Multicenter Double-blind Randomized Comparative Placebo-controlled 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

Page  1 
Clinical Study Protocol IA/PAAG-SI/OA/2019
HBISA Endoprosthesis of synovial fluid NOLTREXTM 
Multicenter, Double-blind, Randomized, Placebo-controlled Comparative Study of 
Efficacy and Safety of Intra-articular Polyacrylamide Hydrogel with Silver Ions (NOLTREX#) 
in patients with Knee Osteoarthritis K-L grades II-III  
ClinicalTrials.gov Identifier: NCT03897686 
Version 3.0: October 30, 2020
Study sponsor
<RC <BIOFORM= LLC
7 bld. 2 Comintern St. Babushkinsky District 
Moscow, 129327, Russian Federation

Protocol 7 IA/PAAG-SI/OA/2019
NCT03897686
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List of abbreviations 
Abbreviation 
Interpretation 
100-mm VAS
100-millimeter visual analogue scale
BP 
Blood pressure 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
APTT 
Activated partial thromboplastin time 
HIV 
Human immunodeficiency virus 
KOA 
Knee osteoarthrosis 
GGTP 
Gamma-glutamyl transpeptidase 
HA 
Hyaluronic acid 
CRO 
Contract Research Organization 
MD 
Medical device 
GCP 
Good Clinical Practice 
NSAID 
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 
JSW 
Joint space width 
WOMAC 
Index of Western Ontario and McMaster Universities Osteoarthritis 

Protocol 7 IA/PAAG-SI/OA/2019
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Synopsis 
Study title 
Multicenter Double-blind Randomized Placebo-controlled Comparative 
Study of Efficacy and Safety of Intra-articular Polyacrylamide 
Hydrogel with Silver Ions (NOLTREX#) in patients with Knee 
Osteoarthritis K-L grades II-III 
Protocol number 
IA/PAAG-SI/OA/2019 
Study MD 
HBISA Endoprosthesis of synovial fluid NOLTREXTM (4.0 ml for one 
injection with one-week interval between injections. Course - 2 
injections). 
Placebo 
Sodium chloride solution 0.9% BUFUS®, in ampoules 10 ml (to be used 
with syringes 2.5 ml). (4.0 ml for one injection with one-week interval 
between injections. Course - 2 injections.) 
Study period, number 
of 
study 
sites 
and 
patients 
Proposed total study period 3 12 months.
Participation of each patient in the study 3 not more than 179 days:
" Screening 3 days -7&0;
" Treatment period: weeks 1-2;
" Follow-up period: weeks 3-25.
Number of study sites 3 4.
Number of patients: 
- 170 screened patients;
- 144 randomizations (72 patients in each group);
- 130 patients that should complete the study (65 patients in each group).
Study aim 
The aim of this double-blinded controlled study is to assess clinical 
efficacy and safety of intra-articular polyacrylamide hydrogel with ions 
of silver in comparison with placebo (0.9% sodium chloride solution) in 
Kellgren Lawrence radiological grade II-III knee osteoarthritis 
Study goals 
" Assessment of a change in knee joint functionality, stifnes and
joint pain intensity estimated per the corresponding subscales 
and total arthritis index score developed by Western Ontario 
and McMaster Universities (WOMAC) during administration of 
intra-articular MD NOLTREX# in comparison with placebo

