Osteoarthritis
Conditions
Keywords
intra-articular, polyacrylamide hydrogel, PAAG, Hydrous biopolymer with silver ions Argiform (HBISA), NOLTREX
Brief summary
The aim of this double-blinded controlled study is to assess clinical efficacy and safety of intra-articular HBISA Endoprosthesis of Synovial Fluid (polyacrylamide hydrogel) in comparison with placebo (0.9% sodium chloride solution) in Kellgren Lawrence radiological grade II-III knee osteoarthritis
Detailed description
Polyacrylamide hydrogel (hereinafter - PAAG) is intended for a symptomatic effect leading to decrease of joint pain intensity and improvement of functional joint characteristics. Therefore PAAG is regarded as symptom-modifying therapy for joint osteoarthritis (hereinafter - OA). The aim of this study was to estimate efficacy and safety of intra-articular injections of PAAG in comparison with saline solution. Men and women above 50 years with verified knee osteoarthritis in accordance with the American College of Rheumatology (ACR) criteria were randomly assigned to one of 2 groups (PAAG or saline solution). Each patient received to the target knee joint one injection of 4.0 ml either PAAG or placebo with one-week interval. Course - 2 injections. To avoid the joint overfilling with the dense, slowly resorbing material in patients with a good clinical result, the course of injections was to be stopped. Primary and secondary efficacy endpoints, and safety parameters were assessed at weeks 6, 13 and 25 visits .
Interventions
DEVICEsaline solution
2 once-weekly intra-articular injections of saline solution 4 ml
DEVICEhydrous biopolymer with silver ions Argiform
2 once-weekly intra-articular injections of NOLTREX™ 4.0 ml
Sponsors
Research Centre BIOFORM
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
A patient, study investigator and Sponsor representative (monitoring specialist) will not know to which group a patient is included. to preserve blinding of any patient and study team, an independent unblended 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.
Intervention model description
multicenter double-blind randomized comparative placebo-controlled
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women above 50 years; * 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; * Joint space width (JSW) of the target knee joint at least 2.5 mm.
Exclusion criteria
1. History of any injury or surgical intervention on the target knee joint (except for diagnostic arthroscopy made not longer than 60 days at the study entry); 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 spondyloarthritis and reactive arthritis; 9. Inflammatory diseases of the skin and soft tissues in the proposed injection site for the test MD or placebo in the target joint; 10. History of venous thrombosis and thromboembolia; 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 μmol/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: * Noltrex - within 24 months prior patient's inclusion to the study; * hyaluronates - within 6 months prior patient's inclusion to the study; * glucocorticosteroids - within 1 month prior the study inclusion; * non-steroidal anti-inflammatory drugs (NSAID) - within 3 weeks prior patient's inclusion to the study. 20. Oral administration of non-steroidal anti-inflammatory drugs (NSAID) within 2 weeks prior the study inclusion; 21. Necessity of systemic glucocorticosteroids in any dosage form; 22. Paracetamol administration within 48 hours prior the study inclusion; 23. Pregnancy and lactation; 24. Hypersensitivity to components of the test 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 manifest 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 patient's participation in the study or affect the study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of the Total WOMAC Score (WOMAC-T) | baseline (week 1), week 25 | Mean change from baseline (week 1) to visit 5 (Week 25) in the total WOMAC score. Patients were asked to complete the questionnaire during the study visit 5. The Western Ontario and McMaster Universities Osteoarthritis Index Version 3.1 Visual Analog Scale Format (WOMAC VA 3.1) applies a 100 mm VAS and consists of three subscales: pain (5 questions), stiffness (2 questions), and physical function (17 questions). The scores for each subscale are summed up, with a possible score range of 0-500 for Pain, 0-200 for Stiffness, and 0-1700 for Physical Function. Higher scores represent worse pain, stiffness, and functional limitations. A sum of the scores for all three subscales gives a total WOMAC score (0-2400), where 0 represents the best health status and 2400 the worst possible status. The higher the score, the poorer the function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Pain Subscale Score WOMAC-A Changes | baseline (week 1), week 6 (visit 3), 13 (visit 4) and 25 (visit 5) | Mean change from baseline (week 1) to week 6 (visit 3), 13 (visit 4) and 25 (visit 5) in the WOMAC Pain score (WOMAC-A). