Development of a Polyphenol-rich Dietary Preparation for Treating Veterans With Gulf War Illness

Gulf War Illness (GWI) is a multi-symptom disorder that is characterized by complex traits such as fatigue, headaches, joint pain, insomnia, and memory problems. With no treatment for GWI currently available, there is an urgent need to develop novel interventions to alleviate major GWI clinical complications. Recent evidence highlights the potential value of flavonoids, a subclass of organic chemical called polyphenols abundantly found in some plants and common dietary preparations, in helping relieve clinical complications in Veterans with GWI. The overall goal is to test whether daily consumption of commercially available Concord grape juice, which is very Flavonoid-rich, is effective for treating cognitive deficits and chronic fatigue in Veterans with GWI.

Study Overview

• Status: Completed
• Conditions: Gulf War Illness
• Intervention / Treatment: Dietary supplement: Concord grape juice; Dietary supplement: Placebo Beverage

Detailed Description

Gulf War Illness (GWI) is a multi-symptom disorder that is characterized by complex traits. Clinical complications of GWI typically persist over long-term, cause significant pain and suffering, and interfere with the ability of affected Veterans to successfully integrate back into civilian society. There is no treatment for GWI and there is an urgent need to develop novel interventions either to resolve underlying GWI mechanisms, or to alleviate major GWI clinical complications.

Recent Evidence highlights the potential value of flavonoids, a subclass of organic chemical called polyphenols that are abundantly found in some plants and common dietary preparations may help alleviate chronic fatigue and preserve cognitive functions. Based on this, the overall goal is to test whether the potential efficacy of dietary supplementation with a commercially available flavonoid-rich product, alleviates clinical complications in Veterans with GWI. In particular, the researchers propose a randomized, double-blind, placebo-controlled Phase I/IIA study to test the feasibility and potential efficacy of Concord grape juice dietary supplementation to treat cognitive deficits and chronic fatigue in Veterans with GWI.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • East Orange, New Jersey, United States, 07018
      • VA- New Jersey Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gulf War Veterans deployed to the Persian Gulf theatre between August 1990 and August 1991. GWI will be defined according to the Kansas Case Definition. The Kansas Case Definition identifies 6 symptom domains and requires endorsement of moderately severe and/or multiple symptoms in at least 3 of those domains. To meet the case definition, the Veterans must also indicate that each symptom first became problematic during or within one year of the Gulf War.

Exclusion Criteria:

