A Study of Duloxetine in Fibromyalgia

Study Overview
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Brief Summary
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The purpose of the study is to assess the effectiveness and safety of duloxetine in participants with fibromyalgia.

Official Title
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A Phase III Clinical Trial of Duloxetine in Participants With Fibromyalgia

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: Duloxetine 60 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants fulfilling the following criteria in the American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia Participants with pain rated severity 4 or over by Brief Pain Inventory (BPI) - average pain severity item (Question 3) Exclusion Criteria: Participants with serious cardiovascular, hepatic, renal, respiratory, or hematological disease, or clinically significant laboratory or electrocardiogram abnormality which indicate a serious medical problem or require significant intervention in the judgment of the investigators Participants with alanine aminotransferase/aspartate aminotransferase of not less than 100 international units per liter (IU/L) or total bilirubin of not less than 1.6 milligrams per deciliter (mg/dL) Participants with serum creatinine level of not less than 2.0 mg/dL, participant who has undergone kidney transplantation or hemodialysis Participants with pain difficult to discriminate from pain associated with fibromyalgia or disease which disturbs the assessment Participants with treatment-refractory fibromyalgia Participants with thyroidal dysfunction, excluding those assessed by the investigator that the disorder is controlled as appropriate by 3-month or longer drug therapy Participants with present or past history of rheumatoid arthritis, inflammatory arthritis, infectious arthritis, or auto immune disease rather than thyroid deficiency Participants with an axis I condition according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV), currently or within the past year, except for major depressive disorders Participants with a lifetime diagnosis of bipolar disorder or schizoaffective disorder; or any other disorder with psychotic symptoms - based on the clinical opinion of the investigator Participants with personality disorder or mental retardation Participants with uncontrolled angle closure glaucoma Participants with present or past history of uncontrolled seizures or convulsion disorders Participants with suicidal ideation within past 6 months, with suicidal attempt within past 1 year Participants answering yes to any of the questions about active suicidal ideation/intent/behaviors occurring within the past 6 months (Columbia Suicide Severity Rating Scale, Suicide Ideation section - Questions 4 and 5; Suicidal Behavior section) Participants with past history of multiple episodes of drug allergy Female participants who are pregnant, lactating, or who want to get pregnant during the study period. Male participants who want his partner to get pregnant Females of child-bearing potential who can't agree to utilize medically. acceptable and reliable means of birth control during the study and for 1 month following the last dose of the study Participants with a history of alcohol or any psychoactive substance abuse or dependence (including alcohol, but excluding nicotine and caffeine) within the past 1 year Participants who have a positive urine drug screen for any substance of abuse (phencyclidine, cocaine, antihypnotic agent, or cannabis) Participants previously treated with duloxetine

