groups were mild and resolved completely. 
The most common AEs in both RPH-104 and placebo subjects were headache (44%-30%), 
nausea (12%-30%) and nasopharyngitis (8%-20%), respectively. There was no significant 
difference in AEs between the placebo and RPH-10 groups. 


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Table 4.2 
Adverse events reported in a phase 1 study of RPH-104 in healthy volunteers 
n (%) 
 
Dose group 1 
(4 mg) 
Dose group 2 
(20 mg) 
Dose group 3 
(40 mg) 
Dose group 4 
(80 mg) 
Dose group 5 
(160 mg) 
System Organ Class 
Preferred term 
RPH-104 
N=5 
Placebo 
N=2 
RPH-104 
N=5 
Placebo 
N=2 
RPH-104 
N=5 
Placebo 
N=2 
RPH-104 
N=5 
Placebo 
N=2 
RPH-104 
N=5 
Placebo 
N=2 
Any Adverse Events 
5 (100%) 
1 (50%) 
3 (60%) 
2 (100%) 
4 (80%) 
2 (100%) 
5 (100%) 
1 (50%) 
5 (100%) 
1 (50%) 
Nervous system disorders 
1 (20%) 
1 (50%) 
3 (60%) 
1 (50%) 
1 (20%) 
2 (100%) 
5 (100%) 
- 
3 (60%) 
- 
Headache 
1 (20%) 
- 
1 (20%) 
1 (50%) 
1 (20%) 
2 (100%) 
5 (100%) 
- 
3 (60%) 
- 
Dizziness 
- 
1 (50%) 
1 (20%) 
- 
- 
1 (50%) 
- 
- 
- 
- 
Fainting 
- 
- 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
Attention disorder 
- 
- 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
Gastrointestinal Disorders 
3 (60%) 
1 (50%) 
3 (60%) 
1 (50%) 
1 (20%) 
1 (50%) 
- 
1 (50%) 
1 (20%) 
- 
Nausea 
1 (20%) 
1 (50%) 
2 (40%) 
1 (50%) 
- 
- 
- 
1 (50%) 
- 
- 
Vomiting 
1 (20%) 
- 
- 
- 
1 (20%) 
- 
- 
- 
- 
- 
Diarrhea 
- 
- 
1 (20%) 
- 
- 
- 
- 
- 
1 (20%) 
- 
Dysphagia 
1 (20%) 
- 
 
- 
- 
- 
- 
- 
- 
- 
Abdominal pain 
- 
- 
1 (20%) 
- 
- 
1 (50%) 
- 
- 
- 
- 
Aphthous ulcer 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Infections 
 and infestations 
2 (40%) 
1 (50%) 
- 
- 
2 (40%) 
1 (50%) 
- 
- 
2 (40%) 
1 (50%) 
Nasopharyngitis 
- 
- 
- 
- 
- 
1 (50%) 
- 
- 
2 (40%) 
1 (50%) 
Gingivitis 
2 (40%) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Pyuria 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Pharyngitis 
- 
- 
- 
- 
1 (20%) 
- 
- 
- 
- 
- 
Upper respiratory tract infection 
- 
- 
- 
- 
1 (20%) 
- 
- 
- 
- 
- 
Bacteriuria 
- 
1 (50%) 
- 
- 
- 
- 
- 
- 
- 
- 
Asymptomatic bacteriuria 
- 
1 (50%) 
- 
- 
- 
- 
- 
- 
- 
- 
General disorders and administration 
site conditions 
2 (40%) 
- 
- 
- 
- 
1 (50%) 
- 
1 (50%) 
1 (20%) 
- 
Asthenia 
2 (40%) 
- 
- 
- 
- 
- 
- 
1 (50%) 
- 
- 
Soft tissue inflammation 
- 
- 
- 
- 
- 
- 
- 
- 
1 (20%) 
- 
Hyperthermia 
- 
- 
- 
- 
- 
1 (50%) 
- 
- 
- 
- 


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Musculoskeletal and connective tissue 
disorders 
- 
- 
1 (20%) 
- 
- 
1 (50%) 
1 (20%) 
1 (50%) 
- 
- 
Arthralgia 
- 
- 
1 (20%) 
- 
- 
- 
1 (20%) 
1 (50%) 
- 
- 
Myalgia 
- 
- 
- 
- 
- 
1 (50%) 
- 
- 
- 
- 
Muscle spasm 
- 
- 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
Skin and subcutaneous tissue disorders 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
1 (20%) 
- 
Hyperhidrosis 
- 
- 
- 
- 
- 
- 
- 
- 
1 (20%) 
- 
Ecchymosis 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Investigations 
- 
- 
- 
- 
1 (20%) 
- 
- 
- 
1 (20%) 
- 
Blood creatine phosphokinase 
increased 
- 
- 
- 
- 
1 (20%) 
- 
- 
- 
1 (20%) 
- 
Ear and labyrinth disorders 
- 
- 
1 (20%) 
1 (50%) 
- 
- 
- 
- 
- 
- 
Pain in the external ear 
- 
- 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
Ear itching 
- 
- 
- 
1 (50%) 
- 
- 
- 
- 
- 
- 
Pollakiuria 
- 
- 
- 
- 
- 
- 
- 
- 
2 (40%) 
- 
Pollakiuria 
- 
- 
- 
- 
- 
- 
- 
- 
2 (40%) 
- 
Cardiac disorders 
- 
- 
- 
1 (50%) 
- 
- 
- 
- 
- 
- 
Right bundle branch block 
- 
- 
- 
1 (50%) 
- 
- 
- 
- 
- 
- 
Respiratory, thoracic and mediastinal 
disorders 
- 
- 
- 
- 
- 
- 
- 
- 
1 (20%) 
- 
Cough 
- 
- 
- 
- 
- 
- 
- 
- 
1 (20%) 
- 
Psychiatric disorders 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Emotional reactivity 
1 (20%) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Reproductive system and breast 
disorders 
- 
1 (50%) 
- 
- 
- 
- 
- 
- 
- 
- 
Dysmenorrhoea 
- 
1 (50%) 
- 
- 
- 
- 
- 
- 
- 
- 


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4.4 
Concise description of known risks and potential benefits associated with the 
use of the investigational product 
Given the available information on the use of RPH-104 in healthy volunteers, it can be expected 
that a single subcutaneous administration of the drug in patients with gout in doses up to 160 mg 
inclusive will not cause severe adverse drug reactions in patients. 
The patient may benefit from the use of RPH-104 , for example, pain and other manifestations of 
gouty arthritis exacerbation may decrease or disappear or the risk of gouty arthritis exacerbation 
may decrease. 
Voltaren® (diclofenac) may cause side effects. For more information about the side effects of 
Voltaren® (diclofenac), see the instructions for medical use. In order to prevent one of these side 
effects: damage to the gastric or duodenal mucous membrane, patients using Voltaren® 
(diclofenac) will receive the concomitant drug Ortanol® (omeprazole). The patient may benefit 
from the use of Voltaren® (diclofenac), for example, pain and other manifestations of gouty 
arthritis exacerbation may decrease or disappear. 
None of the investigational products is likely to help achieve a sufficient analgesic effect in 
100% of patients who receive these drugs in this study. In this regard, this study provides for the 
use of a rescue medication, triamcinolone acetonide, which is effective in a subset of patients 
with an acute gout attack (see Section 4.2.4). If triamcinolone acetonide is ineffective, other 
drugs for the treatment of a gout attack may be used. In addition, at the discretion of the patient, 
he/she may withdraw from the study at any time. 
4.5 
Justification for the sample size 
The assumption about the efficacy of RPH-104 in patients with an acute gout attack was based 
on the similarity in the mechanism of action of RPH-104 and Canakinumab (Ilaris®). 
Canakinumab (fully human anti-IL-1β monoclonal antibody) is approved in the EU and Russia 
for the treatment of patients with acute gouty arthritis and intolerance of other inflammatory 
therapies [8, 9]. The results of double-blind, randomized trials of canakinumab versus 
triamcinolone showed that patients with an acute gout attack treated with canakinumab had 
lower pain intensity 72 hours after starting therapy and a lower risk of new gout attacks, 
compared with patients who received triamcinolone [11]. 
Justification of the patient's age. According to epidemiological data, the prevalence of gout 
increases with age and reaches a plateau at 80 years [21,22]. Patients aged 70-79 years are 5 
times more likely to suffer from gouty arthritis compared with patients under 50 years old [23]. 
The incidence of gout has a linear dependence on age, reaching the peak of the disease in the age 
of 80-84 years [21, 22]. The age of patients included in the study of drugs (NSAIDs, type 2 
cyclooxygenase inhibitors, glucocorticosteroids, IL-1 inhibitors) for treatment of an acute gout 
attack was 18 years or older or was limited to 80 years [24, 25, 26, 27]. Given the 
epidemiological data on gout, as well as information on the age of patients included in various 
studies of treatment of acute gout attacks, the age of patients in this study is limited to 18-80 
years (≥ 18 and ≤ 80 years). 
4.6 
Justification for the method of administration, dosing, dosing regimen, and 
treatment course 
It is expected that in this study, subcutaneous administration of RPH-104 at doses from 4 to 160 
mg may reduce pain intensity in patients with an acute gout attack. 
The rationale for effective doses of RPH-104 is based on the following assumptions: 
1. The blood IL-1β level in patients with gout does not exceed 100 pg/mL [11], 
2. The blood IL-1β level in healthy volunteers is about 0.3 pg/mL [13]. 


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3. Dissociation constant of RPH-104 and IL-1β does not exceed 43.9 fM [7]. 
4. The molecular weight of RPH-104 is 152.7 kDa, 
5. The molecular weight of IL-1β is 17.5 kDa. 
6. The dissociation constant of RPH-104 and IL-1β relationship to the concentrations of 
RPH-104, IL-1β, and RPH-104:IL-1beta complex is described by the following equation: 
Kd = 
[RPH-104]* [IL-1β] 
[RPH-104:IL-1β] 
where [RPH-104], [IL-1beta], and [RPH-104:IL-1β] are the molar concentrations for RPH-104, 
IL-1β, and the RPH-104:IL-1β complex, respectively. 
Thus, based on the above equation, the calculated concentration of RPH-104 in the blood capable 
of reducing the free blood IL-1β level from 100 pg/mL to 0.3 pg/mL is 20 pM or 3 ng/mL. It is 
expected that this concentration of RPH-104 may reduce pain in patients with gout. 
According to a Phase 1 study in healthy volunteers, a blood concentration of RPH-104 of 3 
ng/mL will be reached approximately 2 hours after subcutaneous injection of RPH-104 4 mg and 
less than 30 minutes after subcutaneous injection of RPH-104 20 mg and higher. 
The results of the phase 1 study of RPH-104 showed that a single subcutaneous injection of 
RPH-104 at doses from 4 to 160 mg was well tolerated by healthy volunteers (see Section 4.3.3). 
Based on these results, it is assumed that RPH-104 will be well tolerated by patients following a 
single subcutaneous injection at doses ranging from 4 to 160 mg in this clinical study. 
The duration of use of Voltaren® (diclofenac) was selected based on the ACR guidelines for the 
management of acute gout attacks, according to which the use of NSAIDs at a full dose (if 
necessary) is indicated until the gout attack completely resolves [17]. According to the 
classification criteria for gout, a gout attack can last for up to 14 days, consequently, drugs that 
relieve a gout attack are indicated during this time [17]. A stepwise approach to relieve a gout 
attack is used with NSAIDs. In this case, NSAIDs are used at a full dose during the first 3 days, 
then at a lower dose in the next 7 days [19]. According to an article on a phase III study of 
rilonacept, for the relief of an acute gout attack, the reference product from NSAIDs was used at 
the full dose for 3 days (150 mg per day), then at a lower dose (75 mg per day) for 9 days [19]. 
In accordance with the Voltaren® (diclofenac) labeling, the recommended initial dose of the drug 
is 150 mg per day and 75-100 mg per day for long-term therapy [20]. In this study, Voltaren® 
(diclofenac) will be used as a reference product in the first 3 days at the full dose of 150 mg per 
day, then at a lower dose of 75 mg per day for the next 9 days. 
4.7 
Conformity of the principles of this study to international, regional, and other 
standards 
This study is conducted in accordance with this protocol, the ethical principles set forth in the 
Declaration of Helsinki of the World Medical Association (last revision), and the current edition 
of Good Clinical Practice (ICH GCP E6), the legislation and standards of the Russian 
Federation: the Constitution of the Russian Federation; the current edition of Federal Law No. 
61-FZ of the Russian Federation of April 12, 2010 On the circulation of medicinal products; the 
current edition of Federal Law No. 323-FZ of the Russian Federation of November 21, 2011 On 
the basics of protecting the health of citizens in the Russian Federation; Decree No. 714 of the 
Government of the Russian Federation of September 13, 2010 On Approval of Model Rules for 
Compulsory Life and Health Insurance of a Patient Participating in Clinical Trials of a 
Medicinal Product” (as amended on September 4, 2012); Decree No. 393 of the Government of 
the Russian Federation of May 18, 2011 On Amendments to the Model Rules for Compulsory 


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Life and Health Insurance of a Patient Participating in Clinical Trials of a Medicinal Product; 
Order No. 703n of the Ministry of Health and Social Development of Russia of August 23, 2010 
On Approval of the Notification Form for the Completion, Suspension or Termination of a 
Clinical Trial of a Medicinal Product for Medical Use; Order No. 774n of the Ministry of Health 
and Social Development of Russia of August 31, 2010 On the Ethics Council, Order No. 200n of 
the Ministry of Health of Russia of April 1, 2016 On Approval of Good Clinical Practice 
Guidelines, GOST R52379-2005 Good Clinical Practice and other applicable legislative acts. 
5 
STUDY GOAL AND OBJECTIVES 
5.1 
Study goal 
To evaluate the efficacy, pharmacokinetics, pharmacodynamics, safety and tolerability of RPH-
104 following a single injection in adult patients with an acute gout attack. 
5.2 
Study objectives 
 To investigate the efficacy of RPH-104 in the treatment of acute gouty arthritis following 
a single subcutaneous injection at doses of 4, 20, 40, 80 and 160 mg; 
 To investigate the pharmacokinetics of RPH-104 following its single subcutaneous 
injection; 
 To investigate the effect of RPH-104 following its single subcutaneous injection on 
concentrations of high-sensitivity C-reactive protein (hs-CRP), serum amyloid A protein, 
blood cytokines (IL-1α, IL-1β, IL-1RA, IL-6, IL-8, TNF-α); 
 To investigate the safety parameters of RPH-104 in adult patients with an acute gout 
attack. 
6 
STUDY DESIGN 
6.1 
Primary and secondary endpoints 
6.1.1 Primary efficacy variable 
Change in pain intensity in the assessed joint at 72 hours after start of the investigational product 
therapy compared to baseline, as measured on the visual analogue scale (VAS). 
6.1.2 Other efficacy variables 
 Change in pain intensity in the assessed joint at 15, 30, 45 minutes, 1, 1.5, 2, 4, 8, 24, 48, 
72 hours, on days 5, 6, 10, 15, 18, 22, 29 and 45 after start of the investigational product 
therapy compared to baseline (as measured on VAS). 
 Proportion of patients who rated the response to the investigational product therapy as 
"Excellent" or "Good" at 15, 30, 45 minutes, 1, 1.5 hours, 2, 4, 8, 24, 48, 72 hours, on 
days 5, 6, 10 15, 18, 22, 29, and 45 after initiation of the investigational product therapy; 
 Change in the degree of swelling, tenderness, erythema in the assessed joint at 24, 48, 72 
hours, on days 5, 6, 10, 15, 18, 22, 29 and 45 after start of the investigational product 
therapy compared to baseline; 
 Change in movement restriction in the assessed joint at 24, 48, 72 hours, on days 5, 6, 10, 
15, 18, 22, 29 and 45 after start of the investigational product therapy compared to 
baseline; 
 Time to 50% reduction in pain intensity in the assessed joint relative to the baseline level 
according to the VAS; 
 Time to use of the rescue medication; 


