Importance: Osteoarthritis (OA) is a major cause of disability in the US, with no approved treatments to slow progression, but animal models suggest that pulsed low-intensity ultrasonography (PLIUS) may promote cartilage growth. Objective: To evaluate the efficacy of PLIUS in providing symptom reduction and decreased loss of tibiofemoral cartilage thickness in patients with knee OA. Design, Setting, and Participants: A phase 2A, sham-controlled, parallel, double-blind randomized clinical trial was conducted at 2 Veterans Affairs hospitals in Salt Lake City, Utah, and San Diego, California, from May 22, 2015, to January 31, 2019. Data were analyzed from June 27, 2020, to October 20, 2020. Participants recruited through the US Department of Veterans Affairs (N = 132) with clinical and radiographic evidence of early knee OA were randomly assigned to receive PLIUS or a sham device, self-administered for 20 minutes daily over the medial compartment of the knee. All enrollees participated in a 4-week prerandomization sham run-in period, followed by a 48-week treatment period. Randomization was stratified by study site and Kellgren-Lawrence grades 1 (n = 15), 2 (n = 51), and 3 (n = 66). Intervention: Participants either received 48 weeks of PLIUS or sham ultrasonography. Main Outcomes and Measures: The trial incorporated 2 coprimary outcomes: symptomatic improvement assessed by Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International Responder Criteria (ie, met if either >50% improvement in pain and function with at least a 20% absolute improvement of at least 2 of the following 3 factors: improvement by at least 20% [pain, function, and patient global assessment] with at least a 10-mm absolute improvement), and cartilage preservation assessed as change in central medial femoral condyle cartilage thickness by magnetic resonance imaging. Intention-to-treat analysis was used. Results: The mean (SD) participant age was 63.6 (10.7) years and 119 were men (90.2%). The mean (SD) duration of OA symptoms was 13.4 (12.3) years. In the PLIUS group, 70.4% (95% CI, 58.2%-82.6%) of the participants experienced symptomatic improvement, compared with 67.3% (95% CI, 54.9%-79.7%) of participants in the sham group (P = .84); there was no statistically significant difference in response rates between the treatment groups, and the between-group rate difference of 3.1% (95% CI, -14.3% to 20.5%) did not meet the predefined 10% threshold for clinically significant symptomatic improvement from application of PLIUS. At 48 weeks of treatment, central medial femoral condyle cartilage thickness decreased by a mean (SD) of 73.8 (168.1) μm in the PLIUS group and by 42.2 (297.0) μm in the sham group. This 48-week mean change between the 2 groups did not reach statistical significance (P = .44), and the between-group 48-week difference of -31.7 μm (95% CI, -129.0 μm to 65.7 μm) did not meet the predefined threshold. There were 99 nonserious adverse events in the PLIUS group and 89 in the sham group during the trial. No serious adverse events were deemed related to the study device. Conclusions and Relevance: PLIUS, as implemented in this study, demonstrated neither symptomatic benefit nor a decrease in loss of tibiofemoral cartilage thickness in knee OA. Trial Registration: ClinicalTrials.gov Identifier: NCT02034409.
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