• Individuals not meeting the inclusion criteria for Gulf War deployment and definition of GWI, or with conditions that might interfere with their ability to report their symptoms (e.g., drug use) are excluded.
• Additional exclusion criteria are current medical conditions that may explain the symptoms (diabetes, heart disease, among others) or significant current (in the past six months) unstable (requiring significant medication adjustments or hospitalization) psychiatric conditions, including suicidal or homicidal ideation, schizophrenia or bipolar disorder according to subject responses to the interview and review by the principal investigator.
• Subjects who usually consume abnormally high contents of dietary polyphenol based on a self-reported diet diary will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Low Dose - Concord grape juice; Daily dietary supplementation with 4 oz. of a commercially available Concord grape juice.	Dietary supplement: Concord grape juice; Daily dietary supplementation with a commercially available Concord grape juice.
EXPERIMENTAL: Moderate Dose - Concord grape juice; Daily dietary supplementation with 8 oz. of a commercially available Concord grape juice.	Dietary supplement: Concord grape juice; Daily dietary supplementation with a commercially available Concord grape juice.
EXPERIMENTAL: High Dose - Concord grape juice; Daily dietary supplementation with 16 oz. of a commercially available Concord grape juice.	Dietary supplement: Concord grape juice; Daily dietary supplementation with a commercially available Concord grape juice.
PLACEBO_COMPARATOR: Low dose - placebo beverage; Daily dietary supplementation with 4 oz. of a placebo beverage	Dietary supplement: Placebo Beverage; Daily dietary supplementation with a placebo beverage consisting of water, sugar, artificial flavoring and color that is formulated to look and taste like grape juice and have the same carbohydrate composition and energy load.
PLACEBO_COMPARATOR: Moderate Dose - placebo beverage; Daily dietary supplementation with 8 oz. of a placebo beverage	Dietary supplement: Placebo Beverage; Daily dietary supplementation with a placebo beverage consisting of water, sugar, artificial flavoring and color that is formulated to look and taste like grape juice and have the same carbohydrate composition and energy load.
PLACEBO_COMPARATOR: High Dose - placebo beverage; Daily dietary supplementation with 16 oz. of a placebo beverage	Dietary supplement: Placebo Beverage; Daily dietary supplementation with a placebo beverage consisting of water, sugar, artificial flavoring and color that is formulated to look and taste like grape juice and have the same carbohydrate composition and energy load.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brief Symptom Inventory (BSI)	to assess safety and tolerability to treatment. The test is a 53-item self report scale that uses the 5 point Likert scale.	6 months
Patient Health Questionnaire-15 (PHQ-15)	to assess safety and tolerability to treatment. The Patient Health Questionnaire 15 (PHQ 15) is a validated measure of somatic symptom severity in functional somatic syndromes (FSS). Scale ranges from 0-30 (mild to severe).	6 months
California Verbal Learning Test-Second Edition (CVLT-II)	This test looks at cognitive functioning by assessing immediate recall and long-delayed recall.	6 months
The Chalder Fatigue Questionnaire	The Chalder Fatigue Questionnaire assess chronic fatigue. Each of the 11 items are answered on a 4-point scale ranging from the asymptomatic to maximum symptomology	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wechsler Adult Intelligence Scale (WAIS-IV)	The Digit Span subtest is a widely used measure of auditory attention that is well-normed and sensitive. The subtest has three parts - digits forward, backward, and sequencing.	6 months
the Conner's Continuous Performance Test-3 (CPT-3)	The CPT-3 assist in clinical assessment of attention problems. The patient is instructed to press the space bar (or mouse button) immediately following the presentation of specific letters on screen. The test normally takes 14 minutes to administer.	6 months
the Trail Making Test (TMT)	The TMT consists of two forms, parts A and B. This measure taps both simple graphomotor speed (Part A) and adds in a rapid set-shifting paradigm that taps executive functioning (Part B).	6 months
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Block Design Subtest	A tool for testing adult intelligence level.	6 months
the Stroop Test	The Stroop Color and Word Test consists of a Word Page with color words printed in black ink, a Color Page with 'Xs' printed in color, and a color-Word Page with words from the first page printed in colors from the second page (the color and the word do not match). The respondent goes down each sheet reading words or naming the ink colors as quickly as possible within a time limit. The test yields three scores based on the number of items completed on each of the three stimulus sheets. An Interference score, which is useful in determining the individual's cognitive flexibility, creativity, and reaction to cognitive pressures also can be calculated.	6 months
Halstead Category Test	This test takes approximately 30 minutes and consists of 120 items, presented visually. The participant must decipher the underlying principle of the stimulus set. Total number of errors will be used.	6 months
Brief Visuospatial Memory Test-Revised (BVMT-R)	A tool to measure visuospatial learning and memory abilities.	6 months
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Digit Span Subtest	Digit Span measures short-term auditory memory and attention.	6 months

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: United States Department of Defense; Department of Veterans Affairs, New Jersey
• Investigators: Principal Investigator: Giulio Maria Pasinetti, MD, PhD, Icahn School of Medicine at Mount Sinai; Study Director: Brett Chaney, MD, United States Department of Defense

Publications and helpful links

General Publications

• Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. 2000 Nov 15;152(10):992-1002. doi: 10.1093/aje/152.10.992.
• Helmer DA, Van Doren WW, Litke DR, Tseng CL, Ho L, Osinubi O, Pasinetti GM. Safety, Tolerability and Efficacy of Dietary Supplementation with Concord Grape Juice in Gulf War Veterans with Gulf War Illness: A Phase I/IIA, Randomized, Double-Blind, Placebo-Controlled Trial. Int J Environ Res Public Health. 2020 May 19;17(10):3546. doi: 10.3390/ijerph17103546.

Helpful Links

• Web link for research studies that are open to Gulf War Veteran research at the New Jersey War Related Illness and Injury Study Center

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (ACTUAL): January 17, 2019
• Study Completion (ACTUAL): January 17, 2019

Study Registration Dates

• First Submitted: September 23, 2016
• First Submitted That Met QC Criteria: September 23, 2016
• First Posted (ESTIMATE): September 26, 2016

Study Record Updates

• Last Update Posted (ACTUAL): June 29, 2020
• Last Update Submitted That Met QC Criteria: June 25, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Veterans; Gulf War Illness; Gulf War Veterans's Illness; Gulf War Veterans' Medically Unexplained Illnesses
• Other Study ID Numbers: GCO 13-1398

Plan for Individual participant data (IPD)

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