Knee OsteoarthritisPhase 2NCT04111627

Exercise Plus Duloxetine for Knee Osteoarthritis

A Phase 2 study testing Aerobic exercise and Duloxetine in people with Knee Osteoarthritis and Depression, run by University of Maryland, Baltimore at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This study evaluates the addition of duloxetine to aerobic exercise in the treatment of symptomatic knee osteoarthritis and depressive symptoms in adults. All participants will receive the receive the treatment protocol, which will first be evaluated in terms of feasibility and then pilot tested. Read more about this study

Who is it for?: Ages 40 years and older
Conditions the study is for: Knee Osteoarthritis, Depression
What is being tested?: Aerobic exercise and Duloxetine
Type of treatment: Lifestyle or therapy programme
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 43 participants
Where: 1 siteUnited States
Study dates: 7 Oct 2021to 11 Aug 2025
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 40 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

English speaking
40 years or older
Symptomatic knee osteoarthritis fulfilling 1986 American College of Rheumatology criteria
No plan for surgical knee osteoarthritis intervention within six months of enrollment
Major depressive disorder satisfying diagnostic criteria according to the DSM-V
Ability to participate in a supervised aerobic exercise program

Who cannot join

Already performing aerobic or resistive exercise 2x/week or more
Taking duloxetine, antipsychotics, benzodiazepines, or opioid analgesics
Other medications deemed by study team to endanger the health of the participant or unduly confound the results
Cognitive impairment (Mini-Mental State Examination score < 20)
Past or current bipolar disorder or psychotic symptoms according to the DSM-V
Substance abuse disorder or suicidal ideation within the previous year

Show all 10Show fewer

Not able to participate in a supervised exercise program based on the presence of unstable angina, recent MI (within last 3 months), hemiparetic gait, inability to walk at least 1mph on treadmill safely, poorly controlled hypertension (resting blood pressure > 190/110), peripheral arterial disease with current foot or leg ulcers, or cardiac or pulmonary disease with exercise tolerance NYHA class 3 or higher.
Active cancer that is currently undergoing treatment (receiving chemotherapy and/or radiation therapy)
Pregnant or lactating women
Other conditions deemed by study team to endanger the health of the participant or unduly confound the results

Trial locations and contacts

1 site in 1 country.

United States1 site

University of Maryland School of Medicine
Baltimore, Maryland, 21201

Other trials in United States

About this study

Official title: A Feasibility and Pilot Study of Combined Treatment Protocol Using Aerobic Exercise and Duloxetine in Older Adults With Symptomatic Knee Osteoarthritis and Comorbid Depression

Read the detailed description

Symptomatic knee osteoarthritis (OA) affects 10% of men and 13% of women 60 years or older, and depressive symptoms are common, occurring in one-fifth of these patients. Depressive symptoms worsen knee OA disease severity and are a barrier to pain management and engagement in physical activity. Guidelines recommend depression treatment in older adults with knee OA but provide no direction on how to simultaneously manage the co-occurrence of physical and mental morbidity. Treatment recommendations advise exercise to manage pain and disability and improve psychosocial health in knee OA patients; however, compliance to exercise programs is low in persons with chronic pain and disability and is only made worse by comorbid depression. Adherence is critical to the efficacy of depression treatments using exercise training, and no such exercise program has ever been designed for and tested in OA patients with co-occurring depressive symptoms in a way to enhance compliance. Duloxetine is the only antidepressant medication indicated for pain management in knee OA patients that has demonstrated efficacy and tolerability when treating depression in older adults and is a viable pharmacological complement to exercise. There are no protocols that combine treatments using interventions that affect symptoms of both knee OA and depression, and the study goals are to evaluate the feasibility of and then pilot test a protocol comprised of aerobic exercise training plus duloxetine for the treatment of symptomatic knee OA and comorbid depression.

Conditions: Knee Osteoarthritis, Depression
Being tested: Aerobic exercise, Duloxetine
Medical subject headings: Osteoarthritis, Knee, Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Aerobic exerciseBehavioural
Participants with symptomatic knee osteoarthritis and depressive symptoms will be enrolled in a progressive walking program designed to reduce pain and disability and improve psychosocial health.
DuloxetineDrug
Duloxetine is an FDA-approved selective serotonin and norepinephrine reuptake inhibitor antidepressant approved for the treatment of neuropathic pain in symptomatic knee osteoarthritis as well as depression in adults. Participants with symptomatic knee osteoarthritis and depressive symptoms will receive duloxetine to decrease pain and depression severity to enhance their ability to engage in aerobic exercise.

Study groups in NCT04111627
Study group	Role	What they receive
Aerobic exercise plus Duloxetine	Experimental	Participants will have a starting duloxetine dosage of 30 mg/day and be titrated up to a daily optimal dosage of 60 mg/day as tolerated during the first 12-weeks of the study. Twelve weeks after the receipt of their prescription, participants will be evaluated for the need to increase medication dosage to 90 mg/day. After duloxetine initiation, participants will be provided an exercise prescription that includes a progressive walking program aiming to achieve 50 minutes of moderate-intensity physical activity, three times per week, over 24 weeks. Receives: Behavioral: Aerobic exercise; Drug: Duloxetine

What is being measured

The primary outcome is the main question the study is designed to answer.

