Treatment Study of Carnosine Versus Placebo in Gulf War Illness (GWI)

Study Overview
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Brief Summary
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The purpose of this study is to perform a randomized double-blind, placebo-controlled, 12 week study of the effects of carnosine on cognitive, psychometric, autonomic, and muscle strength outcomes in 100 GWI subjects.

Detailed Description
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Background: Homocarnosine (beta-alanine - gamma-aminobutyric acid) is one of the most abundant dipeptides in the brain. It has important antioxidant properties. Both beta-alanine and GABA are neurotransmitters, suggesting that cleavage of this dipeptide by carnosine dipeptidase 1 (CNDP1) may have important regulatory functions in vivo. Drug: Homocarnosine is not available. Carnosine (beta-alanine - histidine) is an over-the-counter dietary supplement that shares the antioxidant properties. We proposed that oral carnosine would be absorbed from the gut, cross the blood brain barrier, reduce presumed brain oxidant stress that participated in illness pathology, and improve subject health. Hypothesis: Carnosine supplementation for 12 weeks by mouth in Gulf War Illness subjects would improve cognitive and other outcomes compared to placebo treatment. Subjects: Gulf War Illness subjects met 1996 Fukuda criteria for Chronic Multisymptom Illness. Design: Pilot study. Double blind randomized placebo controlled with comparisons between Week 0 (Baseline, pre-randomization) and Week 12 (end of study) Outcomes: This pilot study included included cognitive testing, magnetic resonance imaging during the 2-back working memory task, self-report of psychometric and other subjective symptoms, tenderness testing by dolormetry, and pain threshold to assess reproducibility in the placebo-treated subjects, and potential treatment effects in the active study drug subjects. The study and each of the outcomes at weeks 0 and 12 are described in detail in the final published paper and in its extensive supplementary on-line materials (Baraniuk JN et al. Glob J Health Sci. 2013 5:69-81. PMID:23618477 PMCID:PMC4209301). An improvement on accuracy on the 2-back working memory task between 0 and 12 weeks was the primary outcome. Other evaluations were secondary outcomes.

Official Title
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Carnosine Versus Placebo Treatment Study in Gulf War Illness (GWI)

Conditions
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Persian Gulf Syndrome

Intervention / Treatment
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* Drug: Carnosine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of military enlistment between August 1, 1990 and July 31, 1991, and deployment for 30 consecutive days to: Persian Gulf waters and adjacent land areas, Other global locations, or, U.S. only. 1990-1991 enlistment status: Active duty National Guard Reserves Exclusion Criteria: HIV/AIDS Pregnant Women Active Duty Military Personnel Children Incarceration

Ages Eligible for Study
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Minimum Age: 34 Years
Maximum Age: 82 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Carnosine treatment group<br>Carnosine treatment group | Drug: Carnosine<br>* 500mg Carnosine x2 daily<br>* Other names: Pathway Carnosine supplied by Village Green Apothecary;|
| Placebo Comparator: Placebo control group<br>Placebo control group | Drug: Placebo<br>* Microcrystalline cellulose placebo tablets x2 daily<br>* Other names: Village Green Apothecary;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Carnosine Supplementation on Chronic Fatigue Syndrome Severity Scores | CFS Severity Score (Δ ≥ 5 / 36) (Baraniuk et al., 1998; Baraniuk et al., 2000a; Baraniuk, Naranch, Maibach, & Clauw, 2000b). Subjects scored the severity of the 9 CFS criteria (Fatigue, memory/concentration, sore throat, sore lymph nodes, sore muscles, sore joints, headache, sleep disturbances, exertional exhaustion from Fukuda et al. 1994) on a scale of none (score=0), trivial (1), mild (2), moderate (3) and severe (4). The sum was 36. Individuals taking carnosine were predicted to show a decrease of ≥ 5 at week 12 compared to week 0, compared to no change for placebo subjects. 2-tailed paired t-tests were used to determine significant incremental changes for individuals in the carnosine group compared to the placebo group. | Weeks 0 and 12 | 
| Subjects With Improved Diarrhea Symptoms | Patients were given questionnaires assessing common symptom complaints of diarrhea. | Weeks 0 and 12 | 
| Incremental Change in Fatigue Score From Baseline to Week 12 | Instantaneous Fatigue was scored as none (0) to severe (10) at week 0 and week 12. The difference between the Week 12 minus the Week 0 values was the incremental change. If the incremental change was greater than 0, then the Instantaneous Fatigue was worse at week 12 than week 0. If the incremental change was less than 0, then the Instantaneous Fatigue was improved at week 12 compared to week 0. The total potential range for incremental change was from -10 to +10. | Week 0 and Week 12 | 
| SF36 Bodily Pain | Incremental change in Medical Outcome Survey Short Form 36 questionnaire (SF36) Bodily Pain score from baseline to week 12. The Medical Outcome Survey Short Form 36 questionnaire (SF36) Bodily Pain score ranges from 0 (very bad bodily pain) to 100 (no bodily pain). The incremental change was the Medical Outcome Survey Short Form 36 questionnaire (SF36) Bodily Pain score at week 12 minus the Medical Outcome Survey Short Form 36 questionnaire (SF36) Bodily Pain score at baseline. The range of scores for incremental change was from -100 to +100. Scores of 0 for Medical Outcome Survey Short Form 36 questionnaire (SF36) Bodily Pain score at baseline and +100 at week 12 indicate an incremental change of 100 - 0 = +100. A score of 100 at baseline for the Medical Outcome Survey Short Form 36 questionnaire (SF36) Bodily Pain score at baseline of +100 at week 12 gives an incremental change of 0 - 100 = -100. | Week 0 and Week 12 | 
| Incremental Change in Generalized Anxiety Scale (GAD) Scores From Baseline to Week 12 | Each item on the Generalized Anxiety Scale (GAD) scores was scored as none (0), trivial (1), mild (2), moderate (3), or severe (4) and the sum of the 7 items calculated (range 0 to 28). The incremental change between Week 0 and Week 12 was determined for each treatment. | Week 0 and Week 12 | 
| Incremental Change in SF36 General Health Between Baseline and Week 12 | Incremental change in SF36 General Health score from baseline to week 12. The SF36 General Health score ranges from 0 (very bad General Health) to 100 (very good General Health). The incremental change was the SF36 General Health score at week 12 minus the SF36 General Health score at baseline. The range of scores for incremental change was from -100 to +100. Scores of 0 for SF36 General Health score at baseline and +100 at week 12 indicate an incremental change of 100 - 0 = +100. A score of 100 at baseline for the SF36 General Health score at baseline of +100 at week 12 gives an incremental change of 0 - 100 = -100. | Week 0 and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Digit Symbol Substitution (WAIS) | Digit Symbol Substitution (WAIS) test (Joy et al., 2000): Subjects were given a table of numerals with matching symbols, and a form with random numerals with open spaces. The objective was to write in as many symbols that corresponded to the random numerals within a 90 second period. Each subject was their own control. The outcome measure was the incremental change in this score between Week 0 and Week 12 (units on a scale). Higher scores indicate better performance. | Difference between Week 0 and Week 12 (end of study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carnosine, antioxidant, Persian Gulf War, Gulf War Syndrome, GWI, Gulf War Illness, Exercise, Chronic Fatigue, Fibromyalgia, Veterans, Irritable Bowel Syndrome, Migraine headaches, Neuropathy, Multiple Chemical Sensitivity