An Open-label Multicenter Postmarketing Extension Study of Efficacy and Safety of Intra-articular HBISA Endoprosthesis of Synovial Fluid NOLTREX™ in Knee Osteoarthritis
Phase: NA
Conditions: Osteoarthritis
Sponsor: Research Centre BIOFORM

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Clinical Study Protocol IA/PAAG-SI/OA/2020
 HBISA Endoprosthesis of synovial fluid NOLTREXTM
Open-label Multicenter Postmarketing Extension Study of Efficacy and Safety of 
Intra-articular HBISA Endoprosthesis of Synovial Fluid NOLTREX™ per TU 
9398-00152820385-2015 in Knee Osteoarthritis   
ClinicalTrials.gov Identifier: NCT06429319 
Version 3.0: October 30, 2020
Study sponsor
"RC "BIOFORM" LLC
7 bld. 2 Comintern St. Babushkinsky District
Moscow, 129327, Russian Federation

 
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List of abbreviations 
Abbreviation 
Meaning 
BP 
Blood pressure 
ALT 
Alanine aminotransferase 
anti-HCV 
Total antibodies to Hepatitis C Virus 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-therapeutic-chemical classification 
APTT 
Activated partial thromboplastin time 
VAS 
Visual-analog scale 
HIV 
Human immunodeficiency virus 
GGTP 
Gamma-glutamyl transpeptidase 
DEE 
Confidence interval 
CS 
Clinical study 
CRO 
Contract research organization 
MD 
Medical device 
GCP 
Good clinical practice 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
IEC 
Independent ethics committee  
AE 
Adverse event 
OA 
Osteoarthrosis 
PT 
Prothrombin time 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
ESR 
Erythrocyte sedimentation rate 
CRD 
Chronic renal disease 
RR 
Respiration rate 
HR 
Heart rate 
ALP 
Alkaline phosphatase 
eCRF 
electronic Case Report Form 
ACR 
American College of Rheumatology 
HBs-Ag 
hepatitis B surface antigen 

 
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ICH 
International council for harmonization of technical requirements for 
pharmaceuticals for human use 
JSN 
Joint space narrowing 
JSW 
Joint space width 
MedDRA 
Medical Dictionary for Regulatory Activities 
OEI 
Evaluation of the treatment effectiveness by the investigator 
OEP 
Evaluation of the treatment effectiveness by the patient 
WOMAC  
Western Ontario and McMaster Universities Osteoarthritis 
WOMAC-A 
Subscale of pain according to the osteoarthritis index developed by 
researchers at the Western Ontario and McMaster Universities 
Osteoarthritis 
WOMAC-B 
Subscale of stiffness according to the osteoarthritis index developed 
by researchers at the Western Ontario and McMaster Universities 
Osteoarthritis 
WOMAC-C 
Subscale of function according to the osteoarthritis index developed 
by researchers at the Western Ontario and McMaster Universities 
Osteoarthritis 
WOMAC-T 
Change in the total score on the scale of the osteoarthritis index, 
developed by the researchers at the Western Ontario and McMaster 
Universities Osteoarthritis 
 
 
 

 
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Synopsis 
Name of the study 
Multicenter open post-registration study of the safety and effectiveness of the medical device HBIS 
endoprosthesis of synovial fluid NOLTREX™ for intraarticular administration in the treatment of 
gonarthrosis. 
Protocol number 
IA/PAAG-SI/OA/2020  
Studied MD 
HBIS endoprosthesis of synovial fluid NOLTREX™ according to TU 9398-00152820385-2015 
(hereinafter referred to as NOLTREX™) 
Comparison MD 
Not applicable 
The duration of the study, the number of research centers and patients 
From 29.05.2020 to 31.05.2021, the number of research centers is 4. 
Number of patients: a maximum of 72 
Purpose of research 
Evaluation of the safety and effectiveness of the medical device (MD) NOLTREX™ for intraarticular 
administration in the treatment of gonarthrosis of the II–III x–ray stage according to Kellgren-
Lawrence.  
Tasks of research 
1. 
Evaluation of the safety of MD NOLTREX™ at intraarticular administration in the 
treatment of gonarthrosis of the II-III radiological stage by Kellgren-Lawrence; 
2. 
Evaluation of the effect of MD NOLTREX™ at intraarticular administration in the 
treatment of Kellgren-Lawrence stage II–III gonarthrosis on knee function and the need for 
paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). 
Research method 
Study design: 
Open-label interventional study in one group with gonarthrosis patients who received a single or 
double course of injections of MD NOLTREX™ as part of the IA/PAAG-SI/OA/2019 study. 
MD NOLTREX™ (synovial fluid endoprosthesis) has been registered for the treatment of 
osteoarthritis since 2003, and according to annual post-marketing observations it is an effective and 
safe medical device. A multicenter, double-blind, randomized, comparative, placebo-controlled study 
of the efficacy and safety of NOLTREX™ for intraarticular administration in the treatment of 

