A Phase 1/2 interventional study of Pulsed Low Intensity Ultrasound and Sham Comparator in Osteoarthritis, Degenerative, sponsored by VA Office of Research and Development. Completed at 3 sites in United States. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2021-10-18.
Sponsored by VA Office of Research and Development · Phase 1/2, Interventional, and Treatment
The purpose of this exploratory trial is to investigate whether PLIUS is potentially effective as a disease and symptom modifying intervention in patients with early knee OA.
Osteoarthritis (OA), the most common form of arthritis, is a prevalent and debilitating disease without therapies that alter disease progress and is currently managed with symptom-modifying therapies that are only modestly effective. In spite of substantial progress in understanding the pathogenesis of OA, no effective disease modifying interventions have been established. Degenerative joint cartilage is a central feature of OA, yet joint cartilage has a limited capacity for repair. Results from animal research demonstrate that pulsed low intensity ultrasound (PLIUS) mechanically stimulates, and may promote, cartilage repair. This exploratory trial will investigate whether PLIUS is potentially effective as a disease and symptom modifying intervention in patients with early knee OA.
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This study's enrollment of 140 is above the median of 70 across 3,440 interventional studies indexed under Osteoarthritis.
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Exclusion Criteria:
Treatment to index knee with sham device for 48 weeks
Device: Sham Comparator
Treatment to index knee with PLIUS device for 48 weeks
Device: Pulsed Low Intensity Ultrasound
20 minutes daily for 48 weeks
20 minutes daily for 48 weeks
Co-Primary Measure: a) Symptom Reduction: OMERACT-OARSI Treatment Responsiveness
Outcome Measures in Rheumatology Clinical Trials- Osteoarthritis Research Society International (OMERACT-OARSI) Response incorporates changes in pain and global assessment to define response in OA clinical trials. A response is classified as: 1) An improvement in either pain or function of at least 50 percent accompanied by an absolute decrease of at least 20 mm on the visual-analogue scale for pain or function, OR 2) The occurrence of at least two of the following: a) a decrease in pain of at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale; b) an improvement in function of at least 20 percent and a decrease of at least 10 mm on the visual-analogue scale; c) an increase in the patient's global assessment score by at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale
Time frame: 48 weeks
Co-Primary Measure: b) Disease Modification as Measured by Change From Baseline in Cartilage Thickness of the Central Medial Femoral Condyle Disease
The study has been designed to determine if PLIUS potentially diminishes articular cartilage thinning by measuring cartilage thickness in the tibial femoral joint. The measure selected to best evaluate this is cartilage thickness of the central medial femoral condyle because studies of the OAI (Osteoarthritis Initiative) data have shown this region to be among those most sensitive to change and, due to the anatomical positioning of the device, the most likely to be affected by treatment.
Time frame: Baseline, 48 weeks
Change From Baseline in WOMAC Stiffness Subscale Score
The WOMAC® Index questionnaire is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 200. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Change From Baseline in WOMAC Pain Subscale Score
The WOMAC® Index questionnaire \[33\] is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. WOMAC pain scores from 0-500 mm. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Change From Baseline in WOMAC Functional Limits Subscale Score
The WOMAC® Index questionnaire \[33\] is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 1700. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Change From Baseline in Total WOMAC Score
The WOMAC® Index questionnaire is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 2400. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Change From Baseline in Patient Global Assessment of Disease Status
A patient global assessment of disease status on a Visual Analog Scale (VAS) will be measured at each clinic visit. Patients will be asked to quantify their disease status on a 100 mm VAS as follows: "Considering all the ways your arthritis of the knee affects you, mark 'X' on the scale for how well you are doing." The scale shows the left hand marker "Very Well", and the right hand marker "Very Poor." Range 0 to 100 mm. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Change From Baseline in Investigator Global Assessment of Disease Status
An investigator global assessment of disease status on a 100 mm VAS was measured at each clinic visit as follows: "Make a global assessment of the patient's disease status, with regard to the index knee, by marking an 'X' on the scale below.", with left hand marker "Very Well" and right hand marker "Very Poor." Range 0 to 100 mm. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Change From Baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Constant Pain Subscale
This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered. Study participants are asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants responded to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Change From Baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Intermittent Pain Subscale
This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered and takes less than 10 minutes to complete. Study participants will be asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants will respond to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Change From Baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Total Pain Score
This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered and takes less than 10 minutes to complete. Study participants will be asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants will respond to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the symptoms.
Time frame: Baseline, week 24, week 48
Number of Participants Discontinuing the Study Device Due to an Adverse Device Event
Difference between study groups in number of participants who discontinued usage of the study device due to adverse device events at 4, 8, 12, 24, 36, and 48-week visits.
