Fatigue Syndrome, Chronic
Conditions
Keywords
Fatigue, Fatigue syndrome, chronic, Chronic fatigue syndrome, CFS, Fibromyalgia
Brief summary
The purpose of this study is to determine the safety and efficacy of duloxetine compared with placebo for reducing fatigue in patients diagnosed with Chronic Fatigue Syndrome (CFS).
Detailed description
Chronic fatigue syndrome (CFS) is characterized by severe disabling fatigue of at least six months duration that cannot be fully explained by an identifiable medical condition . Pain symptoms are also a part of the diagnostic criteria for CFS, and include muscle pain, multi-joint pain, and headaches. The prevalence of CFS ranges from 0.007 to 2.8 % in the general adult population and 0.006 to 3.0% in primary care practice (2). Although most who receive a CFS diagnosis are 30-40 years of age, Caucasian, and female, CFS affects both women and men, adults and children, and all racial and socioeconomic classes. Patients with CFS have 2-4 times the rate of depression and anxiety compared with the general population. CFS is also commonly comorbid with fibromyalgia, a disorder characterized by chronic widespread pain, tenderness, fatigue, sleep and mood disturbances. In some samples, 70% of patients with fibromyalgia also meet criteria for CFS. CFS and fibromyalgia are characterized by greater similarities than differences and may share pathophysiologic features. Like fibromyalgia, CFS is associated with chronic pain, sleep and mood disturbances. Because fibromyalgia responds to treatment with antidepressants, particularly the dual serotonin and norepinephrine reuptake inhibitors, including duloxetine, antidepressant trials in CFS are clearly needed.
Interventions
DRUGDuloxetine
Duloxetine po 60-120 mg/day for 12 weeks
DRUGPlacebo
Sugar pill dose comparable to duloxetine
Sponsors
Eli Lilly and Company
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Female and male outpatients between 18-65 years of age. 2. Meet criteria for revised Center for Disease Control (CDC) definition of Chronic Fatigue Syndrome (CFS) (at least 6 months of persistent fatigue that substantially reduces the person's level of activity; 4 or more of the following symptoms that must occur with fatigue in a 6-month period: impaired memory or concentration, sore throat, tender glands, aching or stiff muscles, multijoint pain, new headaches, unrefreshing sleep, and post-exertional fatigue. Medical conditions that may explain the fatigue and psychiatric disorders, including eating disorders, psychotic disorders, bipolar disorder, melancholic depression, and substance abuse within 2 years of the onset of fatigue, are excluded). 3. Provision of written informed consent for participation in the trial. 4. Educational level and degree of understanding such that the patient can communicate intelligibly with the investigator and study staff. 5. Judged to be reliable and agree to keep all appointments for clinic visits, tests, and procedures required by the protocol.
Exclusion criteria
1. Current melancholic major depressive disorder, or a previous diagnosis of psychosis, eating disorder, or bipolar disorder. 2. History of substance abuse or dependence within the past year, excluding nicotine and caffeine. 3. A positive urine drug screen for any substance of abuse (may be retested if positive test was for a prescribed medication that was not washed out). 4. Women who are pregnant or breast feeding; women must test negative for pregnancy at Visit 1. 5. Women of childbearing potential who are not using a medically accepted means of contraceptive when engaging in sexual intercourse. 6. Patients who, in the opinion of the investigator, are treatment-refractory or whose response is likely to be compromised by existing or future disability compensation issues. 7. Serious unstable medical illness, including cardiovascular, hepatic, renal, respiratory, or hematologic illness, or other unstable medical or psychiatric conditions that in the opinion of the investigator would compromise participation or would likely lead to hospitalization during the duration of the study. Abnormal thyroid stimulating hormone (TSH) concentrations (unless treatment for hypothyroidism has been stable for at least the past 3 months and the patient is clinically euthyroid). 8. Patients who have uncontrolled narrow-angle glaucoma. 9. Patients who have acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C). 10. Patients who are judged prior to randomization to be at suicidal risk by the clinical investigator. 11. Treatment with antidepressant medication within 14 days prior to randomization with the exception of fluoxetine, which cannot be used within 30 days prior to randomization. Potential need to use a monoamine oxidase inhibitor (MAOI) during the study or within 2 weeks of discontinuation of study treatment. 12. Patients who have previously taken duloxetine 13. Patients who are taking any excluded medications that cannot be discontinued at Visit 1. 14. Treatment within the last 30 days with a drug that has not received regulatory approval at the time of study entry. 