A Study Comparing Duloxetine Versus Placebo in Patients Taking a Nonsteroidal Anti-inflammatory Drug (NSAID) for Knee Pain Due to Osteoarthritis

Study Overview
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Brief Summary
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The study will test the hypothesis that, in patients with knee pain due to osteoarthritis (OA) who are taking nonsteroidal anti-inflammatory drugs (NSAIDs) but still have significant knee pain, duloxetine 60 to 120 milligrams (mg) daily for 10 weeks will provide additional reduction in pain.

Detailed Description
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Duloxetine has been studied in pain due to osteoarthritis (OA) in 2 previous placebo controlled clinical trials. In clinical practice, when nonsteroidal anti-inflammatory drugs (NSAIDs) are ineffective in reducing pain due to OA, clinicians often add a second agent without discontinuing NSAIDs. In this study, we will investigate whether adding duloxetine to NSAIDs provides additional pain relief and functional improvement in patients with knee pain due to OA.

Official Title
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A Randomized, Placebo-Controlled Trial of Duloxetine Added to Nonsteroidal Anti-inflammatory Drugs in Patients With Knee Pain Due to Osteoarthritis Who Have Had Suboptimal Response to Nonsteroidal Anti-inflammatory Drug Treatment.

Conditions
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Osteoarthritis Knee Pain

