Osteoarthritis
Conditions
Keywords
intra-articular, polyacrylamide hydrogel, PAAG, HBISA (Hydrous biopolymer with silver ions Argiform), NOLTREX
Brief summary
The OLE was aimed to assess long-term safety and efficacy of one and two courses of IA HBISA in patients with knee osteoarthritis.
Detailed description
HBISA (polyacrylamide hydrogel) endoprosthesis of synovial fluid NOLTREX™ is intended for the symptomatic treatment of adult patients with osteoarthritis (OA) reducing pain and improving mobility. The aim of the 6-month OLE was to evaluate the long-term safety and efficacy of one and two courses of IA Polyacrylamide hydrogel with silver ions in patients with knee osteoarthritis who had received at least one IA injection of NOLTREX™ and completed the visit 5 in the IA/PAAG-SI/OA/2019 study. In OLE patients who had received a course of treatment (one or two weekly intra-articular injections of 4.0 NOLTREX™ depending on the stage of OA and the clinical response to treatment) in the parent study might receive a single repeat course of NOLTREX™ at the visits 1/2 or 3/4 when clinically indicated. The WOMAC was the primary outcome measure.
Interventions
DEVICEHydrous biopolymer with silver ions Argiform (HBISA) endoprosthesis of synovial fluid NOLTREX™
If clinically indicated patients received a repeat course of NOLTREX™ (one or two weekly intra-articular injections of 4.0 NOLTREX™ at the investigator's discretion depending on the stage of OA and clinical response to treatment).
Sponsors
Research Centre BIOFORM
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This was an open-label extension (OLE) of the IA/PAAG-SI/OA/2019 study designed to evaluate the long-term safety and efficacy of MD NOLTREX™ in patients with knee osteoarthritis (OA). The study was expected to enroll 72 patients who had completed the parent study. Actually 67 patients rolled over into the OLE, 2 of them were classified as screen failures and 65 were enrolled into the trial.
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women over 50 years of age; * Provision of signed informed consent form; * Patients met ACR classification criteria for knee osteoarthritis (pain in the knee and at least three of the following: age \>50 years, stiffness \<30 min, crepitus, bony tenderness, bony enlargement and no palpable warmth); * OA grades 2 and 3 on the Kellgren-Lawrence scale with the predominant involvement of the medial tibiofemoral region of the knee joint; * Patients from the NOLTREX™ group of the parent study (IA/PAAG-SI/OA/2019) who completed all (5) study visits
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 trial except that IA/PAAG-SI/OA/2019 within 90 days prior to enrollment in the OLE.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Total WOMAC Score (WOMAC-T) | baseline (OLE visit 0 and visit 1 study 1 [week 1]), OLE visits 3 (week 11) and 5 (week 23) | Mean change in WOMAC-T from baseline (visit 0 \[screening\] of OLE and visit 1 (week 1) of the parent study) to visit 3 (week 11) and visit 5 (week 23). Patients were asked to complete the questionnaire during the study visits. 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 and 2400 the worst possible health status. The higher the score, the poorer the function. Therefore, an improvement was achieved by reducing the overall score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the WOMAC Stiffness (WOMAC-B) Score | baseline (OLE visit 0 and parent study visit 1 [week 1]), visits 3 (week 11) and 5 (week 23) | Mean change in WOMAC-B from baseline (visit 0 \[screening\] of the OLE and visit 1 \[week 1\] of the parent study) to visits 3 (week 11) and 5 (week 23). Patients were asked to complete the questionnaire during the study visits. 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. Therefore, an improvement was achieved by reducing the overall score. |
| Change in the WOMAC Physical Function (WOMAC-C) Score | baseline (OLE visit 0 and parent study visit 1 [week 1]), visits 3 (week 11) and 5 (week 23) | Mean change in WOMAC-C from baseline (visit 0 \[screening\] of the OLE and visit 1 \[week 1\] of the parent study) to visits 3 (week 11) and 5 (week 23). Patients were asked to complete the questionnaire during the study visits. 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. Therefore, an improvement was achieved by reducing the overall score. |
| Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | baseline (OLE visit 0 and study 1 visit 1 [week 1]), OLE visits 3 (week 11) and 5 (week 23) | Mean change in the VAS pain score from baseline (visit 0 \[screening\] of the OLE and visit 1 \[week 1\] of the parent study to visit 2 (week 1), visit 3 (week 11) and visit 5 (week 23). The 0 to 100 mm visual analogue scale (VAS) was used for measuring pain intensity. VAS ratings between 0 and 4 mm were interpreted as no pain, 5 to 44 mm, mild pain; 45 to 74 mm, moderate pain; and 75 to 100 mm, severe pain. The pain VAS was self-completed by the patients. |
| Patient's Assessment of the Treatment Efficacy | visits 3 (week 13) and 5 (week 25) | Patient satisfaction with treatment was measured by a 6-point Likert scale (evident aggravation, aggravation, without changes, weak improvement, improvement, significant improvement) at the study visits 3 (week 11) and 5 (week 23). |
| Change in the WOMAC Pain Score (WOMAC-A) | baseline (OLE visit 0 and visit 1 study 1 [week 1]), OLE visits 3 (week 11) and 5 (week 23) | Mean change in WOMAC-A from baseline (visit 1 (week 1) of the parent study AND visit 0 \[screening\] of OLE) to visit 3 (week 11) and visit 5 (week 23). Patients were asked to complete the questionnaire during the study visits. 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. |
| Total Number of Paracetamol Tablets Taken | visits 3 (week 13) and 5 (week 25) | A patient diary was used to capture data about the number of paracetamol 500 mg tablets taken. |
| Total Number of NSAID Tablets Taken | visits 3 (week 11) and 5 (week 23) | 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 at certain doses. |
| The JSN in the Target Knee | baseline (visit 1 of the parent study IA/PAAG-SI/OA/2019), visit 5 (week 23) of OLE | Joint space narrowing (JSN) was scored by comparison of subsequent radiographs taken over time. An increase in the radiographic knee JSN is associated with osteoarthritis progression. |
| Investigator's Assessment of the Treatment Efficacy | visits 3 (week 13) and 5 (week 25) | Investigator satisfaction with treatment was measured by a 6-point Likert scale (evident aggravation, aggravation, without changes, weak improvement, improvement, significant improvement) at the study visits 3 (week 11) and 5 (week 23). |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A Group A consisted of 5 patients who received 2 NOLTREX™ courses, the first course in the IA/PAAG-SI/OA/2019 study and the second one at Visits 1/2 of OLE (IA/PAAG-SI/OA/2020) study. | 5 |
| Group B Group B comprised 43 patients who received 2 NOLTREX™ courses, the first course in the IA/PAAG-SI/OA/2019 study and the second one at Visits 3/4 of OLE. | 43 |
| Group C Group C consisted of 17 patients who had received only 1 NOLTREX™ course in the parent study. | 17 |
| Total | 65 |
Baseline characteristics
| Characteristic | Total | Group A | Group B | Group C |
|---|---|---|---|---|
| Age, Continuous Age | 63.72 years STANDARD_DEVIATION 7.06 | 71.60 years STANDARD_DEVIATION 11.15 | 63.53 years STANDARD_DEVIATION 5.93 | 61.88 years STANDARD_DEVIATION 7.27 |
| Body Mass Index (BMI) | 28.68 kg/m^2 STANDARD_DEVIATION 2.98 | 31.28 kg/m^2 STANDARD_DEVIATION 2.32 | 28.97 kg/m^2 STANDARD_DEVIATION 3.15 | 27.18 kg/m^2 STANDARD_DEVIATION 1.82 |
| Obesity | 19 Participants | 4 Participants | 14 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 65 Participants | 5 Participants | 43 Participants | 17 Participants |
| Sex: Female, Male Female | 53 Participants | 5 Participants | 37 Participants | 11 Participants |
| Sex: Female, Male Male | 12 Participants | 0 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 43 | 0 / 17 |
| other Total, other adverse events | 1 / 5 | 0 / 43 | 0 / 17 |
| serious Total, serious adverse events | 0 / 5 | 0 / 43 | 0 / 17 |
Outcome results
Primary
Change in the Total WOMAC Score (WOMAC-T)
Mean change in WOMAC-T from baseline (visit 0 \[screening\] of OLE and visit 1 (week 1) of the parent study) to visit 3 (week 11) and visit 5 (week 23). Patients were asked to complete the questionnaire during the study visits. 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 and 2400 the worst possible health status. The higher the score, the poorer the function. Therefore, an improvement was achieved by reducing the overall score.