15. Known hypersensitivity to duloxetine or any of the inactive ingredients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Multidimensional Fatigue Inventory (MFI)--General Fatigue Subscale Score | Baseline to endpoint at 12 weeks | The MFI is a self-reported instrument that contains 20 statements covering different aspects of fatigue. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced concentration. Each subscale includes 4 items with 5-point Likert scales. Scores on each subscale range from 4-20 with higher scores indicating greater fatigue. A decrease in the score indicates improvement. The general fatigue subscale (primary measure) includes general statements about tiredness, feeling rested, and overall feelings of being fit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Brief Pain Inventory (BPI) --Average Pain Severity Score | Baseline to endpoint at 12 weeks | The BPI is a self-administered scale that measures the severity of pain. Pain severity is rated on a 0 \[no pain\] to 10 \[pain as bad a you can imagine\] scale. Average pain is rated over the previous 24 hours. Higher scores indicate greater pain severity. A decrease in the score indicates improvement (i.e. decrease in pain severity). |
| Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) --Depression Subscale | baseline to endpoint at 12 weeks | The HADS is a self-reported instrument designed as a brief assessment tool of anxiety and depression in nonpsychiatric populations. It is a 14-item questionnaire that consistes of 2 subscales of 7 items designed to measure levels of both anxiety and depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. Higher scores indicate greater levels of anxiety or depression. A decrease in the score indicates improvement. |
| Number of Participants Who Discontinued Use of Treatment Due to Adverse Events | Any time after randomization up to 12 weeks. | Paticipants who dropped out of the study because of intolerable adverse events. |
| Patient Global Impression of Improvement (PGI-I) | baseline to endpoint at 12 weeks. | Patient rated assessment of change on a 1 (very much better) to 7 (very much worse) scale. |
| Number of Participants Who Discontinued the Study for Any Reason | Any time after randomization up to 12 weeks. | Description of discontinuation rates of participants; all participants who dropped out of the study after randomization were included. The reasons for drop outs included lack of efficacy, adverse event, lost to follow-up, personal conflict or other patient decision, withdrawal of informed consent, and non-compliance. |
| Change From Baseline in the Clinical Global Impression of Severity (CGI-S) | baseline to endpoint at 12 weeks | Clinician rated assessment of severity on a 1 (normal)-7 (extremely ill) scale. A decrease in the score indicates improvement. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Duloxetine Duloxetine po 60-120 mg/day for 12 weeks
Duloxetine: Duloxetine po 60-120 mg/day for 12 weeks | 30 |
| Placebo Placebo comparator to Duloxetine
Placebo: Sugar pill dose comparable to duloxetine | 30 |
| Total | 60 |
Baseline characteristics
| Characteristic | Placebo | Duloxetine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 30 Participants | 60 Participants |
| Age, Continuous | 44.3 years STANDARD_DEVIATION 11 | 43.0 years STANDARD_DEVIATION 11.8 | 43.6 years STANDARD_DEVIATION 11.4 |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 26 Participants | 26 Participants | 52 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 29 / 29 | 30 / 30 |
| serious Total, serious adverse events | 1 / 29 | 0 / 30 |
Outcome results
Primary
Change From Baseline in Multidimensional Fatigue Inventory (MFI)--General Fatigue Subscale Score
The MFI is a self-reported instrument that contains 20 statements covering different aspects of fatigue. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced concentration. Each subscale includes 4 items with 5-point Likert scales. Scores on each subscale range from 4-20 with higher scores indicating greater fatigue. A decrease in the score indicates improvement. The general fatigue subscale (primary measure) includes general statements about tiredness, feeling rested, and overall feelings of being fit.
Time frame: Baseline to endpoint at 12 weeks
Population: For the efficacy analysis, in the duloxetine group, 3 patients were not included in analysis for the following reasons: one patient's treatment group assignment was unblinded owing to a serious adverse event of suicidal ideation; 2 other patients did not have compliant postbaseline visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Change From Baseline in Multidimensional Fatigue Inventory (MFI)--General Fatigue Subscale Score | -3.3 units on a scale | Standard Deviation 4.2 |
| Placebo | Change From Baseline in Multidimensional Fatigue Inventory (MFI)--General Fatigue Subscale Score | -1.8 units on a scale | Standard Deviation 2.8 |
p-value: 0.23Regression, Linear
Secondary
Change From Baseline in Brief Pain Inventory (BPI) --Average Pain Severity Score
The BPI is a self-administered scale that measures the severity of pain. Pain severity is rated on a 0 \[no pain\] to 10 \[pain as bad a you can imagine\] scale. Average pain is rated over the previous 24 hours. Higher scores indicate greater pain severity. A decrease in the score indicates improvement (i.e. decrease in pain severity).
