## Protocol Section
### Identification Module
**NCT ID:** NCT06429319

**Brief Title:** Intra-articular Polyacrylamide Hydrogel in Gonarthrosis

**Official Title:** Multicenter Open Post-registration Study of the Safety and Effectiveness of the Medical Device HBIS Endoprosthesis of Synovial Fluid NOLTREX™ According to TU 9398-00152820385-2015 for Intraarticular Administration in the Treatment of Gonarthrosis.

#### Organization Study ID Info
**ID:** IA/PAAG-SI/OA/2020
#### Organization
**Class:** INDUSTRY
**Full Name:** Research Centre BIOFORM
### Status Module
#### Completion Date
**Date:** 2024-02-20

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-24

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-20

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2021-05-12

**Type:** ACTUAL

#### Start Date
**Date:** 2020-05-28

**Type:** ACTUAL

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-24
**Type:** ACTUAL
**Study First Submit Date:** 2020-08-14
**Study First Submit QC Date:** 2024-05-20
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** Research Centre BIOFORM

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

### Description Module

**Brief Summary:** The aim of this open post-marketing study is to assess safety and efficacy duration of HBIS IA injection after 1st and 2nd course in patients with gonarthrosis with long-term follow-up

**Detailed Description:** Hydrous biopolymer with silver ions (further - HBIS) under trademark NOLTREX™ based on polyacrylamide hydrogel is intended for a symptomatic effect leading to the decrease of joint pain intensity and improvement of functional joint characteristics. Therefore, HBIS is intended for symptom-modifying therapy of joint osteoarthritis (hereinafter - OA). The aim of this study is to estimate safety and efficacy of intra-articular injections of HBIS after 1st and 2nd course in patients with gonarthrosis with long-term follow-up. Patients, who received 1 сourse - 2 injections of NOLTREX™ in first 6-month study IA/PAAG-SI/OA/2019, will receive a repeated course of treatment strictly according to indications. The scheme of the 2nd Course is one or two 4.0 ml dosage injections of NOLTREX™ with 1-week interval on week 0 or week 13 of the study. Outcomes will estimate by WOMAC Index at Week 13 and at Week 25.

### Conditions Module

**Conditions:**

- Osteoarthritis

**Keywords:**

- intra-articular

- polyacrylamide hydrogel

- PAAG

- HBIS (Hydrous biopolymer with silver ions)

- NOLTREX

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

**Intervention Model Description:** This is open-label MD NOLTREX™ safety assessment study includes eligible and non-eligible patients who received study MD as part of the IA/PAAG-SI/OA/2019 study. It was planned that 72 patients would take part in the study. In fact, 67 patients were screened into the study because not all patients from CS1 progressed to CS2; 2 of these patients failed screening measures, so the final population included 65 patients.

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 67

**Type:** ACTUAL

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Sixty-seven patients were screened for the study; 2 of them were screening failures, therefore, 65 patients were randomized to participate in the study, who were conventionally divided into subgroups:

* Group A included 5 patients. Patients in group A received 2 courses of therapy: both within IA/PAAG-SI/OA/2019 study and at Visit 1 (and as indicated at Visit 2) of the IA/PAAG-SI/OA/2020 study.
* Group B - 43 patients. Patients in group B also received 2 courses of therapy: both within IA/PAAG-SI/OA/2019 study and at Visit 3 (and as indicated at Visit 4) of the IA/PAAG-SI/OA/2020 study.
* Group C - 17 patients. Group C included patients who received only one course of injections in the placebo-controlled study IA/PAAG-SI/OA/2019. There were no early withdrawals from the study.

**Intervention Names:**

- Device: hydrous biopolymer with silver ions "Argiform"

**Label:** hydrous biopolymer with silver ions "Argiform"

**Type:** OTHER

### Interventions

#### Intervention 1

**Arm Group Labels:**

- hydrous biopolymer with silver ions "Argiform"

**Description:** Patients will receive an injection of MD NOLTREX™ into the target knee joint. 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 within this open study is a maximum of 2 injections. The number of injections is determined by the doctor depending on the stage of gonarthrosis and the clinical response

**Name:** hydrous biopolymer with silver ions "Argiform"

**Other Names:**

- Polyacrylamide hydrogel with silver ions

- Synovial fluid endoprosthesis NOLTREX™

**Type:** DEVICE

### Outcomes Module

#### Primary Outcomes

**Description:** By Visit 3, the mean WOMAC-T (Osteoarthritis Index Total Score) compared to Visit 1 of the IA/PAAG-SI/OA/2019 study has changed by 430.20 ± 470.50 (95% CI -1014.40 - 154.00) in patients from group A, by 727.16 ± 353.78 (95% CI -836.04 - -618.28) in patients from group B, by 654.35 ± 241.28 (95% CI -778.41 - -530 ,30) in patients from group C. Intergroup differences were not statistically significant (p = 0.169).

