Duloxetine for Multiple Sclerosis Pain

• ClinicalTrials.gov Identifier: NCT00755807
• Recruitment Status: Completed
• First Posted: September 19, 2008
• Results First Posted: December 9, 2011
• Last Update Posted: December 9, 2011
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

Brief Summary:

This study is designed to primarily assess the efficacy and safety of duloxetine 60-120 mg once daily (QD) compared with placebo on the reduction of pain severity in participants with central neuropathic pain due to Multiple Sclerosis.

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis	Drug: Duloxetine Hydrochloride (HCI); Drug: Placebo	Phase 3

Detailed Description:

Study is a multicenter, randomized, double-blind, parallel, placebo-controlled, 20-week trial with 4 study periods. Participants who screen successfully (Study Period I) will be randomized in a 1:1 fashion to duloxetine 60 mg QD or placebo. Starting with Study Period II, participants will be treated in a double-blind manner for 6 weeks. Participants who complete the 6-week, double-blind period will have the opportunity to participate in a 12-week, open-label, flexible-dose portion of the study (Study Period III). Study Period IV is a taper phase designed to reduce the occurrence of discontinuation adverse events. Participants may enter Study Period IV at any time after Visit 3.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 239 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Duloxetine in Patients With Central Neuropathic Pain Due to Multiple Sclerosis.
• Study Start Date: October 2008
• Actual Primary Completion Date: August 2010
• Actual Study Completion Date: November 2010

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo	Drug: Placebo; Participants received placebo oral (po), once daily (QD) for 6 weeks (acute phase). If the participant completes the 6-week double-blind portion of the trial, the participant will be offered the option to participate in the open-label extension period (given 60, 90, or 120 milligrams [mg] QD for 12 weeks).
Experimental: Duloxetine	Drug: Duloxetine Hydrochloride (HCI); Participants received 30 mg duloxetine (po, QD) for 1 week followed by 5 weeks at 60 mg in the acute placebo-controlled period. If the participant completes the double-blind portion of the trial, the participant will be offered the option to participate in the open-label extension period (given 60, 90, or 120 mg QD for 12 weeks).; Other Names: LY248686; Cymbalta

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in the Weekly 24-Hour Average Pain Scores at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   24-hour average pain severity scores recorded daily on an 11-point Likert scale, evaluated as a weekly mean, with scores ranging from 0 (no pain) to 10 (worst possible pain). Participants should complete electronic diary each day upon awakening. The 11-point Likert scale was used for assessment of 24-hour average pain and evaluated as weekly means. Scores range from 0 (no pain) to 10 (worst possible pain). The Least Squares Mean (LS Mean) Value was adjusted for investigative site and baseline severity.

Secondary Outcome Measures :