Intervention / Treatment
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* Drug: Duloxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Present with knee pain due to osteoarthritis (OA) based on OA clinical and radiographic diagnostic criteria. Knee Pain for > 14 days of each month for the 3 months directly preceding study entry. Taking nonsteroidal anti-inflammatory drugs (NSAIDs) for knee pain due to OA on most days in the 3 months immediately preceding study entry. Exclusion Criteria: History of intolerance or nonresponsiveness to an adequate trial of duloxetine used for any indication, in the opinion of the investigator. Previous diagnosis of psychosis, bipolar disorder, or schizoaffective disorder. Have major depressive disorder (MDD) as determined using depression module of the Mini International Neuropsychiatric Interview (MINI). Judged clinically by the investigator to be at suicidal risk by examination or using the Columbia Suicide Severity Rating Scale (C-SSRS). History of substance abuse or dependence within the past year, excluding nicotine and caffeine. Positive urine drug screen for any substance of abuse or excluded medication. Opioid dependent in the opinion of the investigator, taking opioids more than 3 days a week, or unwilling to discontinue opioids during the study period. Known hypersensitivity to duloxetine or its inactive ingredients. History of intolerance or hypersensitivity to NSAIDS, Cyclooxygenase (COX-2) inhibitors, or proton pump inhibitors. History of peptic ulcer disease, bleeding disorder, gastrointestinal bleeding, or any abnormal bleeding. Baseline hemoglobin measurement of <11 grams per deciliter (g/dL) for males, or <10 g/dL for females. Serious or unstable cardiovascular, hepatic, renal, metabolic, respiratory, or hematologic illness, symptomatic peripheral vascular disease, or any other medical or psychiatric condition that would compromise participation or be likely to lead to hospitalization or a change in medication during the course of the study. Uncorrected thyroid disease, uncontrolled narrow-angle glaucoma, uncontrolled or poorly controlled hypertension, or history of seizures. Active liver injury (such as hepatitis) or any degree of hepatic insufficiency (Child-Pugh Class C). Frequent falls that could result in hospitalization or could compromise response to treatment. Confounding painful condition that may interfere with assessment of the index knee. Chronic widespread pain affecting all four quadrants of the body, or diagnosis of fibromyalgia. Received intra-articular hyaluronate (Synvisc), steroids, joint lavage, or other invasive therapies to the knee in the past 6 months. Arthroscopy of the index knee within the past year or joint replacement of the index knee at anytime. Diagnosis of inflammatory arthritis (that is, rheumatoid arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, etc.) or an autoimmune disorder (excluding inactive Hashimoto's thyroiditis). Prior synovial fluid analysis showing a white blood cell count greater than or equal to 2000 cubic millimeters (mm^3) that is indicative of a diagnosis other than OA, or have a history of gout or pseudogout. Radiographic evidence of end-stage (bone on bone) OA in either knee. Knee replacement surgery planned within the next 6 months. Nonambulatory or requiring the use of crutches, a walker, or more than 1 cane. Body mass index (BMI) >40.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Taken by mouth, once daily for 10 weeks<br>|
| Experimental: Duloxetine<br> | Drug: Duloxetine<br>* 30 milligrams (mg) taken by mouth, once daily for 1 week, followed by 60 to 120 mg taken by mouth, once daily for 9 weeks.<br>* Other names: LY248686;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Weekly Mean of the 24-Hour Average Pain Score at 8 Weeks | The weekly mean 24-hour average pain score was calculated from the participant's daily 24-hour average pain ratings using an 11-point numeric rating scale, with scores from 0 (indicating no pain) to 10 (indicating the worst possible pain). The Least Squares Mean estimates were adjusted for baseline, treatment, investigator (pooled), week, treatment*week, and baseline*week. | Baseline, 8 weeks (blinded endpoint) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Global Impression of Improvement (PGI-I) at 8 Weeks | A scale that measures the participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). The Least Squares Mean estimates were adjusted for baseline value of Patient Global Impression of Severity (PGI-S), treatment, investigator (pooled), visit, and treatment*visit. The PGI-S measures participant's perception of severity of illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (extremely ill). | 8 weeks (blinded endpoint) | 
| Change From Baseline in the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) Pain, Stiffness, and Physical Function Subscale Scores at 8 Weeks | Self-administered questionnaire captures elements of pain, stiffness, and physical disability in participants with osteoarthritis of the knee and/or hip. Index has 24 questions (5 on pain, 2 on stiffness, 17 on physical function). Each question uses a 5-point numeric rating scale ranging from 0 (none) to 4 (extreme). Pain scores range: 0 to 20. Stiffness scores range: 0 to 8. Physical function scores range: 0 to 68. Higher scores=greater impairment. Least Squares Mean estimates were adjusted for baseline value, treatment, investigator (pooled), visit, treatment*visit, and baseline value*visit. | Baseline, 8 weeks (blinded endpoint) | 
| Change From Baseline in the Weekly Mean of the 24-Hour Night Pain and Worst Pain Scores at 8 Weeks | Weekly mean 24-hour night pain and worst pain values are calculated from the participant's daily assessments of pain at night and worst pain during the previous 24 hours on an 11-point numeric rating scale, with scores from 0 (indicating no pain) to 10 (indicating the worst possible pain). The Least Squares Mean estimates were adjusted for baseline value, treatment, investigator (pooled), week, treatment*week, and baseline*week. | Baseline, 8 weeks (blinded endpoint) | 
| Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) Scores at 8 Weeks | Measures pain severity and pain interference with function. Severity scores: 0 (no pain) to 10 (severe pain) on each question. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Mean interference is the average across the 7 interference items. The Least Squares Mean estimates were adjusted for baseline value, treatment, investigator (pooled), visit, treatment*visit, and baseline*visit. | Baseline, 8 weeks (blinded endpoint) | 
| Change From Baseline in the Clinical Global Impression of Severity (CGI-S) at 8 Weeks | The CGI-S scale evaluates the severity of illness at the time of assessment. The scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). The CGI-S must be administered by a study physician in the presence of the participant or after having been in the presence of the participant. The Least Squares Mean estimates were adjusted for baseline, treatment, investigator (pooled), visit, treatment*visit, and baseline*visit. | Baseline, 8 weeks (blinded endpoint) | 
| Change From Baseline in the Patient Global Assessment of Illness (PGAI) at 8 Weeks | The PGAI is a participant-rated measure of the severity of osteoarthritis (OA) of the knee the participant has experienced in the past week as indicated on an 11-point numeric rating scale, with scores ranging from 0 to 10, where greater numbers reflect greater severity. The Least Squares Mean estimates were adjusted for baseline value, treatment, investigator (pooled), visit, treatment*visit, and baseline*visit. | Baseline, 8 weeks (blinded endpoint) | 
| Change From Baseline in the Profile of Mood States-Brief Form (BPOMS) Total and Subscale Scores at 8 Weeks | 30-item BPOMS measures positive and negative aspects of mood states (item score: 0=not at all to 4=extremely). 5 negative factors: tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia, confusion-bewilderment; 1 positive factor: vigor-activity. Factor scores range: 0 to 20; high scores=negative mood (positive mood for vigor). Total score=sum of 5 negative factor scores minus vigor score; range: -20=least disturbed to 100=most disturbed. Least Squares Mean estimates adjusted for baseline value, treatment, investigator (pooled), visit, treatment*visit, and baseline value*visit. | Baseline, 8 weeks (blinded endpoint) | 
| Percentage of Participants Using Acetaminophen Weekly During the 10-Week Treatment Period | The Least Squares (LS) Mean percentage estimates of participants using acetaminophen was determined during each week individually over the full 10-week treatment period based on participant's daily Yes/No assessments for the use of acetaminophen. The LS Mean estimates for the main effect of treatment (average weekly use) were adjusted for baseline value, treatment, investigator (pooled), week, and treatment*week. | Baseline through 10 weeks (blinded endpoint) | 
| Percentage of Responders as Assessed by the Osteoarthritis Research Society International (OARSI) Response Criteria up to 8 Weeks | OARSI response is composite Yes/No response assessed at 8 weeks based on decrease in 24-hour average pain ratings, range: 0 (no pain) to 10 (worst possible pain), improvement in functioning (using WOMAC physical function scores, range: 0 [no difficulty] to 68 [extreme difficulty]), and improvement in participant's impression of illness (using PGAI scores, range: 0 to 10; 10=greatest severity). OARSI responder=large response in pain or function components (50% relative and 20% absolute improvement), or moderate response (20% relative and 10% absolute improvement) in 2 of 3 components. | Up to 8 weeks (blinded endpoint) | 
| Percentage of Participants Who Achieved a 30 Percent or 50 Percent Reduction in the Weekly Mean of the 24-Hour Average Pain Score up to 8 Weeks | Response is a dichotomous outcome (Yes/No) indicating at least 30% (or 50%) reduction from baseline to endpoint for the weekly mean of the 24-hour average pain ratings. The weekly mean 24-hour average pain score was calculated from the participant's daily 24-hour average pain rating assessed on an 11-point numeric rating scale, with scores from 0 (no pain) to 10 (worst possible pain). | Up to 8 weeks (blinded endpoint) | 
| Percentage of Participants Who Achieved a 30 Percent or 50 Percent Reduction in the Brief Pain Inventory-Severity (BPI-S) Average Pain Score up to 8 Weeks | Response is a dichotomous outcome (Yes/No) indicating at least 30% (or 50%) reduction from baseline to endpoint for BPI-S average pain rating. The BPI-S self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). | Up to 8 weeks (blinded endpoint) | 
| Percentage of Participants Who Discontinued Due to an Adverse Event During the 10-Week Treatment Period |  | Baseline through 10 weeks |