Multimodal Investigation of the Neuroprotective Effects of Resveratrol (MINER) (MINER)

September 7, 2018 updated by: Dena Davidson, VISN 17 Center of Excellence

A Pilot RCT on the Effect of Resveratrol on Mood, Memory Deficits, Hippocampal Inflammation and Neurogenesis in Veterans With Gulf War Illness

Since their return from military service in the 1990-1991 Gulf War, many Veterans have been affected by debilitating symptoms that are not easily explained. A leading hypothesis states that the combination of exposure to toxic chemicals and environmental stressors are responsible for a cluster of debilitating symptoms known as Gulf War Illness (GWI). Research has found that over-the-counter antioxidant supplements such as resveratrol may reverse the damage that causes these debilitating symptoms. Resveratrol is a nutrient found abundantly in the skin of red grapes that is known to have robust antioxidant and anti-inflammatory properties. The investigators predict that resveratrol treatment will improve memory issues, difficulties with thinking and mood problems in Veterans with GWI and that resveratrol will do so with minimal risk.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

A randomized controlled trial is proposed that will employ well-validated instruments and state-of-the-art techniques to assess improvements in cognitive functioning, functional status, mood, hippocampal neurogenesis and functional connectivity as well as anti-inflammatory and antioxidant effects of treatment with resveratrol. Design: The proposed study will be an intent-to-treat outpatient, randomized, double-blind, clinical trial of 93 Veterans who meet the Centers for Disease Control and Prevention and Kansas case definitions for GWI.

The study involves a comparison of resveratrol at a dose of 2000 mg and placebo. All doses will be administered orally once or twice daily. Doses of resveratrol at 500 mg will begin with a dose titration period. In order to reach a maximum dose of 2000 mg for the resveratrol, titration will begin at 500 mg for 6 weeks, then increased to 1000 mg for 6 weeks and increased to 1500 mg for 6 weeks and increased to 2000 mg for the remaining 6 weeks on treatment. Morning dosing will be taken with or before breakfast. Evening dosing will be taken with or before dinner.

Study Type

Interventional

Enrollment (Anticipated)

68

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Texas
      • Waco, Texas, United States, 76711
        • Recruiting
        • VISN 17 Center of Excellence for Research on Returning War Veterans
        • Contact:
        • Contact:
        • Principal Investigator:
          • Dena Davidson, Ph.D.
        • Sub-Investigator:
          • Bryann DeBeer, Ph.D.
        • Sub-Investigator:
          • Geoffrey May, MD
        • Sub-Investigator:
          • Steven Nelson, Ph.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

42 years to 66 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Served on active military duty and deployed to the Persian Gulf region August 1990 - July 1991;
  2. English speaking and able to understand the consent form and study questionnaires;
  3. Willing and able to be randomized to treatment and to commit to a 26-week study;
  4. Men and women between the ages of 44 to 68 (the number of 1990-1991 Gulf War Veterans who are older than 68 dramatically decreases because many of those with GWI have died prematurely);
  5. Meet the Kansas case definition for the diagnosis of GWI as well as the more inclusive CDC definition
  6. Stabilization on any psychiatric medication (≥3 months on selective serotonin reuptake inhibitor or monoamine oxidase inhibitor, ≥1 month on anxiolytic or beta-blockers);
  7. Female subjects of childbearing potential must test negative for pregnancy at the time of enrollment based on a serum pregnancy test and agree to use 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. 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:

  1. Unstable or poorly controlled diabetes type II (HbA1C >9.0);
  2. Cancer;
  3. Lifetime diagnosis of schizophrenia or bipolar disorder or a history of psychiatric hospitalization for, or current diagnosis (i.e., the past 6 months) of substance dependence;
  4. Major depressive disorder or posttraumatic stress disorder requiring hospitalization;
  5. Significant CNS disease including TIAs or stroke, dementia, syncopal episodes, severe head trauma, multiple sclerosis;
  6. Serious or advanced heart disease or clinically relevant abnormal electrocardiogram (ECG) or postural hypotension;
  7. Untreated sleep apnea or body mass index (BMI) placing patients at risk for undiagnosed sleep apnea (BMI≥35 kg/m2);
  8. Subjects with renal insufficiency or chronic renal disease defined by national Kidney Foundation Disease Outcome Quality Initiative criteria (2000) with a GFR less than or equal to 90 mL/min/1.73m2. Laboratory monitoring of CR and Bun and eGFR will be obtained at baseline and prior to each titration and at study end or early termination. If Cr and Bun increase above upper limit of normal and eGFR drops to <45 or more than 35% the study drug will be discontinued and a nephrology consult will be ordered;
  9. Liver enzymes >3 times normal on 3 consecutive laboratory tests; evidence of significant hepatocellular injury as evidenced by elevated serum levels of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 times the upper limit of normal (ULN); total or indirect bilirubin greater than 1.2 x ULN; alkaline phosphatase greater than 1.5 x ULN; prothrombin time (PT) as INR greater than 2.4 x ULN; or albumin less than 1 times the lower limit of normal (LLN) at baseline. Resveratrol is only anticipated to affect LFTs indirectly, by slowing statin metabolism. Persistent significant elevation of amino transferases are defined as >3x normal of normal upper limit on 2 consecutive measurements. Under the conditions of high dose statin therapy, it is typically addressed by temporarily stopping statin administration, then slowly titrating the dose back up under careful observation. Failure to reduce aminotransferase levels after the temporary cessation of statins (and a third LFT measurement is taken) would necessitate cessation of resveratrol treatment.
  10. Use of cytochrome P450 3A4 substrates with high risk of toxicity (e.g., terfenadine, cisapride, astemizole, disopyramide, amiodarone, dronedarone, colchicine, cyclosporine, quinidine, pimozide, cisapride, amlodipine, felodipine, nicardipine, nifedipine, nisoldipine, nitrendipin, nimodipine and verapamil);
  11. Use of blood thinners (e.g., Coumadin);
  12. Use of resveratrol-containing supplements.