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 The proportion of patients who received the rescue medication within 72 hours of starting 
the investigational product therapy and over the entire treatment period; 
 Changes in the health assessment questionnaire scores 15, 29, and 45 days after start of 
the investigational product therapy compared to baseline. 
6.1.3 Pharmacokinetic variables 
Pharmacokinetic parameters of subcutaneous RPH-104: AUC0-t, AUC0-∞, Cmax, tmax, t1/2, 
Kel. 
6.1.4 Pharmacodynamic variables 
 Change in serum hs-CRP levels at 24, 72 hours, 5, 6, 15, 29 and 45 days after start of the 
investigational product therapy compared to baseline. 
 Change in serum amyloid protein A levels at 24, 72 hours, 5, 6, 15, 29 and 45 days after 
start of the investigational product therapy compared to baseline. 
 Change in serum cytokine (IL-1α, IL-1β, IL-1RA, IL-6, IL-8, TNF-α) levels at 24, 72 
hours, 5, 6, 15, 29 and 45 days after start of the investigational product therapy compared 
to baseline. 
6.1.5 Safety variables 
Frequency and severity of adverse events, laboratory results, vital signs, physical examination 
findings, ECG findings. 
6.1.6 Immunogenicity assessment 
Blood samples for immunogenicity assessment will be collected from patients treated with RPH-
104 at the following time points: before administration of RPH-104, on Day 15, Day 45. 
Concentrations of anti-RPH-104 antibodies will be assessed, including an assessment for 
neutralizing antibodies. 
6.2 
Study design and study design flowchart 
This clinical study is a multicenter, open-label, single-dose, parallel-group, two-period, 
randomized, phase IIa study to assess the efficacy, pharmacokinetics, pharmacodynamics, safety 
and tolerability of the investigational product RPH-104. 
In study Period 1, eligible patients are enrolled in a group of 22 patients and randomized to 
receive either RPH-104 4 mg or Voltaren® (diclofenac) in a 15:7 ratio (15 RPH-104 : 7 
Voltaren® (diclofenac)). Patients using Voltaren® (diclofenac) will receive the concomitant drug 
Ortanol® (omeprazole) in order to prevent damage to the gastric or duodenal mucous membrane. 
Upon completion of the enrollment of 22 patients, study Period 2 starts. In Period 2, newly 
enrolled patients are randomly assigned to one of 5 treatment groups: RPH-104 20 mg, 40 mg, 
80 mg and 160 mg and active control (Voltaren® (diclofenac)). It is planned to include 14 
patients in the RPH-104 groups in Period 2, and 7 patients in the Voltaren® (diclofenac) group. 
The enrollment of patients in Period 1 and Period 2 is sequential. There is no pause between the 
enrollment of patients in Period 1 and Period 2. Thus, patient enrollment for study Period 2 
begins immediately after all Period 1 patients are enrolled. Information on the planned total 
number of patients in the treatment groups is presented in Table 6.1. 


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Table 6.1 
Number of patients by treatment groups 
Treatment group 
Study therapy 
No. of patients 
RPH-104 4 mg 
RPH-104, 4 mg, SC, single dose 
15 
RPH-104 20 mg 
RPH-104, 20 mg, SC, single dose 
14 
RPH-104 40 mg 
RPH-104, 40 mg, SC, single dose 
14 
RPH-104 80 mg 
RPH-104, 80 mg, SC, single dose 
14 
RPH-104 160 mg 
RPH-104, 160 mg, SC, divided into 2 injections, 
80 mg each at different injection sites 
14 
Voltaren® (diclofenac) 
Voltaren® (diclofenac) 50 mg 3 times a day for 3 
days, then 25 mg 3 times a day for 9 days 
7 in Period 1 and 
Period 2 each, total of 
14 patients 
Total 
85 
Information about the investigational product used for the treatment of acute gout in the patients 
in this study (RPH-104 or Voltaren® (diclofenac)) and the dose of RPH-104 is unblinded to the 
patients and physicians. Patients who do not tolerate pain receive the rescue medication after 2 
hours and until Day 45 of the study after the first use of rescue medication to intensify therapy. 
The rescue medication is triamcinolone 40 mg intramuscularly. If an attack recurred after the use 
of the rescue medication, treatment of acute gout attack is carried out in accordance with the 
standard practice of the hospital. 
The primary efficacy variable is assessed 72 hours after initiation of the investigational product 
use. Secondary efficacy variables are evaluated over a 45 day period of therapy and follow-up. 
The safety of the investigational product is assessed over a 60-day period of therapy and follow-
up. 
The study flow diagram is shown in Figure 6.1. The total duration of the study for one patient 
does not exceed 70 days. 
RPH-104 4 mg once: n=15 


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* Screening procedures must be performed within 24 hours and the patient is randomized during this 
time. If necessary (in exceptional cases), the screening period can be extended, while randomization must 
be carried out no later than120 hours (5 days) after the onset of an attack. 
Figure 6.1 
Flow diagram of the study design. 
6.3 
Subjectivity minimization measures 
6.3.1 Randomization 
In Period 1, eligible patients are randomized to receive either RPH-104 4 mg or Voltaren® 
(diclofenac) in a 15:7 ration, i.e. 15 RPH-104 : 7 Voltaren® (diclofenac)). 
In Period 2, eligible patients are randomized to receive either RPH-104 20 mg, 40 mg, 80 mg and 
160 mg or Voltaren® (diclofenac) in a 2:2:2:2:1 ratio, respectively. 
A summary of the treatment groups and the number of patients per group is provided in Table 
6.1. 
The randomization will be carried out on the basis of a pre-generated randomization list with a 
random sequence of randomization of patients generated by the software. 
Period 1 
Period 2 
RPH-104 4 mg once: n=15 
Diclofenac 50 mg 3 times/day and 25 mg 3 times/day; 
RPH-104 20 mg once; n=14 
RPH-104 40 mg once; n=14 
RPH-104 80 mg once; n=14 
RPH-104 160 mg once; n=14 
Diclofenac 50 mg 3 times/day and 25 mg 3 times/day; 
Screening* 
Treatment and follow-
up period 
Day 1 – Day 60 
Day 1 
Randomization 
Day 60 


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The patient will be randomized by assigning the patient a number and a short name of the 
therapy group, for example, RPH-104 4 mg. An Interactive Web Response System (IWRS) with 
technical support service will be used to randomize the patient. Randomization is carried out by 
the investigator Information about the patient group assigned at randomization is to be recorded 
in the source documentation. 
6.3.2 Blinding 
This is an open-label study. Information about the drug for the treatment of acute gout attacks is 
unblinded to patients and investigators. In this study, there are subjective criteria for assessing 
the efficacy of study therapy, and information about the drug taken may affect the evaluation of 
the efficacy of the investigational product by the investigator and the patient. However, since this 
study is exploratory and is conducted with the aim of assessing the possibility of treating patients 
with an acute gout attack with RPH-104 in principle, the open-label design of the study is 
considered acceptable. The efficacy data from this study are not intended to be used to determine 
the sample size in blind studies. 
7 
SELECTION OF THE PATIENT POPULATION 
In this study, up to 135 adult patients with an acute gout attack will sign the main informed 
consent form and undergo screening procedures. 
At screening, it is planned to select 85 patients meeting all the eligibility criteria for the study 
described in this section for further participation in the study and initiation of treatment with the 
investigational product. 
7.1 
Principal diagnosis 
Adult patients with an acute gout attack are eligible for the study. 
7.2 
Inclusion criteria 
To initiate treatment of patients with the investigational product and to carry out the investigation 
procedures specified by the protocol after the screening visit, patients had to meet all the 
inclusion criteria: 
1. The patient gave his / her informed consent to participation in this study; the Informed 
Consent Form was signed both by the patient and the Investigator; 
2. Male and female patients aged 18 to 80 years inclusive; 
3. Established diagnosis of gout according to the criteria established by the American College 
of Rheumatology (ACR) and European League against Rheumatism (EULAR) in 2015; 
4. Pain in at least one joint at the screening and immediately prior to initiation of therapy with 
the investigational products, with intensity of 50 mm to 100 mm on the Visual Analogue 
Scale (VAS); 
5. Development of acute gout attack within 120 hours (5 days) prior to the randomization date; 
6. A history of 1 or more acute gout attacks prior to the Screening Visit; 
7. Patients receiving uric acid-lowering agents had to continue receiving these drugs at a stable 
dose for at least 4 weeks prior to enrolment to the study and throughout the study; the 
patients not receiving uric acid-lowering drugs might start receiving this treatment after the 
end of the study; 
8. Body mass index ≤ 40 kg/m2; 
9. QTcF interval ≤ 450 msec for menand ≤ 470 msec for women on ECG at screening; 
10. For women with childbearing potential: negative serum pregnancy test at screening; 


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11. Consent of women of childbearing potential and men who have female partners of 
childbearing potential to abstain from sexual intercourse or to use effective methods of 
contraception throughout the study and for 60 days after RPH-104 administration (if the 
patient receives RPH-104), as described in Section 9.9; 
12. The patient's ability to fulfil the requirements of the Study Protocol, as judged by the 
Investigator. 
7.3 
Exclusion criteria 
Patients are not eligible for the study after the screening period if they meet any of the following 
criteria: 
1. The patient received therapy with ibuprofen at a dose of up to 400 mg inclusive within 4 
hours or >400 mg within 8 hours prior to the randomization; 
2. The patient received therapy with diclofenac at a dose of up to 50 mg inclusive within 8 
hours or >50 mg within 24 hours prior to the randomization; 
3. The patient received any other non-steroidal anti-inflammatory drug (NSAID) within 24 
hours prior to the randomization; 
4. The patient received opioids within 48 hours prior to the randomization; 
5. The patient received metamizole or metamizole-containing drugs within 12 hours prior to the 
randomization; 
6. The patient received any analgesic drug (including paracetamol) within 6 hours prior to the 
randomization; 
7. The patient received a long-acting NSAID (half-life ≥24 hours) within 5 half-life periods or 1 
month prior to the randomization, whichever is longer; 
8. The patient received naproxen, meloxicam, nabumetone, celecoxib, etoricoxib or extended-
release indomethacin within 5 days prior to the randomization; 
9. The patient received corticosteroids (including intra-articular and inhaled) within 4 weeks 
prior to the randomization; 
10. The patient received colchicine within 7 days prior to the randomization; 
11. Intolerance of or contraindications to NSAIDs; 
12. Contraindications to Ortanol® capsules 20 mg; 
13. Chronic heart failure, NYHA functional class II-IV; 
14. A history of or current clinically significant ventricular arrhythmias or clinically significant 
atrial tachyarrhythmias; 
15. Unstable angina or stable exercise-induced angina, functional class III or IV; 
16. Secondary gout, chemotherapy-induced gout, lead- or transplantation-induced gout; 
17. Rheumatoid arthritis, confirmed or suspected infectious septic arthritis or any other type of 
acute inflammatory arthritis; 
18. Clinically significant renal impairment determined based on creatinine clearance (estimated 
using the Cockcroft-Gault formula) <60 mL/min, or patients on hemodialysis; 
19. Blood coagulation disorders; a history of gastrointestinal bleedings or perforation; 
20. Pregnant or breast-feeding women; 


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21. Elective surgery or major surgical intervention (minor surgical procedures, such as catheter 
placement or bone marrow biopsy, are not exclusion criteria) within 14 days before the first 
dose of the investigational medicinal product; 
22. Current or suspected HIV-infection, HBsAg, Hepatitis C Virus antibodies (HCVAb), other 
acute or chronic bacterial, fungal or viral infections at the time of enrolment to the study; 
23. Presence of any risk factors for tuberculosis based on the results of assessment using the 
Tuberculosis Risk Assessment Questionnaire at the screening or confirmed tuberculosis or 
any other infectious disease of the lungs or bronchi based on chest X-ray (2 views) findings 
performed within 3 months prior to the screening visit, or the need for anti-TB medications, 
such as isoniazid during the study; 
24. Neutropenia, leukopenia, or thrombocytopenia determined based on the following laboratory 
parameters assessed at screening: 
а. Absolute neutrophil count (ANC) below 1.5 х 109/L; 
б. White blood cell count below 4.0 х 109/L; 
в. Platelet count below 150 х 109/L; 
25. Immunization with live vaccines within 3 months prior to the subject's enrolment to the study 
or planned vaccination within 60 days after the expected date of the first dose of the 
investigational product; 
26. A history of allergic reactions to biological drugs, Voltaren® (diclofenac) or Ortanol® 
(omeprazole); 
27. Contraindications to subcutaneous, intramuscular, intravenous or intra-articular injections; 
28. A history of malignancy (except for patients with localized in situ basal cell carcinoma of the 
skin or in situ cervical cancer, who could be enrolled to the study immediately after the 
treatment for this disease), unless it is in remission for ≥5 years, as well as patients who are 
investigated for cancer or patients with a suspected malignancy; 
29. A condition or disease, which, in the Investigator's opinion, could jeopardize the patient's 
safety or affect the investigational product safety assessment; 
30. Any other conditions and diseases, such as uncontrolled diabetes mellitus, uncontrolled 
hypertension, congestive heart failure, exacerbation of peptic ulcer disease, clinically 
significant liver diseases, kidney diseases, uncontrolled thyroid dysfunction, unhealed 
wounds, ulcers or bone fractures, psychiatric disorders, uncontrolled epilepsy, drug 
dependence, which could prevent the patient from complying with this Study Protocol; 
31. Use of biologicals or investigational medicinal products within 5 half-life periods of these 
drugs or 3 month prior to the randomization, whichever is longer; 
32. Blood donation or blood loss of ≥400 mL within 8 weeks prior to the randomization. 
33. The patient was already randomized in this clinical study. 
8 
WITHDRAWAL 
FROM 
THE 
STUDY 
AND 
PREMATURE 
TERMINATION OF THE STUDY 
If a decision has been made to withdraw a patient early from the study following the study drug 
administration, the investigator must schedule a follow-up visit for the patient within 7 days, if 
possible. If this is not possible, the patient must be invited for a follow-up visit as soon as 
possible in the period exceeding 7 days. At this visit, it is necessary to carry out all the 
assessments specified for this visit (see Section 10.3). 