 
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gonarthrosis (IA/PAAG-SI/OA/2019) was conducted, in which 72 patients aged over 50 years with a 
verified diagnosis of gonarthrosis in accordance with the criteria of the American College of 
Rheumatology (ACR) II-III radiological stage classification Kellgren-Lawrence received 1 to 2 
injections (at 1-week intervals) of 4 mL of MD NOLTREX™ into the most affected (target) knee 
joint. The second injection was not performed if the severity of pain in the target knee joint decreased 
by 40─ or more a week after the first injection. The study was performed to evaluate the effectiveness 
and safety of MD NOLTREX™ with this method of use in comparison with placebo. 
The current study is planned to include patients who received at least one intra-articular injection of 
MY NOLTREX™ in IA/PAAG-SI/OA/2019 study and underwent procedures during the 5-week 
Visit (25 weeks – 6 months after the injection). After completing all the procedures of Visit 5 and 
completing the corresponding electronic individual registration card (eCRF) forms in the IA/PAAG-
SI/OA/2019 study, the investigator receives information about which group in the IA/PAAG-
SI/OA/2019 study the patient was assigned to, i.e. whether he received injections of the study MD or 
placebo. After that, patients who received the studied MD will be asked to sign an informed consent 
form to participate in the open clinical trial IA/PAAG-SI/OA/2020. 
Procedures of Visit 5 (25 weeks - 6 months after injection) of the placebo-controlled trial IA/PAAG-
SI/OA/2019, if they coincide with the screening procedures of Visit 0 of the open trial IA/PAAG-
SI/OA/2020 for patients who have agreed to participate in this study and are eligible to participate, 
will be considered as procedures Visit 0 of the open trial IA/PAAG-SI/OA/2020. Thus, Visit 5 of the 
IA/PAAG-SI/OA/2019 study coincides with the screening Visit (Visit 0) of the IA/PAAG-
SI/OA/2020 study. 
Patients who signed the informed consent form to participate in an open study IA/PAAG-SI/OA/2020 
to evaluate the safety and effectiveness of MD NOLTREX™, in the case when pain in the target knee 
joint in the study IA/PAAG-SI/OA/2019 remained the same or increased (on a 100-mm visual 
analogue scale [VAS]) compared to the rating at Visit 1 of the study IA/PAAG-SI/OA/2019 (or if a 
decrease in pain severity is less than 40─ compared to the rating at Visit 1 of the study IA/PAAG-
SI/OA/2019), will receive the injection of MD NOLTREX™ in the target knee (Group A). MD will 
be administered in accordance with the instructions for use of MD NOLTREX™: 4.0 ml per injection 
(2.5 + 1.5 ml, or 2.0 + 2.0 ml from two syringes through one needle [one puncture]) at intervals of 
one week. The course in an open study is a maximum of 2 injections (the first - at Visit 1, the second 
- at Visit 2). The number of injections is determined by the doctor depending on the stage of 
gonarthrosis and the clinical response. In order to avoid overfilling the joint with dense slowly 
resorbable material, at the good clinical result (reducing the pain severity on a 100 mm VAS by Visit 

