Curcumin, Resveratrol, and Stinging Nettle as Treatments for GWI

Study Overview
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Brief Summary
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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.

Detailed Description
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The project is funded by the Congressionally Directed Medical Research Programs (CDMRP) of the U.S. Department of Defense. The study uses a prospective, 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. 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. 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. All potential participants will undergo a live phone or zoom meeting with a member of the study staff before signing the consent form. A physical copy of the consent form will be sent to the individual, or they can print a copy of the blank 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 signed during the meeting. A hard paper copy of the consent form must be signed (no electronic consent signing will be used) and returned to the study staff via a provided envelope. After providing informed consent, they will begin the study protocol. They 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 daily symptom severity reports and the weekly 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 daily and weekly measures on a computer, tablet, or phone. Individuals without an appropriate device will be sent one by the research team. The daily reports will be given at each night before bed. The VR-12 and PGIC secondary outcomes will be given once per week with the daily questionnaire. The 30-day period will serve as the baseline phase for all analyses. During the baseline phase, individuals will also complete the renal and hepatic safety tests. 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 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 Quest Diagnostics site to have blood drawn for stand 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. Or, they can complete an at-home test with LetsGetChecked.com that requires a blood sample through a finger-prick. Results from the blood test will be sent to the participant and the study coordinator from testing site. The information will be identified and only associated with individualized study identifier. Consented individuals will be randomized in a double-blind fashion to either the curcumin, resveratrol, or stinging nettle treatment using a random process implemented with the Dacima clinical trial management software. This program will generate a botanical line code that can be broken only by the pharmacy technician or the PI, Dr. Younger. The randomization schedule will be held by Dr. Nancy Klimas and Dr. Amanpreet Cheema from Nova Southeastern University. 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. During the baseline phase and after checking that there were no exclusionary kidney or liver concerns, participants will be sent capsules for the placebo period. Capsules will be sent via FedEx in blister packs that track when medications are taken by scannable barcodes. On Day 30, individuals will being taking the assigned capsules in the morning and again in the evening. They will continue taking the placebo capsules for two months. During this time, they will continue completing daily symptom reports, and weekly primary and secondary outcome reports. The first shipment of capsules will contain two months of placebo, and the first month of the low-dose condition. 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 tracked in real-time using the MyMeds application. Each dose is packaged in blister packs with a scannable Quick Response (QR) code. The research staff will be alerted automatically if doses are missed or incorrectly used. All botanicals used in this study are commercially available, and there are no critical reagents to obtain. The botanicals are provided by PureEncapsulations and Nature's Way. Daily symptom reports begin on Day 0 at the start of 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 day for the entire duration of participation, and primary outcome assessments (the Veterans Rand 12-Item Health Survey) are given once per week. They will complete one month of baseline and eight months of capsules. At Day 300, their participation will be successfully completed, and they will be fully debriefed.

Official Title
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Curcumin, Resveratrol, and Stinging Nettle as Treatments for Gulf War Illness

Conditions
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Gulf War Syndrome

Intervention / Treatment
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* Dietary Supplement: Curcumin
* Dietary Supplement: Resveratrol
* Dietary Supplement: Stinging Nettle


Participation Criteria
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Eligibility Criteria
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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) Antiplatelet or anticoagulant medication use (contraindicated with all three botanicals)

Ages Eligible for Study
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Minimum Age: 45 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: Single Group Assignment
Interventional Model Description: The study uses a prospective, randomized, placebo-controlled, blinded, within-person clinical trial design. Individuals will be randomized in a double-blind fashion to either the curcumin, resveratrol, or stinging nettle treatment.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gulf War Veterans, Curcumin<br>All GWI Veterans will undergo the same screening and experimental procedures. 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. This trial tests three interventions, which are all tested independently. Participants will receive only one of the three interventions. The curcumin, resveratrol, and stinging nettle trials all follow the same design and procedures. Participants will complete one month of baseline, eight months of capsules, and one month of endline measurements. | Dietary Supplement: Curcumin<br>* 100 participants will be randomized to receive curcumin. Participants may receive placebo, low-dose (1000mg/day), medium-dose (2000mg/day), and/or high dose (3000mg/day) curcumin.<br>|
| Experimental: Gulf War Veterans, Resveratrol<br>All GWI Veterans will undergo the same screening and experimental procedures. 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. This trial tests three interventions, which are all tested independently. Participants will receive only one of the three interventions. The curcumin, resveratrol, and stinging nettle trials all follow the same design and procedures. Participants will complete one month of baseline, eight months of capsules, and one month of endline measurements. | Dietary Supplement: Resveratrol<br>* 100 participants will be randomized to receive resveratrol. Participants may receive placebo, low-dose (100mg/day), medium-dose (500mg/day), and/or high dose (1000mg/day) resveratrol.<br>|
| Experimental: Gulf War Veterans, Stinging Nettle<br>All GWI Veterans will undergo the same screening and experimental procedures. 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. This trial tests three interventions, which are all tested independently. Participants will receive only one of the three interventions. The curcumin, resveratrol, and stinging nettle trials all follow the same design and procedures. Participants will complete one month of baseline, eight months of capsules, and one month of endline measurements. | Dietary Supplement: Stinging Nettle<br>* 100 participants will be randomized to receive stinging nettle. Participants may receive placebo, low-dose (435mg/day), medium-dose (870mg/day), and/or high dose (2610mg/day) stinging nettle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Veterans Rand 12-Item Health Survey (VR-12) | This survey yields two scores: physical functioning (PCS) and mental functioning (MCS). These two scores will be tested as separate primary outcomes | 5 minutes per survey. This outcome will be assessed weekly, for up to 44 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Global Impression of Change (PGIC) | The Patient Global Impression of Change (PGIC) assesses overall quality of life improvement and is widely used in clinical trials. | 5 minutes per survey. This outcome will be assessed weekly, for up to 44 weeks. | 
| Number needed to treat (NNT) | The number needed to treat (NNT) is popular in clinical trial research and indicates the expected number of responders when used in the general GWI population. | This outcome will be assessed once, through study completion, an average of 44 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gulf War Illness, Botanicals, Remote, Clinical Trial