Protocol 7 IA/PAAG-SI/OA/2019
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(0.9% sodium chloride solution) in Kellgren Lawrence 
radiological grade II-III knee osteoarthritis; 
" Assessment of the need in paracetamol and NSAID (in case of
ineffective therapy with paracetamol) intake to relieve the 
knee pain during administration of intra-articular MD 
NOLTREX# in comparison with placebo (0.9% sodium chloride 
solution) in Kellgren Lawrence radiological grade II-III knee 
osteoarthritis; 
" Assessment of efficacy of MD NOLTREX# in comparison with 
placebo (0.9% sodium chloride solution) in Kellgren Lawrence 
radiological grade II-III knee osteoarthritis as subjectively 
assessed by a patient; 
" Assessment of efficacy of MD NOLTREX# in comparison with 
placebo (0.9% sodium chloride solution) in Kellgren Lawrence 
radiological grade II-III knee osteoarthritis as subjectively 
assessed by the investigator; 
" Assessment of safety of intra-articular MD NOLTREX# in 
comparison with placebo (0.9% sodium chloride solution) in 
Kellgren Lawrence radiological grade II-III knee osteoarthritis. 
Study methodology 
The study MD 3 synovial fluid endoprosthesis NOLTREX# 3 is 
intended for a symptomatic treatment leading to the decrease of joint pain 
intensity and improvement of functional characteristics of joint. 
Therefore the study MD is intended for symptom-modifying therapy of 
joint osteoarthritis (osteoarthrosis). The study design including the 
selection of the study population, endpoints, is developed in accordance 
with  the recommendations laid down in the Guidelines on clinical 
investigations of medicinal products intended for osteoarthritis treatment 
[1], on products intended for symptom-modifying therapy of 
osteoarthritis (osteoarthrosis): multicenter randomized double blind 
placebo-controlled, in parallel groups study. 
With regards to a slow but stable onset of the effect assumed in 
accordance with the mode of action of the medical device, the assessment 
of the primary endpoint (change of total WOMAC score 3 WOMAC total 
in the affected joint) is planned on Week 25, in addition, the effect onset 
in 3 months after the product administration, will be assessed on Week 
13. 
Patients meeting the inclusion criteria and not having the exclusion 
criteria, will be randomized on Visit 1 to 2 groups: 
" MD NOLTREX#;

 
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" Placebo. 
On the Screening visit, it is determined whether a patient meets the 
inclusion/non-inclusion criteria, as well, the target knee joint is 
determined. The target knee joint is selected by the investigator using the 
following algorithm. If bilateral knee osteoarthritis is present, the target 
knee joint is selected in accordance with the greater pain intensity per 
WOMAC A scale, with the same tenderness of both knee joints 3 per 
radiologic changes (greater degree per Kellgren3Lawrence classification 
and/or lower value of the joint space width 3 JSW). If the same tenderness 
occurs in both knee joints, and the same picture of radiographic changes 
is observed, target knee joint is determined by the investigator at his/her 
discretion. 
The study MD or placebo will be injected to the target knee joint in the 
corresponding volume using the standard method: a patient being supine 
on his back, to the external superior recess, beginning from Visit 1 
(randomization, start of treatment). Intra-articular injections will be made 
only if there are no signs of active joint inflammation (hyperemia, edema, 
joint effusion) and signs of skin inflammation or some other damage in 
the injection site for intra-articular administration of MD or placebo. The 
product will be administered in accordance with the instruction for the 
medical use of medical device NOLTREX#: 4.0 ml for one injection 
(2.5 + 1.5 ml, or 2.0 + 2.0 ml from two syringes through one needle [one 
puncture]) with one week interval. Course 3 2 injections. The number of 
injections is determined by the physician depending on the stage of knee 
osteoarthritis and clinical response. To avoid the joint overfilling with 
the dense, slowly resorbing material, with a good clinical result (over 
40% pain decrease per 100-mm VAS scale in comparison with baseline 
[2]), the course of injections will be stopped. Placebo will be 
administered per the analogous scheme.. 
Primary and secondary efficacy endpoints, and safety parameters will be 
assessed on Visits on Week 6, 13 and 25 (primary endpoint). 
 Patient visits 
Visit 0 (day -7&0): Screening  
The following procedures will be done: 
" Obtaining the informed consent form for the study participation; 
" Collection of demographic data (date of birth, age); 
" Measurement of body weight and height; 
" Collection of complaints and medical history; 
" Recording of concomitant therapy; 