Knee Osteoarthritis Outcomes Scale (KOOS) Pain Subscale
The self-reported KOOS pain subscale is sensitive to changes in knee OA symptoms, and consists of nine items scored on a Likert scale (0 [No problems] to 4 [Extreme Problems]) that ranges from 0-36, with higher values indicating greater severity.
Measured: Change from Baseline Pain Severity at 12 weeks
Hamilton Depression Rating Scale (HAM-D)
The HAM-D is clinician-administered, 21-item questionnaire, designed to rate the severity of depression in patients. Individual scores are based on the first 17 items, each with a possible score of 0-4 (0=Absent; 4=Extreme Symptoms) or 0-2 (0=Absent; 2=Frequent), yielding an overall range of 0-54. Higher scores indicate greater depression severity.
Measured: Change from Baseline Depression Severity at 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

7 Oct 202111 Aug 2025

First posted1 Oct 2019
Study start7 Oct 2021
Primary completion11 Aug 2025
Study completion11 Aug 2025

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Knee OsteoarthritisStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 43 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04111627
Sponsor's protocol ID: HP-00089160
Other IDs: K01AG064041
Status last verified: Oct 2026
First submitted: 18 Sep 2019
Last updated: 29 Oct 2026
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

Rathbun AM, Ryan AS, Dong Y, Beamer BA, Luborsky M, Shardell MD, Golden J, Campbell CM, Lo GH, Peer JE, Hochberg MC. Pilot study of duloxetine plus aerobic exercise for pain and depressive symptoms in knee osteoarthritis. Rheumatol Adv Pract. 2026 Oct 6;10(4):rkag116. doi: 10.1093/rap/rkag116. eCollection 2026.
PubMed 42936867
Rathbun AM, Mehta R, Ryan AS, Dong Y, Beamer B, Golden J, Gallo JJ, Luborsky M, Shardell MD, Peer JE, Hochberg MC. Duloxetine plus exercise for knee osteoarthritis and depression: A feasibility study. Osteoarthr Cartil Open. 2023 Dec 8;6(1):100426. doi: 10.1016/j.ocarto.2023.100426. eCollection 2024 Mar.
PubMed 38130375

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Knee Osteoarthritis trials

Study at a glance

From the registry record, last updated by the sponsor on 29 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Feasibility and Pilot Study of Combined Treatment Protocol Using Aerobic Exercise and Duloxetine in Older Adults With Symptomatic Knee Osteoarthritis and Comorbid Depression
ClinicalTrials.gov ID: NCT04111627
Acronym / sponsor ID: HP-00089160
Conditions: Knee Osteoarthritis, Depression
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 43 participants (actual)
Lead sponsor: University of Maryland, BaltimoreUniversity, hospital or other
Collaborators: National Institute on Aging (NIA)
Study start: 7 Oct 2021 (actual)
Primary completion: 11 Aug 2025 (actual)
Study completion: 11 Aug 2025 (actual)
First posted: 1 Oct 2019 (actual)
Results: Posted 29 Oct 2026

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Aerobic exercise plus Duloxetine	Experimental	Behavioral: Aerobic exercise, Drug: DuloxetineParticipants will have a starting duloxetine dosage of 30 mg/day and be titrated up to a daily optimal dosage of 60 mg/day as tolerated during the first 12-weeks of the study. Twelve weeks after the receipt of their prescription, participants will be evaluated for the need to increase medication dosage to 90 mg/day. After duloxetine initiation, participants will be provided an exercise prescription that includes a progressive walking program aiming to achieve 50 minutes of moderate-intensity physical activity, three times per week, over 24 weeks.

Who may qualify

Ages: 40 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

English speaking
40 years or older
Symptomatic knee osteoarthritis fulfilling 1986 American College of Rheumatology criteria
No plan for surgical knee osteoarthritis intervention within six months of enrollment
Major depressive disorder satisfying diagnostic criteria according to the DSM-V

Key exclusion criteria (10 listed)

Already performing aerobic or resistive exercise 2x/week or more
Taking duloxetine, antipsychotics, benzodiazepines, or opioid analgesics
Other medications deemed by study team to endanger the health of the participant or unduly confound the results
Cognitive impairment (Mini-Mental State Examination score < 20)
Past or current bipolar disorder or psychotic symptoms according to the DSM-V