    Participation in the scanning portion of the study is not required to participate in the clinical trial. Subjects who are interested in the scanning study will be asked to sign a second consent and will be screened for MRI-specific exclusion criteria. The additional exclusion criteria for participating in the MRI portion are listed below.

  13. General medical conditions that would prevent the participant from completing MRI scanning (active seizure disorder, dementia, active back or muscle spasms);
  14. Positive MRI safety screen for metal or history of penetrating head or eye wound without subsequent radiological evidence that the wound is metal-free;
  15. Participants that are (were) welders or that have had metal surgically removed from their eyes without radiological evidence that the wound is metal-free;
  16. MRI quality problems (tremors, significant claustrophobia);
  17. Shrapnel or other metal embedded in the body;
  18. Implanted orthopedic devices (e.g., metal rods, plates or screws but excluding nonferrous material);
  19. Implanted metal devices or prosthetics, or mechanical implants (e.g., pacemakers, electrical implants, cochlear implants);
  20. Implanted contraceptive devices (excluding those made of nonferrous material);
  21. Outside devices made of metal (e.g., neck braces, surgical staples, or artificial limbs), or non-removable dentures, braces or other metal orthodontics;
  22. Tattoos not done professionally or non-removable body piercings.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Resveratrol
Doses of resveratrol at 500 mg will begin with a dose titration period. In order to reach a maximum dose of 2000 mg for the resveratrol, titration will begin at 500 mg for 6 weeks, then increased to 1000 mg for 6 weeks and increased to 1500 mg for 6 weeks and increased to 2000 mg for the remaining 6 weeks on treatment.
resveratrol is an OTC supplement
Placebo Comparator: Placebo
Doses of placebo at 500 mg will begin with a dose titration period. In order to reach a maximum dose of 2000 mg for the placebo, titration will begin at 500 mg for 6 weeks, then increased to 1000 mg for 6 weeks and increased to 1500 mg for 6 weeks and increased to 2000 mg for the remaining 6 weeks on treatment
resveratrol is an OTC supplement

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in Cognitive Function
Time Frame: Baseline & Post (week 26)
CVLT-II: measure of cognitive functioning and memory
Baseline & Post (week 26)
Change from baseline in Mood
Time Frame: Baseline, Mid (week 13) and Post (week 26)
Beck Depression Inventory II
Baseline, Mid (week 13) and Post (week 26)
Change from baseline in Daily Functioning
Time Frame: Baseline and Post (week 26)
WHODAS 2.0: measure of disability and global health
Baseline and Post (week 26)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in Structural MRI Scans
Time Frame: Baseline & Post (Week 26)
Structural MRI scanning of hippocampus
Baseline & Post (Week 26)
Change from baseline in Diffusion Tensor Imaging
Time Frame: Baseline & Post (Week 26)
A diffusion tensor imaging scan of hippocampus
Baseline & Post (Week 26)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in Pro-inflammatory cytokines
Time Frame: Baseline & Post (Week 26)
IL-1β; TNF-α; IL-6; IL-1α; Interferon-Y; G-CSF/CSF3; GM_CSF/CSF2; IL-8; IP-10; RANTES; Resistin; PAI-1; IL-12; IL-13; Eotaxin-3; MCP-1; MIP-1α; IL-2; Leptin; Adiponectin; IL-17α; IL-4; IL10
Baseline & Post (Week 26)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Dena Davidson, Ph.D., VISN 17 Center of Excellence

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2018

Primary Completion (Anticipated)

August 31, 2022

Study Completion (Anticipated)

August 31, 2022

Study Registration Dates

First Submitted

August 8, 2018

First Submitted That Met QC Criteria

September 7, 2018

First Posted (Actual)

September 11, 2018

Study Record Updates

Last Update Posted (Actual)

September 11, 2018

Last Update Submitted That Met QC Criteria

September 7, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Gulf War Illness

Clinical Trials on Resveratrol

3
Subscribe