 
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" Assessment of vital signs (blood pressure [BP], heart rate [HR], 
respiratory rate [RR], body temperature); 
" Physical joint examination; 
" Radiography of knee joints (or assessment of study X-rays made 
within 3 months prior the study inclusion). 
Screening examinations are continued if a patient meets the inclusion 
criteria. 
" Complete blood count; 
" Blood biochemistry: glucose, alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], alkaline phosphatase [ALP], 
gamma-glutamyl 
transpeptidase 
[GGTP], 
total 
bilirubin, 
creatinine, uric acid, rheumatoid factor; 
" Coagulogram (activated partial thromboplastin time [APTT], 
prothrombin time [PT], prothrombin index, fibrinogen); 
" Urine analysis; 
" Express urine pregnancy test for women with the preserved 
reproductive potential; 
" Test for human immunodeficiency virus (HIV), HBs-Ag, anti-
HCV, RW; 
" Assessment of the inclusion/non-inclusion criteria; 
" Assessment of serious adverse events (SAE) related to study 
procedures. 
Treatment period (Week 1 3 Week 2) 
Visit 1 (Week 1, Day 1), randomization, start of treatment 
The following procedures will be made: 
" Collection of complaints and medical history; 
" Recording of concomitant therapy; 
" Measurement of body weight; 
" Assessment of vital signs (BP, HR, RR, body temperature); 
" Physical joint examination; 
" Completion of algofunctional questionnaire WOMAC with the 
assessment of pain (WOMAC-A), stiffness (WOMAC-B), 
functionality (WOMAC-C) subscales and total score (WOMAC-
T) (baseline values 3 WOMAC-X-w1) 

 
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" Assessment of compliance with the inclusion/non-inclusion 
criteria; 
" Selection of the target knee joint; 
" Assessment of pain intensity in the target knee joint per 100-mm 
visual analogue scale (100-mm VAS); 
" Randomization; 
" Injection 7 1 of the study MD or placebo into the target joint; 
" Issuing of the patient diary; 
" Assessment of adverse events (AE); 
" Assessment of the subject exclusion criteria. 
Visit 2 (Week 2, Day 8) 
The following procedures will be made: 
" Collection of complaints and medical history; 
" Recording of concomitant therapy; 
" Measurement of body weight; 
" Assessment of vital signs (BP, HR, RR, body temperature); 
" Physical joint examination; 
" Assessment of the patient diary; 
" Return of the diary to the patient; 
" Express urine pregnancy test for women with the preserved 
reproductive potential; 
" Assessment of the subject exclusion criteria (the decision is made 
whether the intra-articular injection can be done); 
" Assessment of pain intensity in the target knee joint per 100-mm 
VAS; 
" By the decision of the research investigator, with regards to the 
rules for administration of the study MD determined by the 
protocol and the instruction for use of the medical device - 
injection 7 2 of the study MD or placebo into the target joint; 
" AE assessment; 
" Repeat assessment of the subject exclusion criteria (after intra-
articular injection). 

 
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Every week between Visits 2 and 3 (weeks 3, 4 and 5), the study personnel 
contacts a patient by the phone to learn about complaints, AE and need of 
paracetamol and NSAID intake for the previous 2 weeks. If any AE or need of 
paracetamol and NSAID intake for over 4 days a week during each of the 
successive 2 weeks is found, the patient is invited to the clinic for the 
Unscheduled visit or Premature study discontinuation visit (depending on the 
visit reason). 
 
Follow-up period (Weeks 3325) 
Visit 3 (Week 6, Day 36 ± 2) 
The following procedures will be done: 
" Collection of complaints and medical history; 
" Recording of concomitant therapy; 
" Measurement of body weight; 
" Assessment of vital signs (BP, HR, RR, body temperature); 
" Physical joint examination; 
" Assessment of the patient diary; 
" Dispensing of the new patient diary to the patient; 
" Completion of algofunctional questionnaire WOMAC with the 
assessment of pain (WOMAC-A-w6), stiffness (WOMAC-B-w6), 
functionality (WOMAC-C-w6) subscales and total score 
(WOMAC-T-w6) (<Week 6= values); 
" Patient9s assessment of the treatment efficacy, OEP-w6 value (per 
the scale from 1 3 evident aggravation to 6 3 significant 
improvement); 
" Investigator9s assessment of the treatment efficacy, OEI-w6 value 
(per the scale from 1 3 evident aggravation to 6 3 significant 
improvement); 
" Assessment of the total number of paracetamol tablets taken per 
the patient diary (one tablet = 500 mg), value PARACETAMOL-
w6; 
" Assessment of the total number of NSAID tablets taken, value 
NSAID-w6 
" Complete blood count; 