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If a patient is excluded from the study due to an AE or a laboratory abnormality, the patient must 
be monitored until the AE resolved or his/her condition stabilized. 
8.1 
Early withdrawal from the study 
The withdrawal criteria are: 
 Withdrawal of informed consent. 
 Patient's death. 
 Patient’s pregnancy. 
 A significant protocol deviation, which, in the opinion of the Investigator, and upon 
agreement with the Sponsor, could result in an incorrect interpretation of the study 
results. 
The use of a rescue medication, prohibited drugs, and missing certain procedures or individual 
visits are generally not the reasons for discontinuation of the patient from the study. In these 
cases, the patient should be offered to continue the visits and examinations in accordance with 
the clinical study protocol. 
The Investigator should make all reasonable efforts to determine the reason of the patient's 
withdrawal from the study. The date and reason for the patient's early withdrawal from the study 
had to be clearly described in the CRF for any patient who received at least one dose of the 
investigational product. 
If a patient is withdrawn from the study due to pregnancy, the Investigator provides the Sponsor 
with information concerning the pregnancy outcome (see Section 12.7). 
Regardless of the reasons for early withdrawal from the study, no replacement of withdrawn 
patients is to be made. 
8.2 
Premature termination of the study at an individual study site and premature 
termination of the study in general 
The sponsor reserves the right to terminate the study at an individual study site or at all sites at 
any time due to reasons of medical and/or administrative nature. 
In case of premature study termination, the Investigator should, regardless of the reason for this 
decision, immediately notify all patients and ensure their follow-up and further treatment. The 
sponsoring company will notify in writing the Investigator and regulatory authorities about the 
termination of the study, indicating the reasons for this decision. 
In case of premature termination of the study, the Investigator should, if possible, conduct the 
procedures and evaluations scheduled for the follow-up visit for early withdrawal in all patients 
who have not completed their participation in the study by this time (see Section 10.3). 


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9 
PATIENT TREATMENT 
9.1 
Description of investigational products and concomitant therapy 
Investigational product provided by the Sponsor 
RPH-104 solution for subcutaneous injection, 40 mg/mL is provided by the Sponsor of the study. 
Name 
RPH-104/L04018 
Dosage form 
RPH-104 solution for subcutaneous injection, 40 mg/ml, 2 mL 
Active substance 
RPH-104/L04018 
Excipients 
Sucrose, Polyethylene glycol (PEG) 3350, sodium chloride, L-histidine 
Appearance 
A clear or slightly opalescent solution 
Packaging 
4 mL glass vial with RPH-104 solution for subcutaneous injection, 2 mL 
Manufacturer 
Branch of R-Pharm JSC, Yaroslavl Factory of Finished Dosage Forms, 150061, 
Yaroslavl, Gromova str. 15 phone/fax +7 (4852) 40-30-20. 
Reference product 
Voltaren® (diclofenac) enteric-coated tablets, 25 and 50 mg is provided by the study Sponsor. 
Marketing authorization holder (owner): Novartis Pharma Limited, Switzerland. 
Trade name: Voltaren® tablets 25 mg and 50 mg 
Name 
Voltaren® 
INN 
diclofenac 
Dosage form 
Enteric coated tablets 25 mg and 50 mg 
Active substance 
diclofenac sodium 
Excipients 
anhydrous colloidal silicon dioxide, microcrystalline cellulose, lactose 
monohydrate, magnesium stearate, corn starch, povidone K30, sodium 
carboxymethyl starch 
Coating composition: 
For 25 mg: hypromellose, macrogolglycerol hydroxystearate, dye iron oxide 
yellow, talc, titanium dioxide 
For 50 mg: hypromellose, macrogolglycerol hydroxystearate, dye iron oxide 
yellow, dye iron oxide red, talc, titanium dioxide 
Enteric coating 
composition 
copolymer of methacrylic acid and ethyl acrylate (1:1), macrogol 8000, 
silicone antifoam emulsion SE2, talc 
Colored coating 
composition 
For 25 mg: hypromellose, macrogolglycerol hydroxystearate, dye iron oxide 
yellow, talc, titanium dioxide 
For 50 mg: hypromellose, macrogolglycerol hydroxystearate, dye iron oxide 
yellow, dye iron oxide red, talc, titanium dioxide 
Appearance 
For 25 mg: yellow, round, biconvex, bevelled-edged enteric-coated tablets 
embedded with "CG" on one side of the tablet and "BZ" on the other 
For 50 mg: light brown, round, biconvex, bevelled-edged enteric-coated 
tablets embedded with "CG" on one side of the tablet and "GT" on the other 
Packaging 
For 25 mg and 50 mg: 
2 10-tablet blisters per carton 


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3 10-tablet blisters per carton 
Manufacturer 
NOVARTIS Saglik Gida ve Tarim Urunlery Sanayi ve Ticaret, A.S., Turkey 
Concomitant drug for patients receiving Voltaren® (diclofenac) 
Ortanol® (omeprazole) 20 mg capsule is provided by the study sponsor. 
Marketing authorization holder (owner): Sandoz dd, Slovenia. 
Trade name: Ortanol®, capsules, 20 mg 
Name 
Ortanol® 
INN 
omeprazole 
Dosage form 
Capsule 
Active substance 
omeprazole 
Excipients 
Low-substituted hydroxypropyl cellulose, MCC, anhydrous lactose, 
croscarmellose sodium, povidone, polysorbate 80, hypromellose phthalate, 
dibutyl sebacate, talc 
Capsule coating 
Hypromellose, carrageenan, potassium chloride, titanium dioxide, iron (III) 
oxide yellow (for 40 mg), iron (III) oxide red (for 40 mg), water, printing 
ink: iron (III) oxide black ( E172), shellac, anhydrous ethanol, anhydrous 
isopropanol, propylene glycol, butanol, ammonium hydroxide, potassium 
hydroxide, purified water 
Appearance 
Hard capsules No. 2, white body and cap inscribed with "OME 20" in black 
ink on both parts of the capsule 
Packaging 
7 capsules per blister, 4 blisters per carton 
Manufacturer 
Lek Pharmaceuticals dd, Slovenia 
 
9.2 
Packaging and labelling 
Investigational product RPH-104 solution for subcutaneous injection, 40 mg/mL, 2 mL will be 
supplied in 4 mL vials. 1 vial per carton. 
Voltaren® (diclofenac) will be supplied as 25 and 50 mg film-coated tablets in the manufacturer's 
original packaging. 
Ortanol® (omeprazole) will be supplied in the form of 20 mg capsules in the manufacturer's 
original packaging. 
The investigational product RPH-104, Voltaren® (diclofenac), Ortanol® (omeprazole) and 
Kenalog® (triamcinolone) are labeled in accordance with the requirements of the Russian 
legislation. 
9.3 
Storage conditions 
Storage of products used in this study is the responsibility of an authorized employee or 
pharmacist of the study site. RPH-104 must be stored under the following conditions: 
 At 2°C to 8°C. Do not freeze. 
Voltaren® (diclofenac) and Ortanol® (omeprazole) should be stored under the following 
conditions: 
 In a dry, dark place, below 25 °C. 


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Kenalog® (triamcinolone) must be stored under the following conditions: 
 In a dark place, at 8°C to 25°C. Do not freeze. 
The drugs must be stored in commercial packaging in a secured place with limited access. An 
authorized employee or pharmacist of the study site should monitor the temperature regime in 
the refrigerator in which the drugs are stored, and record the temperature on weekdays, taking 
into account the minimum and maximum temperatures from the previous measurement. 
9.4 
Accounting and destruction of investigational products and concomitant 
therapy 
The authorized employee or pharmacist of the study site is responsible for the receipt of all study 
drugs at the study site. Upon delivery of a product lot to the study site, the authorized employee 
examines the cargo and fills out the reception confirmation form. A copy of this form should be 
retained at the study site, and the original should be sent to the Sponsor or an organization 
designated by the Sponsor. 
During the study, the investigational products RPH-104, Voltaren® (diclofenac), Kenalog® 
(triamcinolone) and the concomitant drug Ortanol® (omeprazole) should be accounted for. The 
patient must return all Voltaren® (diclofenac), Kenalog® (triamcinolone) and Ortanol® 
(omeprazole) issued to the patient and unused and all packages from used Voltaren® 
(diclofenac), Kenalog® (triamcinolone) and Ortanol® (omeprazole) to the investigator. Returned 
Voltaren® (diclofenac), Kenalog® (triamcinolone) and Ortanol® (omeprazole) are accountable. 
Voltaren® (diclofenac), Kenalog® (triamcinolone) and Ortanol® (omeprazole) returned by the 
patient cannot be re-dispensed. 
Returned unused Voltaren® (diclofenac), Kenalog® (triamcinolone) and Ortanol® (omeprazole) 
and used Voltaren® (diclofenac), Kenalog® (triamcinolone) and Ortanol® (omeprazole) packages 
must be retained at the Study Center until specifically instructed by the Sponsor. 
The procedure for destruction of the investigational products will be determined by the Study 
Sponsor. 
9.5 
Dose, method of administration, dosing regimen, and duration of therapy 
9.5.1 Use of the investigational product RPH-104 
RPH-104 is administered to patients randomized to one of the RPH-104 groups. The dose of 
RPH-104 for administration to a patient is selected based on information on the patient's therapy 
group. 
To administer RPH-104 4 mg to a patient, 0.1 mL of RPH-104 solution is injected to the patient. 
To administer RPH-104 20 mg to a patient, 0.5 mL of RPH-104 solution is injected to the 
patient. To administer RPH-104 40 mg, 1 mL of RPH-104 solution is injected to the patient. To 
administer RPH-104 80 mg, 2 mL of RPH-104 solution is injected to the patient. To administer 
RPH-104 160 mg, the patient received two injections of 2 mL RPH-104 solution at different 
injection sites (Table 9.1). 
RPH-104 is injected subcutaneously into the anterior abdominal region in one of the areas 
indicated in Figure 9.1. 
 
 


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Table 9.1 
Injected volume of RPH-104 to patients 
Treatment 
group 
Volume of RPH-104 solution 
for administration to the patient 
RPH-104 
4 mg 
0.1 mL 
RPH-104 
20mg 
0.5 mL 
RPH-104 
40 mg 
1 mL 
RPH-104 
80mg 
2 mL 
RPH-104 
160 mg 
Two 2 mL injections at 
different injection sites 
 
 
Figure 9.1 
Areas of the anterior abdominal wall where RPH-104 should be 
administered. 
9.5.2 Voltaren® (diclofenac) intake 
Voltaren® (diclofenac) is given to patients randomized to the Voltaren® (diclofenac) group. 
On the first day of therapy, Voltaren® (diclofenac) is dispensed in an amount sufficient to take 
the drug until the end of the therapy period. The patient takes the first dose of the drug at the 
study site. Patients who, by the decision of the Investigator, continue to participate on an 
outpatient basis subsequently take the drug at home on their own in accordance with the study 
protocol. Hospitalized patients continue to take the drug in a hospital setting until discharge. 
Patients take Voltaren® (diclofenac) orally, at a dose of 50 mg 3 times a day for 3 days, then 25 
mg 3 times a day for 9 days (12 days in total). 
Voltaren® (diclofenac) will be used with Ortanol® (omeprazole), see Section 9.8.1. 
9.5.3 Duration of treatment 
In all cases, RPH-104 is administered as a single injection; in the case of a 160-mg dose, the drug 
is administered as two consecutive 80 mg injections at different injection sites. 
The duration of therapy with Voltaren® (diclofenac) is 12 days. 
The duration of use of Voltaren® (diclofenac) was selected based on the ACR guidelines for the 
management of acute gout attacks, according to which the use of NSAIDs at a full dose (if 
necessary) is indicated until the gout attack completely resolves [17]. According to the 
classification criteria for gout, a gout attack can last for up to 14 days, consequently, drugs that 


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relieve a gout attack are indicated during this time [18]. A stepwise approach to relieve a gout 
attack is used with NSAIDs. In this case, NSAIDs are used at a full dose during the first 3 days, 
then at a lower dose in the next 7 days [19]. According to an article on a phase III study of 
rilonacept, for the relief of an acute gout attack, the reference product from NSAIDs was used at 
the full dose for 3 days (150 mg per day), then at a lower dose (75 mg per day) for 9 days [20]. 
In accordance with the Voltaren® (diclofenac) labeling, the recommended initial dose of the drug 
is 150 mg per day and 75-100 mg per day for long-term therapy. In this study, Voltaren® 
(diclofenac) will be used as a reference product in the first 3 days at the full dose of 150 mg per 
day, then at a lower dose of 75 mg per day for the next 9 days. 
By the decision of the investigator, patients can be hospitalized after the use of the 
investigational products. Patients who, in the investigator's opinion, are not eligible for 
hospitalization, are followed up for at least 3 hours after the investigational product 
administration, after which they can leave the study site and continue to participate in the study 
with all assessments performed on an outpatient basis. 
9.6 
Overdose with the sponsor’s investigational product 
Cases of RPH-104 overdose are not known. Symptomatic treatment should be used in the event 
of an overdose. 
9.7 
Compliance assessment 
Patients treated with Voltaren® (diclofenac) are given diaries to record the date, time and dose of 
Voltaren® (diclofenac) taken. All missed doses should be recorded in the Patient's Diary. 
The information on the number of Voltaren® (diclofenac) tablets dispensed to and received from 
the patient, as well as information from the patient's diary is recorded. It is automatically 
calculated using the formula: the number of tablets taken by the patient/the number of tablets that 
the patient had to take * 100%. 
If, based on the results of compliance assessment, the patient took less than 80% of the 
prescribed dose of Voltaren® (diclofenac), the investigator must discuss with the sponsor the 
appropriateness of the patient's further participation in the study and the possible premature 
discontinuation of the patient from the study. 
9.8 
Previous and concomitant therapies 
9.8.1 Orthanol® (omeprazole) 
In order to prevent damage to the gastric and duodenal mucosa caused by Voltaren® (diclofenac), 
all patients receiving Voltaren® (diclofenac) will simultaneously take Ortanol® (omeprazole) as 
follows: 20 mg, orally daily before breakfast throughout the course of Voltaren® (diclofenac) 
treatment. 
Method of administration of Ortanol® (omeprazole): orally, with a sufficient amount of liquid. 
The capsule must be swallowed whole. If the patient cannot swallow the capsule whole, it is 
possible to dissolve its contents in a small amount of water or fruit juice (for example, apple or 
orange). The capsule may not be dissolved in carbonated drinks or used with milk. The resulting 
solution of the drug should be drunk immediately after preparation, washed down with an 
additional ½ glass of water. 
On the first day of therapy in the study, it is possible to take it regardless of meals and at a later 
time. 
9.8.2 Rescue therapy for a gout attack 
Patients who do not tolerate pain will receive the rescue medication 2 hours after the first use of 
the investigational product to intensify therapy. The rescue medication is triamcinolone 40 mg 


