This project's objective is to identify effective treatments for Gulf War Illness (GWI). The project tests three potential treatments: curcumin, stinging nettle, and resveratrol. The project uses a decentralized clinical trial (DCT) design in which individuals can participate from anywhere in the United States. Recruitment efforts will be designed to obtain a geographically and demographically diverse study sample.

The project is funded by the Congressionally Directed Medical Research Programs (CDMRP) of the U.S. Department of Defense.

The study uses a prospective, pseudo-randomized, placebo-controlled, blinded, within-person clinical trial design. The trials are conducted decentralized, with all protocols performed remotely. Three-hundred individuals will be recruited in the study.

Recruitment for this study will come from a database of participant who have agreed to be contacted about future studies from our previous studies. Participants will also be recruited through the Gulf War Illness Clinical Trials and Intervention Consortium (GWICTIC) through our collaboration with Nova Southeastern University. The Consortium includes a database of individuals with Gulf War Illness who had agreed to be contacted for research studies. No other information will be shared with Nova Southeastern University unless specified and agreed upon. We will also use social media advertisements in partnership with High Level Marketing to recruit for this trial.

In accordance with the Institute of Medicine (IOM) 2014 guidance, participants must meet both the Kansas and CDC (Centers for Disease Control and Prevention) Case Definitions of GWI. Participants must have been deployed to the Persian Gulf Region during the 1990-1991 Gulf War, meet symptom domain criteria, and not have other exclusionary medical conditions.

All potential participants will fill out a online screening survey to assess eligibility. If they are deemed eligible for consent, participants will undergo a zoom meeting with a member of the study staff to sign the consent form. During that meeting, the study staff will explain the consent form in detail and answer any questions about the study or the consent form. The consenting process will follow the same procedure as typically done in face-to-face consenting, and the consent form will be digitally signed during or within 24 hours after the meeting. After providing informed consent, participants will take a post-consent survey to confirm eligibility before entering the study protocol.

Participants will also be required to obtain safety tests via LabCorp or Quest Diagnostics to assess renal and hepatic function, along with collecting C-Reactive Protein readings. Because kidney and liver function are important in the metabolism and excretion of the botanicals, it must be determined that these systems can tolerate the addition of a new daily treatment. All participants will received a baseline and mid-point test of kidney and liver function. Individuals with abnormal results on these tests will not proceed with the study or receive study botanicals. Participants can obtain the tests either at a local LabCorp or Quest Diagnostics site to have blood drawn for standard hepatic and renal panels. The hepatic panel includes measuring protein, albumin, globulin, albumin/globulin ratio, total bilirubin, indirect bilirubin, alkaline phosphatase, aspartate transaminase, and alanine transaminase. Results from the blood test will be sent to the participant at their request and to the study coordinator to confirm eligibility. The information will be de-identified and only associated with the individualized study identifier.

If eligible, participants will be randomly assigned a botanical in a double-blind fashion. Participants will then begin the baseline phase of 30 days. During that time, they will complete all baseline questionnaires and will also begin the weekly symptom severity reports and primary outcome measures. A research team member will speak with the participant to set up their electronic device connections and will verify the information is received. Participants will complete all weekly measures on a computer, tablet, or phone. Individuals without an appropriate device will be sent one by the research team. The VR-12 and PGIC secondary outcomes will be given once per week during the weekly questionnaire. The 30-day period will serve as the baseline phase for all analyses. During the baseline phase and after checking that there were no exclusionary kidney or liver concerns, participants will be sent capsules. Capsules will be sent via FedEx in blister packs that indicate what order to take the botanicals. The first shipment of capsules will contain two months of capsules. On Day 31, individuals will being taking the assigned capsules in the morning and again in the evening. During this time, they will continue completing weekly symptom reports, and weekly primary and secondary outcome reports. Participants will complete one month of baseline, eight months of capsules, and one month of endline. At Day 300, their participation will be successfully completed, and they will be fully debriefed by a member of the study team soon after completion.

Consented individuals will be randomized in a double-blind fashion to either the curcumin, resveratrol, or stinging nettle treatment. The curcumin, resveratrol, and stinging nettle trials all follow the same design and procedures. Participants will be blinded not only to the botanical they receive, but also to the schedule of receiving placebo and dosage changes. The randomization schedule will be held by Dr. Nancy Klimas and Dr. Amanpreet Cheema from Nova Southeastern University.

Placebo capsules will be created to keep the same appearance to treatment capsules. Both placebo (microcrystalline cellulose) and active treatment capsules will be over-encapsulated with the same gel caps. Participants will take the same number of capsules in the morning and night throughout participation so that individuals cannot determine when active treatment is initiated and when dosage is changed. Capsules for each day are stored in well-marked, daily blister packs that ensure the participants are taking the correct capsules.

Treatment adherence is using weekly surveys. All botanicals used in this study are commercially available, and there are no critical reagents to obtain. The botanicals are provided by Pure Encapsulations and Nature's Way. Weekly symptom reports begin during baseline. Participants are not aware of when they change conditions, as the appearance and number of capsules are kept the same throughout participation. Symptom severity reports are provided at the end of each week for the entire duration of participation, and primary outcome assessments (the Veterans Rand 12-Item Health Survey) are also given once per week.

In accordance with the Institute of Medicine (IOM) 2014 guidance, participants must meet both the Kansas and CDC (Centers for Disease Control and Prevention) Case Definitions of GWI. Participants must have been deployed to the Persian Gulf Region during the 1990-1991 Gulf War, meet symptom domain criteria, and not have exclusionary medical conditions. The case definitions will be used for inclusionary screening purposes.

Inclusion Criteria:

• Meets Kansas GWI Case Definition
• Meets CDC GWI Case Definition
• Able to commit to a 10-month study

Exclusion Criteria:

• Currently involved in an experimental treatment study
• Abnormal liver function values
• Abnormal kidney function values
• Currently pregnant
• Blood clotting disorder (contraindicated with all three botanicals)
• Reported diagnosis of diabetes with an A1C greater than 9
• The use of contraindicated medications (see below):
• Anticoagulant medications (such as warfarin, heparin, etc.)
• Lithium
• Tacrolimus (Prograf)
• Cancer medications (Alkylating agents, antitumor antibiotics, Topoisomerase I inhibitors, Tamoxifen)

The participant, the study PI, and the main research team will be blinded.