Research Examining Gulf War Illness in Our Nations Service Members

Study Overview
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Brief Summary
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At least 1 in 4 of the 700,000 U.S. Veterans who served in the 1990-1991 Gulf War suffer from Gulf War Illness (GWI). Despite considerable research, effective treatments remain elusive. GWI refers to a complex of symptoms that typically include widespread chronic pain, persistent headache, memory and concentration problems, gastrointestinal difficulties, sleep disturbances and unexplained fatigue. These symptoms are similar to that of fibromyalgia syndrome (FMS), another multi-symptom condition. Whereas, effective treatments for GWI have yet to be found, the FDA has approved duloxetine and pregabalin for the treatment of FMS. The lack of progress in finding effective treatments for GWI, and the similarities between GWI and FMS, provides a rationale for determining if these medications can provide relief to Veterans who suffer from GWI. This randomized controlled trial will test the efficacy of Duloxetine and Pregabalin for treating Gulf War Veterans who suffer from GWI.

Detailed Description
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At least 1 in 4 of the 700,000 U.S. Veterans who served in the 1990-1991 Gulf War suffer from Gulf War Illness (GWI). Despite considerable research, effective treatments remain elusive. GWI refers to a complex of symptoms that typically include widespread chronic pain, persistent headache, memory and concentration problems, gastrointestinal difficulties, sleep disturbances and unexplained fatigue. This symptom profile is similar to that of fibromyalgia syndrome (FMS), a multi-symptom condition similar to GWI. Whereas, effective treatments for GWI have yet to be found, progress has been made in identifying medications to treat FMS. For example, the FDA has approved a number of medications including Duloxetine and Pregabalin for the treatment of FMS. Compared to placebo (PBO) Duloxetine (a serotonin norepinephrine reuptake inhibitor) and Pregabalin (an alpha-2-alpha-subunit calcium-channel ligand) significantly improved pain responses and fatigue. The capacity of Duloxetine to increase central levels of serotonin and norepinephrine as well as the more complex alterations of neurotransmitters and central nervous system (CNS) mediators of pain attributed to pregabalin are thought to be responsible for the medication's effects on pain, mood and sleep. Clinical practice and one open-label trial support the use of these medications in combination to achieve optimal symptom improvement amongst GWI sufferers; however, such combinations have not been formally tested in randomized controlled trials. The lack of progress in finding effective treatments for GWI, and the similarities between GWI and FMS, provides a rationale for determining if these FDA approved medications can provide significant symptomatic relief to Veterans who suffer from GWI. Central Texas is home to one of the highest number of Gulf War Veterans in the nation, thus the investigators' research team is ideally situated to conduct the proposed study. In a randomized, double-blind, controlled trial, 180 Veterans who meet defining criteria for GWI and whose symptom profile includes chronic widespread pain and sleep disturbances will be treated with one of the following medications; 1) AM Duloxetine+ PM placebo (PBO); 2) PM Pregabalin + AM PBO or 3) AM PBO + PM PBO. All active treatments will titrate from a lower dose in 2-week increments to the full therapeutic doses (FDA-approved for FMS). The outcome of the PBO double-dummy period will be compared statistically with 18 weeks of active therapy (weeks 5-22).

Official Title
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RCT of Duloxetine & Pregabalin for the Treatment of Gulf War Illness in Veterans

Conditions
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Gulf War Illness

Intervention / Treatment
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* Drug: Duloxetine
* Drug: Pregabalin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Living in Central Texas near Killeen, Austin, Temple or Waco Served on active military duty and deployed to the Persian Gulf region for some period between August 1990 & July 1991 English speaking and able to understand the consent form and study questionnaires Willing to be randomized to treatment and participate in 1-month follow up men & women between the ages of 43 to 70 meet Kansas GWI case definition for the diagnosis of GWI report a baseline score > 4 on a 10-point Pain Visual Analog Scale (VAS) female participants of childbearing potential must test negative for pregnancy at the time of enrollment based on a urine pregnancy test and agree to use a reliable method of birth control (for example, oral contraceptives or Norplant; a reliable barrier method of birth control [diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam); intrauterine devices; partner with vasectomy; or abstinence) during the study and for 2 months following the last dose of the study drug. [Note that this inclusion criterion applies only to females of childbearing potential. Females of childbearing potential are defined as women not surgically sterilized and between menarche and 2 years post-menopause.] Exclusion Criteria: Unstable or poorly controlled chronic medical illness such as Diabetes type-II, Hypertension (HTN), heart disease, endocrine disorders, narrow angle glaucoma Significant Central Nervous System disease including transient ischemic attacks (TIAs) or stroke, Dementia, syncopal episodes, severe head trauma, multiple sclerosis Serious or advanced heart disease or clinically relevant abnormal electrocardiogram (ECG), postural hypotension Untreated sleep apnea or body mass index placing patients at risk for undiagnosed sleep apnea (BMI> 35 kg/m2) Diabetes type-I and patients with Diabetes type-II associated with peripheral neuropathy, hepatitis, liver failure/cirrhosis End stage renal disease History of hypersensitivity reaction to pregabalin, duloxetine, venlafaxine; active treatment with duloxetine or pregabalin; History of failure of duloxetine or pregabalin at therapeutic doses; history of angioedema reaction to pregabalin Active systemic infectious disease such as tuberculosis and HIV, shingles Autoimmune mediated illnesses such as systemic lupus erythematosis, rheumatoid arthritis, scleroderma History of mental illness requiring hospitalization (depression, bipolar illness, post traumatic stress disorder, history of suicide attempts, psychosis, schizophrenia spectrum); Current major depression of dysthymia; patients lacking capacity to make medical decisions Use of monoamine oxidase inhibitors (MAOIs) within 2 weeks of evaluation; Active ongoing use of the following agents: desvenlafaxine, fenfluramine, linezolid, milnacipran, phentermine, tryptophan, tramadol, opiates Current (meets criterion within the last 6 months) for drug or alcohol dependence (except for nicotine and caffeine) Cancer other than non-melanoma skin cancers Women who are pregnant or desire to become pregnant, breastfeeding, who use unreliable contraception methods Those with occupations requiring use and/or operation of hazardous heavy equipment or professional drivers Patients for whom the potential risk outweighs the potential benefit in the opinion of the treating psychiatrist

Ages Eligible for Study
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Minimum Age: 44 Years
Maximum Age: 70 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
Interventional Model Description: Three arms comparing placebo to duloxetine and pregabalin
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>60 mg of duloxetine in the AM for 20 weeks and placebo in PM | Drug: Duloxetine<br>* serotonin norepinephrine reuptake inhibitor<br>* Other names: Cymbalta;Drug: Placebo<br>* Placebo<br>|
| Active Comparator: Group 2<br>300 mg of pregabalin in the PM for 20 weeks and placebo in AM | Drug: Pregabalin<br>* alpha-2-alpha subunit calcium channel ligand<br>* Other names: Lyrica;Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Group 3<br>placebo in the AM & PM for 20 weeks | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain by Likert Scale | Likert scale of pain rating | 120 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Side Effects | Side effects checklist | Assessed every 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gulf War Illness, Pregabalin, Duloxetine, Gulf War Veterans, Cymbalta, Lyrica