Duloxetine and aeRobic Exercise to Improve Function in VEterans With Knee Osteoarthritis (DRIVE) (DRIVE)

Duloxetine Plus Exercise to Improve Physical Function in Veterans With Knee Osteoarthritis, Pain, and Psychological Comorbidity

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Depression; Pain; Knee Osteoarthritis
• Intervention / Treatment: Behavioral: Exercise; Drug: Duloxetine; Behavioral: PT referral; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 102
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alice S Ryan, PhD; Phone Number: (410) 605-7851; Email: Alice.Ryan@va.gov
• Study Contact Backup: Name: Kristina Marcus, MS; Phone Number: (410) 605-7000; Email: kristina.marcus@va.gov

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD
      • Principal Investigator: Alice S. Ryan, PhD
      • Contact: Alice S Ryan, PhD; Phone Number: 410-605-7851; Email: Alice.Ryan@va.gov
      • Principal Investigator: Alan M Rathbun, PhD MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Veterans aged ≥40 years
• English-speaking
• symptomatic KOA based on American College of Rheumatology (ACR) criteria
• Patient Health Questionnaire-9 (PHQ-9) scores indicating mild to severe depressive symptoms
• no planned knee surgery within the next 6 months
• ability to participate in supervised aerobic exercise

Exclusion Criteria:

• current use of antidepressants, opioids, benzodiazepines, or antipsychotics
• engaging in structured aerobic or resistance exercise ≥3 times per week
• cognitive impairment defined as a Mini-Mental State Examination (MMSE) score <20
• diagnosis of bipolar disorder, psychosis, recent substance use disorder, or suicidal ideation per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
• medical conditions contraindicating exercise (e.g., recent myocardial infarction, unstable angina, peripheral arterial disease with ulcers, -uncontrolled hypertension >190/110, or New York Heart Association class ≥3 cardiac or pulmonary disease)
• pregnant or lactating individuals
• active cancer that is currently undergoing treatment (receiving chemotherapy and/or radiation therapy
• other conditions deemed by study team to endanger the health of the participant

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Exercise+Duloxetine; hybrid supervised aerobic exercise plus duloxetine	Behavioral: Exercise; 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.; Drug: Duloxetine; Participants will receive study medication - duloxetine - and take medication as directed.
Active Comparator: Duloxetine+PT referral; duloxetine plus physical therapy (PT) referral	Drug: Duloxetine; Participants will receive study medication - duloxetine - and take medication as directed.; Behavioral: PT referral; Participants will be referred to physical therapy with treatment as part of usual care and individualized to the Veteran's needs.
Active Comparator: Exercise+Placebo; hybrid supervised aerobic exercise plus placebo	Behavioral: Exercise; 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.; Drug: Placebo; Participants will receive study medication - matched placebo- and take as directed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	baseline, 12-week follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	baseline, 12-week follow-up

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Baltimore VA Medical Center
• Investigators: Principal Investigator: Alice S. Ryan, PhD, Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD; Principal Investigator: Alan M Rathbun, PhD MPH, Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2027
• Primary Completion (Estimated): September 1, 2031
• Study Completion (Estimated): September 1, 2032

Study Registration Dates

• First Submitted: June 10, 2026
• First Submitted That Met QC Criteria: June 10, 2026
• First Posted (Actual): June 16, 2026

Study Record Updates

• Last Update Posted (Actual): June 16, 2026
• Last Update Submitted That Met QC Criteria: June 10, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Exercise; Pain; Physical Function; Duloxetine; Depressive symptoms
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Behavioral Symptoms; Osteoarthritis; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Pain; Osteoarthritis, Knee; Depression; Motor Activity; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiophenes; Duloxetine Hydrochloride; Exercise
• Other Study ID Numbers: RRD2-005-25W; 1 I01 RD002117 (Other Grant/Funding Number: Department of Veterans Affairs)

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