 
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" Blood biochemistry: glucose, ALT, AST, ALP, GGTP, total 
bilirubin, creatinine, uric acid; 
" Coagulogram (APTT, PT, prothrombin index, fibrinogen); 
" Urine analysis; 
" Express urine pregnancy test for women with the preserved 
reproductive potential; 
" AE assessment; 
" Assessment of the subject exclusion criteria. 
On Weeks 8, 10 and 12, the study personnel contacts the patient by the 
phone to learn about complaints, adverse events (AE) and need of 
paracetamol and NSAID intake for the previous 2 weeks. If any AE or 
need of paracetamol intake for over 4 days a week during each of the 
successive 2 weeks is revealed, the patient is invited to the clinic for the 
unscheduled visit or premature study discontinuation visit (depending 
on the visit reason). 
Visit 4 (Week 13, Day 84 ± 2) 
The following procedures will be done: 
" Collection of complaints and medical history; 
" Recording of concomitant therapy; 
" Measurement of body weight; 
" Assessment of vital signs (BP, HR, RR, body temperature); 
" Physical joint examination; 
" Assessment of the patient diary; 
" Dispensing of the new patient diary to the patient; 
" Completion of algofunctional questionnaire WOMAC with the 
assessment of pain (WOMAC-A-w13), stiffness (WOMAC-B-
w13), functionality (WOMAC-C-w13) subscales and total score 
(WOMAC-T-w13) (<Week 13= values); 
" Patient9s assessment of the treatment efficacy, OEP-w6 value (per 
the scale from 1 3 evident aggravation to 6 3 significant 
improvement); 
" Investigator9s assessment of the treatment efficacy, OEI-w13 
value (per the scale from 1 3 evident aggravation to 6 3 significant 
improvement); 

 
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" Assessment of the total number of paracetamol tablets taken per 
the patient diary (one tablet = 500 mg) beginning from day 1, 
value PARACETAMOL-w13; 
" Assessment of the total number of NSAID tablets taken, value 
NSAID-w13 
" Complete blood count; 
" Blood biochemistry: glucose, ALT, AST, ALP, GGTP, total 
bilirubin, creatinine, uric acid; 
" Coagulogram (APTT, PT, prothrombin index, fibrinogen); 
" Urine analysis; 
" Express urine pregnancy test for women with the preserved 
reproductive potential; 
" AE assessment; 
" Assessment of the subject exclusion criteria. 
On Weeks 15, 17, 19, 21 and 23, the study personnel contacts the patient 
by the phone to learn about complaints, adverse events (AE) and need 
of paracetamol and NSAID intake for the previous 2 weeks. If any AE 
or need of paracetamol or NSAID intake for over 4 days a week during 
each of the successive 2 weeks is revealed, the patient is invited to the 
clinic for an unscheduled visit or premature study discontinuation visit 
(depending on the visit reason). 
Visit 5 (Week 25, Day 169 ± 2) 
The following procedures will be made: 
" Collection of complaints and medical history; 
" Recording of concomitant therapy; 
" Measurement of body weight; 
" Assessment of vital signs (BP, HR, RR, body temperature); 
" Physical joint examination; 
" Assessment of the patient diary; 
" Completion of algofunctional questionnaire WOMAC with the 
assessment of pain (WOMAC-A-w25), stiffness (WOMAC-B-
w25), functionality (WOMAC-C-w25) subscales and total score 
(WOMAC-T-w25) (<Week 25= values); 

 
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" Patient9s assessment of the treatment efficacy, OEP-w25 value 
(per the scale from 1 3 evident aggravation to 6 3 significant 
improvement); 
" Investigator9s assessment of the treatment efficacy, OEI-w25 
value (per the scale from 1 3 evident aggravation to 6 3 significant 
improvement); 
" Assessment of the total number of paracetamol tablets taken per 
the patient diary (one tablet = 500 mg) starting from day 1, value 
PARACETAMOL-w25; 
" Assessment of the total number of NSAID tablets taken per the 
patient diary starting from day 1, value NSAID-w25, 
" Complete blood count; 
" Blood biochemistry: glucose, ALT, AST, ALP, GGTP, total 
bilirubin, creatinine, uric acid; 
" Coagulogram (APTT, PT, prothrombin index, fibrinogen); 
" Urine analysis; 
" Express urine pregnancy test for women with the preserved 
reproductive potential; 
" AE assessment. 
" In case of planned completion of the study and completion of all 
procedures provided in the clinical study protocol, the patient will 
be provided with studied medical device NOLTREX regardless 
of the treatment group to which the patient was assigned. In this 
case the patient will receive 4 packages of NOLTREX which 
corresponds to one treatment course. 
Unscheduled visit 
Unscheduled visits will be made as necessary, for example, in the event 
of aggravation of the studied medical condition, AE or intolerability of 
the study MD or placebo therapy. When an unscheduled visit is made, 
regardless of its reason, the investigator makes the following procedures 
and completes corresponding eCRF pages (Unscheduled visit): 
" Collection of complaints and medical history; 
" Recording of concomitant therapy; 
" Measurement of body weight; 
" Assessment of vital signs (BP, HR, RR, body temperature); 

