Osteoarthritis, Knee
Conditions
Keywords
Autologous Protein Solution (APS), Intra-articular Injection, Osteoarthritis
Brief summary
This is a two-phase multicenter, double-blind, randomized, prospective evaluation of intra-articular injection(s) comparing APS to intra-articular HA injection(s). The maximum study duration for each subject will be 50 months; 48 months from treatment to last follow-up, and two additional months if the maximum visit window is realized. A total of 246 patients will be enrolled. These patients will meet specific inclusion and exclusion criteria, but can be generally characterized as patients with painful unilateral knee OA who have been unable to achieve satisfactory pain relief with previous conservative OA treatment.
Interventions
DEVICEnSTRIDE APS
Intra-articular injection
DEVICESynvisc-One
Intra-articular injection
Sponsors
Zimmer Biomet
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blind study where subjects and evaluators are blinded to treatment up to 12-months. During the long-term follow-up phase (12 - 48 months), only subjects will be blinded to the study treatment resulting in single-blind design following 12-month follow-up time point.
Intervention model description
During the long-term follow-up phase (12 - 48 months), subjects may also elect to cross over to the other treatment arm and receive additional injections of the other treatment as frequently as needed, provided they did not experience any significant clinical concerns after previous treatment administrations and are benefiting from it, as determined by the investigator. Subjects may only cross over from their originally assigned treatment group to the other treatment group one time during the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female at least 18 years of age at time of screening. * Willingness and ability to comply with study procedures and visit schedules and able to follow oral and written instructions. * A standing knee radiograph showing a K-L grade of 2 to 4 * Body mass index ≤ 40 kg/m2 * A qualifying WOMAC LK 3.1 pain subscale total score * Signed an ethics committee-reviewed and approved informed consent form.
Exclusion criteria
* Presence of clinically observed active infection in the index knee * Presence of symptomatic OA in the non-study knee at screening * Diagnosed with rheumatoid arthritis, Reiter's syndrome, psoriatic arthritis, gout, ankylosing spondylitis, or arthritis secondary to other inflammatory diseases; HIV, viral hepatitis; chondrocalcinosis, Paget's disease, or villonodular synovitis * Diagnosed with leukemia, known presence of metastatic malignant cells, or ongoing or planned chemotherapeutic treatment * Presence of venous or lymphatic stasis in the index leg * A history of local anesthetic allergy * Previously documented failed treatment with nSTRIDE APS or Synvisc One
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 12 Months Post-injection in Mean WOMAC LK3.1 Pain Score in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 months | The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is widely used in the evaluation of Hip and Knee Osteoarthritis. It is a self-administered questionnaire consisting of 24 items divided into 3 subscales: pain (5), stiffness (2), and physical function (17). 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. The sum of the scores for all three subscales gives a total WOMAC score. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. 0 represents the best health status and 96 the worst possible status. This section will only analyze the WOMAC pain score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 12 Months Post-injection in Mean NRS Pain Scale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 months | In a Numerical Rating Scale (NRS) pain scale, patients are asked to circle (in an horizontal bar or line) the number between 0 and 10 that fits best to their average pain intensity. 0 = No pain at all; 5 = Moderate pain; 10 = Worst possible pain |
| Number or Participants Achieving Clinical Success as Defined by OMERACT-OARSI Responder Criteria in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 months | The Outcome Measures in Rheumatology workgroup (OMERACT), together with the Osteoarthritis Research Society International (OARSI) developed the OMERACT-OARSI responder criteria. These criteria are used to determine if a patient with osteoarthritis (OA) 'responds' to therapy, meaning experiences a clinically relevant effect of therapy. It includes three symptomatic domains (pain, function, and patient's global assessment). To the question: High improvement in pain or in function (≥50%) and absolute change ≥20%, a positive answer is understood as Response. A negative answer leads to an additional analysis, which seeks improvement in at least 2 of the 3 following: 1. pain ≥20% and absolute change ≥10; 2. function ≥20% and absolute change ≥10; 3. patient's global assessment ≥20% and absolute change ≥10. A positive answer here is understood as Response. A negative answer is a No response |
| Change From Baseline to 12 Months Post-injection in Mean WOMAC LK 3.1 Function Subscale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 months | The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is widely used in the evaluation of Hip and Knee Osteoarthritis. It is a self-administered questionnaire consisting of 24 items divided into 3 subscales: pain (5), stiffness (2), and physical function (17). 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. The sum of the scores for all three subscales gives a total WOMAC score. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. 0 represents the best health status and 96 the worst possible status. This section will analyze the WOMAC Function subscale. A subject is considered an MCID Function responder if they show an absolute improvement of \>= 20 points in WOMAC Function from baseline to 12 Months. |
| Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - VAS Score | 12 months | The EurpoQol five-dimensional (EQ-5D) is a standardized instrument for measuring the health-related quality of life. Part of the Eq-5Q questionnaire consist of a visual analogue score (VAS), a vertical calibrated line, on which a patient rates his/her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health). Respondents indicate where they perceive their present state of health to lie, relative to these anchors. |
| Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - Health Status Score | 12 months | The EurpoQol five-dimensional (EQ-5D), section Health Status, is a standardized instrument for measuring the health-related quality of life, which assesses health status in terms of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety depression. Each question has five levels of response (no problem, slight problem, moderate problems, severe problems, extreme problems/unable to), which are singularly rated and then combined into a health status score. The health status ranges from less than 0 (where 0 is the value of a health state equivalent to dead; negative values representing values as worse than dead) to 1 (the value of full health), with higher score indicating higher health utility. |
Countries
Belgium, Denmark, Germany, Italy, Netherlands, Norway, Spain, Switzerland, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
The clinical investigation began on 25 July 2017 when the first subject received treatment. Subject recruitment was completed on 20 September 2018, when the last subject was randomized and received injection.