 
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2 by more than 40─ compared to the basal level in the open study[1] ), the course of injections will 
be discontinued. 
Patients included in the open part of the study, who have the severity of pain in the target knee joint 
at the time of inclusion in the open part of the study decreased by 40─ or more compared to the 
assessment on Visit 1 of the IA/PAAG-SI/OA/2019 study, or those who cannot be re-injected with 
MD NOLTREX™, a re-injection of MD NOLTREX™ will not be performed on Visits 1 and 2 of 
the open study (Group B). 
A repeated course of MD NOLTREX™ injections in an open study is not possible if any of the 
following criteria are met: 
1. Documented intolerance of the studied MD NOLTREX™; 
2. Active inflammation in the target knee joint (edema, hyperemia, effusion) at the time of 
inclusion in the study; 
3. Inflammatory diseases of the skin and soft tissues in the area of the intended introduction 
of the studied MD into the target joint; 
4. History of venous thrombosis and thromboembolism; 
5. Deviations from the norm in the coagulogram (activated partial thromboplastin time 
[APTT], prothrombin time [PT], prothrombin index, fibrinogen); 
6. Hemophilia and other hemorrhagic diatheses, as well as taking anticoagulants and 
disaggregants; 
7. Inflammatory changes in clinical blood analysis (leukocytosis, increased erythrocyte 
sedimentation rate [ESR]); 
8. Deviation from the norm (in accordance with the standards of the local laboratory) of the 
number of platelets; 
9. Type 1 or type 2 diabetes; 
10. Acute infectious diseases or infectious exacerbations of chronic diseases (including 
respiratory tract infections) during the month prior to inclusion in the study. 
At Visit 3 additional evaluation will be conducted to assess the feasibility and possibility of re-
injections with MD NOLTREX™ among patients of group B. If at Visit 3 of the open study pain 
remains the same in the target joint of the study IA/PAAG-SI/OA/2019 or increases in intensity (as 
per 100-mm VAS) in comparison with the assessment at Visit 1 of the study IA/PAAG-SI/OA/2019 
(or if a decrease in pain severity is less than 40% when compared to the rating at Visit 1 of the study 
IA/PAAG-SI/OA/2019), in the absence of the above criteria for non-treatment with the studied MD, 
at Visit 3 of open study the injection of MD NOLTREX™ into the target knee joint will be performed. 
MD will be administered in accordance with the instructions for medical use of MD NOLTREX™: 

 
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4.0 ml per injection (2.5 + 1.5 ml, or 2.0 + 2.0 ml from two syringes through one needle [one 
puncture]) once or twice at intervals of one week. The treatment course in the framework of an open 
study among patients of Group B is a maximum of 2 injections (the first  - at Visit 3, the second - at 
Visit 4). The number of injections is determined by the doctor depending on the stage of gonarthrosis 
and the clinical response. In order to avoid overfilling the joint with dense slowly resorbable material, 
at the good clinical result (reducing the pain severity on a 100 mm VAS by Visit 2 by more than 40─ 
compared to the basal level in the open study[1]), the course of injections will be discontinued. 
The open nature of the study in one group is determined by the main purpose of the study - to assess 
the safety of MD NOLTREX™ with a single or repeated course of use. Placebo safety data at the 6-
month point (visit 5) in the IA/PAAG-SI/OA/2019 study will be used as a control. It is assumed that 
continued monitoring of patients in the placebo group will not lead to the detection of new adverse 
events (AE), the frequency of which should be compared with the frequency in the active therapy 
group, and is connected to unethical restriction of patients in the placebo group in the possibility of 
using potentially effective synovial fluid endoprostheses. 
 
The open study provides follow-up of patients for 6 months (up to 25 weeks from Visit 1). 
Thus, the maximum duration of participation in the study for one patient will be a maximum of 172 
days. 
Patient visits 
Visit 0 (Day 0, -24 h -0 h, screening)  
Procedures at Visit 5 of study IA/PAAG-SI/OA/2019 (hereinafter referred to in the Protocol as 
Clinical study 1 - CS1) that coincide with the screening Visit procedures (Visit 0) in study IA/PAAG-
SI/OA/2020 will be counted as the procedures of Visit 0 of study IA/PAAG-SI/OA/2020, there is no 
need to repeat the identical procedures of these visits. 
The following procedures must be performed during the visit: 
• The signing of the informed consent; 
• The collection of demographic data; 
• Measurement of the body weight; 
• Collection of complaints and anamnesis; 
• Registration of concomitant therapy; 
• Assessment of the main vital signs (blood pressure [BP], heart rate [HR], number of 
respiratory movements [RR], body temperature); 
• Physical examination of joints; 