Time frame: Baseline, 4, 8, 12, 24, 36, and 48-week visits
Participants were recruited at 2 medical centers between May 2015 and January 2019. The first participant was enrolled May 2017 and the last participant was enrolled in January 2019.
| Milestone | Sham | PLIUS (Pulsed Low Intensity UltraSound) |
|---|---|---|
| Started | 140 | 0 |
| Completed | 136 | 0 |
| Not completed | 4 | 0 |
| Withdrew: Participants withdrawn per protocol because less than 80% treatment compliance | 4 | 0 |
| Milestone | Sham | PLIUS (Pulsed Low Intensity UltraSound) |
|---|---|---|
| Started | 67 | 69 |
| Completed | 55 | 54 |
| Not completed | 12 | 15 |
| Withdrew: Adverse event | 1 | 1 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: Withdrawal by subject | 8 | 8 |
| Withdrew: Physician decision | 1 | 3 |
| Withdrew: Misrandomized | 2 | 2 |
Outcome Measures in Rheumatology Clinical Trials- Osteoarthritis Research Society International (OMERACT-OARSI) Response incorporates changes in pain and global assessment to define response in OA clinical trials. A response is classified as: 1) An improvement in either pain or function of at least 50 percent accompanied by an absolute decrease of at least 20 mm on the visual-analogue scale for pain or function, OR 2) The occurrence of at least two of the following: a) a decrease in pain of at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale; b) an improvement in function of at least 20 percent and a decrease of at least 10 mm on the visual-analogue scale; c) an increase in the patient's global assessment score by at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale
| Participants | Sham | PLIUS |
|---|---|---|
| OMERACT-OARSI responders | 37 | 38 |
| OMERACT-OARSI non-responders | 18 | 16 |
The study has been designed to determine if PLIUS potentially diminishes articular cartilage thinning by measuring cartilage thickness in the tibial femoral joint. The measure selected to best evaluate this is cartilage thickness of the central medial femoral condyle because studies of the OAI (Osteoarthritis Initiative) data have shown this region to be among those most sensitive to change and, due to the anatomical positioning of the device, the most likely to be affected by treatment.
| μm | Sham | PLIUS |
|---|---|---|
| Co-Primary Measure: b) Disease Modification as Measured by Change From Baseline in Cartilage Thickness of the Central Medial Femoral Condyle Disease | -42.2 ± 297.0 | -73.8 ± 168.1 |
The WOMAC® Index questionnaire is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 200. The higher the score, the worse the symptoms.
| Visual Analog Scale (mm) | Sham | PLIUS |
|---|---|---|
| Change from Baseline to week 24 | -33.6 (-47.6 to -19.7) | -27.7 (-40.2 to -15.1) |
| Change from Baseline to week 48 | -49.8 (-64.6 to -35.1) | -37.1 (-51.6 to -22.6) |
The WOMAC® Index questionnaire \[33\] is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. WOMAC pain scores from 0-500 mm. The higher the score, the worse the symptoms.
| Visual Analog Scale mm | Sham | PLIUS |
|---|---|---|
| Change from Baseline to week 24 | -84.2 (-109.4 to -58.9) | -91.4 (-111.1 to -71.7) |
| Change from Baseline to week 48 | -117.1 (-146.2 to -87.9) | -93.4 (-124.4 to -62.3) |
The WOMAC® Index questionnaire \[33\] is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 1700. The higher the score, the worse the symptoms.
| Visual Analog Scale (mm) | Sham | PLIUS |
|---|---|---|
| Change from Baseline to week 24 | -285.2 (-377.1 to -193.2) | -241.1 (-316.9 to -165.4) |
| Change from Baseline to week 48 | -407.3 (-510.8 to -303.7) | -283.1 (-399.7 to -166.5) |
The WOMAC® Index questionnaire is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 2400. The higher the score, the worse the symptoms.
| Visual Analog Scale (mm) | Sham | PLIUS |
|---|---|---|
| Change from Baseline to week 24 | -403.0 (-527.3 to -278.6) | -360.2 (-460.8 to -259.5) |
| Change from Baseline to week 48 | -574.1 (-713.8 to -434.4) | -413.6 (-571.4 to -255.7) |
A patient global assessment of disease status on a Visual Analog Scale (VAS) will be measured at each clinic visit. Patients will be asked to quantify their disease status on a 100 mm VAS as follows: "Considering all the ways your arthritis of the knee affects you, mark 'X' on the scale for how well you are doing." The scale shows the left hand marker "Very Well", and the right hand marker "Very Poor." Range 0 to 100 mm. The higher the score, the worse the symptoms.
| Visual Analog Scale (mm) | Sham | PLIUS |
|---|---|---|
| Change from Baseline to Week 24 | -16.6 (-23.3 to -9.9) | -15.0 (-21.4 to -8.7) |
| Change from Baseline to Week 48 | -23.7 (-30.8 to -16.5) | -17.6 (-26.3 to -9.0) |
An investigator global assessment of disease status on a 100 mm VAS was measured at each clinic visit as follows: "Make a global assessment of the patient's disease status, with regard to the index knee, by marking an 'X' on the scale below.", with left hand marker "Very Well" and right hand marker "Very Poor." Range 0 to 100 mm. The higher the score, the worse the symptoms.