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a set of standardized questionnaires used by health professionals to evaluate pain, stiffness and physical functioning of the joints in patients with knee and/or hip osteoarthritis. The WOMAC Index Version 3.1 Visual Analog Scale Format (WOMAC VA 3.1) applies a 100 mm VAS. The WOMAC pain scale consists of five items: (1) walking on flat ground; (2) going up or down stairs; (3) at night while in bed; (4) sitting or lying; and (5) standing upright. The scores for the Pain subscale are summed up, with a possible score range of 0-500. Higher scores represent worse pain. Patients were asked to complete the questionnaire during the study visits 1, 3, 4, 5. |
| The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | baseline (week 1), week 6 (visit 3), 13 (visit 4) and 25 (visit 5) | Mean change from baseline (week 1) to week 6 (visit 3), 13 (visit 4) and 25 (visit 5) in the WOMAC Stiffness (WOMAC-B) and WOMAC Physical Function (WOMAC-C) scores. Patients were asked to complete the questionnaire during the study visit 5. The Western Ontario and McMaster Universities Osteoarthritis Index Version 3.1 Visual Analog Scale Format (WOMAC VA 3.1) applies a 100 mm VAS and consists of three subscales: pain (5 questions), stiffness (2 questions), and physical function (17 questions). The scores for each subscale are summed up, with a possible score range of 0-200 for Stiffness, and 0-1700 for Physical Function. Higher scores represent worse stiffness and functional limitations. The higher the score, the poorer the function. |
| Patient Assessment of Treatment Efficacy | Week 6, Week 13 and Week 25 | Patient satisfaction with treatment was measured by a 6-point scale Likert scale (evident aggravation, aggravation, without changes, weak improvement, improvement, significant improvement) at the study visits 3 (week 6), 4 (week 13) and 5 (week 25). |
| Investigator Assessment of Treatment Efficacy | Week 6, Week 13 and Week 25 | Investigator satisfaction with treatment was measured by a 6-point scale Likert scale (evident aggravation, aggravation, without changes, weak improvement, improvement, significant improvement) at the study visits 3 (week 6), 4 (week 13) and 5 (week 25). |
| Change of the Total WOMAC Score (WOMAC-T) | baseline (week 1), week 13 (visit 4) | Mean change from baseline (week 1) to Week 13 in the total WOMAC score. Patients were asked to complete the questionnaire during the study visits 1, 3, 4, 5. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The WOMAC consists of three subscales: pain (5 questions), stiffness (2 questions), and physical function (17 questions). The test questions are scored on a scale of 0-4, which correspond to: None (0), Mild (1), Moderate (2), Severe (3), and Extreme (4). The scores for each subscale are summed up, with a possible score range of 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. Higher scores represent worse pain, stiffness, and functional limitations. A sum of the scores for all three subscales gives a total WOMAC score (0-96), where 0 represents the best health status and 96 the worst possible status. The higher the score, the poorer the function. |
| Assessment of the Total Number of Paracetamol Tablets Taken | week 6 (visit 3), week 13 (visit 4), week 25 (visit 5) | A patient diary was used to capture data about the number of paracetamol tablets taken. |
| Patient Exclusion Rates Due to Safety | Week 25 | According to protocol the reasons for withdrawal included health status deterioration, investigator's decision, need in paracetamol use ≥4 days a week during 2 consecutive weeks, individual intolerance or contraindications to the study MD, placebo, paracetamol or any of the protocol-permitted NSAIDs; development of a AE/SAE requiring examination and/or treatment that can significantly affect the study procedures |
| Exclusion Rate Due to Poor Patient Compliance | Week 25 | According to the protocol the reasons for patients drop-out included major protocol deviations (poor compliance) and withdrawal of informed consent. |
| Assessment of the Total Number of NSAID Tablets Taken | week 6 (visit 3), week 13 (visit 4), week 25 (visit 5) | A patient diary was used to capture data about the number of NSAID Tablets Taken. In case of paracetamol ineffectiveness and pain persistence patient was allowed to take Protocol-permitted NSAID in certain doses. |
Countries
Russia
Participant flow
Recruitment details
151 patients were selected for the study, of which 144 were randomised at 4 study sites from November 2019 to November 2020.