Pre-assignment details
Subjects giving written informed consent underwent screening assessments including demographics, medical history, physical examination, knee examination, a urine pregnancy test (if applicable) and the WOMAC LK 3.1. Upon confirmation of eligibility, subjects were scheduled for a treatment visit, and a baseline X-ray and MRI were performed.
Participants by arm
| Arm | Count |
|---|---|
| nSTRIDE APS The nSTRIDE APS Kit is designed to be used for the safe and rapid preparation of APS from a small sample of blood at the patient's point of care. The APS is to be injected intra-articularly for the treatment of knee osteoarthritis and associated symptoms.
nSTRIDE APS: Intra-articular injection | 125 |
| Synvisc-One Synvisc-One is only intended for intra-articular use by a physician to treat pain associated with osteoarthritis of the knee
Synvisc-One: Intra-articular injection | 127 |
| Total | 252 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | exit for non-compliance | 1 | 1 |
| Overall Study | Lack of Efficacy | 8 | 14 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | one subject was randomized but not treated | 1 | 0 |
| Overall Study | Other reasons | 0 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | nSTRIDE APS | Synvisc-One | Total |
|---|---|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 10.52 | 57.9 years STANDARD_DEVIATION 10.82 | 58.9 years STANDARD_DEVIATION 10.5 |
| BMI | 28.20 kg/m^2 STANDARD_DEVIATION 4.211 | 27.53 kg/m^2 STANDARD_DEVIATION 4.217 | 27.86 kg/m^2 STANDARD_DEVIATION 4.214 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 75 Participants | 78 Participants | 153 Participants |
| Sex: Female, Male Male | 50 Participants | 49 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 124 | 0 / 127 |
| other Total, other adverse events | 34 / 124 | 21 / 127 |
| serious Total, serious adverse events | 8 / 124 | 9 / 127 |
Outcome results
Primary
Change From Baseline to 12 Months Post-injection in Mean WOMAC LK3.1 Pain Score in Both Arms of the Study (nSTRIDE APS and Synvisc One)
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is widely used in the evaluation of Hip and Knee Osteoarthritis. It is a self-administered questionnaire consisting of 24 items divided into 3 subscales: pain (5), stiffness (2), and physical function (17). 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. The sum of the scores for all three subscales gives a total WOMAC score. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. 0 represents the best health status and 96 the worst possible status. This section will only analyze the WOMAC pain score.
Time frame: 12 months
Population: ITT population, with imputations for missing data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean WOMAC LK3.1 Pain Score in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Baseline | 11.5 score on a scale | Standard Deviation 2.36 |
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean WOMAC LK3.1 Pain Score in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 month Follow-up | 6.7 score on a scale | Standard Deviation 3.93 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean WOMAC LK3.1 Pain Score in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Baseline | 11.9 score on a scale | Standard Deviation 2.45 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean WOMAC LK3.1 Pain Score in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 month Follow-up | 7.2 score on a scale | Standard Deviation 4.26 |
p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - Health Status Score
The EurpoQol five-dimensional (EQ-5D), section Health Status, is a standardized instrument for measuring the health-related quality of life, which assesses health status in terms of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety depression. Each question has five levels of response (no problem, slight problem, moderate problems, severe problems, extreme problems/unable to), which are singularly rated and then combined into a health status score. The health status ranges from less than 0 (where 0 is the value of a health state equivalent to dead; negative values representing values as worse than dead) to 1 (the value of full health), with higher score indicating higher health utility.
Time frame: 12 months
Population: patients lost during follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - Health Status Score | Baseline | 0.6 score on a scale | Standard Deviation 0.27 |
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - Health Status Score | 12 month follow-up | 0.7 score on a scale | Standard Deviation 0.2 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - Health Status Score | Baseline | 0.6 score on a scale | Standard Deviation 0.27 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - Health Status Score | 12 month follow-up | 0.7 score on a scale | Standard Deviation 0.24 |
p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - VAS Score
The EurpoQol five-dimensional (EQ-5D) is a standardized instrument for measuring the health-related quality of life. Part of the Eq-5Q questionnaire consist of a visual analogue score (VAS), a vertical calibrated line, on which a patient rates his/her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health). Respondents indicate where they perceive their present state of health to lie, relative to these anchors.