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intramuscularly. Before administration of the rescue medication, pain relief efficacy in the 
assessed joint must be evaluated on VAS and the patient global assessment of efficacy must be 
performed using a categorical scale and the time of administration of the rescue medication must 
be recorded. 
Triamcinolone suspension for injection is provided by the study sponsor. 
Name 
Kenalog® 
INN 
Triamcinolone 
Dosage form 
Suspension for injection 
Active substance 
Triamcinolone acetonide 
Excipients 
Benzyl alcohol, sodium chloride, carmellose sodium, polysorbate 80, 
hydrochloric acid, sodium hydroxide, water for injection 
Packaging 
Ampoules, 40 mg/mL, 1 mL No. 5 (1 blister, 5 ampoules per blister) 
Manufacturer 
JSC KRKA, dd. Novo mesto, Slovenia 
If an attack recurs after the use of the rescue medication, treatment is carried out in accordance 
with the standard practice of the hospital. 
9.8.3 Recording information on prior and concomitant therapy 
Prior therapy 
The following information about the therapy that the patient has previously received for gout (all 
prior therapy for gout during the gout therapy period), as well as other prior therapy within 30 
days prior to screening is recorded in the CRF: 
 The names of the drugs, their doses, and the dates of use; 
 The names of any investigational medicinal products used by the patient with treatment 
dates. 
To do this, the information should be transferred from the patient's chart or case record into the 
CRF. 
Concomitant therapy 
Information about all concomitant therapies received by the patient from the signing of the 
Informed Consent Form until the completion of the study by the patient must be recorded in the 
source documentation and in the CRF for each patient (including information on the date of the 
start and end of concomitant therapy or a mark on the continuation of concomitant therapy at the 
last visit). 
9.8.4 Allowed concomitant therapy 
Uric acid-lowering agents 
Uric acid-lowering agents are allowed provided that patients have received a stable dose of these 
drugs for at least 4 weeks prior to the intended date of randomization, and the dose of these drugs 
remains stable throughout the study. 
9.8.5 Prohibited concomitant therapy 
The following therapy is prohibited from the moment of signing the informed consent (start of 
screening) until the end of the study (except in cases of inefficacy of sequential therapy with the 
investigational product and the rescue medication): 


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 Analgesics/NSAIDs (including selective type 2 cyclooxygenase inhibitors, analgesic 
antipyretics and opioids); The exception is acetylsalicylic acid at a dose of <325 mg/day, 
when the patient is taking it as an antiplatelet agent; 
 Systemic or intra-articular corticosteroids, inhaled corticosteroids, excluding rescue 
medications; 
 Colchicine; 
 Any other biological products, excluding the investigational product; 
 Any investigational medicinal product or medical device other than RPH-104; 
 Herbal preparations are prohibited within 2 weeks before the first RPH-104 dose and 
throughout the study. 
 It is prohibited to prescribe uric acid-lowering agents for the first time. 
Vaccination with live vaccines is prohibited during the study participation or within 60 days after 
RPH-104 administration. 
9.9 
Contraception during the study 
Women with child-bearing potential, as well as men who have female partners with child-
bearing potential, should use highly effective methods of contraception for the entire duration of 
the study, and also for 60 days after the administration of RPH-104. 
Highly effective methods of contraception: 
1. Complete sexual abstinence if it is preferred by the patient and is the patient's normal 
lifestyle. Therefore, periodic sexual abstinence during ovulation based on symptoms, 
body temperature measurements, during the post-ovulation period, calendar-based 
methods, interrupted sexual intercourse, and combinations of these methods are not 
acceptable contraception methods. 
2. Female surgical contraception: bilateral oophorectomy, tubal ligation carried out at least 
6 weeks before the administration of the investigational medicinal product. 
3. Vasectomy in men carried out at least 6 months before the administration of the 
investigational medicinal product, with a documented absence of sperm in ejaculate. 
4. Use of an intrauterine contraceptive—intrauterine device (IUD): IUD made of copper or 
IUD with progesterone. 
5. Double barrier method (condom and intrauterine spermicide, spermicidal cervical caps or 
spermicidal diaphragms). 
10 
CLINICAL EVALUATION PLAN AND STUDY VISITS 
The time frames established by the Study Protocol should be observed for all the visits described 
below. 
The study site personnel should make all efforts to conduct the assigned schedule of procedures 
and visits exactly as required by the Study Protocol. 
All deviations from the study flow chart and procedures scheduled for the visits should be 
documented in the CRF. 
10.1 Pre-screening 
A pre-screening visit is carried out for patients with gout who visit the physician-investigator as 
part of routine patient follow-up and do not experience an acute gout attack. At this visit, the 


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patient is informed about the study procedures and the patient signs the Informed Consent to 
participate in the screening. The patient receives a copy of the Patient Information Sheet with 
Informed Consent Form for review and making a decision about participation in the study in the 
event of an acute gout attack. 
10.2 Screening and treatment period 
Screening procedures must be performed within 24 hours and the patient is randomized during 
this time. If necessary (in exceptional cases), the screening period can be extended, while 
randomization must be carried out no later than 120 hours (5 days) after the onset of an attack. 
Patients randomized to the Voltaren® (diclofenac) group do not have to come to the study site on 
study days 10, 18 and 22, but they should complete the diary, if applicable, and the patient 
questionnaire on these days. 
Screening day (screening procedures and baseline assessments) 
The patients are invited to participate in the study and are given a copy of the Patient Information 
Sheet with Informed Consent Form for review and making a decision about their participation. 
The patient's written informed consent to participation in the study must be obtained before any 
procedures scheduled in this study, including the screening procedures, are carried out. 
Patients who have read the Patient Information Sheet and signed the Informed Consent Form will 
be assigned numbers by the online randomization system in the order in which they visit the 
study site during the screening visit procedures. The number for each patient will consist of two 
parts: the first two digits will indicate the site number, the next three digits will indicate the 
assigned serial number of the patient. The individual patient number is retained for subsequent 
randomization. 
Example of patient number assignment: At site 1, the first patient who signs the informed 
consent form will be assigned number 01001, which will be retained through randomization. The 
second patient who signs the informed consent form is assigned number 01002. Let us assume 
that the second patient was not randomized. Then he drops out of the study with number 01002. 
The third patient receives number 01003. The number assigned to the patient will be indicated on 
all study documents and in the source documentation. 
If a patient is withdrawn from the study during the screening period (an exclusion criterion 
identified, patient's refusal to participate, etc.), the reason for withdrawal should be specified in 
the screening log. In this case, the patient can take part in the study again. 
After signing the informed consent form for participation in the clinical study, the following 
procedures are performed at screening: 
 Confirmation of the diagnosis, documenting the information about the primary disease; 
NOTE. The diagnosis of gout can be made at a visit to the study site during a current gout 
attack based on the American College of Rheumatology (ACR) and European League 
Against Rheumatism (EULAR) criteria of 2015 with the total score of 8. Uric acid level as 
the diagnostic criterion can be determined earlier, regardless of when. The highest uric acid 
levels ever measured must be used. 
 Collection of demographic data, medical history, information about previous and 
concomitant therapy; 
 Patient assessment using the TB risk assessment questionnaire; 
 Measurement of height and weighing, calculation of body mass index (body mass index 
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 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS (screening score); 
o Health assessment questionnaire score (baseline value); 
 Physician assessment of the degree of swelling, tenderness, erythema and movement 
restriction in the assessed joint (baseline value); 
 Blood sampling for the following analyses: 
o Diagnosis of infections: HIV, HBsAg and HCV Ab (rapid tests, the results must 
be evaluated before randomization); 
o Diagnosis of infections: HIV, HBsAg, HCV Ab (central laboratory); 
o Complete blood count with WBC differential (absolute neutrophil count, 
leukocyte and platelet counts must be assessed prior to patient randomization); 
o Blood creatinine level (local laboratory, creatinine levels must be assessed prior to 
patient randomization); 
o Diagnosis of tuberculosis: T-SPOT.TB test performed at screening or during the 
hospital stay (central laboratory); 
o Calculation of creatinine clearance (automatically in CRF using the Cockcroft-
Gault formula); 
o Blood chemistry with blood lipids (central laboratory); 
o Blood clotting tests (central laboratory); 
o Baseline sample for hs-CRP (central laboratory); 
o Baseline sample for serum amyloid protein A (central laboratory); 
o Baseline sample for cytokines (central laboratory); 
o Serum pregnancy test for women of childbearing potential (the results must be 
assessed prior to patient randomization); 
 Urinalysis; 
 Physical examination (the results must be assessed prior to patient randomization); 
 Vital signs (the results must be assessed prior to patient randomization); 
 12-lead ECG (the results must be assessed prior to patient randomization); 
 Chest X-ray in 2 views (the results must be assessed prior to patient randomization); 
 Serious adverse event recording; 
 Eligibility assessment. 
For patients meeting the eligibility criteria, the following procedures are performed immediately 
prior to randomization: 
 Handing over to the patient a questionnaire for recording pain intensity in the assessed 
joint according to the VAS (baseline value recorded immediately (within 1 hour) before 
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Day 1 (randomization and initiation of therapy) 
Patients meeting the eligibility criteria are randomized to receive therapy with either of the 
investigational products, RPH-104 or Voltaren® (diclofenac). 
After randomization, the patients undergo the following procedures: 
 Blood collection for the following tests (only for patients randomized to the RPH-104 
group, prior to drug administration): 
o Baseline blood sample to study the RPH-104 pharmacokinetics (central 
laboratory); 
o Baseline blood sample to study anti-RPH-104 antibody levels (central laboratory); 
 Subcutaneous injection of RPH-104 (only for patients randomized to RPH-104 groups); 
NOTE. The time of administration of RPH-104 is recorded in the source documentation and 
CRF. Sampling time for subsequent blood samples to assess pharmacokinetics, pain intensity 
in the assessed joint, and patient global assessment of efficacy are counted from this time. 
The acceptable time intervals for these procedures are indicated in the Study Procedure 
Table (see Section 3). 
Evaluation of pain intensity in the assessed joint and patient global assessment of efficacy 
are performed before pharmacokinetic blood sampling in accordance with the pre-specified 
time intervals for these procedures. 
 Dispensing Voltaren® (diclofenac) and Ortanol® (omeprazole) to the patient in an amount 
sufficient for use until the end of the treatment period (only for patients randomized to 
the Voltaren® (diclofenac) group); 
NOTE. Subcutaneous injection of RPH-104 or the first dose of Voltaren® (diclofenac) must 
be given within 30 minutes after randomization. 
By the decision of the investigator, after the use of the investigational products, patients can 
be hospitalized and remain under observation in the hospital or continue to participate in the 
study on an outpatient basis. 
After administration of the investigational products, outpatients remain under the 
supervision of the investigator for at least 3 hours, after which they are allowed to leave the 
study site. These patients should return to the study site for all analyses and assessments in 
accordance with the study procedure schedule (Table 3.1). 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS (at 15, 30, 45 minutes, 1, 1.5 
h after the use of the investigational product); 
o Patient global assessment of the efficacy using a categorical scale (at 15, 30, 45 
minutes, 1, 1.5 h); 
 Evaluation of RPH-104 injection site reactions 15 minutes after injection (only for 
patients who received RPH-104); 
 Collecting information on concomitant therapy and adverse events; 
 Handing over the Patient Diary. 
 


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Day 1 (2 and 8 hours after the start of therapy) – only for patients randomized to RPH-104 
groups 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (central laboratory); 
 Evaluation of RPH-104 injection site reactions; 
 Collection of information on concomitant therapy and adverse events. 
 
Day 1 (4 hours after the start of therapy) – only for patients randomized to RPH-104 groups 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale; 
 Evaluation of RPH-104 injection site reactions; 
 Collection of information on concomitant therapy and adverse events. 
 
Day 2 (24 hours after the start of therapy) 
 Assessment of vital signs; 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
o hs-CRP (central laboratory); 
o Serum amyloid protein A (central laboratory); 
o Cytokines (central laboratory); 
 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collection of information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 


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Day 3 (48 hours after the start of therapy) 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 
Day 4 (72 hours after the start of therapy) 
 Assessment of vital signs; 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
o hs-CRP (central laboratory); 
o Serum amyloid protein A (central laboratory); 
o Cytokines (central laboratory); 
 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 
Day 5 (96 hours after the start of therapy) 
 12-lead ECG; 
 Urinalysis; 


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 Assessment of vital signs; 
 Weighing; 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
o Complete blood count (local laboratory); 
o Blood creatinine level (local laboratory); 
o Calculation of creatinine clearance (automatically in CRF using the Cockcroft-
Gault formula); 
o Blood chemistry with blood lipids (central laboratory); 
o Blood clotting tests (central laboratory); 
o hs-CRP (central laboratory); 
o Serum amyloid protein A (central laboratory); 
o Cytokines (central laboratory). 
 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 
Day 6 (120 hours after the start of therapy) 
 Assessment of vital signs; 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
o hs-CRP (central laboratory); 
o Serum amyloid protein A (central laboratory); 
o Cytokines (central laboratory); 


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 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 
Day 10 (216 hours after the start of therapy) and Day 18 (408 hours after the start of therapy) 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 
Day 15 (336 hours after the start of therapy) 
 Urinalysis; 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
o Health assessment questionnaire completion; 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
o A study of anti-RPH-104 antibodies (only for patients randomized to the RPH-
104 groups, central laboratory); 
o Complete blood count (local laboratory); 
o Blood creatinine level (local laboratory); 
o Calculation of creatinine clearance (automatically in CRF using the Cockcroft-
Gault formula); 


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o Blood chemistry with blood lipids (central laboratory); 
o Blood clotting tests (central laboratory); 
o hs-CRP (central laboratory); 
o Serum amyloid protein A (central laboratory); 
o Cytokines (central laboratory); 
 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Assessment of vital signs; 
 Weighing; 
 Physical examination; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 
Day 22 (504 hours after the start of therapy) 
 Assessment of vital signs; 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale. 
 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 
Day 29 (672 hours after the start of therapy) 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale; 
o Health assessment questionnaire completion; 


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 Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
o hs-CRP (central laboratory); 
o Serum amyloid protein A (central laboratory); 
o Cytokines (central laboratory); 
 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Assessment of vital signs; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data; 
 Handing over the Patient Diary. 
 