Time frame: Baseline to endpoint at 12 weeks
Population: For the efficacy analysis, in the duloxetine group, 3 patients were not included in analysis for the following reasons: one patient's treatment group assignment was unblinded owing to a serious adverse event of suicidal ideation; 2 other patients did not have compliant postbaseline visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Change From Baseline in Brief Pain Inventory (BPI) --Average Pain Severity Score | -1.6 units on a scale | Standard Deviation 1.5 |
| Placebo | Change From Baseline in Brief Pain Inventory (BPI) --Average Pain Severity Score | -0.8 units on a scale | Standard Deviation 2.3 |
p-value: 0.05Regression, Linear
Secondary
Change From Baseline in the Clinical Global Impression of Severity (CGI-S)
Clinician rated assessment of severity on a 1 (normal)-7 (extremely ill) scale. A decrease in the score indicates improvement.
Time frame: baseline to endpoint at 12 weeks
Population: For the efficacy analysis, in the duloxetine group, 3 patients were not included in analysis for the following reasons: one patient's treatment group assignment was unblinded owing to a serious adverse event of suicidal ideation; 2 other patients did not have compliant postbaseline visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Change From Baseline in the Clinical Global Impression of Severity (CGI-S) | -1.1 units on a scale | Standard Deviation 1.2 |
| Placebo | Change From Baseline in the Clinical Global Impression of Severity (CGI-S) | -0.4 units on a scale | Standard Deviation 1 |
p-value: 0.02Regression, Linear
Secondary
Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) --Depression Subscale
The HADS is a self-reported instrument designed as a brief assessment tool of anxiety and depression in nonpsychiatric populations. It is a 14-item questionnaire that consistes of 2 subscales of 7 items designed to measure levels of both anxiety and depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. Higher scores indicate greater levels of anxiety or depression. A decrease in the score indicates improvement.
Time frame: baseline to endpoint at 12 weeks
Population: For the efficacy analysis, in the duloxetine group, 3 patients were not included in analysis for the following reasons: one patient's treatment group assignment was unblinded owing to a serious adverse event of suicidal ideation; 2 other patients did not have compliant postbaseline visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) --Depression Subscale | -1.6 units on a scale | Standard Deviation 2.9 |
| Placebo | Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) --Depression Subscale | -1.9 units on a scale | Standard Deviation 3 |
p-value: 0.67Regression, Linear
Secondary
Number of Participants Who Discontinued the Study for Any Reason
Description of discontinuation rates of participants; all participants who dropped out of the study after randomization were included. The reasons for drop outs included lack of efficacy, adverse event, lost to follow-up, personal conflict or other patient decision, withdrawal of informed consent, and non-compliance.
Time frame: Any time after randomization up to 12 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine | Number of Participants Who Discontinued the Study for Any Reason | 10 participants |
| Placebo | Number of Participants Who Discontinued the Study for Any Reason | 2 participants |
p-value: 0.02Fisher Exact
Secondary
Number of Participants Who Discontinued Use of Treatment Due to Adverse Events
Paticipants who dropped out of the study because of intolerable adverse events.
Time frame: Any time after randomization up to 12 weeks.
Population: One patient in the duloxetine group did not have post-baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine | Number of Participants Who Discontinued Use of Treatment Due to Adverse Events | 3 participants |
| Placebo | Number of Participants Who Discontinued Use of Treatment Due to Adverse Events | 0 participants |
p-value: 0.24Fisher Exact
Secondary
Patient Global Impression of Improvement (PGI-I)
Patient rated assessment of change on a 1 (very much better) to 7 (very much worse) scale.
Time frame: baseline to endpoint at 12 weeks.
Population: For the efficacy analysis, in the duloxetine group, 3 patients were not included in analysis for the following reasons: one patient's treatment group assignment was unblinded owing to a serious adverse event of suicidal ideation; 2 other patients did not have compliant postbaseline visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine | Patient Global Impression of Improvement (PGI-I) | 3.2 units on a scale | Standard Deviation 1.2 |
| Placebo | Patient Global Impression of Improvement (PGI-I) | 3.3 units on a scale | Standard Deviation 1.2 |
p-value: 0.06Regression, Linear