Time frame: baseline (OLE visit 0 and visit 1 study 1 [week 1]), OLE visits 3 (week 11) and 5 (week 23)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | Change in the Total WOMAC Score (WOMAC-T) | OLE visits 5 | 179.20 score on a scale | Standard Deviation 64.87 |
| Group A | Change in the Total WOMAC Score (WOMAC-T) | visit 1 study 1 | 649.80 score on a scale | Standard Deviation 509.54 |
| Group A | Change in the Total WOMAC Score (WOMAC-T) | OLE visit 0 | 293.60 score on a scale | Standard Deviation 243.62 |
| Group A | Change in the Total WOMAC Score (WOMAC-T) | OLE visits 3 | 219.60 score on a scale | Standard Deviation 53.07 |
| Group B | Change in the Total WOMAC Score (WOMAC-T) | visit 1 study 1 | 1091.70 score on a scale | Standard Deviation 362.11 |
| Group B | Change in the Total WOMAC Score (WOMAC-T) | OLE visits 3 | 364.53 score on a scale | Standard Deviation 272.42 |
| Group B | Change in the Total WOMAC Score (WOMAC-T) | OLE visit 0 | 376.00 score on a scale | Standard Deviation 274.06 |
| Group B | Change in the Total WOMAC Score (WOMAC-T) | OLE visits 5 | 262.16 score on a scale | Standard Deviation 216.67 |
| Group C | Change in the Total WOMAC Score (WOMAC-T) | OLE visit 0 | 260.29 score on a scale | Standard Deviation 150.02 |
| Group C | Change in the Total WOMAC Score (WOMAC-T) | visit 1 study 1 | 767.47 score on a scale | Standard Deviation 227.42 |
| Group C | Change in the Total WOMAC Score (WOMAC-T) | OLE visits 5 | 78.94 score on a scale | Standard Deviation 20.77 |
| Group C | Change in the Total WOMAC Score (WOMAC-T) | OLE visits 3 | 113.12 score on a scale | Standard Deviation 31.37 |
Comparison: No sample size calculation was performed. Maximum expected number of participants for OLE was 72 patients randomized to the NOLTREX™ group in the parent study (IA/PAAG-SI/OA/2019). A total of 65 patients entered the OLE. The study did not have a formal hypothesis. The between-group comparison of changes from baseline (OLE visit 0) in the WOMAC-T at visit 5 was conducted using analysis of covariance (ANCOVA) and, as a post hoc test, the Tukey test.p-value: 0.004ANCOVA
Comparison: Post-hoc pairwise comparisons were performed using Tukey test.p-value: 0.78395% CI: [-172.98, 97.7]Tukey's HSD
Comparison: Post-hoc pairwise comparisons were performed using Tukey test.p-value: 0.3795% CI: [-63.28, 227.16]Tukey's HSD
Comparison: Post-hoc pairwise comparisons were performed using Tukey test.p-value: 0.00395% CI: [36.09, 203.07]Tukey's HSD
Comparison: The between-group comparison of changes from baseline (visit 1 study 1) in the WOMAC-T at visit 5 was conducted using analysis of covariance (ANCOVA) and, as a post hoc test, the Tukey test.p-value: 0.07ANCOVA
Secondary
Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS)
Mean change in the VAS pain score from baseline (visit 0 \[screening\] of the OLE and visit 1 \[week 1\] of the parent study to visit 2 (week 1), visit 3 (week 11) and visit 5 (week 23). The 0 to 100 mm visual analogue scale (VAS) was used for measuring pain intensity. VAS ratings between 0 and 4 mm were interpreted as no pain, 5 to 44 mm, mild pain; 45 to 74 mm, moderate pain; and 75 to 100 mm, severe pain. The pain VAS was self-completed by the patients.
