Conditions: Gulf War Illness Chronic Fatigue Ubiquinol Coenzyme Q10
Keywords: Chronic Pain Cognitive Disorders Inflammation Neurologic manifestations Dementia Mental Disorders Ubiquinol/ubiquinone Pathologic Processes Nervous System Diseases Hormones, Hormone Substitutes, and Hormone Antagon Anti-Inflammatory Agents Pharmacologic Actions Therapeutic Uses Physiological Effects of Drugs Gulf war illness Chronic fatigue
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: no

Brief summary:
The primary objective of this clinical trial is to determine if treatment with ubiquinol, a form of coenzyme Q10, improves the physical function of men and women Veterans suffering from Gulf War Illness (GWI). The primary outcome measure is a change from baseline on the Short Form Health Survey 36-item (SF-36), with respect to physical functioning and symptoms. Secondary outcome measures include changes from baseline levels on GWI-associated biomarkers in peripheral blood and GWI-associated symptoms of chronic pain, fatigue, insomnia, activity level, and cognitive and mental functioning.

Detailed description:
As many as a third of the nearly 700,000 military personnel deployed during Desert Shield and Desert Storm (Aug 2, 1990 to July 31, 1991) in the Kuwaiti Theater of Operations are suffering from Gulf War Illness (GWI), an unexplained chronic illness characterized by multiple symptoms. Gulf War Veterans experienced environmental exposures that are known to be oxidative stressors which contribute to cell injury, resulting in mitochondrial dysfunction Exploratory studies using interventions that support cell functioning and prevent or repair stress mediators suggest a role for these targeted interventions, such as Coenzyme Q10. The goal of this clinical trial is to determine if Coenzyme Q10 is effective in increasing physical functioning for Veterans with Gulf War Illness.

This is a randomized, two group, double blind, placebo controlled, Phase III clinical trial. The treatment group will receive a (2x200 mg for 2 months and 1x200 mg for 4 months) once a day of ubiquinol for 6 months. The placebo group will receive matching placebo (2x200 mg for 2 months and 1x200 mg for 4 months) once a day of ubiquinol for 6 months. The primary outcome measure for this clinical trial is a change from baseline of SF-36, with respect to physical functioning and symptoms. The secondary outcome measures include changes from baseline of peripheral blood levels of biomarkers, and of GWI-associated symptoms of chronic pain, fatigue, sleep issues, and cognitive impairment.

Arms:
arm 1: Take oral tablets as directed (2x200 mg for 2 months; 1x200 mg for 4 months) with food each morning- upon waking arm 2: Take oral tablets as directed (2x200 mg for 2 months; 1x 200 mg for 4 months) with food each morning-upon waking

Interventions: intervention 1: Ubiquinol intervention 2: Placebo
Intervention descriptions: intervention 1: Take oral tablets as directed (2x200 mg for 2 months; 1x200 mg for 4 months) with food each morning- upon waking intervention 2: Take oral tablets as directed (2x200 mg for 2 months; 1x200 mg for 4 months) with food each morning- upon waking

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
A Randomized, Double-blind, Placebo-controlled, Phase III Trial of 
Coenzyme Q10 in Gulf War Illness 
 