By Visit 5, the mean WOMAC-T score compared to Visit 1 of the IA/PAAG-SI/OA/2019 study has changed by 470.60 ± 495.56 (95% CI -1085.92 - 144.72) in patients from group A, by 829.53 ± 367.38 (95% CI -942.60 - -716.47) in patients from group B, by 688.53 ± 231.50 (95% CI -807.56 - -569 .50) in patients from group C. Intergroup differences were not statistically significant (p = 0.057).

**Measure:** Change of the total score of WOMAC scale (WOMAC-T)

**Time Frame:** Change in WOMAC Total Score (WOMAC-T) at Visit 3 (Week 11), Visit 5 (Week 23) from baseline at Visit 0 (Screening) of the open-label study and from baseline at Visit 1 (Week 1) of IA/PAAG-SI/OA/2019 study;

#### Secondary Outcomes

**Description:** By Visit 3, the mean WOMAC-A (pain subscale) score compared to Visit 1 of the IA/PAAG-SI/OA/2019 study has decreased by 87.80 ± 87.45 (95% CI -196.38 - 20.78) in patients from group A, by 146.00 ± 74.46 (95% CI -168.91 - -123.09) in patients from group B, by 151.88 ± 64.56 (95% CI -185.07 - -118 .69) in patients from group C. Intergroup differences were not statistically significant (p = 0.212).

By Visit 5, the mean WOMAC-A score compared to Visit 1 of the IA/PAAG-SI/OA/2019 study has decreased by 95.80 ± 95.49 (95% CI -214.37 - 22.77) in patients from group A, by 163.05 ± 75.82 (95% CI -186.38 - -139.71) in patients from group B, by 155.06 ± 63.49 (95% CI -187.70 - -122 .41) in patients from group C. Intergroup differences were not statistically significant (p = 0.168).

**Measure:** Change of the pain subscale score (WOMAC-A)

**Time Frame:** Change in the subscale of pain (WOMAC-A) at Visit 3 (Week 11), Visit 5 (Week 23) from baseline at Visit 0 (Screening) of the open-label study and from baseline at Visit 1 (Week 1) of IA/PAAG-SI/OA/2019 study;

**Description:** By Visit 3, the mean WOMAC-B (subscale for assessing stiffness) score compared to Visit 1 of the IA/PAAG-SI/OA/2019 study has decreased by 62.80 ± 69.82 (95% CI -149.49 - 23.89) in patients from group A, by 67.19 ± 40.91 (95% CI -79.78 - -54.60) in patients from group B, by 48.71 ± 28.08 (95% CI -63.14 - -34 .27) in patients from group C. Intergroup differences were not statistically significant (p = 0.291).

By Visit 5, the mean WOMAC-B score compared to Visit 1 of the IA/PAAG-SI/OA/2019 study has decreased by 66.40 ± 70.26 (95% CI -153.64 - 20.84) in patients from group A, by 74.60 ± 42.67 (95% CI -87.74 - -61.47) in patients from group B, by 57.82 ± 28.11 (95% CI -72.27 - -43 .37) in patients from group C. Intergroup differences were not statistically significant (p = 0.376).

**Measure:** Change of rigidity (WOMAC-B) and functionality (WOMAC-C) subscale scores

**Time Frame:** Change in the subscale of stiffness (WOMAC-B) and functionality (WOMAC-C) at Visit 3 (Week 11), Visit 5 (Week 23) from baseline at Visit 0 (Screening) of the open-label study and from baseline at Visit 1 (Week 1) of IA/PAAG-SI/OA/2019 study;

**Description:** During the period of this study (CS2), the decrease of this indicator continued, and at Visit 3, VAS scores of groups A, B and C patients were 11.2 ± 6.53, 29.07 ± 15.29 and 21.53 ± 6.32 mm, respectively, and by Visit 5 the indicators decreased to 6.2 ± 5.59, 16.56 ± 12.32 and 4.88 ± 3.14 mm, respectively. At both visits, the between-group differences were statistically significant, which was due to the higher scores in group B. Combined score of groups A and B was compared with the score in group C, and there were also statistically significant between-group differences (p \< 0.05 from Visit 3 to Visit 5), which was consistent with the approach to dividing patients into groups: patients in group C received only one course of injections in the placebo-controlled study CS1 (IA/PAAG-SI/OA/2019) and had no indications for repeated injections, while patients in groups A and B have a requirement to receive two courses of therapy

