Study to Evaluate the Efficacy of Milnacipran in the Treatment of Pain Due to Osteoarthritis

Study Overview
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Brief Summary
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The present study will aim to evaluate the efficacy of milnacipran in the treatment of pain due to osteoarthritis (OA), that is, to determine whether milnacipran provides superior efficacy to placebo in patients with OA. Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) that is currently approved in the United States in the treatment of major depressive disorder and fibromyalgia. There is increased evidence to suggest that SNRIs may be effective in the treatment of chronic pain conditions, such as OA. The hypothesis in this study is that the survival time (time from randomization to loss of efficacy) of milnacipran group is superior to that of placebo group.

Detailed Description
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The study design is a Double-Blind, Placebo-Controlled, Enriched Enrollment Randomized Withdrawal Study. This means that, upon entry into the study, all subjects will enter an open-label period during which they will take milnacipran for 4 weeks. Subjects will taper their dose up to one 100mg tablet twice daily for a total of 200mg per day. After 4 weeks, the subject will return to the clinic and be re-evaluated. Only subjects who meet certain criteria are then randomized to continue in the double-blind period of the study. Once a subject is randomized, he or she will take either milnacipran or placebo for another 4 weeks. Following the double-blind period, subjects will be tapered off the study medication and will receive a phone call once each week for 2 weeks for follow-up assessments. Throughout the study, subjects will complete various questionnaires and other test procedures aimed at sub-typing subjects based on pain mechanisms.

Official Title
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A Double-Blind, Placebo-Controlled, Enriched Enrollment Randomized Withdrawal Study to Evaluate the Efficacy of Milnacipran in the Treatment of Pain Due to Osteoarthritis

Conditions
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Osteoarthritis

Intervention / Treatment
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* Drug: Milnacipran
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be 21-75 years of age and in good general medical and psychological health Be able to speak, read, write, and understand English, understand the consent form, complete study related procedures, and communicate with the study staff Have a negative urine pregnancy test at screening, and use appropriate birth control Have documented painful Osteoarthritis (OA) of at least one knee for at least 6 months; OA should be of Class I-III and meet the American College of Rheumatology (ACR) clinical classification criteria, defined as: Knee pain and at least 3 of the following 6: Age > 50 Morning stiffness < 30 minutes Crepitus on active motion Bony tenderness Bony enlargement No palpable warmth of synovium The target joint must not contain any type of orthopedic and/or prosthetic device Have a target joint pain average of 5 days per week and have an average pain intensity of at least 4/10 on the 0-10 NRS over the last 24 hours prior to screening Have stable treatment modalities, e.g. acupuncture, physical therapy Be willing to stop taking Non-steroidal Anti-inflammatory drugs (NSAIDs) and opioids for the duration of the study Exclusion Criteria: Are allergic or intolerant to SNRI; have a previous poor response to a SNRI for OA pain; are currently taking an SNRI or tricyclic antidepressant Have a body mass index (BMI) >40 kg/m2 Have an Hospital Anxiety and Depression Scale (HADS) score >12 on either subscale or has an established history of major depressive disorder not controlled with medication Have significant pain outside the target knee, including significant hip or back pain. (Bilateral knee OA allowed.) Have pain affecting the target knee that is due to any other etiology than OA Have documented history of inflammatory arthritis including rheumatoid arthritis Have had local injections in target joint within the past 3 months prior to screening Have had oral or intramuscular corticosteroids within the past 30 days Have had worker's compensation claim, disability, or litigation Have a known history of uncontrolled narrow-angle glaucoma Have a known history of suicidal ideation Use monoamine oxidase inhibitors (MAOI) concomitantly Are allergic or intolerant to acetaminophen Using opioids 4 or more days per week during the month preceding the screening visit Have significant history or renal impairment/failure.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Milnacipran<br>If subjects meet the criteria to enter the Double-Blind Period, they will be randomized at a 1:1 ratio to take either milnacipran or placebo for 4 weeks. The milnacipran arm will take milnacipran at 200mg/day (100mg twice daily). | Drug: Milnacipran<br>* 1 tablet (100mg) by mouth twice daily for 28 days<br>|
| Placebo Comparator: Placebo<br>If subjects meet the criteria to enter the Double-Blind Period, they will be randomized at a 1:1 ratio to take either milnacipran or placebo for 4 weeks. The placebo group will take 1 tablet twice daily. | Drug: Placebo<br>* 1 tablet by mouth twice daily for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to loss of efficacy in the Double-Blind Period | The time to pain worsening by 30% compared to the value at baseline and a pain score of at least 4 on the 0-10 numerical rating scale on weekly pain assessment. Subjects who drop out due to lack of efficacy will be counted as efficacy failures regardless of their pain scores. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in pain intensity | Mean change in pain intensity on the 0-10 numerical rating scale from baseline in the Double-Blind Period. | 28 days | 
| Mean change in Western Ontario and McMaster Osteoarthritis Index (WOMAC) scores | Mean change in Western Ontario and McMaster Osteoarthritis Index (WOMAC) scores from Baseline in the Open-Label Period and Double-Blind Period. | 28 days | 
| The efficacy of milnacipran vs. placebo by time to dropout for all causes |  | 70 days | 
| The efficacy of milnacipran in the Open-Label Period | The efficacy of milnacipran in the Open-Label Period defined by the change in pain intensity from Baseline to the end of the period and responder proportion. | 28 days | 
| The difference between milnacipran and placebo in responder proportion in the Double-Blind Period |  | 28 days | 
| The predictive value of OA sensory sub-type for predicting the response to milnacipran vs. placebo |  | 70 days | 
| Safety and tolerability by monitoring adverse events |  | 70 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoarthritis (OA), Milnacipran, Serotonin-norepinephrine reuptake inhibitor (SNRI), Knee pain