 
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• Completing an algofunctional questionnaire for evaluating the osteoarthritis index 
developed by researchers at the Western Ontario and McMaster Universities 
Osteoarthritis, WOMAC with an assessment of subscale pain (WOMAC-A), stiffness 
(WOMAC-B), and functional performance (WOMAC-C) (from Visit 5 of CS1); 
• Assessment of the severity of pain in the target knee joint by 100-mm VAS (from Visit 5 
of CS1); 
• Evaluation of the effectiveness of treatment by the patient, parameter OEP (from Visit 5 
of CS1); 
• Evaluation of the effectiveness of treatment by the investigator, parameter OEI (from Visit 
5 of CS1); 
• Documenting the target knee joint (the same joint that was identified as the target in the 
IA/PAAG-SI/OA/2019 study); 
• Clinical blood test (hemoglobin level, hematocrit, red blood cell count, white blood cell 
count, white blood cell formula, platelet count, ESR) (from Visit 5 of CS1); 
• Biochemical analysis of blood (glucose, alanine aminotransferase [SPGT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], gamma-glutamyltranspeptidase 
[GGTP], total bilirubin, creatinine, uric acid, rheumatoid factor) (from Visit 5 of CS1); 
• Coagulogram (APTT, PT, prothrombin index, fibrinogen) (from Visit 5 of CS1); 
• Blood tests for antibodies to human immunodeficiency virus (HIV), hepatitis b surface 
antigen (HBsAg) and antibodies to Hepatitis C Virus (anti-HCV]), syphilis (RW); 
• General urinalysis (color, transparency, relative density, pH, glucose, protein, ketone 
bodies, urobilinogen) (from Visit 5 of CS1); 
• Rapid urine test for pregnancy in women with preserved reproductive potential (from Visit 
5 of CS1); 
• Evaluation of inclusion/non-inclusion criteria; 
• Issuing a patient's diary; 
• Check AE and serious AE (SAE). 
 
Visit 1 (Week 0, Day 1, start of treatment)  
The following procedures must be performed during the visit: 
• Measurement of the body weight; 
• Collection of complaints and anamnesis; 
• Registration of concomitant therapy; 

 
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• Assessment of the main vital signs (BP, HR, RR, body temperature); 
• Physical examination of joints; 
• Evaluation of inclusion/non-inclusion criteria; 
• Injection of the studies MD into the cavity of the target joint (only for group A patients 
who are shown to receive the injection in accordance with the criteria specified in the 
Protocol); 
• Registration of AE and SAE; 
• Evaluation of exclusion criteria. 
Every 2 weeks between Visit 1 and Visit 3 (weeks 3, 5, 7, 9 and 11), telephone contacts are made 
with the patient to clarify complaints, AE and the need for taking paracetamol or NSAIDs for the past 
2 weeks. If AE is detected, or the need to take paracetamol or NSAIDs more than 4 days a week in 
each of the consecutive 2 weeks, the patient is invited to the clinic for an unscheduled Visit or a Visit 
to prematurely complete participation in the study (depending on the reason for the visit). 
Visit 2 (Week 1, Day 8, treatment and follow-up) - as indicated 
Only patients who received an injection of MD NOLTREX™ into the target knee joint on Visit 1 are 
eligible for Visit 2. 
The following procedures must be performed during the visit: 
• 
Measurement of the body weight; 
• 
Collection of complaints and anamnesis; 
• 
Registration of concomitant therapy; 
• 
Assessment of the main vital signs (BP, HR, RR, body temperature); 
• 
Physical examination of joints; 
• 
Assessment of the severity of pain in the target knee joint using 100-mm VAS; 
• 
Injection of the studied MD into the target joint cavity (only for patients of group A, in 
which the severity of pain in the target knee joint using 100 mm VAS did not decrease 
by 40% or more compared to the assessment on the Visit 0); 
• 
Evaluation of the patient's diary; 
• 
Return of the diary to the patient; 
• 
Registration of AE and SAE; 
• 
Evaluation of exclusion criteria. 
 
Visit 3 (Week 13, Day 84 ± 2, treatment and follow-up)  
The following procedures must be performed during the visit: 