 
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" Physical joint examination; 
" Assessment of the patient diary; 
" AE assessment. 
If clinically indicated and meeting the criteria, any of the study 
procedures can be additionally made on the unscheduled visit by the 
decision of the Principal Investigator. 
Premature study discontinuation visit 
" On the premature study discontinuation visit, the same procedures 
are made as on Visit 5 
 Main 
parameters 
of 
efficacy 
and 
safety 
assessment 
Primary endpoint 3 change of the total WOMAC score (WOMAC-T) 
on Visit 5 (Week 25) in comparison with baseline on visit 1 (Week 1). 
Secondary endpoints: 
" Change of the total WOMAC score (WOMAC-T) on Visit 4 
(Week 13) in comparison with baseline on Visit 1 (Week 1); 
" Change of the pain subscale score (WOMAC-A) on Visit 3 (Week 
6), Visit 4 (Week 13) and Visit 5 (Week 25) and in comparison 
with baseline on Visit 1 (Week 1); 
" Change of stiffness (WOMAC-B) and functionality (WOMAC-
C) subscale scores on Visit 3 (Week 6), Visit 4 (Week 13) and 
Visit 5 (Week 25) in comparison with baseline on Visit 1 (Week 
1); 
" Patient9s assessment of the treatment efficacy, value OEP (per 
scale from 1 3 evident aggravation to 6 3 significant 
improvement) on Visits 5, 6 and 7 (values OEP-w6, OEP-w13, 
OEP-w25); 
" Investigator9s assessment of the treatment efficacy, value OEI 
(per scale from 1 3 evident aggravation to 6 3 significant 
improvement) on Visits 3, 4 and 5 (values OEI-w6, OEI-w13, OEI-
w25); 
" Assessment of the total number of paracetamol tablets taken (one 
tablet = 500 mg) beginning from day 1, on Visits 3, 4 and 5 
(values 
PARACETAMOL-w6, 
PARACETAMOL-w13 
and 
PARACETAMOL-w25, correspondingly); 
 

 
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" Assessment of the total number of NSAID tablets taken starting 
from day1, on Visits 3, 5 and 5 (values NSAID-w6, NSAID-w13, 
NSAID-w25 correspondingly);  
" Patient exclusion rates due to safety (subject exclusion criteria 2, 
3, 6, 7); 
" Patient exclusion rates due to poor patient9s treatment compliance 
(criteria 4 and 5). 
Safety assessment parameters: 
" Frequency of AE and/or SAE reporting in treatment groups; 
" Global study physician and patient assessment of the therapy 
intolerability; 
" Vital signs (HR, BP, body temperature, RR); 
" Laboratory test results. 
AE description will be presented per the following scheme: 
" AE description; 
" Severity of manifestation; 
" Duration; 
" Relationship with the study product; 
" Outcome. 
AE will be encoded in accordance with the Medical Dictionary for 
Regulatory Activities MedDRA. 
 Inclusion criteria 
1) Men and women above 50 years; 
2) Verified knee osteoarthritis in accordance with the ACR criteria 
(knee pain combined with one of the following signs: age above 50 
years, knee crepitus or morning joint stiffness lasting for less than 30 
minutes combined with radiologic signs of knee osteoarthritis); 
3) Kellgren Lawrence radiological grade II-III knee osteoarthritis with 
the predominant involvement of the medial tibiofemoral region of the 
knee joint; 
4) Joint space width (JSW) of the target knee joint at least 2.5 mm. 
 Non-inclusion criteria 
1) History of any injury or surgical intervention on the target knee joint 
(except for diagnostic arthroscopy made more than 60 days before 
study entry); 