Time frame: 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - VAS Score | Baseline | 68.7 score on a scale | Standard Deviation 16.92 |
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - VAS Score | 12 month follow-up | 73.4 score on a scale | Standard Deviation 16.02 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - VAS Score | Baseline | 68.0 score on a scale | Standard Deviation 16.88 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean EQ-5D in Both Arms of the Study (nSTRIDE APS and Synvisc One) - VAS Score | 12 month follow-up | 71.7 score on a scale | Standard Deviation 16.8 |
p-value: <0.05t-test, 2 sided
Secondary
Change From Baseline to 12 Months Post-injection in Mean NRS Pain Scale in Both Arms of the Study (nSTRIDE APS and Synvisc One)
In a Numerical Rating Scale (NRS) pain scale, patients are asked to circle (in an horizontal bar or line) the number between 0 and 10 that fits best to their average pain intensity. 0 = No pain at all; 5 = Moderate pain; 10 = Worst possible pain
Time frame: 12 months
Population: PP Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean NRS Pain Scale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Baseline | 5.8 score on a scale | Standard Deviation 2 |
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean NRS Pain Scale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 month follow-up | 4.0 score on a scale | Standard Deviation 2.53 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean NRS Pain Scale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Baseline | 6.2 score on a scale | Standard Deviation 1.8 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean NRS Pain Scale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 month follow-up | 4.4 score on a scale | Standard Deviation 2.51 |
p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline to 12 Months Post-injection in Mean WOMAC LK 3.1 Function Subscale in Both Arms of the Study (nSTRIDE APS and Synvisc One)
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is widely used in the evaluation of Hip and Knee Osteoarthritis. It is a self-administered questionnaire consisting of 24 items divided into 3 subscales: pain (5), stiffness (2), and physical function (17). 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. The sum of the scores for all three subscales gives a total WOMAC score. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. 0 represents the best health status and 96 the worst possible status. This section will analyze the WOMAC Function subscale. A subject is considered an MCID Function responder if they show an absolute improvement of \>= 20 points in WOMAC Function from baseline to 12 Months.
Time frame: 12 months
Population: MCID Function Responder analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean WOMAC LK 3.1 Function Subscale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Baseline | 35.4 score on a scale | Standard Deviation 11.47 |
| nSTRIDE APS | Change From Baseline to 12 Months Post-injection in Mean WOMAC LK 3.1 Function Subscale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 month follow-up | 20.5 score on a scale | Standard Deviation 13.46 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean WOMAC LK 3.1 Function Subscale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Baseline | 39.5 score on a scale | Standard Deviation 11.6 |
| Synvisc-One | Change From Baseline to 12 Months Post-injection in Mean WOMAC LK 3.1 Function Subscale in Both Arms of the Study (nSTRIDE APS and Synvisc One) | 12 month follow-up | 23.0 score on a scale | Standard Deviation 14.62 |
p-value: <0.0001t-test, 2 sided
Secondary
Number or Participants Achieving Clinical Success as Defined by OMERACT-OARSI Responder Criteria in Both Arms of the Study (nSTRIDE APS and Synvisc One)
The Outcome Measures in Rheumatology workgroup (OMERACT), together with the Osteoarthritis Research Society International (OARSI) developed the OMERACT-OARSI responder criteria. These criteria are used to determine if a patient with osteoarthritis (OA) 'responds' to therapy, meaning experiences a clinically relevant effect of therapy. It includes three symptomatic domains (pain, function, and patient's global assessment). To the question: High improvement in pain or in function (≥50%) and absolute change ≥20%, a positive answer is understood as Response. A negative answer leads to an additional analysis, which seeks improvement in at least 2 of the 3 following: 1. pain ≥20% and absolute change ≥10; 2. function ≥20% and absolute change ≥10; 3. patient's global assessment ≥20% and absolute change ≥10. A positive answer here is understood as Response. A negative answer is a No response
Time frame: 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| nSTRIDE APS | Number or Participants Achieving Clinical Success as Defined by OMERACT-OARSI Responder Criteria in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Responder | 60 Participants |
| nSTRIDE APS | Number or Participants Achieving Clinical Success as Defined by OMERACT-OARSI Responder Criteria in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Non-responder | 42 Participants |
| Synvisc-One | Number or Participants Achieving Clinical Success as Defined by OMERACT-OARSI Responder Criteria in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Responder | 61 Participants |
| Synvisc-One | Number or Participants Achieving Clinical Success as Defined by OMERACT-OARSI Responder Criteria in Both Arms of the Study (nSTRIDE APS and Synvisc One) | Non-responder | 37 Participants |
p-value: 0.6655t-test, 2 sided