Time frame: baseline (OLE visit 0 and study 1 visit 1 [week 1]), OLE visits 3 (week 11) and 5 (week 23)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | study 1 visit 1 | 47.20 score on a scale | Standard Deviation 19.25 |
| Group A | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 0 | 30.80 score on a scale | Standard Deviation 16.33 |
| Group A | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 3 | 11.20 score on a scale | Standard Deviation 6.53 |
| Group A | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 5 | 6.20 score on a scale | Standard Deviation 5.59 |
| Group B | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 5 | 16.56 score on a scale | Standard Deviation 12.32 |
| Group B | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | study 1 visit 1 | 58.63 score on a scale | Standard Deviation 11.36 |
| Group B | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 3 | 29.07 score on a scale | Standard Deviation 15.29 |
| Group B | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 0 | 17.33 score on a scale | Standard Deviation 10.18 |
| Group C | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 5 | 4.88 score on a scale | Standard Deviation 3.14 |
| Group C | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 0 | 9.47 score on a scale | Standard Deviation 5.51 |
| Group C | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | visit 3 | 21.53 score on a scale | Standard Deviation 6.32 |
| Group C | Change in the 100-mm VAS Pain Score Visual Analogue Scale (100 mm VAS) | study 1 visit 1 | 64.35 score on a scale | Standard Deviation 10.86 |
Comparison: BASELINE (study 1 visit 1)~To determine a statistically significant difference between 3 groups the one-way ANOVA (for normally distributed data; aov) or the Kruskal-Wallis test (for non-normally distributed data; kw) was used. The Shapiro-Wilk test was employed to assess the normality of the data distribution.p-value: 0.03Kruskal-Wallis
Comparison: BASELINE (OLE visit 0)~To determine a statistically significant difference between 3 groups the one-way ANOVA (for normally distributed data; aov) or the Kruskal-Wallis test (for non-normally distributed data; kw) was used. The Shapiro-Wilk test was employed to assess the normality of the data distribution.p-value: 0.002Kruskal-Wallis
Comparison: visit 3~To determine a statistically significant difference between 3 groups the one-way ANOVA (for normally distributed data; aov) or the Kruskal-Wallis test (for non-normally distributed data; kw) was used. The Shapiro-Wilk test was employed to assess the normality of the data distribution.p-value: 0.007ANOVA
Comparison: visit 5~To determine a statistically significant difference between 3 groups the one-way ANOVA (for normally distributed data; aov) or the Kruskal-Wallis test (for non-normally distributed data; kw) was used. The Shapiro-Wilk test was employed to assess the normality of the data distribution.p-value: <0.001Kruskal-Wallis
Secondary
Change in the WOMAC Pain Score (WOMAC-A)
Mean change in WOMAC-A from baseline (visit 1 (week 1) of the parent study AND visit 0 \[screening\] of OLE) to visit 3 (week 11) and visit 5 (week 23). Patients were asked to complete the questionnaire during the study visits. 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.