 
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• Measurement of the body weight; 
• Collection of complaints and anamnesis; 
• Registration of concomitant therapy; 
• Assessment of the main vital signs (BP, HR, RR, body temperature); 
• Physical examination of joints; 
• Filling out algofunctional questionnaire WOMAC with an assessment of the subscales of 
pain (WOMAC-A), stiffness (WOMAC-B) and functional performance (WOMAC-C); 
• Assessment of the severity of pain in the target knee joint using 100-mm VAS; 
• Evaluation of the effectiveness of treatment by the patient, OEP parameter; 
• Evaluation of the effectiveness of treatment by the investigator, OEI parameter; 
• Clinical blood test (hemoglobin level, hematocrit, red blood cell count, white blood cell 
count, white blood cell formula, platelet count, ESR); 
• Biochemical blood test (glucose, ALT, AST, ALP, GGTP, total bilirubin, creatinine, uric 
acid, rheumatoid factor); 
• Coagulogram (APTT, PT, prothrombin index, fibrinogen) 
• General urinalysis (color, transparency, relative density, pH, glucose, protein, ketone 
bodies, urobilinogen); 
• Injection of the studied MD into the cavity of the target joint (only for patients of Group 
B who are shown to receive the injection according to the criteria specified in the Protocol, 
and didn't receive the injection at Visit 1); 
• Evaluation of the patient's diary; 
• Evaluation of the total number of paracetamol tablets taken (one tablet = 500 mg) using 
patient's diary, PARACETAMOL parameter; 
• Evaluation of the patient's diary of the total number of NSAIDs allowed by the Protocol 
in case of paracetamol inefficiency (NSAIDs allowed by the Protocol in case of 
paracetamol inefficiency: diclofenac potassium tablets 50 mg, diclofenac sodium tablets 
75 mg, naproxen tablets 500 mg, naproxen sodium tablets 550 mg, meloxicam tablets 7.5 
mg, celecoxib tablets 200 mg), NSAID parameter; 
• Issuing a new patient diary to the patient; 
• Registration of AE and SAE; 
• Evaluation of exclusion criteria. 
Every 2 weeks, between Visit 3 and Visit 4 (weeks 15, 17, 19, 21 and 23), telephone contacts are 
made with the patient to clarify complaints, AE and the need for taking paracetamol or NSAIDs for 
the past 2 weeks. If AE is detected, or the need to take paracetamol or NSAIDs more than 4 days a 

 
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week in each of the consecutive 2 weeks, the patient is invited to the clinic for an unscheduled Visit 
or a Visit to prematurely complete participation in the study (depending on the reason for the visit). 
 
Visit 4 (Week 14, Day 91 ± 2, treatment and follow-up) - as indicated 
Only patients who received an injection of MD NOLTREX™ into the target knee joint on Visit 3 are 
eligible for Visit 4. 
The following procedures must be performed during the visit: 
• Measurement of the body weight; 
• Collection of complaints and anamnesis; 
• Registration of concomitant therapy; 
• Assessment of the main vital signs (BP, HR, RR, body temperature); 
• Physical examination of joints; 
• Assessment of the severity of pain in the target knee joint using 100-mm VAS; 
• Injection of the studied MD into the target joint cavity (only for patients of Group B, in 
which the severity of pain in the target knee joint using 100 mm VAS did not decrease by 
40% or more compared to the assessment at Visit 3) 
• Evaluation of the patient's diary; 
• Return of the diary to the patient; 
• Registration of AE and SAE; 
• Evaluation of exclusion criteria. 
 
Visit 5 (Week 25, Day 169 ± 2, follow-up) 
The following procedures must be performed during the visit: 
• Measurement of the body weight; 
• Collection of complaints and anamnesis; 
• Registration of concomitant therapy; 
• Assessment of the main vital signs (BP, HR, RR, body temperature); 
• Physical examination of joints; 
• Radiography of the knee joints and documentation of parameters of joint space width 
(JSW) and joint space narrowing (JSN); 
• Filling out algofunctional questionnaire WOMAC with an assessment of the subscales of 
pain (WOMAC-A), stiffness (WOMAC-B) and functional performance (WOMAC-C); 

 
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• Assessment of the severity of pain in the target knee joint using 100-mm VAS; 
• Evaluation of the effectiveness of treatment by the patient, OEP parameter; 
• Evaluation of the effectiveness of treatment by the investigator, OEI parameter; 
• Clinical blood test (hemoglobin level, hematocrit, red blood cell count, white blood cell 
count, white blood cell formula, platelet count, ESR); 
• Biochemical blood test (glucose, ALT, AST, ALP, GGTP, total bilirubin, creatinine, uric 
acid, rheumatoid factor); 
• Coagulogram (APTT, PT, prothrombin index, fibrinogen); 
• General urinalysis (color, transparency, relative density, pH, glucose, protein, ketone 
bodies, urobilinogen); 
• Evaluation of the patient's diary; 
• Evaluation of the total number of paracetamol tablets taken (one tablet = 500 mg) using 
patient's diary, PARACETAMOL parameter; 
• As per patient’s diary, evaluation of the total number of NSAIDs allowed by the Protocol 
in case of paracetamol inefficiency (NSAIDs allowed by the Protocol in case of 
paracetamol inefficiency: diclofenac potassium tablets 50 mg, diclofenac sodium tablets 
75 mg, naproxen tablets 500 mg, naproxen sodium tablets 550 mg, meloxicam tablets 7.5 
mg, celecoxib tablets 200 mg), NSAID parameter; 
• Registration of AE and SAE; 
• Evaluation of exclusion criteria. 
 