**Measure:** Intensity of pain in the target knee joint (100-mm VAS)

**Time Frame:** Change in the severity of pain in the target knee joint according to 100 mm visual analogue scale (100 mm VAS) at Visit 2 (week 1), Visit 3 (week 11), Visit 5 (week 23) from baseline at Visit 0 (Screening) of the open-label safety study and from baseli

**Description:** At visit 3 patients evaluation scores from Group B as, significant improvement was indicated by 3 patients, improvement - by 23 patients, weak improvement - 15 patients and no changes -0 patients. from patients Group C improvement was indicated by - 4 patients, weak improvement - 8 patients and no changes - 5 patients and from Group A patients was not indicate any changes with p (between the groups \<0.001) At visit 5 patients Group B scores as, significant improvement was indicated by 6 patients, improvement - by 25 patients, weak improvement - 12 patients and no changes -0 patients. from patients Group C improvement was indicated by - 16 patients, weak improvement - 1 patient and no changes - 0 patients and from Group A patients - significant improvement was indicated by - 4 patients and improvement were indicated by 1 patient, no changes were indicated by 0 patients with p (between the groups \<0.001)

**Measure:** Patient's assessment of the treatment efficacy

**Time Frame:** Evaluation of treatment effectiveness by the patient (using a scale from 1 - a definitive deterioration to 6 - a significant improvement) at Visits 3 and 5 (OEP-w11 and OEP-w23 scores, respectively);

**Description:** At visit 3 investigators evaluation for Group B scores as significant improvement was indicated by 3 investigators - improvement - by 23, weak improvement - 14 and no changes -3 investigators. from Group C - improvement was indicated by - 4 investigators, weak improvement - 8 and no changes - 5 and from Group A- significant improvement was indicated by - 2 investigators improvement - by 2 and weak improvement by 2 investigators with p (between the groups \<0.001) At visit 5 investigators evaluation for Group B scores as significant improvement was indicated by 3 investigators, improvement - by 23, weak improvement - 14 and no changes -3 from Group C - improvement was indicated by - 4, weak improvement - 8 and no changes - 5 and from Group A significant improvement was indicated by - 2 investigators improvement were indicated by 2 and weak improvement by 2 investigators with p (between the groups \<0.001)

**Measure:** Investigator's assessment of the treatment efficacy

**Time Frame:** Evaluation of treatment effectiveness by the investigator (using a scale from 1 - a definitive deterioration to 6 - a significant improvement) at Visits 3 and 5 (OEI-w11 and OEI-w23 scores, respectively);

**Description:** The results obtained show a favorable long-term effect of intra-articular NOLTREX™ in the treatment of Kellgren-Lawrence radiological stage II-III knee osteoarthritis on the function of the knee joint. It was impossible to evaluate the need for NSAID due to the fact during the study period of CS 2, no such cases were recorded.

**Measure:** Total number of NSAID tablets taken

**Time Frame:** Assessment of the total number of NSAID tablets taken according to the patient's diary starting from Day 1, at Visits 3 and 5 (NSAID-w11 and NSAID-w23, respectively);

**Description:** The JSN score of the target knee at Visit 5 of the open-label study compared with the baseline at Visit 0 of the IA/PAAG-SI/OA/2019 study in patients from group A was -0.02 ± 0.05, in patients from group B - 0.00 ± 0.19, in patients from group C - 0.02 ± 0.08. Intergroup differences were not statistically significant (p = 0.379). The JSN index of the target knee joint reflects the disease progression, and the absence of changes or a decrease in the index indicates a protective effect of NOLTREX™.

**Measure:** The JSN score of the target knee

**Time Frame:** The JSN score of the target knee at Visit 5 of the open-label study compared with the baseline at Visit 0 of the IA/PAAG-SI/OA/2019 study retrospectively.

**Description:** The results obtained show a favorable long-term effect of intra-articular NOLTREX™ in the treatment of Kellgren-Lawrence radiological stage II-III knee osteoarthritis on the function of the knee joint. It was impossible to evaluate the need for paracetamol due to the fact during the study period of CS 2, no such cases were recorded.