Time frame: baseline (OLE visit 0 and visit 1 study 1 [week 1]), OLE visits 3 (week 11) and 5 (week 23)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | Change in the WOMAC Pain Score (WOMAC-A) | visit 1 study 1 | 125.80 score on a scale | Standard Deviation 99.55 |
| Group A | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 0 | 60.00 score on a scale | Standard Deviation 51.53 |
| Group A | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 5 | 30.00 score on a scale | Standard Deviation 25.67 |
| Group A | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 3 | 38.00 score on a scale | Standard Deviation 18.33 |
| Group B | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 5 | 47.98 score on a scale | Standard Deviation 44.8 |
| Group B | Change in the WOMAC Pain Score (WOMAC-A) | visit 1 study 1 | 211.02 score on a scale | Standard Deviation 77.97 |
| Group B | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 0 | 67.26 score on a scale | Standard Deviation 52.72 |
| Group B | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 3 | 65.02 score on a scale | Standard Deviation 51.23 |
| Group C | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 0 | 44.24 score on a scale | Standard Deviation 28.77 |
| Group C | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 5 | 3.12 score on a scale | Standard Deviation 2.87 |
| Group C | Change in the WOMAC Pain Score (WOMAC-A) | visit 1 study 1 | 158.18 score on a scale | Standard Deviation 63.77 |
| Group C | Change in the WOMAC Pain Score (WOMAC-A) | OLE visit 3 | 6.29 score on a scale | Standard Deviation 3.89 |
Secondary
Change in the WOMAC Physical Function (WOMAC-C) Score
Mean change in WOMAC-C from baseline (visit 0 \[screening\] of the OLE and visit 1 \[week 1\] of the parent study) to visits 3 (week 11) and 5 (week 23). Patients were asked to complete the questionnaire during the study visits. 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. Therefore, an improvement was achieved by reducing the overall score.
Time frame: baseline (OLE visit 0 and parent study visit 1 [week 1]), visits 3 (week 11) and 5 (week 23)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | Change in the WOMAC Physical Function (WOMAC-C) Score | visit 1 study 1 | 445.40 score on a scale | Standard Deviation 364.01 |
| Group A | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 0 | 207.60 score on a scale | Standard Deviation 165.18 |
| Group A | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 3 | 165.80 score on a scale | Standard Deviation 32.77 |
| Group A | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 5 | 137.00 score on a scale | Standard Deviation 37.14 |
| Group B | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 5 | 193.56 score on a scale | Standard Deviation 154.29 |
| Group B | Change in the WOMAC Physical Function (WOMAC-C) Score | visit 1 study 1 | 785.44 score on a scale | Standard Deviation 280.73 |
| Group B | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 3 | 271.47 score on a scale | Standard Deviation 200.43 |
| Group B | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 0 | 278.58 score on a scale | Standard Deviation 200.64 |
| Group C | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 5 | 63.71 score on a scale | Standard Deviation 16.15 |
| Group C | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 0 | 189.76 score on a scale | Standard Deviation 109.22 |
| Group C | Change in the WOMAC Physical Function (WOMAC-C) Score | OLE visit 3 | 85.59 score on a scale | Standard Deviation 24.11 |
| Group C | Change in the WOMAC Physical Function (WOMAC-C) Score | visit 1 study 1 | 539.35 score on a scale | Standard Deviation 170.29 |
Secondary
Change in the WOMAC Stiffness (WOMAC-B) Score
Mean change in WOMAC-B from baseline (visit 0 \[screening\] of the OLE and visit 1 \[week 1\] of the parent study) to visits 3 (week 11) and 5 (week 23). Patients were asked to complete the questionnaire during the study visits. 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. Therefore, an improvement was achieved by reducing the overall score.