An unscheduled visit 
The following procedures must be performed during the visit: 
• Measurement of the body weight  
• Collection of complaints and anamnesis; 
• Registration of concomitant therapy; 
• Assessment of the main vital signs (BP, HR, RR, body temperature); 
• Physical examination of joints; 
• Evaluation of the patient's diary; 
• Registration of AE and SAE; 
• Evaluation of exclusion criteria. 
At the time of unscheduled Visit, any of the research procedures can be additionally performed by 
the decision of the Chief investigator. 

 
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Visit to the prematurely end the participation in the study 
The following procedures must be performed during the visit: 
• Measurement of the body weight 
• Collection of complaints and anamnesis; 
• Registration of concomitant therapy; 
• Assessment of the main vital signs (BP, HR, RR, body temperature); 
• Physical examination of joints; 
• Filling out algofunctional questionnaire WOMAC with an assessment of the subscales of 
pain (WOMAC-A), stiffness (WOMAC-B) and functional performance (WOMAC-C); 
• Assessment of the severity of pain in the target knee joint on a 100-mm visual-analog 
scale (100-mm VAS); 
• Evaluation of the effectiveness of treatment by the patient, OEP parameter; 
• Evaluation of the effectiveness of treatment by the investigator, OEI parameter; 
• Clinical blood test (hemoglobin level, hematocrit, red blood cell count, white blood cell 
count, white blood cell formula, platelet count, ESR); 
• Biochemical blood test (glucose, ALT, AST, ALP, GGTP, total bilirubin, creatinine, uric 
acid, rheumatoid factor); 
• Coagulogram (APTT, PT, prothrombin index, fibrinogen); 
• General urinalysis (color, transparency, relative density, pH, glucose, protein, ketone 
bodies, urobilinogen); 
• Rapid urine test for pregnancy in women with preserved reproductive potential; 
• Evaluation of the patient's diary; 
• Evaluation of the total number of paracetamol tablets taken (one tablet = 500 mg) using 
patient's diary, PARACETAMOL parameter; 
• As per patient’s diary, evaluation of the total number of NSAIDs allowed by the Protocol 
in case of paracetamol inefficiency (NSAIDs allowed by the Protocol in case of 
paracetamol inefficiency: diclofenac potassium tablets 50 mg, diclofenac sodium tablets 
75 mg, naproxen tablets 500 mg, naproxen sodium tablets 550 mg, meloxicam tablets 7.5 
mg, celecoxib tablets 200 mg), NSAID parameter; 
• Registration of AE and SAE; 
• Evaluation of exclusion criteria. 
 
The main parameters of evaluation of efficacy and safety 

 
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Basic safety parameters: 
1.  
The frequency of AE and/or SAE; 
2.  
Overall assessment of the tolerability of therapy by the investigator and the patient; 
3.  
The main parameters of vital signs (HR, BP, RR, body temperature) 
4.  
Results of physical examination; 
5.  
Results of laboratory and instrumental examination. 
Separately, it is planned to evaluate the cumulative (in the framework of a double-blind and open 
study) frequency of the most likely complications associated with periprocedural or temporary 
postprocedural (no more than 72 hours) pain or burning.  These AE can be stopped with paracetamol 
or non-steroidal anti-inflammatory drugs. 
Other possible side effects and complications of special interest related to the method of 
administration by intra-articular injection:  
• pain or swelling at the injection site, feeling of bursting, burning, arthralgia, effusion in the 
joint, synovitis, aseptic acute arthritis;  
• infections (pyogenic arthritis, direct infection of the joint at infectious diseases, osteomyelitis, 
sepsis, etc.);  
• subcutaneous neuropathies, drug-induced vascular embolism. 
It is assumed that the AEs are divided into groups: somatic AEs and AEs associated with the 
pathology of the target joint, as well as the frequency of both these groups and each AE, according to 
the following classification: 
• Very common ≥10%; 
• Common (frequent) < 10%, but ≥ 1%; 
• Uncommon < 1%, but ≥ 0.1%; 
• Rare < 0.1%, but ≥ 0.01%; 
• Very rare < 0.01%. 
 