**Measure:** Total number of paracetamol tablets taken

**Time Frame:** Assessment of the total number of paracetamol tablets taken according to the patient's diary (one tablet = 500 mg) starting from Day 1, at Visits 3 and 5 (PARACETAMOL-w11 and PARACETAMOL-w23 scores, respectively);

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Men and women above 50 years;
* A signed Patient Informed Consent Form by the study participant;
* Verified knee osteoarthritis in accordance with the ACR (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);
* Kellgren Lawrence radiological grade II-III knee osteoarthritis with the predominant involvement of the medial tibiofemoral region of the knee joint;
* Completion of participation in clinical study protocol IA / PAAG-SI / OA / 2019 in the NOLTREX ™ medical device group with the completion of all 5 visits (25 weeks)

Exclusion Criteria:

1. Pregnancy and breastfeeding;
2. History of trauma or surgery on the target knee joint;
3. Instability of the target knee joint;
4. Microcrystalline arthropathies (according to the history and taking into account clinical manifestations);
5. History of systemic inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.);
6. Seronegative spondyloarthritis and reactive arthritis;
7. Increased rheumatoid factor;
8. Increased uric acid \> 360 µmol/l;
9. Intra-articular injection into the target knee joint:

   * hyaluronates - within 12 months prior to patient enrollment in the study;
   * other synovial fluid endoprostheses (except for NOLTREX™ in the IA/PAAG- SI/OA/2019 study) within 24 months;
   * glucocorticoids - within 1 month before enrollment in the study;
   * NSAIDs - intra-articular injection at any time in the history.
10. Systemic pain medications (NSAIDs, opioid analgesics) within 1 week prior to Visit 0;
11. Effusion in the target joint;
12. The presence of inflammation or infection in the target joint, synovitis;
13. The need for continuous use of glucocorticoids in any dosage form;
14. Use of paracetamol within 48 hours prior to Visit 0;
15. A positive blood test result for one or more of the following infections: HIV, hepatitis B and C, syphilis;
16. Severe liver disease, defined as an increase in one of the following: ALT, AST, alkaline phosphatase, total bilirubin, GGT more than 3 times the upper limit of normal;
17. Kidney disease with a glomerular filtration rate as assessed by the Cockcraft-Gault formula less than 60 mL/min/1.73 m2 (stages III-V chronic kidney disease \[CKD\]);
18. Clinical manifest coxarthrosis;
19. Severe decompensated chronic or acute diseases and other conditions or other causes that, in the investigator's opinion, may prevent the patient from participating in the study or affect the study results ;
20. Participation in any other clinical study other than study IA/PAAG-SI/OA/2019 within 90 days prior to enrollment in the study.

**Minimum Age:** 50 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Moscow

**Country:** Russian Federation

**Facility:** Non-budgetary healthcare facility "Railway clinical hospital n.a. Semashko N.A. at Lublino, OJSC "Russian Railways"

**Location 2:**

**City:** Omsk

**Country:** Russian Federation

**Facility:** "Clinical Diagnostic Center "Ultramed", LLC

**Location 3:**

**City:** Saint Petersburg

**Country:** Russian Federation

**Facility:** Private Healthcare Facilty "Clinical hospital "RZHD-Medicina" of the city Saint-Petersburg

**Location 4:**

**City:** Yaroslavl

**Country:** Russian Federation

**Facility:** State budgetary healthcare facility of Yaroslavl Region "Clinical hospital №3"

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000001168

- Term: Arthritis

- ID: D000007592

- Term: Joint Diseases

- ID: D000009140

- Term: Musculoskeletal Diseases

- ID: D000012216

- Term: Rheumatic Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC05

- Name: Musculoskeletal Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

### Condition Browse Module - Browse Leaves

- ID: M12926

- Name: Osteoarthritis

- Relevance: HIGH

- As Found: Osteoarthritis

- ID: M22168

- Name: Osteoarthritis, Knee

- Relevance: HIGH

- As Found: Gonarthrosis

- ID: M4476

- Name: Arthritis

- Relevance: LOW

- As Found: Unknown

- ID: M10621

- Name: Joint Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12097

- Name: Musculoskeletal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M15045

- Name: Rheumatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6323

- Name: Collagen Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000010003

- Term: Osteoarthritis

- ID: D000020370

- Term: Osteoarthritis, Knee

### Misc Info Module

- Version Holder: 2024-05-31
