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Is replacing meloxicam with placebo noninferior to continued meloxicam, and is engaging in a telephone-based cognitive behavioral therapy program noninferior to continuing meloxicam for patients with knee osteoarthritis?
In this multicenter randomized withdrawal trial, the pain scores of patients randomized to stop meloxicam were inferior at 4 weeks to the pain scores of patients who continued meloxicam; the pain scores of patients who engaged in cognitive behavioral therapy after placebo were also inferior to the pain scores of patients who continued meloxicam. However, the pain score differences between the 2 groups were small (less than the minimal clinically important difference), and there were no statistically significant differences in patients’ reported global impression of change or function.
Among patients with knee osteoarthritis, placebo and cognitive behavioral therapy (after placebo) are inferior to meloxicam.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for knee osteoarthritis. However, they are associated with uncertain long-term clinical benefit and significant toxic effects.
To evaluate whether discontinuing NSAIDs and engaging in a telephone-based cognitive behavioral therapy (CBT) program is noninferior to continuing NSAIDs for patients with knee osteoarthritis.
Design, Setting, and Participants
The Stopping NSAIDs for Arthritis Pain multicenter randomized withdrawal trial was conducted for 364 patients taking NSAIDs for knee osteoarthritis pain on most days of the week for at least 3 months between September 1, 2013, and September 30, 2018. Analysis was performed on an intent-to-treat basis.
Participants discontinued their current NSAID and took 15 mg per day of meloxicam daily during a 2-week run-in period. Those who remained eligible were randomized in a 1:1 ratio to receive meloxicam or placebo for 4 weeks (blinded phase 1). Participants receiving meloxicam then continued this medication for 10 weeks, while those receiving placebo participated in a 10-week CBT program (unblinded phase 2).
Main Outcomes and Measures
The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 4 weeks with the noninferiority margin set at 1. Secondary outcomes included the area under the curve of the pain score after 4 weeks as well as the WOMAC pain score, area under the curve of the pain score, WOMAC disability score, and global impression of change after treatment at 14 weeks.
A total of 180 participants (161 men; mean [SD] age, 58. 2 [11.8] years) were randomized to receive placebo followed by CBT, and a total of 184 participants (154 men; mean [SD] age, 58.5 [10.0] years) were randomized to receive meloxicam. After adjustment for baseline pain and study site, the estimated mean difference in WOMAC pain score between the placebo and meloxicam groups after 4 weeks was 1.4 (95% CI, 0.8-2.0; noninferiority test P = .92). At week 14, the adjusted mean difference in WOMAC pain score between the placebo (followed by CBT) and meloxicam groups was 0.8 (95% CI, 0.2-1.4; noninferiority P = .28). There was no statistically significant difference in the global impression of change (mean difference in scores, –0.2; 95% CI, –0.4 to 0.1; P = .15) or lower extremity disability (mean difference in scores, 0.9; 95% CI, –1.4 to 3.2; P = .45) between the 2 groups after 14 weeks.
Conclusions and Relevance
Among patients with knee osteoarthritis, placebo and CBT (after placebo) are inferior to meloxicam. However, the WOMAC pain score differences between the 2 groups were small, and there were no statistically significant differences in participants’ global impression of change or function after 14 weeks.
ClinicalTrials.gov Identifier: NCT01799213
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Accepted for Publication: May 25, 2020.
Corresponding Author: Liana Fraenkel, MD, MPH, Section of Rheumatology, Yale University School of Medicine, 300 Cedar St, PO Box 208031, TAC Building, Room 525, New Haven, CT 06520 (firstname.lastname@example.org).
Published Online: July 20, 2020. doi:10.1001/jamainternmed.2020.2821
Author Contributions: Drs Fraenkel and Buta had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Fraenkel, Suter, Corn, Kerns, Goulet.
Acquisition, analysis, or interpretation of data: Fraenkel, Buta, Dubreuil, Levy, Najem, Brennan, Corn, Kerns, Goulet.
Drafting of the manuscript: Fraenkel, Buta, Brennan, Goulet.
Critical revision of the manuscript for important intellectual content: Fraenkel, Buta, Suter, Dubreuil, Levy, Najem, Corn, Kerns, Goulet.
Statistical analysis: Buta, Goulet.
Obtained funding: Fraenkel, Kerns, Goulet.
Administrative, technical, or material support: Suter, Levy, Brennan, Corn.
Supervision: Fraenkel, Kerns.
Conflict of Interest Disclosures: Drs Fraenkel and Goulet reported receiving grants from the Veterans Affairs Health Services Research and Development during the conduct of the study. Dr Suter reported other support from Veterans Health Administration during the conduct of the study and other support from the Centers for Medicare & Medicaid Services outside the submitted work. Dr Levy reported receiving salary support from the North Florida/South Georgia Veterans Health System during the conduct of the study. No other disclosures were reported.
Funding/Support: This trial was funded by grant IIR 11-113 from the Veterans Affairs Health Services Research and Development Service.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Additional Information: Research resources generated with funds from this grant will be freely distributed, as available, to qualified academic investigators for noncommercial research. Deidentified data will be shared with the research community once the project has been completed and the resulting manuscripts have been accepted for publication. The study protocol and results will be uploaded to Clinical Trials.gov. The proposed research will include data from all enrolled participants. The final data set will be stripped of identifiers prior to release for sharing. Even so, in order to ensure protection of participants, we will make the data and associated documentation available to users only under a data sharing agreement that provides for (1) a commitment to using the data only for research purposes and not to identify any individual participant, (2) a commitment to securing the data using appropriate computer technology, and (3) a commitment to destroying or returning the data after analyses are completed.
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