The main parameters of the effectiveness of the studied MD: 
1. Change in the overall score on the WOMAC scale (WOMAC-T) at Visit 3 (week 13), Visit 5 
(week 25) compared to the basal value at Visit 0 (screening) of the open study and compared 
to the basal value at Visit 1 (week 1) of the IA/PAAG-SI/OA/2019 study; 
2. Change in the pain subscale score (WOMAC-A) at Visit 3 (week 13), at Visit 5 (week 25) 
compared to the basal value at Visit 0 (screening) of the open study and compared to the basal 
value at Visit 1 (week 1) of the IA/PAAG-SI/OA/2019 study; 

 
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3. Change in the score for stiffness subscale (WOMAC-B) and functional performance 
(WOMAC-C) at Visit 3 (week 13), Visit 5 (week 25) compared to the basal value at Visit 0 
(screening) of open study and compared to the basal value at Visit 1 (week 1) of the study 
IA/PAAG-SI/OA/2019; 
4. The change in the severity of pain in the target knee on a 100-mm visual analogue scale (100 
mm VAS) at Visit 2 (week 1), Visit 3 (week 13), Visit 5 (week 25) compared to the basal 
value at Visit 0 (screening) open security research and compared to the basal value at Visit 1 
(week 1) study IA/PAAG-SI/OA/2019; 
5. Evaluation of the effectiveness of treatment by the patient, parameter (on a scale from 1-clear 
deterioration to 6-significant improvement) on Visits 3 and 5 (parameters OEP-w13 and OEP-
w25, respectively); 
6. Evaluation of the effectiveness of treatment by the investigator, parameter (on a scale from 1-
clear deterioration to 6-significant improvement) on Visits 3 and 5 (parameters OEI-w13, OEI-
w25, respectively); 
7. Assessment of the total number of paracetamol tablets taken (one tablet = 500 mg) starting 
from day 1 at Visit 3 and 5 (parameters PARACETAMOL-w13 and PARACETAMOL-w25, 
respectively); 
8. Assessment of the total number of NSAID tablets taken starting from day 1 at Visits 3 and 5 
(parameters NSAID-w13 and NSAID-w25, respectively); 
9. The parameter JSN of the target knee joint at Visit 5 of the open study compared to the basal 
value on Visit 0 of the IA/PAAG-SI/OA/2019 study retrospectively. 
 
All performance parameters will be analyzed among all patients included in open study no. 
IA/PAAG-SI/OA/2020, as well as in subgroups of patients: 
• who received only one course of injections in the placebo-controlled study IA/PAAG-
SI/OA/2019; 
• those who received two courses of therapy – both in the placebo-controlled and at Visit 1 (and 
as per the indications at Visit 2) of the open study; 
• those who received two courses of therapy – both in the placebo-controlled and at Visit 3 (and 
as per the indications at Visit 4) of the open study. 
 
Inclusion criteria 

 
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The study will include patients who meet all these criteria: 
1.  
Men and women over 50 years of age; 
2.  
Signed informed consent form for the study participants; 
3.  
Verified gonarthrosis according to ACR criteria (knee pain in combination with one of the 
following signs: age over 50 years, crepitation in the joint or morning stiffness in the joint lasting less 
than 30 minutes in combination with radiological signs of gonarthrosis); 
4.  
II-III radiological stage of gonarthrosis according to the Kellgren-Lawrence classification 
with a predominant lesion of the medial tibiofemoral section of the knee joint; 
5. 
Completion of participation in the IA/PAAG-SI/OA/2019 clinical trial in the group with 
NOLTREX™ medical device through Visit 5 (25 weeks). 
 
Non-inclusion criteria 
Patients cannot be included in the study if they have at least one of the following criteria for non-
inclusion: 
1. 
Pregnancy or breast-feeding; 
2. 
History of injury or surgery on the target knee joint; 
3. 
Instability of the target knee joint; 
4. 
Microcrystalline arthropathies (according to anamnesis and taking into account clinical 
manifestations); 
5. 
Systemic inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.); 
6. 
Seronegative spondyloarthritis and reactive arthritis; 
7. 
Increasing the level of rheumatoid factor; 
8. 
Increased uric acid level > 360 mmol/l; 
9. 
Intra-articular injection into the target knee joint: 
• hyaluronates – within past 12 months before the patient is included in the study; 
• other synovial fluid endoprostheses (other than NOLTREX™ in the IA/PAAG-SI/OA/2019 
study) within past 24 months; 
• glucocorticosteroids – within 1 month before inclusion in the study; 
• NSAIDs - intra-articular administration at any time in the anamnesis. 
10. 
Systemic painkillers (NSAIDs, opioid analgesics) within 1 week before the Visit 0; 
11. 
Effusion in the target joint; 
12. 
The presence of inflammation or infection in the target joint, synovitis; 
13. 
The need for stable use of glucocorticosteroids in any dosage form; 