1. Change From Baseline in the Weekly 24-Hour Average Pain Scores up to Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   This is a nominal outcome reflecting whether or not a clinically-important efficacy outcome (≥30% or ≥50% pain reduction from baseline) was achieved at endpoint. It is based on a comparison between baseline and endpoint scores on an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Used were the weekly mean of the scores of the average pain severity over the last 24 hours. The weekly averages were based on daily assessments recorded by participants in their diaries.
2. Patient Global Impressions of Improvement Scale (PGI-I) at 6 Weeks [ Time Frame: 6 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 (LS) Mean Value was adjusted for investigative site and baseline severity.
3. Change From Baseline in the Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   Measures pain severity and interference on function. Severity scores: 0 (no pain) to 10 (severe pain) on each question assessing worst, least, and average pain in past 24 hours, and pain right now. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing pain interference in past 24 hours, such as general activity, mood, normal work, relations with other people, and sleep. Average interference=average of non-missing scores of individual interference items. Least Squares (LS) Mean Value was adjusted for investigative site and baseline severity.
4. Change From Baseline in the Clinical Global Impression of Severity Scale (CGI-S) at 6 Weeks (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   Measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). The Least Squares (LS) Mean Value was adjusted for investigative site and baseline severity.
5. Change From Baseline in the Multiple Sclerosis Quality of Life-54 Instrument (MS-QOL-54) at 6 Weeks (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   A 54 question measure covers 12 domains; assesses mental and physical health. Each domain score is converted into a 0-100 score based on individual item responses; higher scores=better health status. The physical health composite score is a weighted average of the physical health scales, such as physical function, health perceptions, and energy. The mental health composite score is a weighted average of the mental health scales, such as overall quality of life, cognitive function, and health distress. The Least Squares (LS) Mean Value was adjusted for investigative site and baseline severity.
6. Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on The Columbia Suicide Severity Rating Scale (C-SSRS) at Week 6 [ Time Frame: 6 weeks ]
   C-SSRS scale captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal behaviors, ideations, and acts are provided. Suicidal behavior: a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation: a "yes" answer to any one of 5 suicidal ideation questions, which includes wish to be dead, and 4 different categories of active suicidal ideation. Suicidal act: a "yes" answer to actual attempt or completed suicide.
7. Change From Baseline in the Weekly Mean of Night Pain Scores at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   Weekly mean of the night pain severity scores recorded daily on an 11-point Likert scale, an ordinal scale ranging from 0 (no pain) to 10 (worst possible pain). Participants should complete the electronic diary each day upon awakening. The Least Squares (LS) Mean Value was adjusted for investigative site and baseline severity.
8. Change From Baseline in the Beck Depression Inventory II (BDI-II) Question #9 at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   The BDI-II is completed by the participant to rate the severity of depressive symptoms and any improvement during the course of the trial. The total score ranges from 0 to 63 with higher the score indicating more severe depressive symptoms. Question #9 is suicidal thoughts and wishes with a score ranging from 0 to 3.
9. Number of Participants Who Discontinued During the Acute Phase (by Week 6) [ Time Frame: Baseline through 6 weeks ]
10. Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Acute Phase [ Time Frame: Baseline through 6 weeks ]
    Summary tables of serious adverse events (SAEs) and all other non-serious adverse events are located in the Reported Adverse Event Module.
11. Number of Participants With Adverse Events (AEs) Resulting in Discontinuation From Baseline During the Acute Phase [ Time Frame: Baseline through 6 weeks ]
12. Change From Baseline in Blood Pressure at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
13. Change From Baseline in Pulse Rate at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
14. Change From Baseline in Weight at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
15. Patient Global Impressions of Improvement Scale (PGI-I) Score at 18 Weeks [ Time Frame: 18 weeks ]
    A scale that measures the participant's perception of improvement at the time of assessment compared with the start of treatment. The scores range from 1 (very much better) to 7 (very much worse).
16. Change From Baseline in Brief Pain Inventory Severity and Interference Scores (BPI-S/BPI-I) at Week 18 [ Time Frame: Baseline (end of acute phase/Week 6), Endpoint (Week 18) ]
    BPI-S and BPI-I are self-reported scales measuring severity of pain and interference on function. Severity scores: 0 (no pain) to 10 (severe pain) on each question assessing worst pain, least pain, and average pain in past 24 hours, and pain right now. 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. Average interference = average of non-missing scores of individual interference items.
17. Change From Baseline in the Clinical Global Impression of Severity Scale (CGI-S) Score at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), Endpoint (18 weeks) ]
    Measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants).
18. Change From Baseline in Multiple Sclerosis Quality of Life-54 Instrument (MS-QOL-54) at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), Endpoint (18 weeks) ]
    A 54 question measure covers 12 domains; assesses mental and physical health. Each domain score is converted into a 0-100 score based on individual item responses; higher scores=better health status. The physical health composite score is a weighted average of the physical health scales, such as physical function, health perceptions, and energy. The mental health composite score is a weighted average of the mental health scales, such as overall quality of life, cognitive function, and health distress.
19. Number of Participants With Suicidal Behaviors, Ideations, and Acts Based on The Columbia Suicide Severity Rating Scale (C-SSRS) at Week 18 [ Time Frame: 18 weeks ]
    C-SSRS scale captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal behaviors, ideations, and acts are provided. Suicidal behavior: a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation: a "yes" answer to any one of 5 suicidal ideation questions, which includes wish to be dead, and 4 different categories of active suicidal ideation. Suicidal act: a "yes" answer to actual attempt or completed suicide.
20. Change in the Weekly Mean of the Night Pain Scores From Week 6 Through Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks) through Endpoint (18 weeks) ]
    Weekly mean of the night pain severity scores recorded daily on an 11-point Likert scale, an ordinal scale ranging from 0 (no pain) to 10 (worst possible pain). Participants should complete the electronic diary each day upon awakening. Each weekly mean change represents change relative to week 6, the baseline of the extension phase.
21. Change From Baseline in Beck Depression Inventory II (BDI-II), Question #9 at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), Endpoint (18 weeks) ]
    The BDI-II is completed by the participant to rate the severity of depressive symptoms and any improvement during the course of the trial. The total score ranges from 0 to 63 with higher the score indicating more severe depressive symptoms. Question #9 is suicidal thoughts and wishes with the score ranging from 0 to 3.
22. Number of Participants Who Discontinued During the Open-label Extension Phase (by Week 18) [ Time Frame: Baseline (6 weeks) through Endpoint (18 weeks) ]
23. Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Open-label Extension Phase [ Time Frame: Baseline (6 weeks) through Endpoint (18 weeks) ]
    Summary tables of serious adverse events (SAEs) and all other non-serious adverse events are located in the Reported Adverse Event Module.
24. Number of Participants With Adverse Events (AEs) Resulting in Discontinuation During the Open-label Extension Phase [ Time Frame: Baseline (6 weeks) through Endpoint (18 weeks) ]
25. Change From Baseline in Blood Pressure at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), Endpoint (18 weeks) ]
26. Change From Baseline in Pulse Rate at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), endpoint (18 weeks) ]
27. Change From Baseline in Weight at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), Endpoint (18 weeks) ]