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 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 |
| --- | --- |
| Experimental: Duloxetine 60 mg<br>Duloxetine hydrochloride up to 60 milligrams (mg) orally for 15 weeks | Drug: Duloxetine 60 mg<br>* Duloxetine 60 mg taken orally once every day for 15 weeks<br>* Other names: Cymbalta;|
| Placebo Comparator: Placebo<br>Placebo orally for 15 weeks | Drug: Placebo<br>* Placebo taken orally once every day for 15 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 14-Week Endpoint in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) | BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 14 weeks | 
| Change From Baseline to 2 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) | BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 2 weeks | 
| Change From Baseline to 4 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) | BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 4 weeks | 
| Change From Baseline to 6 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) | BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 6 weeks | 
| Change From Baseline to 10 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) | BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 10 weeks | 
| Change From Baseline up to 14-Week Endpoint in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (ANCOVA) | BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an analysis of covariance (ANCOVA) approach including administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates. | Baseline, up to 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients Global Impression of Improvement (PGI-I) at Endpoint | PGI-I measures the participant's perception of improvement at the time of assessment compared with the start of treatment. Scores ranged from 1 (very much better) to 7 (very much worse). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | 14 weeks | 
| Clinical Global Impression of Improvement (CGI-I) at Endpoint | CGI-I measures the clinician's perception of participant improvement at the time of assessment (compared with the start of treatment). Scores ranged from 1 (very much better) to 7 (very much worse). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | 14 weeks | 
| Change From Baseline to 14-Week Endpoint in Fibromyalgia Impact Questionnaire (FIQ) | FIQ is a 20-item, self-administered questionnaire using Likert-type scales to measure participant (pt) outcomes over the past week. Items 1 through 11 measured physical functioning on 4-point scales. Items 12 and 13 measured the number of days a pt felt well and days a pt was unable to work due to fibromyalgia symptoms. Items 14 through 20 were 11-point scales on which a pt rated work difficulty, pain, fatigue, morning tiredness, stiffness, anxiety, and depression. If a pt did not do all the tasks listed, those items were deleted from scoring. Algorithms were used to determine total FIQ scores which ranged from 0 to 100; higher scores indicated a more negative impact. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 14 weeks | 
| Change From Baseline to 14-Week Endpoint in 36-Item Short-Form (SF-36) Health Survey Domain Scores | The SF-36 Health Survey is a generic, health-related survey assessing the participant's quality of life on 8 domains: physical functioning, daily functioning (physical), bodily pain, general health, vitality, social functioning, daily functioning (emotional), and mental health. Each domain was scored by summing individual items pertaining to that domain and transforming scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. LS mean was calculated using an ANCOVA approach including administration groups as fixed effects, and baseline as well as the presence or absence of complication by major depressive disorder as covariates. | Baseline, up to 14 weeks | 
| Change From Baseline to 14-Week Endpoint in Beck Depression Inventory-II (BDI-II) | The BDI-II is a 21-item self-administered questionnaire designed to assess the characteristics of depression. Each item was scored on a 4-point scale ranging from 0 (not present) to 3 (present in the extreme) and was summed to give a total BDI-II score. A total BDI-II score of 0 through 13 was considered minimal, 14 through 19 was mild, 20 through 28 was moderate, and 29 through 63 was severe depression symptoms. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups and as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 14 weeks | 
| Change From Baseline to 14-Week Endpoint in Widespread Pain Index (WPI) and Symptom Severity (SS) in American College of Rheumatology (ACR) Fibromyalgia Diagnostic Criteria 2010 | WPI: Participant-reported areas (out of 19 points on the body) in which the participant had pain in the past week. WPI scores ranged from 0 (no areas) to 19 (all areas). SS: The sum of severity scores for fatigue, waking unrefreshed, and cognitive symptoms [each rated from 0 (no problem) to 3 (severe; life-disturbing problems)] plus the severity of somatic symptoms in general [rated from 0 (no symptoms) to 3 (a great deal of symptoms)]. The total SS score ranged from 0 and 12. LS mean was calculated using an MMRM approach including administration groups, observation points, interaction between the administration groups and the observation points as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 14 weeks | 
| Change From Baseline to 14-Week Endpoint in Average Pain and Worst Pain Severity Score Within 24-Hours in Participant Diary | Each morning participants rated their average pain and worst pain within the past 24 hours on separate 11-point Likert scales with scores ranging from 0 (no pain) through 10 (worst possible pain). These scores were then averaged for the week and compared to baseline. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 14 weeks | 
| Change From Baseline to 14-Week Endpoint in Brief Pain Inventory-Severity (BPI-S) and Brief Pain Inventory-Interference (BPI-I) Scores on the BPI-Modified Short Form | BPI-S and BPI-I are self-reported scales measuring severity of pain and interference on function, respectively. Severity scores ranged from 0 (no pain) to 10 (severe pain) for each question assessing worst pain, least pain, and pain right now. Interference scores ranged from 0 (does not interfere) to 10 (completely interferes) for each question assessing interference of pain in past 24 hours with general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Average interference was the average of non-missing scores of individual interference items. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied. | Baseline, 14 weeks |