Time frame: baseline (OLE visit 0 and parent study visit 1 [week 1]), visits 3 (week 11) and 5 (week 23)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | Change in the WOMAC Stiffness (WOMAC-B) Score | visit 1 study 1 | 78.60 score on a scale | Standard Deviation 69.5 |
| Group A | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 0 | 26.00 score on a scale | Standard Deviation 30.29 |
| Group A | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 3 | 15.80 score on a scale | Standard Deviation 6.83 |
| Group A | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 5 | 12.20 score on a scale | Standard Deviation 7.6 |
| Group B | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 5 | 20.63 score on a scale | Standard Deviation 25.03 |
| Group B | Change in the WOMAC Stiffness (WOMAC-B) Score | visit 1 study 1 | 95.23 score on a scale | Standard Deviation 43.13 |
| Group B | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 3 | 28.05 score on a scale | Standard Deviation 29.85 |
| Group B | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 0 | 30.16 score on a scale | Standard Deviation 29.21 |
| Group C | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 5 | 12.12 score on a scale | Standard Deviation 4.41 |
| Group C | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 0 | 26.29 score on a scale | Standard Deviation 18.11 |
| Group C | Change in the WOMAC Stiffness (WOMAC-B) Score | OLE visit 3 | 21.24 score on a scale | Standard Deviation 6.71 |
| Group C | Change in the WOMAC Stiffness (WOMAC-B) Score | visit 1 study 1 | 69.94 score on a scale | Standard Deviation 26.93 |
Secondary
Investigator's Assessment of the Treatment Efficacy
Investigator satisfaction with treatment was measured by a 6-point Likert scale (evident aggravation, aggravation, without changes, weak improvement, improvement, significant improvement) at the study visits 3 (week 11) and 5 (week 23).
Time frame: visits 3 (week 13) and 5 (week 25)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study).
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 3 | significant improvement | 2 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 3 | evident aggravation | 0 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 3 | aggravation | 0 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 3 | without changes | 0 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 3 | weak improvement | 1 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 3 | improvement | 2 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 5 | evident aggravation | 0 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 5 | aggravation | 0 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 5 | without changes | 0 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 5 | weak improvement | 1 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 5 | improvement | 0 Participants |
| Group A | Investigator's Assessment of the Treatment Efficacy | Visit 5 | significant improvement | 4 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 5 | significant improvement | 6 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 5 | without changes | 1 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 3 | evident aggravation | 0 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 5 | evident aggravation | 0 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 3 | significant improvement | 3 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 3 | aggravation | 0 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 5 | improvement | 25 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 5 | aggravation | 0 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 3 | without changes | 3 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 3 | improvement | 23 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 5 | weak improvement | 11 Participants |
| Group B | Investigator's Assessment of the Treatment Efficacy | Visit 3 | weak improvement | 14 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 5 | improvement | 16 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 5 | weak improvement | 1 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 3 | improvement | 4 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 3 | significant improvement | 0 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 5 | evident aggravation | 0 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 5 | aggravation | 0 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 3 | weak improvement | 8 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 3 | evident aggravation | 0 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 5 | without changes | 0 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 3 | aggravation | 0 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 5 | significant improvement | 0 Participants |
| Group C | Investigator's Assessment of the Treatment Efficacy | Visit 3 | without changes | 5 Participants |
Comparison: visit 3~Fisher's exact test was used to determine whether there was a significant difference between 3 groups.p-value: 0.018Fisher Exact
Comparison: visit 5~Fisher's exact test was used to determine whether there was a significant difference between 3 groups.p-value: <0.001Fisher Exact
Secondary
Patient's Assessment of the Treatment Efficacy
Patient satisfaction with treatment was measured by a 6-point Likert scale (evident aggravation, aggravation, without changes, weak improvement, improvement, significant improvement) at the study visits 3 (week 11) and 5 (week 23).