Day 45 (1056 hours after the start of therapy) 
 12-lead ECG; 
 Urinalysis; 
 Dispensing questionnaires to the patient to record the following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale; 
o Health assessment questionnaire completion. 
o Blood sampling for the following analyses: 
o Assessment of RPH-104 pharmacokinetics (only for patients randomized to the 
RPH-104 groups, central laboratory); 
o A study of anti-RPH-104 antibodies (only for patients randomized to the RPH-
104 groups, central laboratory); 
o Complete blood count (local laboratory); 
o Blood creatinine level (local laboratory); 
o Calculation of creatinine clearance (automatically in CRF using the Cockcroft-
Gault formula); 
o Blood chemistry with blood lipids (central laboratory); 
o Blood clotting tests (central laboratory); 
o hs-CRP (central laboratory); 
o Serum amyloid protein A (central laboratory); 
o Cytokines (central laboratory); 
o Serum pregnancy test for women of childbearing potential; 


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 Assessment of the degree of swelling, tenderness, erythema and movement restriction in 
the assessed joint; 
 Assessment of vital signs; 
 Weighing; 
 Physical examination; 
 Evaluation of RPH-104 injection site reactions (only for patients who received RPH-
104); 
 Collecting information on concomitant therapy and adverse events; 
 Patient diary collection and registration of entered data. 
 
Day 60 (± 7 days) 
On this day, the Investigator contacted the patient over the phone to collect information about 
adverse events, their characteristics (onset time, resolution time, severity, relationship to the 
investigational product, etc. as described in Section 12 of this protocol). 
10.3 Follow-up visit for early patient withdrawal from the study 
The follow-up visit for patients who withdraw from the study early is carried out for 7 days after 
the decision on early withdrawal. The minimum list of examinations at the Follow-up Visit is as 
follows: 
 Adverse event recording 
 Collection of information on concomitant therapy 
 Assessment of vital functions 
 Complete physical examination 
 Weighing 
 12-lead ECG 
 Urinalysis 
 Blood sampling for the following analyses: 
o Complete blood count; 
o Blood chemistry with blood lipids (central laboratory); creatinine (local site 
laboratory); 
o Calculation of creatinine clearance (automatically in CRF using the Cockcroft-
Gault formula); 
o Blood clotting tests (central laboratory); 
o Serum pregnancy test for women of childbearing potential; 
 Blood samples to assess the pharmacokinetics of the investigational product and anti-
drug antibodies (only for patients who received RPH-104, central laboratory). 


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10.4 Assessment of efficacy parameters before using the rescue medication 
In this study, patients with unbearable pain are allowed to use the rescue medication no earlier 
than 2 hours after administration of the investigational drug. For such patients, it is necessary to 
carry out the following procedures: 
 Before using the rescue medication, dispensing questionnaires to the patient to record the 
following: 
o Pain intensity in the assessed joint according to VAS; 
o Patient global assessment of the efficacy using a categorical scale; 
 Registering the time of use of the rescue medication and enter the results in the source 
documentation and CRF. 
10.5 Unscheduled visits 
Patients can ask the investigator to appoint an unscheduled visit at any time if they have adverse 
events, or if their condition requires medical intervention. The investigator may schedule an 
unscheduled visit to the patient to assess the safety of the therapy. 
To register an unscheduled visit, the Investigator shall enter obtained data in the source medical 
documents and the CRF (‘Unscheduled Visit’ page). The Investigator will have to make sure to 
record the following information: the date of the visit, the reasons for it, and the data obtained as 
a result of physical examination and additional tests conducted. 
After an unscheduled visit, the next visit should be conducted as planned, in accordance with the 
Study Protocol. 
11 
DESCRIPTION OF THE VARIABLES AND ASSESSMENT METHODS 
11.1 Baseline characteristics 
11.1.1 Information on the primary disease 
The CRF should contain the following characteristics of the underlying condition: 
 The original diagnosis of the primary condition and the date of diagnosis; 
 Date of diagnosis of acute gout attack; 
 Count of joints affected by gout: 
o 1 joint affected (acute monoarticular gout) 
o 2 to 4 joints affected (acute oligoarticular gout) 
o 5 or more joints affected (polyarticular gout) 
 Information on previous therapy (see Section 9.8) and its outcomes 
11.1.2 Demographic data 
The following demographic data will be registered at the study selection step: 
 Date of birth 
 Sex 
 Race 
11.1.3 Measurement of body weight and height 
The patient's height (barefooted) will be measured at the screening visit, and the result recorded 
in the CRF (rounding to the nearest centimeter). Body weight measurements are taken at 


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screening visits, Days 5, 15 and 45, follow-up visits for early withdrawal of the patient from the 
study, and the result is reported to the nearest kilogram. 
The body mass index is calculated automatically in the CRF after entering data on the patient's 
height and body weight. 
11.1.4 Collection of medical history data and information on concomitant diseases 
Detailed historical data will be collected during the screening period, including information on 
all current diseases and all significant (in the Investigator's opinion) past diseases, as well as 
information on tobacco smoking. 
11.1.5 Evaluation of creatinine, complete blood count parameters, chest X-ray 
At Screening, on Days 5, 15, and 45, the follow-up visit for early withdrawal from the study, the 
following tests are performed at the study site local laboratory: 
 Measurement of creatinine level 
 Complete blood count with an assessment of the following parameters: 
o Absolute neutrophil count 
o Total white blood cell count 
o Platelet count 
Creatinine clearance is calculated automatically in CRF using the Cockcroft-Gault formula: 
For men: 
𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 (𝑚𝐿/𝑚𝑖𝑛) = (140 –  𝑎𝑔𝑒𝑎) × (𝑤𝑒𝑖𝑔ℎ𝑡𝑏) × 1.0
0.81 × serum creatinine (µmol/L) 
For women: 
𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 (𝑚𝐿/𝑚𝑖𝑛) = (140 –  𝑎𝑔𝑒𝑎) × (𝑤𝑒𝑖𝑔ℎ𝑡𝑏) × 0.85
0.81 × serum creatinine (µmol/L) 
 
a. Age expressed in years. 
b. Weight in kilograms. 
Chest X-ray in 2 views is performed at screening if the patient does not have results of chest X-
ray in 2 views or fluorography of the chest in 2 views or chest CT performed within 3 months 
before the expected date of the first injection of the investigational product. 
11.1.6 Diagnosis of infections (HIV, hepatitis B, hepatitis C) 
On Day 1, prior to patient randomization, the investigator will look for symptoms and signs of 
hepatitis B and C, including a medical history data. If a patient is suspected of having hepatitis B 
or C, the patient is not randomized. 
To diagnose infections (HIV, HBsAg, HCV Ab) in patients, blood samples are taken on Day 1 
prior to randomization for the following tests: 
 Express tests for the diagnosis of HIV (OraQuick HIV ½), hepatitis B (SD BIOLINE 
HBsAg) and hepatitis C (OraQuick HCV Ab) 
 Tests for HIV, HBsAg, HCV Ab performed at the central laboratory 
Rapid tests for the study are provided by the sponsor. The Sponsor may provide analogs of the 
above rapid tests for the study. Details on how to perform rapid tests and how to handle blood 
samples to diagnose infections at the central laboratory are provided in the laboratory manual. 


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All rapid tests must be negative to randomize patients into the study. 
Central laboratory testing for HIV, HBsAg, and HCV Ab is performed for all patients who 
signed the informed consent, regardless of rapid test results. The results of these tests will be 
known after administration of the investigational product to the patient(s) or a decision has been 
made to not to include the patient from the study. If the patient’s test result at the central 
laboratory is positive for an infection, it will be communicated to the patient. Such patients will 
be referred to a specialist for further examination and treatment. For such patients, information 
about the identified concomitant infectious disease should be entered in the eCRF in the 
Concomitant Diseases section. 
11.1.7 Diagnosis of tuberculosis 
On Day 1, prior to the patient's randomization, the investigator will ask the patient all questions 
from the TB risk assessment questionnaire (Appendix 1). If the response to any of the questions 
in this questionnaire is yes, the patient will not be randomized. 
The results of the chest x-ray in 2 views taken during the screening will be used to assess the 
patient's eligibility for participation in the study. 
Blood sampling for a T-SPOT.TB test will be carried out either at screening, or during the time 
the patient is in the hospital. 
This test will be carried out in a central laboratory. The results of these tests will be known after 
administration of the investigational product to the patient(s) or a decision has been made to not 
to include the patient from the study. If the patient’s test result at the central laboratory is 
positive for an infection, it will be communicated to the patient. Such patients will be referred to 
a specialist (TB specialist) for further examination and treatment. For such patients, information 
about the identified concomitant infectious disease should be entered in the eCRF in the 
Concomitant Diseases section. A positive test result will be considered an AE. 
11.1.8 Serum Pregnancy Test 
Serum pregnancy test for women of childbearing potential will be performed at the study site. 
Serum pregnancy tests for women of childbearing potential should be performed at screening 
and at the Day 45 visit or follow-up visit if the patient withdraws from the study early. To enroll 
a patient in the study, a pregnancy test at screening must be performed after the patient has 
signed the informed consent from and the result of this test must be negative. 
Women are considered postmenopausal and of non-childbearing potential if spontaneous 
(natural) amenorrhea has lasted at least 24 months with a respective clinical presentation (e.g. 
appropriate age, history of vasomotor symptoms), or if they underwent bilateral surgical removal 
of the ovaries (with or without hysterectomy) or tubal ligation at least 6 weeks before the 
proposed randomization date. In the case of removal of the ovaries only, a woman is of non-
childbearing potential only after confirmation of the reproductive status by a hormone test. 
11.2 Evaluation of pharmacokinetics and anti-drug antibodies 
Evaluation of the RPH-104 pharmacokinetics and anti-drug antibodies is carried out only for 
patients treated with RPH-104. 
The time of blood sampling for pharmacokinetics and anti-antibodies is presented in Table 3.1. 
Acceptable time windows for blood sampling for pharmacokinetics and anti-antibodies are 
shown in Table 3.1. 
It is essential to record in the CRF the real sampling time for each blood sample and to pay 
particular attention to labeling of the samples. 


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The methods used to collect blood samples, obtain plasma, and store samples are described in the 
guideline for laboratory tests. 
Serum samples for the assessment of pharmacokinetics and anti-drug antibodies are sent to 
Covance Central Laboratories. The cargo handling procedure is described in the laboratory 
manual. 
11.2.1 Analytical method 
The assay of RPH-104 and anti-drug antibodies in blood serum will be carried out using a 
validated analytical procedure. The lower limit of quantification (LLoQ) of RPH-104 will not be 
higher than 5% of Cmax. 
11.3 Assessment of pharmacodynamics 
Serum levels of hs-CRP, amyloid protein, and cytokine levels (IL-1α, IL-1β, IL-1RA, IL-6, IL-8, 
TNF-α) are assessed in all randomized patients. 
The time windows for blood sampling to assess levels of hs-CRP, serum amyloid A protein, and 
cytokine levels (IL-1α, IL-1β, IL-1RA, IL-6, IL-8, TNF-α) in serum is presented in Table 3.1. 
The methods used to collect blood samples, obtain plasma, and store samples are described in the 
guideline for laboratory tests. 
Serum samples to assess hs-CRP, serum amyloid protein A, and cytokine levels are sent to the 
Unimed central laboratory. The shipment handling procedure is described in the laboratory 
manual. 
11.4 Efficacy assessment 
11.4.1 Measurement of pain intensity in the assessed joint 
To assess pain intensity, an affected joint with the maximum pain intensity on Day 1 is selected. 
Pain intensity is assessed in all patients using a 100 mm VAS. Pain intensity assessments are 
carried out before the start of therapy with the investigational products, at 15, 30, 45 minutes, 1, 
1.5, 2, 4, 8, 24, 48, 72 hours, 5, 6, 10, 15, 18, 22, 29 and 45 days after the start of the 
investigational product use. In case of the use of the rescue medication, pain intensity must be 
assessed before its administration. 
For each assessment of pain intensity, the patient records the result of the assessment in the 
patient questionnaire. 
Completed questionnaires should be dated with indication of time and signed by the patient. 
When handing over the questionnaires to patients outside the study site, the investigator will 
instruct them on proper completion. 
Patient questionnaires and instructions for completion are provided in a separate document. 
11.4.2 Patient global assessment of efficacy 
All randomized patients evaluate the efficacy of their prescribed therapy. The patients perform 
global assessment of efficacy at 15, 30, 45 minutes, 1, 1.5, 2, 4, 8, 24, 48, 72 hours, 5, 6, 10, 15, 
18, 22, 29 and 45 days after the start of the investigational product use. In case of the use of the 
rescue medication, global assessment of efficacy must be carried out before its administration. 
For global assessment of efficacy, patients use a categorical scale with 5 response options. For 
each assessment of response to therapy, the patient records the result of the assessment in the 
patient questionnaire. 
Completed questionnaires should be dated with indication of time and signed by the patient. 


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When handing over the questionnaires to patients outside the study site, the investigator will 
instruct them on proper completion. 
Patient questionnaires and instructions for completion are provided in a separate document. 
11.4.3 Assessment of the degree of swelling, tenderness, and erythema in the assessed joint 
by physician 
The severity of edema, tenderness, erythema in the assessed joint is assessed for all randomized 
patients at the time points indicated in Table 3.1. For assessment, categorical scales are used in 
accordance with the "Form for Assessment of the Degree of Swelling, Tenderness, Erythema and 
Movement Restriction in the Assessed Joint" (see Appendix 2) with the following response 
options: 
Swelling assessment: 
 "absence" – no swelling 
 "mild" – palpable swelling 
 "moderate" – visible swelling 
 “severe" – bulging outside the joint 
Tenderness assessment: 
 "absence" – no tenderness 
 “mild" – tenderness when touched 
 "moderate" – pain and flinching 
 "severe" – pain, flinching and withdrawal of the limb 
Erythema assessment: 
 absence 
 presence 
 unevaluable 
The assessment results are recorded in the source documentation and eCRF. 
11.4.4 Assessment of the degree of movement restriction in the assessed joint by physician 
The investigator evaluates the range of motion in the assessed joint for all randomized patients at 
the time points indicated in Table 3.1. For assessment, a 5-point categorical scale is used in 
accordance with the "Form for Assessment of the Degree of Swelling, Tenderness, Erythema and 
Movement Restriction in the Assessed Joint" (see Appendix 2) with the following response 
options: 
1. Normal range, 
2. Slightly limited range, 
3. Moderately limited range, 
4. Significantly limited range, 
5. Joint movement is impossible. 
11.4.5 Assessment of the amount of the rescue medication used by the patient 
All cases of the use of the rescue medication are recorded in the source documentation and CRF. 
The name, date, time and dose of the rescue medication used are recorded. 