Pre-assignment details
7 patients were classified as screen failure and 144 patients were randomized (1:1) to receive NOLTREX™ (n = 72) or placebo (n = 72).
Participants by arm
| Arm | Count |
|---|---|
| NOLTREX™, OA Grade II-III Patients with osteoarthritis Grade II-III received 2 weekly injections of the PAHG hydrous biopolymer with silver ions Argiform 4.0 ml (NOLTREX™) at the week 1 and 2 study visits. | 72 |
| Placebo, OA Grade II-III Patients with osteoarthritis Grade II-III received 2 weekly injections of the saline solution (placebo) at the week 1 and 2 study visits. | 72 |
| Total | 144 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | NOLTREX™, OA Grade II-III | Placebo, OA Grade II-III | Total |
|---|---|---|---|
| Age, Continuous Age | 63.40 years STANDARD_DEVIATION 7.26 | 62.15 years STANDARD_DEVIATION 7.54 | 62.775 years STANDARD_DEVIATION 7.4 |
| BMI | 28.75 kg/m^2 STANDARD_DEVIATION 2.97 | 29.44 kg/m^2 STANDARD_DEVIATION 4.35 | 29.095 kg/m^2 STANDARD_DEVIATION 5.1 |
| Race/Ethnicity, Customized Race Caucasoid | 72 Participants | 72 Participants | 144 Participants |
| Race/Ethnicity, Customized Race Mongoloid | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Negroid | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Russia Clinical center 1 | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment Russia Clinical center 2 | 19 Participants | 19 Participants | 38 Participants |
| Region of Enrollment Russia Clinical center 3 | 10 Participants | 10 Participants | 20 Participants |
| Region of Enrollment Russia Clinical center 4 | 40 Participants | 40 Participants | 80 Participants |
| Sex: Female, Male Female | 59 Participants | 58 Participants | 117 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 72 | 0 / 72 |
| other Total, other adverse events | 5 / 72 | 11 / 72 |
| serious Total, serious adverse events | 0 / 72 | 1 / 72 |
Outcome results
Primary
Change of the Total WOMAC Score (WOMAC-T)
Mean change from baseline (week 1) to visit 5 (Week 25) in the total WOMAC score. Patients were asked to complete the questionnaire during the study visit 5. The Western Ontario and McMaster Universities Osteoarthritis Index Version 3.1 Visual Analog Scale Format (WOMAC VA 3.1) applies a 100 mm VAS and consists of three subscales: pain (5 questions), stiffness (2 questions), and physical function (17 questions). The scores for each subscale are summed up, with a possible score range of 0-500 for Pain, 0-200 for Stiffness, and 0-1700 for Physical Function. Higher scores represent worse pain, stiffness, and functional limitations. A sum of the scores for all three subscales gives a total WOMAC score (0-2400), where 0 represents the best health status and 2400 the worst possible status. The higher the score, the poorer the function.