Other Outcome Measures:

1. Change From Baseline in Bicarbonate (HCO3) at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   Change from baseline to acute phase endpoint in laboratory assessment for bicarbonate, HCO3.
2. Change From Baseline in Creatinine at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   Change from baseline to acute phase endpoint in laboratory assessment of creatinine.
3. Change From Baseline in the Platelet Count at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   Change from baseline to acute phase endpoint in laboratory assessment of platelet count.
4. Change From Baseline in Inorganic Phosphorus at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   Change from baseline to acute phase endpoint in laboratory assessment of inorganic phosphorus.
5. Change From Baseline in Uric Acid at Week 6 (Acute Phase) [ Time Frame: Baseline, 6 weeks ]
   Change from baseline to acute phase endpoint in laboratory assessment of uric acid.
6. Change From Baseline in Monocytes at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), Endpoint (18 weeks) ]
7. Change From Baseline in Sodium at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), Endpoint (18 weeks) ]
8. Change From Baseline in Total Protein at Week 18 (Open-label Extension Phase) [ Time Frame: Baseline (6 weeks), Endpoint (18 weeks) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Have central neuropathic pain due to multiple sclerosis (MS) based on the disease diagnostic criteria
• Adult males or females
• Have a score of 4 or greater on the daily 24-hour average pain score
• Females must test negative for pregnancy at study entry
• Complete the daily diaries for at least 70% of the days of the study

• Participants may continue other prescription and nonprescription analgesic pain medications as long as the dose has been stable for 1 month prior to study entry, and they agree to maintain that stable dose throughout the study Disease Diagnostic Criteria:

  • Diagnosis of MS at least 1 year prior to study entry
  • No MS flares or change in disease treatment for the 3 months prior to study entry
  • Daily pain due to MS for a minimum of 3 months prior to study entry

Exclusion Criteria:

• Are currently in a clinical trial of MS disease-modifying therapy
• Have pain that cannot be clearly differentiated from causes other than MS
• Any current or historical diagnosis of mania, bipolar disorder, psychosis, or schizoaffective disorder
• History of substance abuse or dependence
• Are pregnant or breast-feeding

Contacts and Locations

Locations

United States, Alabama

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Birmingham, Alabama, United States, 35294

United States, Arizona

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Phoenix, Arizona, United States, 85018

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Tucson, Arizona, United States, 85741

United States, Colorado

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Aurora, Colorado, United States, 80045

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Denver, Colorado, United States, 80204

United States, Florida

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Bradenton, Florida, United States, 34205

United States, Kansas

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Lenexa, Kansas, United States, 66214

United States, Michigan

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Roseville, Michigan, United States, 48066

United States, Missouri

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St Louis, Missouri, United States, 63141

United States, North Carolina

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Charlotte, North Carolina, United States, 28207

United States, North Dakota

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Bismarck, North Dakota, United States, 58501

United States, Ohio

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Akron, Ohio, United States, 44320

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Cincinnati, Ohio, United States, 45219

United States, Oklahoma

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Oklahoma City, Oklahoma, United States, 73109

United States, Oregon

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Portland, Oregon, United States, 97225

United States, Pennsylvania

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Allentown, Pennsylvania, United States, 18102

Belgium

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Melsbroek, Belgium, 1820

Canada, Manitoba

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Winnipeg, Manitoba, Canada, R3A 1R9

Canada, Quebec

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Greenfield Park, Quebec, Canada, J4V 2J2

Poland

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Lublin, Poland, 20-090

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Szczecin, Poland, 70-215

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Wroclaw, Poland, 50-556

Sponsors and Collaborators

Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 Hours, EST); Eli Lilly and Company

More Information

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00755807
• Other Study ID Numbers: 11666; F1J-US-HMFR ( Other Identifier: Eli Lilly and Company )
• First Posted: September 19, 2008
• Results First Posted: December 9, 2011
• Last Update Posted: December 9, 2011
• Last Verified: November 2011

Keywords provided by Eli Lilly and Company:

Central Neuropathic Pain; Multiple Sclerosis

Additional relevant MeSH terms:

Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Duloxetine Hydrochloride; Serotonin and Noradrenaline Reuptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Antidepressive Agents; Psychotropic Drugs; Dopamine Agents