A Phase 2 interventional study of Exercise and Duloxetine in Knee Osteoarthritis, Pain and Depression, sponsored by VA Office of Research and Development. Not yet recruiting at 1 site in United States. Open to participants aged 40 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-06-16.
Sponsored by VA Office of Research and Development · Phase 2, Interventional, and Treatment
Knee osteoarthritis (KOA) is one of the most common causes of chronic pain, mobility problems, and disability among United States Veterans. Many Veterans with KOA also experience depressive symptoms, which can worsen pain, reduce motivation to exercise, and make recovery more difficult. This study will test whether a structured hybrid aerobic exercise program that combines supervised and home-based walking with the medication duloxetine can improve physical function, reduce pain, lessen depressive symptoms, and improve overall health-related outcomes in Veterans with KOA. The goal of this research is to develop a practical and scalable treatment strategy that could improve rehabilitation and quality of life for Veterans with chronic knee pain and depressive symptoms and potentially be adapted for other chronic musculoskeletal conditions treated within the VA healthcare system.
Knee osteoarthritis (KOA) and depressive symptoms are both common among older adults and Veterans and are major contributors to chronic pain, reduced mobility, declines in physical function, disability, and poorer overall health outcomes. Veterans with KOA frequently experience co-occurring depressive symptoms, which can worsen pain, interfere with rehabilitation, and reduce adherence to exercise and other self-management strategies. Existing VA care guidelines generally treat KOA and depressive symptoms separately, and there remains limited evidence supporting integrated interventions that target both conditions simultaneously while also improving physical function.
Current knowledge gaps include how to optimize adherence to aerobic exercise among individuals with pain and depressive symptoms and whether combining pharmacologic and rehabilitative approaches provides greater benefit than usual care alone. Aerobic exercise is a recommended first-line treatment for KOA and can improve both mood and physical function, but sustained participation is often difficult in individuals with chronic pain and depressive symptoms. Similarly, duloxetine has demonstrated benefits for both depressive symptoms and KOA-related pain, although interventions targeting only one condition have generally produced limited effects.
Preliminary work conducted by the study team demonstrated that combining duloxetine with a hybrid supervised aerobic exercise program that included both center-based and home-based walking components was feasible and acceptable among individuals with symptomatic KOA and depressive symptoms. Participants experienced clinically meaningful improvements in pain, activities of daily living, walking ability, endurance, psychological symptoms, self-efficacy, and willingness to engage in pain self-management strategies. These findings support the rationale for the proposed study and the evaluation of a complementary care model integrating pharmacologic and non-pharmacologic treatments for Veterans with KOA and depressive symptoms. This study is a Phase II, three-arm, randomized clinical trial designed to evaluate the efficacy of a hybrid supervised aerobic exercise program combined with duloxetine among Veterans with symptomatic knee osteoarthritis and depressive symptoms.
3,302 studies on the registry are indexed under Osteoarthritis, Knee; 608 are open to participants now.
This study's planned enrollment of 102 is above the median of 70 across 2,731 interventional studies indexed under Osteoarthritis, Knee.
Browse Osteoarthritis, Knee studies →VA Office of Research and Development is the lead sponsor of 1,733 studies on the registry; 396 are open to participants now.
Of its 206 completed or terminated interventional studies of FDA-regulated products, 180 (87%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
hybrid supervised aerobic exercise plus duloxetine
Behavioral: Exercise · Drug: Duloxetine
duloxetine plus physical therapy (PT) referral
Drug: Duloxetine · Behavioral: PT referral
hybrid supervised aerobic exercise plus placebo
Behavioral: Exercise · Drug: Placebo
Participants will be asked to participate in a 1x/week center-based exercise session and 2x/week walking session conducted on their own for \~12 weeks.
Participants will receive study medication - duloxetine - and take medication as directed.
Participants will receive study medication - matched placebo- and take as directed.
Participants will be referred to physical therapy with treatment as part of usual care and individualized to the Veteran's needs.
20-Meter Walk Test
20m WT (average time to walk 20 meters at usual pace across two trials) from baseline to 12 weeks, and between-group comparison (aerobic exercise + duloxetine vs. PT referral + duloxetine)
Time frame: baseline, 12-week follow-up
Pain severity
The Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale is a patient-reported measure of knee pain consisting of 9 items. Scores are transformed to a 0-100 scale, where 0 represents extreme knee pain and 100 represents no knee pain. Higher scores indicate better outcomes (less pain). KOOS Pain is a self-report measure with five subscales. The pain subscale will be the pain outcome.
Time frame: baseline, 12-week follow-up
Depressive symptoms
The Hamilton Depression Rating Scale (HAM-D) is a clinician-administered measure of depressive symptom severity. Total scores range from 0 to 52, with higher scores indicating more severe depressive symptoms and worse outcomes. Lower scores indicate improvement in depressive symptoms. Hamilton Depression Rating Scale (HAM-D) is a 17-item interviewer-administered scale.
Time frame: baseline, 12-week follow-up
Plan to share: No
No publications or documents are linked to this record.
This study is not yet recruiting, as verified in Jun 2026. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
VA Office of Research and Development