A Pilot Trial to Assess Low-Intensity Ultrasound in Osteoarthritis (PLUS+OA)

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.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis, Degenerative
• Intervention / Treatment: Device: Sham Comparator; Device: Pulsed Low Intensity Ultrasound

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92161
      • VA San Diego Healthcare System, San Diego, CA
  • Texas
    • Dallas, Texas, United States, 75216
      • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
  • Utah
    • Salt Lake City, Utah, United States, 84148
      • VA Salt Lake City Health Care System, Salt Lake City, UT

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 40 years of age or older, and a US Military Veteran
• Clinical symptoms of osteoarthritis for at least 6 months
• Pain in the index knee on motion or weight bearing for the majority of days during the month before screening
• Clinical diagnosis of primary osteoarthritis of the knee based on clinical and radiographic criteria
• American Rheumatism Association Functional Class I, II, or III
• Females of childbearing potential must be willing to use a reliable form of medically acceptable contraception

Exclusion Criteria:

• Concurrent medical/arthritis condition(s), or any other illness per the opinion of the investigator, that could interfere with the evaluation of pain or efficacy
• Spine or hip pain of significant magnitude
• History of significant ligament or meniscal injury of the index joint requiring surgical repair
• Arthroscopy of the index knee within 6 months of study entry
• Unable to undergo MRI of the knee
• Pregnancy or lactation
• Corticosteroid treatment within 1 to 3 months prior to study entry
• Intra-articular injection of hyaluronic acid or congeners to the index knee within 6 months of study entry
• Use of excluded therapy(ies) prior to study entry
• Use of disease modifying anti-rheumatic medications and chronic tetracycline or its derivatives
• Exposure to glucosamine, chondroitin sulfate, or any other investigational treatment, within 1 month of study entry
• Use of any medical therapy, complementary or alternative regimens for the treatment of osteoarthritis within 7 days prior to study entry
• Initiation of physical therapy or muscle conditioning program to the lower extremities within 2 months within 2 months prior to study entry
• Unlikely to comply with study requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham; Treatment to index knee with sham device for 48 weeks	Device: Sham Comparator; 20 minutes daily for 48 weeks
Experimental: PLIUS; Treatment to index knee with PLIUS device for 48 weeks	Device: Pulsed Low Intensity Ultrasound; 20 minutes daily for 48 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Baseline, 48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	Baseline, 4, 8, 12, 24, 36, and 48-week visits

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Daniel O Clegg, MD, VA Salt Lake City Health Care System, Salt Lake City, UT

Publications and helpful links

General Publications

• Sawitzke AD, Jackson CG, Carlson K, Bizien MD, Leiner M, Reda DJ, Sindowski T, Hanrahan C, Spencer RG, Kwoh CK, Lee SJ, Hose K, Robin L, Cain DW, Taylor MD, Bangerter N, Finco M, Clegg DO. Effect of Pulsed Low-Intensity Ultrasonography on Symptom Relief and Tibiofemoral Articular Cartilage Thickness Among Veterans Affairs Enrollees With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA Netw Open. 2022 Mar 1;5(3):e220632. doi: 10.1001/jamanetworkopen.2022.0632.

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2015
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): September 30, 2020

Study Registration Dates

• First Submitted: January 9, 2014
• First Submitted That Met QC Criteria: January 9, 2014
• First Posted (Estimate): January 13, 2014

Study Record Updates

• Last Update Posted (Actual): October 18, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Knee Osteoarthritis; Pulsed Low Intensity Ultrasound
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis
• Other Study ID Numbers: CLIN-006-13S; CXI01CX000954-01A1 (Other Identifier: eRA project Reference)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No