 
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2) Severe degenerative changes in the target knee joint determined as 
the joint space narrowing less than 2 mm; 
3) Varus or valgus deformation of the target knee joint; 
4) Instability of the target knee joint; 
5) Active inflammation of the target knee joint (edema, hyperemia, 
present effusion) at the study entry; 
6) Microcrystalline arthropathies; 
7) Systemic inflammatory disease (rheumatoid arthritis, systemic lupus 
erythematosus, etc.); 
8) Seronegative spondiloarthritis and reactive arthritis; 
9) Inflammatory diseases of the skin and soft tissues in the proposed 
injection site for the study MD or placebo in the target joint; 
10) History of venous thrombosis and thromboembolias; 
11) Coagulogram abnormalities (APTT, prothrombin time, prothrombin 
index, fibrinogen); 
12) Inflammatory changes in the complete blood count (leukocytosis, 
increase of erythrocyte sedimentation rate [ESR]); 
13) Platelet count abnormality (in accordance with the reference  ranges 
of the local laboratory; 
14) Increase of rheumatoid factor level; 
15) Increase of uric acid level > 360 ¿mol/l; 
16) Diabetes mellitus; 
17) Hemophilia and other hemorrhagic diatheses, as well administration 
of anticoagulants and disaggregants; 
18) Positive results of HIV, HBs-Ag, anti-HCV, RW tests; 
19)  Intra-articular injection to the target knee joint: 
" MD NOLTREX# 3 within 24 months prior patient9s 
inclusion to the study; 
" hyaluronates 3 within 6 months prior patient9s inclusion to the 
study; 
" glucocorticosteroids 3 within 1 month prior the study 
inclusion; 
" non-steroidal anti-inflammatory drugs (NSAID) 3 within 3 
weeks prior patient9s inclusion to the study. 

 
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20) Oral administration of non-steroidal anti-inflammatory drugs 
(NSAID) within 2 weeks prior the study inclusion; 
21) Necessity of systemic glucocorticosteroids intake in any dosage 
form; 
22) Paracetamol administration within 48 hours prior the study inclusion; 
23) Pregnancy and lactation; 
24) Hypersensitivity to components of the study MD or placebo; 
25) Severe liver disorder determined as the increase of one of the values: 
ALT, AST, ALP, total bilirubin, GGTP more than 3 times the upper 
limit of normal; 
26) Renal diseases with the glomerular filtration rate estimated per 
Cockraft-Gault formula less than 60 ml/min/1.73 m2 (III-V stage 
chronic renal disease [CRD]); 
27) Clinically manifested hip osteoarthritis; 
28) History of knee and coxofemoral endoprosthesis; 
29) Acute infectious diseases or infectious aggravations of chronic 
diseases (respiratory infections) within one month prior the study 
inclusion; 
30) Severe decompensated chronic or acute diseases and other conditions 
which, by the opinion of the study physician, may preclude the 
patient9s participation in the study or affect the study results. 
 Subject 
exclusion 
criteria 
1) Ethics Committee, regulatory bodies or the Sponsor terminate the 
study or participation of the clinical site in the study for any reasons; 
2) Need in paracetamol or NSAID intake due to knee osteoarthritis 4 
days a week or more during 2 successive weeks; 
3) The investigator makes the decision that a patient should discontinue 
the study in the best interests of the patient; 
4) Informed consent revocation (patient9s unwillingness to continue the 
study); 
5) Major deviation from the study protocol; 
6) Individual intolerability or contraindications to the study MD, 
placebo or paracetamol; 
7) AE/SAE which requires examination and/or treatment affecting 
significantly the study procedures (in particular, development of 
active arthritis or hemarthrosis of the target knee joint); 