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11.4.6 Health assessment questionnaire (HAQ) assessment 
At visits on Day 1 (pre-randomization), Day 15, Day 29, and Day 45, patients are given the HAQ 
for self-completion. 
The HAQ with instructions for completion is provided in a separate document. 
11.5 Safety and tolerability assessment 
11.5.1 Adverse event assessment 
The assessment of adverse events is described in Section 12. 
11.5.2 Assessment of injection site reactions 
The presence of local reactions to the administration of the investigational product is assessed in 
patients who received RPH-104 at the time points indicated in Table 3.1. The Investigator 
assesses the presence of tenderness, redness, swelling, induration, hemorrhage and itching at the 
RPH-104 injection site. All cases of RPH-104 injection site must be followed-up until resolution. 
11.5.3 Physical examination 
Physical examination should be carried out in accordance with the study procedure schedule (see 
Section 3). Information about the completed physical examination and examined organ systems 
should be described in the source documents kept at the study site. Any abnormalities in physical 
examination findings obtained before the first self-administration of the investigational medicinal 
product should be recorded in the CRF, in the ‘Concomitant diseases’ section. Any abnormalities 
in physical examination findings obtained after the first self-administration of the investigational 
medicinal product and meeting the definition of an adverse event should be recorded in the CRF, 
in the ‘Adverse events’ section. 
The CRF will have no section to record normal findings of periodic physical examinations; 
however, such results should be reflected in the source documents. 
Complete physical examination includes: assessment of overall health, skin (presence of rash or 
lesions), head, mouth, eyes, ears, throat, nose, lungs (auscultation), heart (auscultation for 
murmurs, gallop rhythm, pericardial friction rubs), lower extremities (peripheral edema, presence 
of varicose veins), abdomen (palpation and auscultation), nervous system (mental status, gait, 
reflexes, motor and sensory functions, coordination) and lymph nodes. 
11.5.4 Assessment of vital signs 
Vital signs include: body temperature, pulse rate, respiratory rate, and sitting blood pressure 
measured after 5-minute rest. The Day 1 data obtained before the first dose of the investigational 
product are regarded as baseline vital signs. On subsequent days, vital signs should be evaluated 
and registered prior to the administration of Voltaren® (diclofenac) in patients treated with 
Voltaren® (diclofenac). 
Clinically significant abnormalities in vital signs are to be recorded as adverse events. 
11.5.5 Electrocardiography 
A 12-lead electrocardiography should be carried out in accordance with the study flow chart. 
Clinically significant ECG abnormalities detected at the screening visit should be recorded in the 
CRF as concomitant diseases. After that, all new, clinically significant ECG abnormalities 
should be registered as adverse events. 
The ECG intervals (QT, RR, and QTcF) should be registered in the CRF for each ECG test. 


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11.5.6 Laboratory blood tests 
Complete blood count 
Complete blood count is carried out by the local laboratory of the study site in accordance with 
the procedure adopted by the site laboratory. A complete blood count involves assessment of the 
following peripheral blood parameters: 
 Hemoglobin 
 Hematocrit 
 Erythrocytes 
 Platelet count 
 Total white blood cell count 
 Absolute neutrophil count 
 White blood cell differential in relative units: 
 Neutrophils (%) 
 Segmented neutrophils (%) 
 Stabs (%) 
 Eosinophils (%) 
 Basophils (%) 
 Monocytes (%) 
 Lymphocytes (%) 
Blood chemistry, blood lipids, coagulation tests 
Blood tests are carried out in the central laboratory, except for creatinine. Blood samples are 
collected under fasting conditions or before the patient receives the investigational product. 
Sample handling procedures for assessing blood chemistry, blood lipids, and coagulation are 
described in the laboratory manual. 
The blood chemistry will include the following tests: 
 Sodium 
 Potassium 
 Chloride 
 Magnesium 
 Calcium 
 Phosphorus 
 Bicarbonates 
 Blood urea nitrogen (or urea) 
 Uric acid 
 Total protein 
 Albumin 
 Glucose 
 Creatinine (local laboratory) with determination of creatinine clearance using the 
Cockcroft-Gault formula 
 Total bilirubin 


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 Direct bilirubin 
 AST 
 ALT 
 Alkaline phosphatase 
 Lactate dehydrogenase 
 Amylase 
 Lipase 
 GGT 
 Creatine kinase 
 MB-creatine kinase 
Blood lipids include the following parameters: 
 Low-density lipoprotein 
 Triglycerides 
 LDL 
 HDL 
Blood clotting tests includes the following parameters: 
 Fibrinogen 
 INR 
 APTT 
11.5.7 Urinalysis 
Urinalysis is carried out by the local laboratory of the study site in accordance with the procedure 
adopted by the site laboratory. 
The following urinalysis parameters will be assessed: 
Physical parameters: 
 Color 
 Transparency 
 Specific gravity 
 pH value or reaction (acidic, alkaline, neutral) 
Biochemical parameters: 
 Glucose 
 Protein 
 Ketone bodies 
 Bilirubin 
 Urobilinogen 
 Nitrites 
In addition, information on the results of the analysis of sediment microscopy is recorded 
(leukocyte count, erythrocyte count, epithelial cell count with cell type, and bacterial count). 
Epithelial cell count with an indication of the cell type and bacterial count will be assessed as the 
presence or absence in the analysis. 


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12 
ADVERSE EVENTS 
In this study, an adverse event (AE) means any untoward medical event in a patient receiving 
the study drug that does not necessarily have a causal relationship with the drug. Thus, an 
adverse event can be any unintended and untoward symptom (for example, a laboratory 
abnormality), a symptom or a disease with temporal relationship with the use of the drug, 
regardless of whether they are considered to be related with the drug. 
Clinical signs of treatment failure are not adverse events. For example, persistent pain or 
swelling in an affected joint should not be reported as an adverse event. 
Symptoms, syndromes, and diseases noted prior to the study therapy, but after the patient signed 
the informed consent form, are recorded in the CRF as Concomitant Diseases. 
Laboratory and investigation abnormalities should be registered as adverse events if these 
abnormalities are regarded by the investigator as clinically significant. 
An adverse drug reaction is any adverse event with at least a possible (possible, probable, or 
certain) relationship with the use of the investigational medicinal product. 
AE severity is graded according to the CTCAE classification v.5.0. 
All adverse events should be monitored until resolution or stabilization (assessed by the 
investigator). 
12.1 Adverse event recording 
Adverse events are registered either on the basis of complaints spontaneously reported by the 
patient or by the Investigator interviewing the patient or using physical examination findings and 
results of laboratory and instrumental investigations. The investigator should formulate his / her 
questions to the patient so that they do not prompt the patient to report unreliable information. 
Adverse events should be registered in respective sections of the CRF, as well as in the patient's 
source medical documents. 
Serious AEs are recorded from the time of signing the informed consent to participate in the 
study. All other adverse events will be registered beginning from the first dose of the 
investigational medicinal product. Adverse events will be registered until the end of the follow-
up period. Reporting of serious AEs is described in section 12.5. 
The following information should be reported for a registered adverse event: 
 Patient ID 
 Diagnosis of the adverse event (a diagnosis should be preferred to listing symptoms) 
 The onset and resolution dates for the adverse event (and the times if applicable) 
 AE severity 
 Study drug relationship 
 The measures that have been taken due to the adverse manifestation 
 Actions taken in relation to the investigational drug 
 Whether the adverse event meets the serious adverse event criteria 
 Adverse event outcome 
 


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12.2 Causality assessment between the adverse event and the use of the 
investigational product 
To evaluate the causal relationship with the use of the investigational product, all available 
information should be taken into consideration if it can help characterize this relationship, in 
particular the mechanism of action of the investigational product, information about known 
adverse effects of the product from the Investigator's Brochure, characteristics of the adverse 
event, temporal relationship between the adverse event and the use of the study drug, time to 
resolution of the adverse event, and other possible causes of the adverse event, which may 
include the following: 
 Use of other medications or exposure to chemical substances 
 The natural course of the primary disease or other conditions 
 Study procedures 
 Other factors 
The Investigator should determine the causal relationship for the adverse event using the 
definitions below: 
 Unlikely: an adverse event is temporally related to the administration of the 
investigational product, but there are some other factors (such as a concomitant disease or 
an effect of other medications, chemical or physical factors) that appear to be more 
plausible causes of this adverse event; 
 Possible: an adverse event is temporally related to the administration of the 
investigational product, but its development may also be explained by other factors (such 
as a concomitant disease or an effect of other medications, chemical or physical factors); 
 Probable: an adverse event is temporally related to the administration of the 
investigational product. The causal relationship with other factors (such as a concomitant 
disease or an effect of other medications, chemical or physical factors) appears unlikely; 
The adverse event regresses after discontinuation of the investigational product; 
 Certain: an adverse event is temporally related to the administration of the 
investigational product. The adverse event cannot be explained by other factors (such as a 
concomitant disease or an effect of other medications, chemical or physical factors); the 
adverse event regresses after discontinuation of the investigational product. The adverse 
event recurs after rechallenge; 
 Unrelated: no relationship with the medicinal product: in the presence of an apparent 
alternative explanation and/or an unsubstantiated temporal relationship between the 
medicinal product and the event, and/or in the event when the relationship is biologically 
implausible. 
If the assessed relationship changes over time as a result of new or changed information, it may 
be revised. 
 


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12.3 Adverse event severity 
The investigator assesses the severity of all AEs reported during the study based on the following 
categories: 
Mild: 
The study participant tolerates the AE well, with minimal discomfort, does 
not interfere with normal daily activities. 
Moderate: 
The event causes significant discomfort and interferes with daily activities. 
Severe: 
The event does not allow carrying out daily activities. 
In accordance with the standard healthcare practice in the Russian Federation, the following 
interpretation of AE severity by grade, used in the study, is considered correct: 
Mild corresponds to CTCAE v 5.0 Grade 1, 
Moderate corresponds to CTCAE v 5.0 Grade 2 and Grade 3, 
Severe corresponds to CTCAE v 5.0 Grade 4 and Grade 5 
A severe AE should not be confused with a serious AE. Severity is a category for assessing the 
intensity of an event, both non-serious AEs and serious AEs can be severe. A serious adverse 
event is an event that meets at least one of the criteria specified in the definition of a Serious 
Adverse Event (see 12.4). 
12.4 Serious adverse events (SAEs) 
A serious adverse event (SAE) is any adverse event that meets one or more of the criteria listed 
below: 
1. Resulted in the patient's death 
2. Is life-threatening 
3. Requires hospitalization or prolongation of existing hospitalization 
4. Resulted in persistent or significant disability or incapacity 
5. Is a congenital anomaly or developmental defect occurring in children born to patients 
treated with the investigational drug. 
In addition, serious adverse events may include other important medical manifestations if the 
investigator believes, on the basis of his/her medical experience, that this manifestation may 
result in one of the outcomes described above if no medical intervention is undertaken. 
An adverse event is considered to be “life-threatening” if the patient is at an immediate risk of 
death at the time of the event. This category does not include adverse events, which 
hypothetically might have caused the patient's death if they were more severe. 
12.5 SAE reporting procedure 
To ensure safety for study subjects in case of any SAE developing after the patient signs the 
Informed Consent Form and before the end of the study, regardless of the suspected causes of the 
SAE or the relationship with the use of the investigational product, the SAE should be reported 
to the study Sponsor within 24 hours after the investigator becomes aware of the SAE. 
If a study subject is found to develop a serious adverse event related to the use of the 
investigational product, it should be reported even if the study has already been completed. 
Filling out the serious adverse event reporting form. 
SAEs should be reported by sending a scanned copy of the completed Serious Adverse Event 
Reporting Form in paper format by e-mail to 


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Safety@Rpharm.ru. 
or by fax: 
+7 (495) 956-79-38 
The primary contact for any issues related to the safety of the medicinal product is the 
Head of the Department of Drug Safety at R-Pharm JSC, Candidate of Medical Sciences, Sergey 
Alexandrovich Grishin. 
Phone: +7 (495) 956-79-37 ext.1506 
Mob. phone: +7 (963) 683-05-71 
fax: +7 (495) 956-79-38 
email:Safety@rpharm.ru; sa.grishin@rpharm.ru 
The Investigator must notify the LEC about SAEs in accordance with the LEC standard 
operating procedures. 
The Study Sponsor must notify the regulatory authorities of the Russian Federation of all 
suspected unexpected serious adverse reactions within the time frame specified by the Russian 
law. In the context of notifying regulatory authorities and investigators, suspected unexpected 
serious adverse reactions will be deemed to be unexpected serious adverse events assessed by the 
investigator and/or Sponsor to be doubtfully, possibly, probably, or certainly related to the 
investigational therapy. 
12.6 Investigator’s responsibilities related to reporting of serious adverse events 
Reporting suspected unexpected serious adverse reactions (SUSAR). 
The sponsor will inform investigators of all suspected unexpected serious adverse reactions 
recorded during the study. It is the investigator’s responsibility to submit appropriate reports to 
the Local Ethics Committees of healthcare institution. 
Submission of other safety reports. 
The Investigators will report to the Local Ethics Committees of healthcare institutions on other 
treatment safety aspects subject to expedited reporting if they affect the benefit-risk ratio for the 
study therapy or might necessitate significant modification of the study therapy or study 
methods. 
In addition to submitting expedited reports, the Sponsor will annually prepare development 
safety update reports for RPH-104, containing all new relevant safety information received 
during the reporting period. These reports will be forwarded to the investigator for submission to 
the Local Ethics Committees of healthcare institutions once a year. 
12.7 Pregnancy 
In the event of pregnancy in a female patient participating in the study, the investigational 
product will have to be immediately discontinued. 
Pregnancy is not an adverse event as such, except where there is reason to believe that the use of 
the investigational product resulted in decreased effectiveness of the contraceptives used. 
Information concerning pregnancies in female patients or sex partners of male patients 
participating in the study should be registered from the signing of the Informed Consent Form to 
the end of the study. 
If a female patient or a female partner of a male patient participating in the study becomes 
pregnant, the study Sponsor should be notified by filling out the “Pregnancy reporting”. A 