 
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14. 
Use of paracetamol within 48 hours before the Visit 0; 
15. 
A positive blood test result for one or more of the following infections: HIV, viral hepatitis B 
and C, syphilis; 
16. 
Severe liver pathology, defined as an increase in the level of one of the indicators: ALT, AST, 
ALP, total bilirubin, GGTP more than 3 times compared to the upper limit of the norm; 
17. 
Kidney diseases with glomerular filtration rate when evaluated using the Cocraft-Gault 
formula less than 60 ml/min/1.73 m2 (chronic kidney disease stages III–V); 
18. 
Clinically manifested coxarthrosis; 
19. 
Severe decompensated chronic or acute diseases and other conditions or other causes that, in 
the opinion of the research doctor, may hinder the patient's participation in the study or affect 
the results of the study; 
20. 
Participation in any other clinical trial other than the IA/PAAG-SI/OA/2019 trial within past 
90 days prior to inclusion in the study. 
 
Exclusion criteria 
In the following cases, patients will be excluded from the study: 
a. 
The Ethics Committee, regulatory authorities, or the Sponsor will terminate the study or 
participation in the study of this clinical center for any reason; 
b. 
The investigator decided that the patient should be excluded in the interests of the patient; 
c. 
Withdrawal of informed consent (unwillingness of the patient to continue participating in the 
study); 
d. 
Serious deviation from the research Protocol; 
e. 
Erroneous inclusion (for example, the patient was included in violation of the Protocol's 
inclusion/non-inclusion criteria); 
f. 
The patient receives/needs additional treatment that may affect the outcome of the study or 
the patient's safety (for more information, see the section "Prohibited concomitant therapy"); 
g. 
Injury to the target knee joint; 
h. 
Other conditions or events that, in the opinion of the research doctor, require the patient to be 
excluded from the study. 
 
If patients included in the study are found to have reasons for completing the study prematurely, they 
are excluded from the study at the stage of identifying these reasons. Each case of premature 
completion of the study by the patient or withdrawal of the patient from the study must be documented 
with the mandatory indication of the reason for premature completion/withdrawal from the study, as 
well as reporting to the Sponsor within 7 business days. 

 
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Prohibited concomitant therapy 
1. 
Glucocorticosteroids in any dosage form; 
2.  
Any intra-articular and periarticular injections; 
3.  
Use of NSAIDs and painkillers that are not approved by the Protocol, including local ones 
(with the exception of paracetamol and NSAIDs allowed by the Protocol in case of ineffectiveness of 
paracetamol); 
4.  
Use of paracetamol at a dose of more than 4000 mg per day; 
5.  
Use of one of the Protocol-approved NSAIDs in doses exceeding the permitted doses 
(permitted drugs and doses: diclofenac potassium 50 mg 2 times a day, diclofenac sodium tablets 75 
mg 2 times a day, naproxen tablets 500 mg 2 times a day, naproxen sodium tablets 550 mg 2 times a 
day, meloxicam tablets 7.5 mg once a day, celecoxib tablets 200 mg 2 times a day); 
6.  
Use of a combination of paracetamol with NSAIDs or a combination of two or more NSAIDs; 
7.  
Surgical interventions and arthroscopies on the target knee joint. 
Justification of the sample size 
This open-label MD NOLTREX™ safety assessment study includes eligible and non-eligible patients 
who received MD NOLTREX™ as part of the IA/PAAG-SI/OA/2019 study. Therefore, no formal 
calculation of the sample size was performed. The maximum expected number of study participants 
is the number of patients who were randomized to the MD NOLTREX™ group in the IA/PAAG-
SI/OA/2019 study, i.e. 72 patients. 
Blinding, randomization 
This study is planned as an open-label study in a single group with subsequent division into subgroups 
depending on the actual need for treatment. In this regard, the Protocol does not provide for blinding 
and randomization.