 
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8) Erroneous study inclusion (for example, the patient was included 
with a violation of the protocol inclusion/non-inclusion criteria); 
9) A patient has non-inclusion criteria during the study; 
10) A patient takes/needs additional treatment which can affect the study 
result or patient9s safety (see section <Disallowed concomitant 
therapy=); 
11) Other conditions or events which require, by the opinion of the study 
physician, the patient9s exclusion from the study. 
12) Injury of the studied joint. 
 Disallowed concomitant 
therapy 
1. Glucocorticosteroids in any dosage form; 
2. Any intra-articular or peri-articular injections, physical therapy, as 
well other therapeutic or rehabilitation measures for knee 
osteoarthritis, except the study procedures; 
3. NSAIDs and analgesics including the local ones (except for 
paracetamol and NSAIDs permitted by the protocol in cases when 
paracetamol is ineffective); 
4. Paracetamol intake in dose over 4000 mg a day; 
5. the use of one of the NSAIDs permitted by the Protocol in doses 
exceeding those permitted by the Protocol (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 NSAID in combination with paracetamol or combination of 
two or more NSAID; 
7. Rehabilitation measures due to knee osteoarthritis; 
8. Physical therapy in knee osteoarthritis; 
9. Acupuncture; 
10. Surgeries and arthroscopies of the target knee joint. 
48 hours prior the visits where the assessment of pain intensity in the 
knee joint (Screening visit, Visits 1 3 7) is made paracetamol or NSAID 
intake is not allowed. 
 Justification 
of 
the 
sample size 
The calculation of the sample size is based on the study results of product 
Noltex in knee osteoarthritis (osteoarthrosis) (N.V. Zagorodniy et al. 
Administration of new biopolymer material <Noltrex= in complex 
treatment of patients with knee osteoarthritis. 2012, v. 17, 76, p. 49-52) 

 
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[3]. The use of NSAID Movalis in the study during the first 10 days does 
not interfere with assessment of results in 13 and 25 weeks. 
As the study primary endpoint, we selected the change of the total 
WOMAC score of the affected joint (WOMAC total), at Visit 7(Week 
25) in comparison with baseline at Visit 1 (Week 1). The selection of 
assessment point <Week 25= is related to the fact that Noltrex effect was 
the greatest in the abovementioned study in 6 months after the 
administration, subsequently the product effect was reduced. The 
additional endpoint 3 change of total WOMAC score (WOMAC total) on 
Visit 6 (Week 13) in comparison with baseline on Visit 1 (Week 1) will 
be used for assessment of the onset of the MD effect in 3 months after 
the administration. 
The following assumptions were used for calculations: 
1) Two groups (fixed factor A) 3 Noltrex and placebo 
2) The initial value of the WOMAC score and the total dose of 
NSAIDs obtained during the study as covariates 
3) Effect size 3 0.25: calculated based on the data from the 
publication presented above in which the value of intergroup 
differences with regards to variability was up to 100 scores, and 
variability (standard deviation) 3 up to 400 scores 
4) Significance level = 5% (type I error 3 ³ = 0.05) 
5) Power 3 80% (II type error 3 ³ = 0.20) 
6) Statistical model 3 analysis of covariance (baseline-adjusted) 
with fixed factors of group 
7) Study exclusion rate will not exceed 10% 
8) Non-inclusion rate in selection (screening) period will not exceed 
15% 
The sample size (number of completed cases) was calculated using 
applied software package G*Power 3.1.9.2 with the abovementioned 
assumptions: 
F tests - ANCOVA: Fixed effects, main effects and interactions 
Analysis: 
A priori: Compute required sample size  
Input: 
Effect size f 
= 0.25 
 
³ err prob 
= 0.05 
 
Power (1-´ err prob) 
= 0.80 
 
Numerator df 
= 1 
 
Number of groups 
= 2 
 
Number of covariates 
= 2 
Output: 
Noncentrality parameter » 
= 8.0000000 
 
Critical F 
= 3.9175498 

 
Protocol 7 IA/PAAG-SI/OA/2019 
NCT03897686
 
Page  18 
 
Denominator df 
= 124 
 
Total sample size 
= 130 
 
Actual power 
= 0.8013621 
In this case, with regards to approximation, 130 patients (65 in each 
group) should complete the study, for that, 144 patients should be 
randomized (72 in each group). 
Correspondingly, to achieve the necessary number of randomized 
patients, up to 170 patients should be screened. 
 Blinding, 
randomization 
Due to various viscosity (which leads to different exertion efforts in intra-
articular injection) and different appearance of the study MD and 
placebo, to preserve blinding of any patient and study team, an 
independent non-blinded physician is to be engaged, he/she will receive 
the product per randomization code and perform the procedure of intra-
articular injection of the study MD and placebo. 
Patients will be randomized to groups using the simple block 
randomization method.