Time frame: baseline (week 1), week 25
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NOLTREX™, OA Grade II-III | Change of the Total WOMAC Score (WOMAC-T) | ОА grade II | -624.12 score on a scale |
| NOLTREX™, OA Grade II-III | Change of the Total WOMAC Score (WOMAC-T) | ОА grade II-III | -605.61 score on a scale |
| NOLTREX™, OA Grade II-III | Change of the Total WOMAC Score (WOMAC-T) | ОА grade III | -587.11 score on a scale |
| Placebo, ОА Grade II-III | Change of the Total WOMAC Score (WOMAC-T) | ОА grade II | -444.82 score on a scale |
| Placebo, ОА Grade II-III | Change of the Total WOMAC Score (WOMAC-T) | ОА grade II-III | -426.31 score on a scale |
| Placebo, ОА Grade II-III | Change of the Total WOMAC Score (WOMAC-T) | ОА grade III | -407.81 score on a scale |
Comparison: It was determined that 144 participants randomized into 2 groups (1:1) would have at least 80% power to detect an effect size of 0.25. Sample size was calculated based on analysis of covariance adjusted for baseline value with fixed factors of group assuming α = 0.05 and 10% discontinuation rate.~The null hypothesis states that there is no difference between treatment groups in mean change from baseline to Week 25 in the total WOMAC score.p-value: 0.000395% CI: [-274.96, -83.65]ANCOVA
Comparison: After the analysis of covariance were performed pairwise comparisons of NOLTREX and placebo groups for each stage of OA:~1\) Group A (NOLTREX™) OA grade II versus Group B (Placebo) ОА grade IIp-value: 0.001795% CI: [-305.11, -53.5]Tukey's HSD
Comparison: After the analysis of covariance were performed pairwise comparisons of NOLTREX and placebo groups for each stage of OA:~2\) Group A (NOLTREX™) OA grade II versus Group A (NOLTREX™) ОА grade IIIp-value: 0.932495% CI: [-197.83, 123.82]Tukey's HSD
Comparison: After the analysis of covariance were performed pairwise comparisons of NOLTREX and placebo groups for each stage of OA:~3\) Group A (NOLTREX™) OA grade II versus Group B (Placebo) ОА grade IIIp-value: 0.023395% CI: [-411.37, -21.25]Tukey's HSD
Comparison: After the analysis of covariance were performed pairwise comparisons of NOLTREX and placebo groups for each stage of OA:~4\) Group A (NOLTREX™) OA grade III versus Group B (Placebo) ОА grade IIp-value: 0.308295% CI: [-70.63, 355.22]Tukey's HSD
Comparison: After the analysis of covariance were performed pairwise comparisons of NOLTREX and placebo groups for each stage of OA:~5\) versus Group B (Placebo) OA grade II versus Group B (Placebo) ОА grade IIIp-value: 0.932495% CI: [-197.83, 123.82]Tukey's HSD
Comparison: After the analysis of covariance were performed pairwise comparisons of NOLTREX and placebo groups for each stage of OA:~6\) Group A (NOLTREX™) OA grade III versus Group B (Placebo) ОА grade IIIp-value: 0.001795% CI: [-305.11, -53.5]Tukey's HSD
Secondary
Assessment of the Total Number of NSAID Tablets Taken
A patient diary was used to capture data about the number of NSAID Tablets Taken. In case of paracetamol ineffectiveness and pain persistence patient was allowed to take Protocol-permitted NSAID in certain doses.
Time frame: week 6 (visit 3), week 13 (visit 4), week 25 (visit 5)
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NOLTREX™, OA Grade II-III | Assessment of the Total Number of NSAID Tablets Taken | 0 Number of NSAID tablets |
| Placebo, ОА Grade II-III | Assessment of the Total Number of NSAID Tablets Taken | 0 Number of NSAID tablets |
Secondary
Assessment of the Total Number of Paracetamol Tablets Taken
A patient diary was used to capture data about the number of paracetamol tablets taken.