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pregnancy report should be filled out by an authorized employee of the study site within 24 hours 
after the pregnancy information is received. Pregnancy cases should be reported by sending a 
scanned copy of the filled pregnancy reporting form in paper format by e-mail to: 
Safety@Rpharm.ru. 
Collection of pregnancy-related information should continue until the end of the pregnancy. 
After the end of the pregnancy, the study Sponsor should be informed about the outcome of the 
pregnancy (miscarriage, elective abortion, delivery of a healthy infant or infant with congenital 
anomalies or developmental defects). If possible, the newborn health should be monitored until 6 
weeks, 6 months, and 12 months of age. 
Any complications of pregnancy should be recorded as adverse events or serious adverse events 
depending on the seriousness criteria. 
Congenital anomalies and developmental defects in subjects’ children are serious adverse events. 
Miscarriages should be recorded as serious adverse events. Elective abortions carried out at the 
woman’s discretion, without medical indications for abortion and not associated with 
complications, are not adverse events. 
12.8 Actions in emergency situations 
Medical equipment and pharmacological therapy. 
The study site should have appropriate equipment and drugs necessary for emergency care. Their 
use (which may be necessary though unlikely) should be recorded in the CRF. 
12.9 Follow-up of adverse events 
All AEs are followed up until they resolve or stabilize. 
13 
DATA ANALYSIS AND STATISTICAL ANALYSES 
13.1 General provisions 
Standard statistical calculations for continuous data sets will be performed to indicate the number 
of cases (N), mean value, standard deviation, minimum, median, and maximum. Categorical data 
will be reflected by the N value and proportion (%). For all registered types of data, all 
individual patient values will be listed. 
13.1.1 Analysis populations 
Efficacy population 
To assess the treatment efficacy, the population of all randomized patients who received at least 
one dose of the investigational product and who had at least one VAS measurement of the 
patient's pain intensity in the assessed joint after the start of the investigational product therapy 
will be used. 
Safety population 
The treatment safety population will include all subjects who have received at least one dose of 
the investigational medicinal product. This population will be used for all treatment safety 
assessments. The safety analysis of data will be performed based on the actual treatment received 
by the patients. 
Pharmacokinetic population 
The pharmacokinetic population will include all subjects who have received at least one dose of 
the investigational product and for whom sufficient data has been accumulated on the blood 
concentrations of the investigational product to allow pharmacokinetic calculations. 


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Pharmacokinetic data obtained for the investigational product will be analyzed in this patient 
population. 
Pharmacodynamic population 
The pharmacodynamic population will consist of all patients who received the investigational 
product, for whom sufficient data on levels of cytokines, hs-CRP and serum amyloid protein A 
have been obtained to assess the pharmacodynamic parameters of the investigational products. 
13.1.2 Sample size 
The study is planned to randomize 85 patients: 15 patients in the RPH-104 4 mg group, and 14 
patients in the RPH-104 20 mg, 40 mg, 80 mg and 160 mg groups each, a total of 14 patients in 
the Voltaren® (diclofenac) group. This sample size will allow constructing 95% confidence 
intervals around the mean change in pain intensity at 72 hours after the start of the 
investigational product use in each group with an accuracy of 30 mm change in pain intensity. 
In addition, this sample size will allow establishing statistically significant differences between 
the groups in pairwise comparisons, without control for type I error for multiple comparisons, 
taking into account the type I error α = 5%, if the difference between the compared groups is ≥ 
20 mm. The sample size was calculated assuming a standard deviation of 26 mm for change in 
pain intensity at 72 hours [16]. 
13.1.3 Planned number of subjects in each site 
It is planned to enroll approximately 7 to 12 patients at each study site. 
13.1.4 Applicable level of significance 
The observed differences will be considered statistically significant at the two-tailed 5% 
significance level. In view of the exploratory nature of the study, no corrections for multiple 
comparisons are planned. 
13.1.5 Study termination criteria 
Statistical criteria for early termination of the study are not provided for in the present study. 
13.1.6 Missing data 
Efficacy data 
All efficacy data recorded for a patient after the use of the rescue medication or a prohibited drug 
with an analgesic effect by the patient will be considered missing. 
The baseline observation carried forward method (BOCF) will be used to impute missing data 
for the main efficacy analysis. This method assumes that missing patient data will be replaced 
with a baseline value from the time patients withdraws from the study or the rescue medication 
use is started. 
Other data 
Details reflecting incomplete data for assessment of all other variables will be described in the 
statistical analysis plan compiled and approved before the data lock point for interim analysis. 
13.1.7 Deviations from the statistical analysis plan 
The main provisions of the statistical analysis are described in this Study Protocol. More details 
on the statistical analysis plan will be presented in a separate document compiled and approved 
before the data lock point for an interim analysis. All deviations from the statistical analysis plan 
will be described in the Report for this clinical study. 


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13.1.8 Demographics, information concerning the primary disease, and other baseline 
parameters 
The body weight index will be calculated for the patient based on the height and weight before 
the start of the investigational product use. 
Demographic and underlying disease information will be presented using descriptive statistics by 
treatment group for all patients in the safety population. 
Baseline 
parameters 
will 
include 
all 
measurements 
related 
to 
the 
efficacy 
and 
pharmacodynamics, performed on Day 1 prior to the first investigational product administration. 
Baseline parameters related to the pharmacodynamic assessment will be presented using 
descriptive statistics by treatment group for all patients in the pharmacodynamic population. 
Baseline parameters related to the efficacy assessment will be presented using descriptive 
statistics by treatment group for all patients in the efficacy population. 
13.1.9 Concomitant therapy 
Concomitant drugs will be coded according to their international nonproprietary names, using 
the WHO drug terminology. Standard frequency tables and a list of data for all patients in the 
safety population will be presented. 
13.2 Pharmacokinetic analysis 
All types of pharmacokinetic analysis will be conducted for the pharmacokinetic population. 
The following parameters will be assessed to analyze the pharmacokinetic properties of the 
investigational product after single dose administration using a non-compartmental approach: 
 AUC0-t 
 AUC0-∞ 
 Cmax 
 tmax 
 t1/2 
 Kel 
 


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13.3 Analysis of anti-drug antibody levels 
An analysis of anti-drug antibody levels will be carried out in all patients who have received 
RPH-104. Information on anti-drug antibody levels will be presented by end point, treatment 
group, and for all patients regardless of treatment group, using descriptive statistics. 
A list of all measured anti-drug antibody levels will be compiled. 
13.4 Pharmacodynamic analysis 
Pharmacodynamic variables 
 Change in serum hs-CRP levels at 24, 72 hours, 5, 6, 15, 29 and 45 days after start of the 
investigational product therapy compared to baseline. 
 Changes in the level of amyloid A protein in the blood serum at 24, 72 hours, days 5, 6, 
15, 29 and 45 after start of the investigational product therapy compared to baseline. 
 Change in serum cytokine (IL-1α, IL-1β, IL-1RA, IL-6, IL-8, TNF-α) levels at 24, 72 
hours, 5, 6, 15, 29 and 45 days after start of the investigational product therapy compared 
to baseline. 
Analysis of pharmacodynamic data 
The levels of hs-CRP, serum amyloid protein A and cytokines will be presented by measured 
parameters, measurement points and treatment groups using descriptive statistics. 
For hs-CRP, serum amyloid protein A, and cytokines, graphs of changes in the concentration of 
these substances versus time for the treatment groups will be plotted. 
Model mean changes (least squares means) in hs-CRP, serum amyloid protein and cytokine 
levels from baseline and confidence intervals for pairwise differences between each RPH-104 
group and Voltaren® (diclofenac) group will be presented for each parameter and measurement 
point using ANCOVA with the baseline value of the parameter as a covariate. 
All measured hs-CRP, serum amyloid protein A and cytokine levels will be presented as lists. 
13.5 Efficacy analysis 
13.5.1 Efficacy endpoints 
Primary efficacy endpoint 
Change in pain intensity in the assessed joint at 72 hours after start of the investigational product 
therapy compared to baseline, as measured on the visual analogue scale (VAS). 
Secondary efficacy endpoints 
 Change in pain intensity in the assessed joint at 15, 30, 45 minutes, 1, 1.5, 2, 4, 8, 24, 48, 
72 hours, on days 5, 6, 10, 15, 18, 22, 29 and 45 after start of the investigational product 
therapy compared to baseline (as measured on VAS). 
 Proportion of patients who rated the response to the investigational product therapy as 
"Excellent" or "Good" at 15, 30, 45 minutes, 1, 1.5 hours, 2, 4, 8, 24, 48, 72 hours, on 
days 5, 6, 10 15, 18, 22, 29, and 45 after initiation of the investigational product therapy; 
 Change in the degree of swelling, tenderness, erythema in the assessed joint at 24, 48, 72 
hours, on days 5, 6, 10, 15, 18, 22, 29 and 45 after start of the investigational product 
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 Change in movement restriction in the assessed joint at 24, 48, 72 hours, on days 5, 6, 10, 
15, 18, 22, 29 and 45 after start of the investigational product therapy compared to 
baseline; 
 Time to 50% reduction in pain intensity in the assessed joint relative to the baseline level 
according to the VAS; 
 Time to use of the rescue medication 
 The proportion of patients who received the rescue medication within 72 hours of starting 
the investigational product therapy and over the entire treatment period; 
 Changes in the health assessment questionnaire scores 2, 4, and 6 weeks after start of the 
investigational product therapy compared to baseline. 
13.5.2 Analysis of the primary efficacy endpoint 
The results of the primary endpoint assessment will be presented using descriptive statistics. 
The confidence intervals for the change in pain intensity on VAS in each treatment group will be 
calculated by ANCOVA using the baseline values and treatment group as covariates. 
As supplemental analyses for the primary endpoint, model mean values (least squares means) of 
changes in pain intensity and confidence intervals for pairwise differences between each RPH-
104 therapy group and Voltaren® (diclofenac) group will be presented using ANCOVA model 
with factors of the baseline pain intensity score and baseline body mass index (BMI) as 
covariates. 
13.5.3 Analysis of other efficacy endpoints 
All results of patient assessment of pain intensity in the assessed joint on VAS will be presented 
by measurement points and treatment groups using descriptive statistics. 
For all patient assessments of pain intensity in the assessed joint on VAS, pain intensity versus 
time by the treatment groups will be plotted. 
Model means of changes from baseline in pain intensity in the assessed joint on VAS and 
confidence intervals for pairwise differences between each RPH-104 treatment group and the 
Voltaren® (diclofenac) group will be presented for each measurement point using repeated 
measures ANOVA. A model for assessing differences between groups will be selected after 
assessment of the primary endpoint. 
The patient's response to therapy will be presented as frequency tables by assessment point and 
therapy group. 
The results of assessing the degree of swelling, tenderness, erythema and movement restriction 
in the assessed joint will be presented as frequency tables by points of assessment and treatment 
groups. 
Changes in the degree of swelling, tenderness, erythema and movement restriction in the 
assessed joint from baseline will also be presented as continuous variables using descriptive 
statistics by measurement points and treatment groups. 
Graphs of changes in the parameters versus time by the treatment groups will be plotted for 
changes in the degree of swelling, tenderness, erythema and movement restriction in the assessed 
joint from baseline. 
The analysis of time to 50% reduction in pain intensity in the assessed joint will be carried out 
using the Kaplan-Meier method. Comparison between groups will be carried out using a log-rank 
test. 


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More details on the efficacy endpoint analysis methods will be described in the statistical 
analysis plan, which will be developed and approved prior to the data lock point for interim 
analysis. 
13.6 Safety data analysis 
Safety parameters include the frequency and severity of adverse events, the frequency of serious 
adverse events, vital signs, 12-lead ECG findings, echocardiography findings, physical 
examination findings, complete blood count, blood chemistry tests, and urinalysis results. The 
safety population will be used to present the safety data for the study therapy. 
13.6.1 Adverse events 
Adverse events occurring starting from the time of investigational product administration (start 
of use) until 45 days after the investigational product administration will be considered 
treatment-emergent adverse events. 
Serious adverse events developing between the signing by the patient of the Informed Consent 
Form for participation in this study and the administration of the investigational medicinal 
product will be regarded as pre-treatment SAEs. 
Adverse event data will be coded using the last version of the MedDRA medical terminology. 
Frequency rates of adverse events during the study therapy will be calculated for each organ 
system, by primary diagnosis, investigational product dose, and absolute and relative amounts of 
patients developing adverse events. Summary data reflecting the severity of adverse events will 
be presented by organ system and primary disease. Adverse events related to the investigational 
product (‘possibly related,’ ‘probably related,’ and ‘definitely related’) will be presented 
separately. 
Summary data reflecting withdrawals from the study due to adverse events will be presented by 
organ system and primary disease. 
Serious adverse event data will be presented as listings and summary data by organ system and 
primary disease. 
13.6.2 Vital signs 
Results obtained for vital sings and changes from baseline in these parameters (body 
temperature, respiratory rate, systolic blood pressure, diastolic blood pressure, and pulse rate) 
will be presented as listings and as summary data for each measurement point. 
13.6.3 Electrocardiography 
Electrocardiography findings will be presented as listings and as summary data for each 
measurement point. ECG intervals (QT interval, RR and QTcF) will be presented as absolute 
values for each measurement point and changes from baseline for each measurement point. 
13.6.4 Laboratory tests 
Laboratory results (complete blood count, blood chemistry, blood lipids, coagulation tests, and 
urinalysis) will be tabulated by treatment group using descriptive statistics for each measurement 
point and for changes from baseline. 
All laboratory results will be presented as lists with values for each teste and changes from 
baseline. Laboratory findings that are outside of the reference interval will be marked in the 
listings. 
13.6.5 Concomitant therapy 
Data on concomitant therapy will be presented as a patient-specific listing and summary data. 