Time frame: visits 3 (week 13) and 5 (week 25)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study)
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 5 | evident aggravation | 0 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 5 | aggravation | 0 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 5 | without changes | 0 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 5 | weak improvement | 0 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 5 | improvement | 1 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 5 | significant improvement | 4 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 3 | evident aggravation | 0 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 3 | aggravation | 0 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 3 | without changes | 0 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 3 | weak improvement | 0 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 3 | improvement | 2 Participants |
| Group A | Patient's Assessment of the Treatment Efficacy | Visit 3 | significant improvement | 3 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 3 | significant improvement | 3 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 5 | evident aggravation | 0 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 3 | evident aggravation | 0 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 3 | without changes | 2 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 5 | aggravation | 0 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 5 | significant improvement | 6 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 3 | improvement | 23 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 5 | without changes | 0 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 3 | aggravation | 0 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 5 | improvement | 25 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 5 | weak improvement | 12 Participants |
| Group B | Patient's Assessment of the Treatment Efficacy | Visit 3 | weak improvement | 15 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 5 | weak improvement | 1 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 5 | improvement | 16 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 3 | weak improvement | 8 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 5 | significant improvement | 0 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 3 | evident aggravation | 0 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 3 | aggravation | 0 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 3 | improvement | 4 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 5 | evident aggravation | 0 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 5 | aggravation | 0 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 3 | without changes | 5 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 5 | without changes | 0 Participants |
| Group C | Patient's Assessment of the Treatment Efficacy | Visit 3 | significant improvement | 0 Participants |
Comparison: Fisher's exact test was used to determine whether there is a significant difference between 3 groups.~visit 3p-value: <0.001Fisher Exact
Comparison: visit 5~Fisher's exact test was used to determine whether there is a significant difference between 3 groups.p-value: <0.001Fisher Exact
Secondary
The JSN in the Target Knee
Joint space narrowing (JSN) was scored by comparison of subsequent radiographs taken over time. An increase in the radiographic knee JSN is associated with osteoarthritis progression.
Time frame: baseline (visit 1 of the parent study IA/PAAG-SI/OA/2019), visit 5 (week 23) of OLE
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A | The JSN in the Target Knee | -0.02 millimeters | Standard Deviation 0.05 |
| Group B | The JSN in the Target Knee | -0.00 millimeters | Standard Deviation 0.19 |
| Group C | The JSN in the Target Knee | 0.02 millimeters | Standard Deviation 0.08 |
Comparison: To determine a statistically significant difference between 3 groups the one-way ANOVA (for normally distributed data; aov) or the Kruskal-Wallis test (for non-normally distributed data; kw) was used. The Shapiro-Wilk test was employed to assess the normality of the data distribution.p-value: 0.01Kruskal-Wallis
Secondary
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 at certain doses.
Time frame: visits 3 (week 11) and 5 (week 23)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A | Total Number of NSAID Tablets Taken | visit 3 | 0 NSAID tablets |
| Group A | Total Number of NSAID Tablets Taken | visit 5 | 0 NSAID tablets |
| Group B | Total Number of NSAID Tablets Taken | visit 3 | 0 NSAID tablets |
| Group B | Total Number of NSAID Tablets Taken | visit 5 | 0 NSAID tablets |
| Group C | Total Number of NSAID Tablets Taken | visit 3 | 0 NSAID tablets |
| Group C | Total Number of NSAID Tablets Taken | visit 5 | 0 NSAID tablets |
Secondary
Total Number of Paracetamol Tablets Taken
A patient diary was used to capture data about the number of paracetamol 500 mg tablets taken.
Time frame: visits 3 (week 13) and 5 (week 25)
Population: The intent-to-treat (ITT) population (all subjects randomized in the parent study). The mean number of tablets was calculated taking into account only patients who had received paracetamol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A | Total Number of Paracetamol Tablets Taken | visit 3 | 0 paracetamol tablets |
| Group A | Total Number of Paracetamol Tablets Taken | visit 5 | 0 paracetamol tablets |
| Group B | Total Number of Paracetamol Tablets Taken | visit 3 | 0 paracetamol tablets |
| Group B | Total Number of Paracetamol Tablets Taken | visit 5 | 0 paracetamol tablets |
| Group C | Total Number of Paracetamol Tablets Taken | visit 3 | 0 paracetamol tablets |
| Group C | Total Number of Paracetamol Tablets Taken | visit 5 | 0 paracetamol tablets |