Time frame: week 6 (visit 3), week 13 (visit 4), week 25 (visit 5)
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention). The mean number of tablets was calculated taking into account only patients who had received paracetamol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NOLTREX™, OA Grade II-III | Assessment of the Total Number of Paracetamol Tablets Taken | Week 6 | 3.08 mean number of paracetamol taken | Standard Deviation 3.75 |
| NOLTREX™, OA Grade II-III | Assessment of the Total Number of Paracetamol Tablets Taken | Week 13 | 1.75 mean number of paracetamol taken | Standard Deviation 1.39 |
| NOLTREX™, OA Grade II-III | Assessment of the Total Number of Paracetamol Tablets Taken | Week 25 | 1.00 mean number of paracetamol taken | Standard Deviation 0 |
| Placebo, ОА Grade II-III | Assessment of the Total Number of Paracetamol Tablets Taken | Week 6 | 6.00 mean number of paracetamol taken | Standard Deviation 5.63 |
| Placebo, ОА Grade II-III | Assessment of the Total Number of Paracetamol Tablets Taken | Week 13 | 8.47 mean number of paracetamol taken | Standard Deviation 6.67 |
| Placebo, ОА Grade II-III | Assessment of the Total Number of Paracetamol Tablets Taken | Week 25 | 11.79 mean number of paracetamol taken | Standard Deviation 9.6 |
Comparison: The mean number of paracetamol tablets was calculated taking into account only patients who had received paracetamol. ANCOVA was used to detect a difference in means of 2 groups at visit 3 (week 6).p-value: 0.05ANCOVA
Comparison: The mean number of paracetamol tablets was calculated taking into account only patients who had received paracetamol. ANCOVA was used to detect a difference in means of 2 groups at visit 4 (week 13).p-value: 0.004ANCOVA
Secondary
Change of the Total WOMAC Score (WOMAC-T)
Mean change from baseline (week 1) to Week 13 in the total WOMAC score. Patients were asked to complete the questionnaire during the study visits 1, 3, 4, 5. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The WOMAC consists of three subscales: pain (5 questions), stiffness (2 questions), and physical function (17 questions). The test questions are scored on a scale of 0-4, which correspond to: None (0), Mild (1), Moderate (2), Severe (3), and Extreme (4). The scores for each subscale are summed up, with a possible score range of 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. Higher scores represent worse pain, stiffness, and functional limitations. A sum of the scores for all three subscales gives a total WOMAC score (0-96), where 0 represents the best health status and 96 the worst possible status. The higher the score, the poorer the function.
Time frame: baseline (week 1), week 13 (visit 4)
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NOLTREX™, OA Grade II-III | Change of the Total WOMAC Score (WOMAC-T) | -532.57 score on a scale |
| Placebo, ОА Grade II-III | Change of the Total WOMAC Score (WOMAC-T) | -389.18 score on a scale |
Comparison: It was determined that 144 participants randomized into 2 groups (1:1) would have at least 80% power to detect an effect size of 0.25. Sample size was calculated based on analysis of covariance adjusted for baseline value with fixed factors of group assuming α = 0.05 and 10% discontinuation rate.p-value: 0.0026795% CI: [-236.09, -50.69]ANCOVA
Secondary
Exclusion Rate Due to Poor Patient Compliance
According to the protocol the reasons for patients drop-out included major protocol deviations (poor compliance) and withdrawal of informed consent.
Time frame: Week 25
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NOLTREX™, OA Grade II-III | Exclusion Rate Due to Poor Patient Compliance | 1 participants |
| Placebo, ОА Grade II-III | Exclusion Rate Due to Poor Patient Compliance | 1 participants |
Secondary
Investigator Assessment of Treatment Efficacy
Investigator satisfaction with treatment was measured by a 6-point scale Likert scale (evident aggravation, aggravation, without changes, weak improvement, improvement, significant improvement) at the study visits 3 (week 6), 4 (week 13) and 5 (week 25).
