Open-label Milnacipran for Persistent Knee Pain One Year After Total Knee Arthroplasty (TKA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT01780389
First received: January 29, 2013
Last updated: July 14, 2014
Last verified: April 2014
  Purpose

The current study examines the effects of milnacipran in patients who have chronic persistent knee pain one year or longer after total knee arthroplasty (TKA) to evaluate for a pain-relieving effect.


Condition Intervention Phase
Knee Pain After Total Knee Arthroplasty
Osteoarthritis Pain
Drug: Open-label flexibly dosed milnacipran
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open-label Milnacipran for Persistent Knee Pain One Year After Total Knee Arthroplasty (TKA)

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Change in Pain Visual Analogue Scale(VAS). [ Time Frame: baseline and endpoint 12 weeks ] [ Designated as safety issue: No ]

    The primary outcome is change in pain VAS from baseline to 12 weeks (baseline score minus 12 week or endpoint score; positive number reflects reduction in pain score). The effect size was calculated using the VAS scores measured on a scale of 0 to 100 mm:

    0= absence of pain or no pain noted 100 = worst imaginable pain/as bad as can be The higher the score the greater the over all pain intensity.



Secondary Outcome Measures:
  • Change in Knee Society Score (KSS). [ Time Frame: between baseline and endpoint (12 weeks or early termination) ] [ Designated as safety issue: No ]

    KSS measures subjective pain and objective function by joint physical exam. This secondary outcome was the change in Knee Society Score(KSS)from baseline through 12 weeks.

    KSS scores measured on a scale of 0 to 100 mm:

    0 = absence of pain or no pain noted 100= worst imaginable pain/as bad as can be The higher the score the greater the over all pain intensity.


  • Global Rating of Change [ Time Frame: Endpoint (12 weeks or early termination) ] [ Designated as safety issue: No ]
  • Change in Total Score of Multidimensional Fatigue Inventory (MFI-20) [ Time Frame: Baseline to endpoint (12 weeks or early termination) ] [ Designated as safety issue: No ]

    Measures subjective fatigue.20-item self-report instrument consisting of five scales: General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation, and Mental Fatigue.

    Each scale contains four items rated on a scale of one to 5 with the scale score of one having the anchor of entirely true and the scale score of 5 having the anchor of no, not true. The five scales were identified through factor analysis and are assumed to measure different aspects of fatigue. Lowest possible total score = 20 (absent fatigue) Highest possible total score = 100 (maximum fatigue) Total mean cumulative scores were reported


  • Change in the Beck Depression Inventory (BDI-II) [ Time Frame: Baseline to endpoint (12 weeks or early termination) ] [ Designated as safety issue: No ]

    The secondary outcome measure is change in Beck Depression Inventory. The scale for this inventory is:

    0-9: indicates minimal depression 10-18: indicates mild depression 19-29: indicates moderate depression 30-63: indicates severe depression. The higher the score the degree of depression.


  • Change in the Montgomery Asberg Depression Rating Scale [ Time Frame: Between baseline and endpoint (12 weeks or early termination) ] [ Designated as safety issue: No ]

    Staff-rated assessment of depressive symptoms. Scale is as follows:

    0 to 6 - normal /symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression


  • Change in Total Score of State Trait Anxiety Inventory (STAI) [ Time Frame: baseline and endpoint (12 weeks or early termination) ] [ Designated as safety issue: No ]

    Assessment of subjective symptoms of current anxiety and chronic anxiety. There are 20 items for assessing trait anxiety and 20 for state anxiety. State anxiety items include: "I am tense; I am worried" and "I feel calm; I feel secure." Trait anxiety items include: "I worry too much over something that really doesn't matter" and "I am content; I am a steady person." All items are rated on a 4-point scale (e.g., from "Almost Never" to "Almost Always"). Higher scores indicate greater anxiety.

    Lowest total score is 40 (absent anxiety) Highest total score is 160 (maximum anxiety) Total mean cumulative scores were reported.


  • Change in Total Score of Short Form-36 (SF-36), Measuring Perceived Quality of Life [ Time Frame: baseline and endpoint (12 weeks or early termination) ] [ Designated as safety issue: No ]

    Subjective measure of perceived quality of life.The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight.

