Persian Gulf Syndrome
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGCarnosine
500mg Carnosine x2 daily
DRUGPlacebo
Microcrystalline cellulose placebo tablets x2 daily
Sponsors
Georgetown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
34 Years to 82 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjects With Improved Diarrhea Symptoms | Weeks 0 and 12 | Patients were given questionnaires assessing common symptom complaints of diarrhea. |
| Incremental Change in SF36 General Health Between Baseline and Week 12 | Week 0 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. |
| Effect of Carnosine Supplementation on Chronic Fatigue Syndrome Severity Scores | Weeks 0 and 12 | 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. |
| Incremental Change in Generalized Anxiety Scale (GAD) Scores From Baseline to Week 12 | Week 0 and 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. |
| Incremental Change in Fatigue Score From Baseline to Week 12 | Week 0 and 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. |
| SF36 Bodily Pain | Week 0 and Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Digit Symbol Substitution (WAIS) | Difference between Week 0 and Week 12 (end of study) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carnosine Treatment Group A double blinded placebo controlled study. The pharmacy at Georgetown University Medical Center, will blind the Carnosine. Veterans who meet GWI criteria will be given 500mg Carnosine x2 daily for 12 weeks. | 18 |
| Placebo Control Group A double blinded placebo controlled study. The pharmacy at Georgetown University Medical Center, will blind the Placebo. Controls who are aged and gender match and do not meet GWi and other exclusionary criteria microcrystalline cellulose placebo tablets x2 daily for 12 weeks. | 15 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 4 | 2 |
Baseline characteristics
| Characteristic | Carnosine Treatment Group | Placebo Control Group | Total |
|---|---|---|---|
| Age, Continuous | 51.8 years STANDARD_DEVIATION 11.6 | 47.2 years STANDARD_DEVIATION 8.7 | 49.5 years STANDARD_DEVIATION 10.2 |
| Region of Enrollment United States | 18 participants | 15 participants | 33 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 14 Participants | 10 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 12 | 0 / 13 |
| serious Total, serious adverse events | 0 / 12 | 1 / 13 |
Outcome results
Primary
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.
Time frame: Weeks 0 and 12
Population: Significant numbers of subjects dropped out of both arms of the study. The primary reason given was perceived lack of efficacy.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Carnosine Treatment Group | Effect of Carnosine Supplementation on Chronic Fatigue Syndrome Severity Scores | -3.8 units on a scale |
| Placebo Control Group | Effect of Carnosine Supplementation on Chronic Fatigue Syndrome Severity Scores | -2.0 units on a scale |
Comparison: Description of Power Calculation: The planned sample size completing each arm was based on individual incremental improvements in the primary outcomes of : A) CFS Severity Scores (Baraniuk et al., Annals Allergy Astma Immunol, 1998), B) Instantaneous Fatigue (Kim et al. Journal of Rehab Res Dev, 2010), and C) increased accuracy of 4/35 letters for 2 back working memory task (Owen, Human Brain Mapping, 2005).p-value: 0.3t-test, 2 sided
p-value: 0.4t-test, 2 sided
Primary
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.
Time frame: Week 0 and Week 12
Population: Number of participants with evaluable data who completed the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Carnosine Treatment Group | Incremental Change in Fatigue Score From Baseline to Week 12 | 0.3 units on a scale |
| Placebo Control Group | Incremental Change in Fatigue Score From Baseline to Week 12 | -0.6 units on a scale |
Primary
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.
Time frame: Week 0 and Week 12
Population: Number of participants with evaluable data who completed the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Carnosine Treatment Group | Incremental Change in Generalized Anxiety Scale (GAD) Scores From Baseline to Week 12 | 0.2 units on a scale |
| Placebo Control Group | Incremental Change in Generalized Anxiety Scale (GAD) Scores From Baseline to Week 12 | -0.9 units on a scale |
p-value: 0.5t-test, 2 sided
Primary
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.
Time frame: Week 0 and Week 12
Population: Number of participants with evaluable data who completed the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Carnosine Treatment Group | Incremental Change in SF36 General Health Between Baseline and Week 12 | 0.5 units on a scale |
| Placebo Control Group | Incremental Change in SF36 General Health Between Baseline and Week 12 | 6.5 units on a scale |
p-value: 0.5t-test, 2 sided
Primary
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.
Time frame: Week 0 and Week 12
Population: Number of participants with evaluable data who completed the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Carnosine Treatment Group | SF36 Bodily Pain | 5.6 units on a scale |
| Placebo Control Group | SF36 Bodily Pain | -0.5 units on a scale |
p-value: 0.5t-test, 2 sided
Primary
Subjects With Improved Diarrhea Symptoms
Patients were given questionnaires assessing common symptom complaints of diarrhea.
Time frame: Weeks 0 and 12
Population: Participants with evaluable data at the end of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carnosine Treatment Group | Subjects With Improved Diarrhea Symptoms | 5 participants |
| Placebo Control Group | Subjects With Improved Diarrhea Symptoms | 1 participants |
p-value: 0.018Fisher Exact
Secondary
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.
Time frame: Difference between Week 0 and Week 12 (end of study)
Population: 2 carnosine subjects had incomplete data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Carnosine Treatment Group | Digit Symbol Substitution (WAIS) | 10.8 units on a scale |
| Placebo Control Group | Digit Symbol Substitution (WAIS) | 2.7 units on a scale |
p-value: 0.0018t-test, 2 sided
p-value: 0.6t-test, 2 sided