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

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

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.

Study Overview

• Status: Unknown
• Conditions: Osteoarthritis
• Intervention / Treatment: Drug: Milnacipran; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Natick, Massachusetts, United States, 01760
      • Recruiting
      • Analgesic Solutions
      • Contact: Karen Cowles, RN, MPH; Phone Number: 121 781-444-9605; Email: kcowles@analgesicsolutions.com
      • Contact: Courtney Lincoln; Phone Number: 119 781-444-9605; Email: clincoln@analgesicsolutions.com
      • Principal Investigator: Stephen L. Wright, M.D.
      • Sub-Investigator: Nathaniel P. Katz, M.D., M.S.
      • Sub-Investigator: Eric Osgood, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. 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
  2. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Milnacipran; 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; 1 tablet (100mg) by mouth twice daily for 28 days
Placebo Comparator: Placebo; 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; 1 tablet by mouth twice daily for 28 days

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Analgesic Solutions
• Collaborators: Forest Laboratories
• Investigators: Principal Investigator: Stephen L. Wright, M.D., Analgesic Solutions

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Anticipated): February 1, 2012
• Study Completion (Anticipated): September 1, 2012

Study Registration Dates

• First Submitted: April 4, 2011
• First Submitted That Met QC Criteria: April 4, 2011
• First Posted (Estimate): April 5, 2011

Study Record Updates

• Last Update Posted (Estimate): August 17, 2011
• Last Update Submitted That Met QC Criteria: August 16, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: Knee pain; Milnacipran; Osteoarthritis (OA); Serotonin-norepinephrine reuptake inhibitor (SNRI)
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Milnacipran; Levomilnacipran
• Other Study ID Numbers: FRX001-2010