    The eight sections are:

    • vitality,
    • physical functioning,
    • bodily pain,
    • general health perceptions,
    • physical role functioning,
    • emotional role functioning,
    • social role functioning,
    • mental health

    Scale:

    0= lowest quality of life 100= high quality of life Higher scores reflect higher quality of life. Total mean cumulative scores were reported.



Enrollment: 5
Study Start Date: October 2010
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Milnacipran
Open-label flexibly dosed milnacipran
Drug: Open-label flexibly dosed milnacipran
Other Name: Savella

Detailed Description:

The current study proposes to collect pilot data on the utility of open-label milnacipran for the treatment of pain and other outcomes in this unfortunate group of patients with chronic persistent pain after TKA. Among marketed serotonin norepinephrine reuptake inhibitors (SNRIs), milnacipran has a unique property in that it blocks serotonin and norepinephrine reuptake equally. It is plausible that equipotent reuptake inhibition may confer greater analgesic benefit compared to other agents, and in preclinical animal models milnacipran has shown superior effects of ameliorating hyperalgesia and allodynia compared to some other antidepressant drugs. Additionally, milnacipran does not have inhibitory effects on cytochrome P (CYP) 450 enzymes, no binding affinity to neurotransmitter receptors liable to cause adverse events, and simple pharmacokinetics.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject is a male or female adult outpatient age 18 or older at the time of consent.
  2. Subject has chronic persistent pain 1 year after TKA without history of new injury, infection, or implant failure.
  3. Subject has VAS > or = 40 mm at screen and baseline visits.
  4. Subject has an understanding, ability and willingness to fully comply with study procedures and restrictions.
  5. Subject has the ability to provide written, personally signed and dated informed consent to participate in the study, in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 and applicable regulations, before completing any study-related procedures.

Exclusion Criteria:

  1. Subjects unable to complete assessments due to language or cognitive impairment
  2. Subjects with a history of bipolar disorder or psychosis as confirmed by the Mini International Neuropsychiatric Interview (MINI).
  3. Subject currently has (or had a history within the last 6 months of) a drug dependence or substance abuse disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) criteria (excluding nicotine).
  4. Subjects who are currently considered a suicide risk, any subject who has previously made a suicide attempt or who has a prior history of or are currently demonstrating active suicidal ideation.
  5. Subject has any clinically significant ECG or clinically significant laboratory abnormality (including a positive urine drug screen) at Screening.
  6. Subject has a concurrent chronic or acute illness, disability, or other condition that might confound the results of safety assessments administered in the study or that might increase risk to the subject. Similarly, the subject will be excluded if he or she has any additional condition(s) that in the Investigator's opinion would prohibit the subject from completing the study or would not be in the best interest of the subject. This would include any significant illness or unstable medical condition that could lead to difficulty complying with the protocol.
  7. Subjects who do not agree to use adequate and reliable contraception throughout the study.
  8. Subject previously completed, discontinued or was withdrawn from this study.
  9. Subject has taken an investigational drug or taken part in a clinical trial within 30 days prior to Screening.
  10. Subjects treated with antidepressant medication within 4 weeks of screening visit (6 weeks for fluoxetine).
  11. Subjects with known sensitivity to milnacipran.
  12. Subjects with liver disease or reduced liver function
  13. Subjects with obstructive uropathies
  14. Subjects who consume alcohol in amounts viewed by the Investigator to be contraindicated
  15. Subjects taking monoamine oxidase inhibitors
  16. Subjects with uncontrolled narrow angle glaucoma
  17. Subjects who are pregnant, may become pregnant, or who are nursing
  18. Subjects with seizure disorders
  19. Subjects with bleeding disorders or use of other medications that may cause bleeding.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01780389

Locations
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
Investigators
Principal Investigator: Davi M Marks, MD Duke University
  More Information

Publications:
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT01780389     History of Changes
Other Study ID Numbers: Pro00017445, SAV-MD-08
Study First Received: January 29, 2013
Results First Received: June 18, 2013
Last Updated: July 14, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
Knee
Pain
Osteoarthritis

Additional relevant MeSH terms:
Osteoarthritis
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Milnacipran
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Serotonin Agents
Physiological Effects of Drugs
Adrenergic Uptake Inhibitors
Adrenergic Agents

ClinicalTrials.gov processed this record on October 01, 2014