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13.7 Interim data analysis 
Due to the low patient recruitment rate in the study and the adverse impact of the COVID-19 
pandemic on the recruitment, at the decision of the sponsor, an interim analysis of the data of 47 
patients included in the study as of November 2020 will be carried out in order to assess the 
feasibility of continuing recruitment and further conducting the study. All patients whose data 
will be included in the interim analysis completed their participation in the study; follow-up is 
not required in the study. The interim analysis will include the efficacy, safety, pharmacokinetics 
and pharmacodynamics data available and verified at the time of analysis. No changes in the 
declared statistical methods in connection with the interim analysis are planned. The dose 
dependence of the pharmacokinetics and pharmacodynamics of the investigational product, as 
well as the main efficacy measures (reduction in pain intensity) will be studied using descriptive 
statistics, a confidence interval approach, and graphical methods. The safety analysis will be 
carried out using descriptive statistics methods. Formal testing of hypotheses is not planned in 
the study. In view of the exploratory nature of the study, no corrections for multiple comparisons 
are planned. 
14 
DATA 
HANDLING, 
DOCUMENTATION 
MANAGEMENT 
AND 
STORAGE 
14.1 Source documents 
All obtained data should be first recorded in the source documentation on paper or electronic 
media, and only after that recorded in the CRF. It is prohibited in this study to record data 
directly in the CRF without first recording them in source documents, with the exception of 
creatinine clearance, which is calculated automatically in the CRF. 
Source documents may include out-patient charts, in-patient medical records, office visit logs, 
patient questionnaires, laboratory and investigation reports. 
The Investigator and the healthcare institution conducting the study must ensure access to the 
source documentation for study monitors, auditors, and inspectors, as well as representatives of 
the Local Ethics Committee / Institutional Review Board and inspectors of the regulatory 
authorities. 
14.2 Archiving of study documentation at the study site 
After completion of the study, the Investigator must continue to keep all study-related 
documentation (except documents that should be kept by other persons in accordance with local 
regulations) in a safe, secure place. This documentation should be stored so as to allow simple 
access if necessary for audit or inspection, and should be available for verification, along with 
assessment of the study conditions, auxiliary systems, and study site personnel. 
Documentation may be stored only on paper, using media that can ensure long-term storage of 
recorded information. In this regard, source medical documents available on thermal printer 
paper (ECG recording or facsimile copy of a laboratory test report) should be copied to regular 
paper by means of photocopying. Any copy should be dated and authenticated by the study site 
personnel; the original thermal printer paper recording should be stored with the copy even if the 
original becomes illegible. 
The Investigator will be notified by the sponsor of the document retention period. The minimal 
shelf-life is 15 years after completion of the study; it may be prolonged if permitted by the 
Sponsor or allowed by legislation. 
The Investigator should notify the sponsor about all changes in the archiving procedure, 
including, but not limited to, storage of the archives outside of the healthcare institution or 


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transfer of the property rights to the documentation in case the Investigator changes the place of 
employment. 
 


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15 
STUDY MONITORING AND QUALITY ASSURANCE 
15.1 Study monitoring 
Monitoring is carried out by R-Pharm JSC on behalf of the sponsor R-PHARM 
INTERNATIONAL LLC. Monitors and other authorized representatives of the Sponsor may 
contact the Investigator and visit the study site. At request, they should be allowed direct access 
to all study documents (CRFs of study subjects and other documents related to the study), 
provided that the confidentiality requirements are observed in relation to personal patient data 
and the inspection is conducted in accordance with applicable local regulatory requirements. 
Responsibilities of the study site monitor include regular verification of the CRFs throughout the 
study to ensure that they meet the requirements of the Study Protocol, control of the 
completeness, accuracy, and consistency of the study data, as well as the compliance with the 
regulatory requirements and the ICH GCP guidelines. 
The Investigator should assist the Monitor as much as possible and cooperate with the Monitor 
with the aim to resolve any problems identified during monitoring visits. 
The Monitors will be provided with a separate guideline on the control of the study conduct that 
will contain additional instructions concerning the monitoring procedures. 
15.2 Study quality assurance 
Quality of this study will be ensured through audits conducted by representatives of the sponsor 
or authorized representatives. They should be allowed direct access to all study documents 
(CRFs of study subjects and other documents related to the study), provided that the 
confidentiality requirements are observed in relation to patients’ personal data and the inspection 
is conducted in accordance with applicable local regulatory requirements. 
16 
ETHICAL ASPECTS OF THE STUDY 
16.1 General provisions 
This study is conducted in accordance with this protocol, the ethical principles set forth in the 
Declaration of Helsinki of the World Medical Association (last revision), and the current edition 
of Good Clinical Practice (ICH GCP E6), the legislation and standards of the Russian 
Federation: the Constitution of the Russian Federation; the current edition of Federal Law No. 
61-FZ of the Russian Federation of April 12, 2010 On the circulation of medicinal products; the 
current edition of Federal Law No. 323-FZ of the Russian Federation of November 21, 2011 On 
the basics of protecting the health of citizens in the Russian Federation; Decree No. 714 of the 
Government of the Russian Federation of September 13, 2010 On Approval of Model Rules for 
Compulsory Life and Health Insurance of a Patient Participating in Clinical Trials of a 
Medicinal Product” (as amended on September 4, 2012); Decree No. 393 of the Government of 
the Russian Federation of May 18, 2011 On Amendments to the Model Rules for Compulsory 
Life and Health Insurance of a Patient Participating in Clinical Trials of a Medicinal Product; 
Order No. 703n of the Ministry of Health and Social Development of Russia of August 23, 2010 
On Approval of the Notification Form for the Completion, Suspension or Termination of a 
Clinical Trial of a Medicinal Product for Medical Use; Order No. 774n of the Ministry of Health 
and Social Development of Russia of August 31, 2010 On the Ethics Council, Order No. 200n of 
the Ministry of Health of Russia of April 1, 2016 On Approval of Good Clinical Practice 
Guidelines, GOST R52379-2005 Good Clinical Practice and other applicable legislative acts. 


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16.2 Informed Consent Form for participation in the study, consent to transfer 
and management of personal data, and consent to disclosure of confidential 
health information 
Informed consent to participation in the clinical study 
The Investigator is responsible for obtaining the patient's written informed consent to 
participation in the study. A patient's consent should be obtained prior to the commencement of 
any study procedures and after providing the patient with adequate information concerning the 
objectives and methods of the study, expected benefits and potential risks associated with 
participation in the study. The subject should be given one copy of the Patient Information Sheet 
with Informed Consent Form for participation in the study prepared in the subject’s native 
language. The signed and dated Informed Consent Form for participation in the study should be 
stored in the archives of the study site, and may be requested by employees of the sponsoring 
company or representatives of the regulatory authorities during audits and inspections. 
16.3 Confidentiality and identification of study subjects 
The Investigator should ensure preservation of the confidentiality of the patient's identity. Only 
the patient identification number should be used for identification purposes in the CRF and other 
documents forwarded to the contract research organization / sponsor, the central laboratory and 
safety and efficacy committees. Documents that are not forwarded to the contract research 
organization / sponsor (such as signed Informed Consent Forms for participation in the study) 
must be kept confidential by the investigator. 
The Investigator must ensure access to CRFs and source documentation for authorized 
representatives of the sponsor, regulatory authorities, and the Local Ethics Committee / 
Institutional Review Boards for verification during monitoring visits, audits, and inspections. 
16.4 Ethics Committee / Local Ethics Committee 
Prior to the start of the study, the Protocol, any amendments, and the Informed Consent Form 
with Patient Information Sheet, as well as any information that is given to the patient (for 
example, a patient diary) should be approved by the health care authorities (as required by 
current legislation) and the Local Ethics Committee. 
17 
FUNDING AND INSURANCE 
This study is sponsored by the study sponsor. 
Subjects participating in this study are insured in accordance with the requirements of the 
legislation of the Russian Federation (Federal Law No. 61-ФЗ On the circulation of medicinal 
products and Resolution No. 714 of the Government of the Russian Federation On Approval of 
Model Rules for Compulsory Life and Health Insurance of a Patient Participating in Clinical 
Trials of a Medicinal Product of September 13, 2010). 
18 
PUBLICATION 
It is expected that the results of this study will be published as a summary after all patients have 
completed their participation in the study and the data obtained in the course of the study have 
been analyzed. The Investigator may not publish results obtained at the study site until a 
publication is prepared covering the results of the study as a whole. 
Before publishing results of the study or reporting these results, the Investigator undertakes to 
submit the manuscript and draft report to the Sponsor for review at least 30 days in advance. 
The Investigator may not publish results obtained in the study without the prior consent of the 
sponsoring company. 
 


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REFERENCES 
1. Schett G, Dayer J-M, Manger B. Interleukin-1 function and role in rheumatic disease/Nature 
reviews/ Rheumatol, 2016(12):14-24 
2. 2012 American College of Rheumatology. Guidelines for management of gout. Part 2: 
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3. V.G.Barskova Diagnosis and treatment of gout/Institute of Rheumatology of the Russian 
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(#8317-087). Research Report// Covance Laboratories Ltd., UK, 2015 
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http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Summary_for_the_public/human/001109/WC500031677.pdf 
9. Instructions for the use of Ilaris®, Registration number: LP-001414 
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concentrations of interleukin-1 beta in patients with coronary artery disease. Heart. 1996 
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Approved 
v4.0 
Available 
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http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/014901s042lbledt.pdfreviewed 
on February 14, 2017 
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RPH-104 
Version 7.0 of November 19, 2020 
 
CONFIDENTIAL 
 
P. 82 of 84 
17. Neogi 
T 
et 
al 
2015 
Gout 
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criteria: 
an 
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Rheumatology/European League Against Rheumatism collaborative initiative Ann Rheum 
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Silman, Josef S. Smolen, MD, FRCP, Michael E. Weinblatt, MD and Michael H. Weisman, 
MD, 1976 pages, Copyright 2015 
19. Terkeltaub RA et al Rilonacept in the treatment of acute gouty arthritis: a randomized, 
controlled clinical trial using indomethacin as the active comparator. Arthritis Research & 
Therapy 2013, 15:R25 
20. Instructions 
for 
medical 
use 
of 
Voltaren. 
http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=5da8f341-99b7-4918-b051- 
6a6f7582121f&t=. 
21. Kuo C-F, Grainge MJ, Mallen C et al. “Rising burden of gout in the UK but continuing 
suboptimal management: a nationwide population study” Ann Rheum Dis 2015; 74:661- 667 
22. Kuo C-F et al. “Global epidemiology of gout: prevalence, incidence and risk factors” Nat. 
Rev.Rheumatol. 2015 Nov 11 (11): 649-62 
23. Fravel MA et al. “Management of gout in the older adult”. Am. J. Geriatr. Pharmacother. 
2011;9:271-285 
24. Xu L et al. “Comparison of prednisolone, etoricoxib, and indomethacin in treatment of acute 
gout arthritis: an open label, randomized, controlled trials” Med. Sci. Monit. 2016;22: 810-
817 
25. Willburger RE et al. “Lumiracoxib 400 once daily is comparable to indomethacin 50 mg 
three times daily for the treatment of acute flares of gout “ Rheumatology, 2007; 46;1126-
1132 
26. So A, Meulemeester MD, Pikhlak A et al. “ Canakinumab for the treatment of acute flares in 
difficult-to-treat gouty arthritis” Arthritis & Rheumatism Vol.62, No.10, pp 3064-3076 
27. NCT03002974 A Randomized, Double-blind, Active-control, Multicenter, Efficacy and 
Safety Study of 2 Dose Levels of Subcutaneous Anakinra Compared to Intramuscular 
Triamcinolone in the Treatment of Acute Gouty Arthritis, Followed by an Extension Period 
of 
up 
to 
2 
Years 
https://clinicaltrials.gov/ct2/show/NCT03002974?term=NCT+03002974&rank=1 
Accessed on 10.12.2018 
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PubMed PMID: 17910294. 
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pyrophosphate deposition disease in patients with acute arthritis. Rheumatology Science and 
Practice. 2015. No. 4. 
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arthritis // Modern Rheumatology. 2010. No. 3. 
31. L.E. Atakhanova, V.V. Tsurko, I.M. Buleva, I.N. Boyko, S.P. Zheleznov, T.B. Ivanova Gout: 
from etiology and pathogenesis to diagnosis and rational pharmacotherapy. Modern 
rheumatology. 2007;1(1):13-18. 
 


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P. 83 of 84 
APPENDIX 1. 
Tuberculosis risk assessment questionnaire 
The following questions should be asked of each patient at the screening visit to identify 
complaints and symptoms consistent with TB. Responses to each question must be entered in 
this document, which is the source document. 
Question 
Response 
1) Does the patient has current or a history of active TB infection? 
󠇯 
Yes 
󠇯 
No 
2) Has the patient had close contact (i.e. cohabitation or other closed environment) 
with a person with active TB in the last 1.5 years? 
󠇯 
Yes 
󠇯 
No 
3) Does the patient work at a healthcare facility treating patients with suspected TB, 
a medical examiner's office or a mortuary? 
󠇯 
Yes 
󠇯 
No 
4) Does the patient work in or has visited long-stay facilities (e.g., nursing home or 
residential care home, prison, homeless shelter or long-term care facility, etc.)? 
󠇯 
Yes 
󠇯 
No 
5) Has the patient had close contact with underprivileged people (homeless or other 
people in need of social assistance)? 
󠇯 
Yes 
󠇯 
No 
6) Has the patient developed a cough lasting more than 14 days or there has been a 
change in chronic cough? 
󠇯 
Yes 
󠇯 
No 
7) Has the patient experienced night sweats? 
󠇯 
Yes 
󠇯 
No 
8) Has the patient had persistent fever? 
󠇯 
Yes 
󠇯 
No 
9) Has the patient experienced an unintentional weight loss (greater than 10%) in 
the past 3 months? 
󠇯 
Yes 
󠇯 
No 
10) Does the patient look emaciated? 
󠇯 
Yes 
󠇯 
No 
11) Has the patient had abnormal chest x-rays since the previous assessment? 
󠇯 
Yes 
󠇯 
No 
 
Physician’s signature 
 
 


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RPH-104 
Version 7.0 of November 19, 2020 
 
CONFIDENTIAL 
 
P. 84 of 84 
APPENDIX 2. 
Assessment of the degree of swelling, tenderness, erythema 
and movement restriction in the assessed joint 
CL04018054 
Assessment of the degree of swelling, tenderness, 
erythema and movement restriction in the assessed joint 
Patient ID 
Day  
 
(Scheduled visit day: 
01, 02, 03, 04, 05, 06, 10, 15, 
18, 22, 29 or 45) 
 
Assess the severity of SWELLING of the patient's assessed joint: 
"absence" 
󠇯 no swelling 
"mild"  
󠇯 palpable swelling 
"moderate" 
󠇯 visible swelling 
“severe" 
󠇯 bulging outside the joint 
Assess the severity of TENDERNESS of the patient's assessed joint: 
"absence" 
󠇯 no tenderness 
“mild"  
󠇯 tenderness when touched 
"moderate" 
󠇯 pain and flinching 
"severe" 
󠇯 pain, flinching and withdrawal of the limb 
Assess the severity of ERYTHEMA of the patient's assessed joint: 
 
 
󠇯 “absence” 
 
 
󠇯 “presence” 
 
 
󠇯 “unevaluable” 
Assess the RANGE OF MOTION in the assessed joint: 
 
 
󠇯 Normal range 
 
 
󠇯 Slightly limited range 
 
 
󠇯 Moderately limited range 
 
 
󠇯 Severely limited range 
 
 
󠇯 Joint movement is impossible