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Aerobic exerciseParticipants with symptomatic knee osteoarthritis and depressive symptoms will be enrolled in a progressive walking program designed to reduce pain and disability and improve psychosocial health.	Behavioural	Aerobic exercise plus Duloxetine
DuloxetineDuloxetine is an FDA-approved selective serotonin and norepinephrine reuptake inhibitor antidepressant approved for the treatment of neuropathic pain in symptomatic knee osteoarthritis as well as depression in adults. Participants with symptomatic knee osteoarthritis and depressive symptoms will receive duloxetine to decrease pain and depression severity to enhance their ability to engage in aerobic exercise.	Drug	Aerobic exercise plus Duloxetine

Primary outcome

Knee Osteoarthritis Outcomes Scale (KOOS) Pain Subscale
Time frame: Change from Baseline Pain Severity at 12 weeks
The self-reported KOOS pain subscale is sensitive to changes in knee OA symptoms, and consists of nine items scored on a Likert scale (0 [No problems] to 4 [Extreme Problems]) that ranges from 0-36, with higher values indicating greater severity.
Hamilton Depression Rating Scale (HAM-D)
Time frame: Change from Baseline Depression Severity at 12 weeks
The HAM-D is clinician-administered, 21-item questionnaire, designed to rate the severity of depression in patients. Individual scores are based on the first 17 items, each with a possible score of 0-4 (0=Absent; 4=Extreme Symptoms) or 0-2 (0=Absent; 2=Frequent), yielding an overall range of 0-54. Higher scores indicate greater depression severity.

Results and safety

Results posted to the registry on 29 Oct 2026, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Center-Based Aerobic Exercise Plus Duloxetine	9	1
Hybrid Aerobic Exercise Plus Duloxetine	34	17

Primary outcome: Knee Osteoarthritis Outcomes Scale (KOOS) Pain Subscale

Time frame: Change from Baseline Pain Severity at 12 weeks. Mean (Standard Deviation). Unit: score

Measure	Center-Based Aerobic Exercise Plus Duloxetine n = 1	Hybrid Aerobic Exercise Plus Duloxetine n = 17
Value	2.8	14.2 (15.0)

Hybrid Aerobic Exercise Plus Duloxetine: Mean within-participant change from base: 14.2 (95% CI 6.5 to 21.9), p = 0.001267, Two-sided paired t-test

Population analysed: Outcome analyses included participants with available pre- and post-intervention outcome data; therefore, the number analyzed differs from the number enrolled.

Primary outcome: Hamilton Depression Rating Scale (HAM-D)

Time frame: Change from Baseline Depression Severity at 12 weeks. Mean (Standard Deviation). Unit: score

Measure	Center-Based Aerobic Exercise Plus Duloxetine n = 1	Hybrid Aerobic Exercise Plus Duloxetine n = 17
Value	-24	-5.5 (6.8)

Hybrid Aerobic Exercise Plus Duloxetine: Mean within-participant change: -5.529 (95% CI -9.0 to -2.0), p = 0.00413, Two-sided paired t-test.

Population analysed: Outcome analyses included participants with available pre- and post-intervention outcome data; therefore, the number analyzed differs from the number enrolled.

Adverse events

Time frame: Up to 24 weeks. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Center-Based Aerobic Exercise Plus Duloxetine	0 of 9 (0%)	2 of 9 (22.2%)	0 of 9
Hybrid Aerobic Exercise Plus Duloxetine	0 of 34 (0%)	10 of 34 (29.4%)	0 of 34

Limitations and caveats (from the sponsor): Both studies were small single-group feasibility studies without a comparison group. The center-based study had substantial screening exclusions and attrition and only one participant completed treatment. The subsequent hybrid study had improved retention, but clinical outcome analyses were limited to participants with available follow-up data. These limitations preclude conclusions regarding treatment efficacy.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 29 Oct 2026.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 42936867Rathbun AM, Ryan AS, Dong Y, Beamer BA, Luborsky M, Shardell MD, Golden J, Campbell CM, Lo GH, Peer JE, Hochberg MC. Pilot study of duloxetine plus aerobic exercise for pain and depressive symptoms in knee osteoarthritis. Rheumatol Adv Pract. 2026 Oct 6;10(4):rkag116. doi: 10.1093/rap/rkag116. eCollection 2026.
Derived from this study: PubMed 38130375Rathbun AM, Mehta R, Ryan AS, Dong Y, Beamer B, Golden J, Gallo JJ, Luborsky M, Shardell MD, Peer JE, Hochberg MC. Duloxetine plus exercise for knee osteoarthritis and depression: A feasibility study. Osteoarthr Cartil Open. 2023 Dec 8;6(1):100426. doi: 10.1016/j.ocarto.2023.100426. eCollection 2024 Mar.
Individual participant dataSharing planned: No

Related trials for Knee Osteoarthritis

RecruitingPhase 3
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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Aerobic exercise and Duloxetine in people with Knee Osteoarthritis and Depression, run by University of Maryland, Baltimore at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Oct 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Knee Osteoarthritis Outcomes Scale (KOOS) Pain Subscale (time frame: Change from Baseline Pain Severity at 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04111627, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2026.