| Visual Analog Scale (mm) | Sham | PLIUS |
|---|---|---|
| Change from Baseline to Week 24 | -18.4 (-25.0 to -11.9) | -15.8 (-22.5 to -9.0) |
| Change from Baseline to Week 48 | -28.6 (-36.6 to -20.6) | -18.9 (-27.9 to -9.9) |
This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered. Study participants are asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants responded to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the symptoms.
| Visual Analog Scale (mm) | Sham | PLIUS |
|---|---|---|
| Change from Baseline to Week 24 | -14.6 (-20.1 to 9.1) | -12.4 (-18.0 to -6.8) |
| Change from Baseline to Week 48 | -18.4 (-24.0 to -12.8) | -13.7 (-20.7 to -6.7) |
This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered and takes less than 10 minutes to complete. Study participants will be asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants will respond to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the symptoms.
| Visual Analog Scale (mm) | Sham | PLIUS |
|---|---|---|
| Baseline to Week 24 | -17.7 (-23.2 to -12.3) | -13.4 (-18.2 to -8.5) |
| Baseline to Week 48 | -20.2 (-26.8 to -13.6) | -15.0 (-21.5 to -8.5) |
This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered and takes less than 10 minutes to complete. Study participants will be asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants will respond to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the symptoms.
| Visual Analog Scale (mm) | Sham | PLIUS |
|---|---|---|
| Change from Baseline to Week 24 | -16.3 (-21.3 to -11.3) | -12.9 (-17.9 to -8.0) |
| Change from Baseline to Week 48 | -19.4 (-25.2 to 13.6) | -14.4 (-20.8 to -7.9) |
Difference between study groups in number of participants who discontinued usage of the study device due to adverse device events at 4, 8, 12, 24, 36, and 48-week visits.
| participants | Sham | PLIUS |
|---|---|---|
| Number of Participants Discontinuing the Study Device Due to an Adverse Device Event | 0 | 0 |
Collected over Through study completion, an average of 48 weeks.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Sham | 1/65 (1.5%) | 13/65 (20%) | 0/65 (0%) |
| PLIUS | 0/67 (0%) | 19/67 (28.4%) | 0/67 (0%) |
| Event | Sham | PLIUS |
|---|---|---|
| Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders | 2/65 | 0/67 |
| AscitisGastrointestinal disorders | 0/65 | 2/67 |
| Myocardial infarctionCardiac disorders | 0/65 | 2/67 |
| OsteoarthritisMusculoskeletal and connective tissue disorders | 0/65 | 2/67 |
| Abdominal PainGastrointestinal disorders | 1/65 | 0/67 |
| Alcohol PoisoningInjury, poisoning and procedural complications | 1/65 | 0/67 |
| Angina, UnstableCardiac disorders | 1/65 | 0/67 |
| Atrioventricular block, completeCardiac disorders | 1/65 | 0/67 |
| Coronary artery diseaseCardiac disorders | 1/65 | 0/67 |
| Coronary artery stenosisCardiac disorders | 1/65 | 0/67 |
| Age, Continuous(years) | Sham | PLIUS | Total |
|---|---|---|---|
| Mean | 64.4 ± 10.9 | 62.9 ± 10.5 | 63.6 ± 10.7 |
| Sex: Female, Male(Participants) | Sham | PLIUS | Total |
|---|---|---|---|
| Female | 7 | 6 | 13 |
| Male | 58 | 61 | 119 |
| Ethnicity (NIH/OMB)(Participants) | Sham | PLIUS | Total |
|---|---|---|---|
| Hispanic or Latino | 10 | 13 | 23 |
| Not Hispanic or Latino | 55 | 54 | 109 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Sham | PLIUS | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 1 |
| Asian | 3 | 3 | 6 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 5 | 5 | 10 |
| White | 52 | 48 | 100 |
| More than one race | 3 | 9 | 12 |
| Unknown or Not Reported | 1 | 2 | 3 |
| Region of Enrollment(Participants) | Sham | PLIUS | Total |
|---|---|---|---|
| United States | 65 | 67 | 132 |
| BMI(kg/m^2) | Sham | PLIUS | Total |
|---|---|---|---|
| Mean | 31.6 ± 5.5 | 31.8 ± 5.4 | 31.7 ± 5.5 |
| Years with Osteoarthritis(years) | Sham | PLIUS | Total |
|---|---|---|---|
| Mean | 11.7 ± 11.2 | 15.0 ± 13.2 | 13.4 ± 12.3 |
| ARA Functional Class(Participants) | Sham | PLIUS | Total |
|---|---|---|---|
| Class I | 0 | 2 | 2 |
| Class II | 48 | 52 | 100 |
| Class III | 17 | 13 | 30 |
| Class IV | 0 | 0 | 0 |
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