Time frame: Week 6, Week 13 and Week 25
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, evident aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6,aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, without changes | 17 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, weak improvement | 18 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, improvement | 28 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, significant improvement | 8 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13,evident aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13,aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13, without changes | 7 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13, weak improvement | 18 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13, improvement | 35 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13, significant improvement | 11 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, evident aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, aggravation | 1 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, without changes | 7 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, weak improvement | 13 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, improvement | 31 participants |
| NOLTREX™, OA Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, significant improvement | 18 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, aggravation | 1 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, evident aggravation | 0 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13, weak improvement | 23 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6,aggravation | 1 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, significant improvement | 7 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, without changes | 28 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13, improvement | 20 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, weak improvement | 26 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, without changes | 20 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, improvement | 14 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13, significant improvement | 5 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 6, significant improvement | 3 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, improvement | 22 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13,evident aggravation | 0 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, evident aggravation | 1 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13,aggravation | 1 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 25, weak improvement | 19 participants |
| Placebo, ОА Grade II-III | Investigator Assessment of Treatment Efficacy | Week 13, without changes | 23 participants |
Comparison: The Chi-Square test was used to determine whether there was a statistically significant difference in disposition of results between two groups.p-value: <0.005Chi-squared
Secondary
Patient Assessment of Treatment Efficacy
Patient satisfaction with treatment was measured by a 6-point scale Likert scale (evident aggravation, aggravation, without changes, weak improvement, improvement, significant improvement) at the study visits 3 (week 6), 4 (week 13) and 5 (week 25).
Time frame: Week 6, Week 13 and Week 25
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, significant improvement | 9 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 13, weak improvement | 18 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 13, improvement | 33 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, weak improvement | 18 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 13, significant improvement | 15 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 13,evident aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 25,evident aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, without changes | 17 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 13,aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, without changes | 6 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, improvement | 27 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, weak improvement | 14 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 13, without changes | 5 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, improvement | 30 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 6,aggravation | 0 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, significant improvement | 20 participants |
| NOLTREX™, OA Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, evident aggravation | 0 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, significant improvement | 9 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, evident aggravation | 0 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 6,aggravation | 4 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, without changes | 21 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, weak improvement | 30 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, improvement | 13 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 6, significant improvement | 4 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 13,evident aggravation | 0 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 13,aggravation | 4 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 13, without changes | 17 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 13, weak improvement | 25 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 13, improvement | 19 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 13, significant improvement | 7 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 25,evident aggravation | 0 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, aggravation | 2 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, without changes | 19 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, weak improvement | 20 participants |
| Placebo, ОА Grade II-III | Patient Assessment of Treatment Efficacy | Week 25, improvement | 20 participants |
Comparison: The Chi-Square test was used to determine whether there was a statistically significant difference in disposition of results between two groups.p-value: <0.005Chi-squared
Secondary
Patient Exclusion Rates Due to Safety
According to protocol the reasons for withdrawal included health status deterioration, investigator's decision, need in paracetamol use ≥4 days a week during 2 consecutive weeks, individual intolerance or contraindications to the study MD, placebo, paracetamol or any of the protocol-permitted NSAIDs; development of a AE/SAE requiring examination and/or treatment that can significantly affect the study procedures
Time frame: Week 25
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NOLTREX™, OA Grade II-III | Patient Exclusion Rates Due to Safety | 0 participants |
| Placebo, ОА Grade II-III | Patient Exclusion Rates Due to Safety | 0 participants |
Secondary
The Pain Subscale Score WOMAC-A Changes
Mean change from baseline (week 1) to week 6 (visit 3), 13 (visit 4) and 25 (visit 5) in the WOMAC Pain score (WOMAC-A). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a set of standardized questionnaires used by health professionals to evaluate pain, stiffness and physical functioning of the joints in patients with knee and/or hip osteoarthritis. The WOMAC Index Version 3.1 Visual Analog Scale Format (WOMAC VA 3.1) applies a 100 mm VAS. The WOMAC pain scale consists of five items: (1) walking on flat ground; (2) going up or down stairs; (3) at night while in bed; (4) sitting or lying; and (5) standing upright. The scores for the Pain subscale are summed up, with a possible score range of 0-500. Higher scores represent worse pain. Patients were asked to complete the questionnaire during the study visits 1, 3, 4, 5.
