Research Examining Gulf War Illness in Our Nations Service Members (REGIONS)

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

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.

Study Overview

• Status: Terminated
• Conditions: Gulf War Illness
• Intervention / Treatment: Drug: Placebo; Drug: Duloxetine; Drug: Pregabalin

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Temple, Texas, United States, 76504
      • Central Texas Veterans Health Care System, Temple, TX
    • Waco, Texas, United States, 76711
      • Central Texas Veterans Health Care System Waco VA Medical Center, Waco, TX

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 44 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multiple and Unreliable	Reliability of measurement is highly suspect and data are not suitable for analysis.	Assessed every 2 weeks up to 34 weeks

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Texas A&M University
• Investigators: Study Chair: Charles J Foulks, M.D., Central Texas Veterans Health Care System, Temple, TX

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2015
• Primary Completion (Actual): August 1, 2019
• Study Completion (Actual): August 1, 2019

Study Registration Dates

• First Submitted: April 16, 2013
• First Submitted That Met QC Criteria: April 30, 2013
• First Posted (Estimate): May 3, 2013

Study Record Updates

• Last Update Posted (Actual): March 12, 2021
• Last Update Submitted That Met QC Criteria: February 18, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Gulf War Illness; Duloxetine; Pregabalin; Lyrica; Gulf War Veterans; Cymbalta
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Anti-Anxiety Agents; Anticonvulsants; Serotonin and Noradrenaline Reuptake Inhibitors; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Duloxetine Hydrochloride; Pregabalin
• Other Study ID Numbers: SPLD-016-12F; 6125 (Other Identifier: Stanford IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No