Time frame: baseline (week 1), week 6 (visit 3), 13 (visit 4) and 25 (visit 5)
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NOLTREX™, OA Grade II-III | The Pain Subscale Score WOMAC-A Changes | Week 6 | -68.55 score on a scale |
| NOLTREX™, OA Grade II-III | The Pain Subscale Score WOMAC-A Changes | Week 13 | -110.94 score on a scale |
| NOLTREX™, OA Grade II-III | The Pain Subscale Score WOMAC-A Changes | Week 25 | -130.95 score on a scale |
| Placebo, ОА Grade II-III | The Pain Subscale Score WOMAC-A Changes | Week 6 | -55.32 score on a scale |
| Placebo, ОА Grade II-III | The Pain Subscale Score WOMAC-A Changes | Week 13 | -84.24 score on a scale |
| Placebo, ОА Grade II-III | The Pain Subscale Score WOMAC-A Changes | Week 25 | -96.99 score on a scale |
Comparison: Contrasts for changes in pain WOMAC score at visit 3 (week 6)p-value: 0.1678695% CI: [-32.096, 5.638]ANCOVA
Comparison: Contrasts for changes in pain WOMAC score at visit 4 (week 13)p-value: 0.0084795% CI: [-46.46, -6.93]ANCOVA
Comparison: Contrasts for changes in pain WOMAC score at visit 5 (week 25)p-value: 0.0012395% CI: [-54.31, -13.62]ANCOVA
Secondary
The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes
Mean change from baseline (week 1) to week 6 (visit 3), 13 (visit 4) and 25 (visit 5) in the WOMAC Stiffness (WOMAC-B) and WOMAC Physical Function (WOMAC-C) scores. Patients were asked to complete the questionnaire during the study visit 5. The Western Ontario and McMaster Universities Osteoarthritis Index Version 3.1 Visual Analog Scale Format (WOMAC VA 3.1) applies a 100 mm VAS and consists of three subscales: pain (5 questions), stiffness (2 questions), and physical function (17 questions). The scores for each subscale are summed up, with a possible score range of 0-200 for Stiffness, and 0-1700 for Physical Function. Higher scores represent worse stiffness and functional limitations. The higher the score, the poorer the function.
Time frame: baseline (week 1), week 6 (visit 3), 13 (visit 4) and 25 (visit 5)
Population: The intent-to-treat (ITT) population (all randomized patients who received at least one dose of study intervention).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NOLTREX™, OA Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-B /Week 6 | -27.25 score on a scale |
| NOLTREX™, OA Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-B /Week 13 | -48.46 score on a scale |
| NOLTREX™, OA Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-B /Week 25 | -54.79 score on a scale |
| NOLTREX™, OA Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-C /Week 6 | -240.41 score on a scale |
| NOLTREX™, OA Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-C /Week 13 | -374.17 score on a scale |
| NOLTREX™, OA Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-C /Week 25 | -436.92 score on a scale |
| Placebo, ОА Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-C /Week 13 | -270.90 score on a scale |
| Placebo, ОА Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-B /Week 6 | -27.10 score on a scale |
| Placebo, ОА Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-C /Week 6 | -183.26 score on a scale |
| Placebo, ОА Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-B /Week 13 | -33.96 score on a scale |
| Placebo, ОА Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-C /Week 25 | -303.63 score on a scale |
| Placebo, ОА Grade II-III | The Stiffness (WOMAC-B) and Functionality (WOMAC-C) Subscale Scores Changes | WOMAC-B /Week 25 | -38.61 score on a scale |
Comparison: Contrasts for changes in stiffness WOMAC score, visit 3p-value: 0.9773395% CI: [-10.271, 9.98]ANCOVA
Comparison: Contrasts for changes in stiffness WOMAC score, visit 4p-value: 0.0069395% CI: [-24.95, -4.04]ANCOVA
Comparison: Contrasts for changes in pain WOMAC score at visit 5 (week 25)p-value: 0.0007395% CI: [-25.44, -6.92]ANCOVA
Comparison: Contrasts for changes in functionality WOMAC score, visit 3p-value: 0.0772595% CI: [-120.62, 6.33]ANCOVA
Comparison: Contrasts for changes in functionality WOMAC score, visit 4p-value: 0.0027995% CI: [-170.35, -36.2]ANCOVA
Comparison: Contrasts for changes in functionality WOMAC score, visit 5p-value: 0.0002395% CI: [-203.03, -63.55]ANCOVA