NCT 02865460 
February 19, 2020 
 


1 
 
Approval:  Miami VA Healthcare System IRB 2/19/2020
 
 
Background and Rationale 
As many as a third of the 700,000 US troops deployed to the Middle East during the 1990-1991 Gulf War are 
currently ill with a multi-symptom illness termed Gulf War illness (GWI). Investigators have been investigating the 
cause and potential treatments of the illness or its symptoms for two decades, but to date there have been no 
successful Phase III trials, and no established treatments beyond palliation of individual symptoms and behavioral 
aids to coping with chronic illness. There have been significant advances in our understanding of the illness through 
strong epidemiology, clinical, and basic science studies. However, studies revealed problems with detoxification 
pathways and clinicians report high levels of drug intolerance in the population, reducing therapeutic options. Gulf 
War veterans experienced environmental exposures that are known to be oxidative stressors which have contributed 
to cell injury, resulting in OS-induced mitochondrial dysfunction, findings also supported in pathogenesis studies. This 
suggested interventions that would support mitochondrial function and prevent or repair active oxidative stress 
mediators and led to exploratory studies using interventions that target these areas. These early intervention studies 
included a Phase I/II clinical trial of Coenzyme Q10 (CoQ10) by Dr. Beatrice Golomb and her team at the VA in San 
Diego, CA. In a double blind, placebo controlled crossover study of CoQ10, 46 veterans with GWI who met both the 
Kansas and CDC case definition were treated with 100mg or 300mg of a high bioavailability CoQ10 (ubiquinone) 
product or placebo. They found a significant improvement in men with GWI vs. placebo using their selected primary 
outcome variable, the general self-rated health (GSRH), in a sex-stratified analysis. 
Results revealed that women did not see the same degree of improvement and failed to see significant 
change, though the sample size was small (7 female veterans). The GSRH showed no significant benefit in the 
combined-sex sample. The 100 mg product saw a bigger improvement, thought to be secondary to the activating 
effects of the nighttime dose of the 300mg split dose product when given as a bedtime dose, interfering with quality 
of sleep. Physical function (summary performance score, SPS) improved on Q100 vs. placebo. A rise in CoQ10 
levels approached significance as a predictor of improvement in GSRH and significantly predicted SPS 
improvement. Among 20 symptoms each present in half or more of the enrolled veterans, direction-of-difference on 
Q100 vs. placebo was favorable for all except sleep problems; with several symptoms individually significant 
(Golomb, et al., 2014). Significance for these symptoms, despite the small sample, underscores large effect sizes, 
and an apparent relation of key outcomes to CoQ10 change increases prospects for causality. The authors 
concluded that Q100 conferred benefit to physical function and symptoms in veterans with Gulf War illness and 
that examination in a larger sample is warranted; and that findings from this study could inform the conduct of a 
larger trial. The VA GWI Research Advisory Committee encouraged the research service to consider conducting 
Phase III studies for any pilot treatment trials that showed initial positive effects on the symptoms of GWI in Gulf War 
Veterans. Since few treatment studies to date have shown positive results, initiating a Phase III treatment trial of 
CoQ10 at this time is of the utmost importance to providing some relief to ailing GW Veterans who currently have 
very few treatment options. 
 
Relevant Literature on CoQ10 Mechanism of action 
In an excellent review by Than, et al. (2001), a strong case was made for the use of CoQ10 in cardiovascular disease 
and illnesses of low cellular energy states. Coenzyme Q10, a lipid-soluble benzoquinone with a 10 isoprenyl unit side 
chain, is structurally similar to vitamin K (Greenburg et al., 1990). Coenzyme Q is distinguished by the number of 
isoprenoid subunits in the side-chains. The most common Coenzyme Q in human mitochondria is Q10. Q refers to the 
quinone head and 10 refers to the number of isoprene repeats in the tail. 
The biosynthesis of the compound is complex, with the isoprenyl side chain deriving from mevalonate, the 
benzoquinone ring structure from tyrosine, and condensation of these structures through polyprenyl transferase 


2 
 
enzyme activity (Olsen, et al., 1983). The primary regulation of CoQ10 biosynthesis is the 3-hydroxy-methylglutaryl 
coenzyme A (HMG-CoA) reductase reaction, similar to that seen in cholesterol synthesis. Coenzyme Q10 is an 
essential component in the synthesis of ATP and exhibits both antioxidant and membrane-stabilizing properties. 
Present in the inner mitochondrial membrane, it serves as an electron transport carrier during the processes of 
respiration and oxidative phosphorylation, and it has involvement in the manufacture of ATP. Coenzyme Q10 directly 
regulates NADH and succinate dehydrogenase, enabling reversible reactions between these enzymes in the 
mitochondrial electron transport chain (Folkers et al, 1993; Greenburg et al, 1990). Coenzyme Q10 also may prevent 
the depletion of metabolites necessary for the resynthesis of ATP (Greenburg et al., 1990). The compound must be 
reduced to ubiquinol to wield its antioxidative function, and supplementation may inhibit lipid oxidizability. During 
supplementation with CoQ10, the level of lipid peroxidation decreased in healthy subjects, yet levels of another 
antioxidant, vitamin E, remained constant (Weber et al., 1994; Alleva, et al., 1995). Coenzyme Q10 exerts a sparing 
effect on vitamin E and perhaps more efficiently prevents lipid peroxidation by inhibiting both its initiation and 
propagation, whereas vitamin E inhibits only propagation (Ermster et al., 1993). The membrane-stabilizing properties of 
CoQ10 emerge from the reduction of free radicals that may cause damage to structural proteins and lipids found in 
membranes. 
Other important activities may include stabilization of calcium-dependent slow channels, inhibition of 
intracellular phospholipases, and alteration of prostaglandin metabolism (Greenberg et al. 1990). The positive 
inotropic effect of CoQ10 is reported to be similar to the effects of digoxin (Murray et al., 1996). Coenzyme Q10 was 
also recognized to have an effect on gene expression that might account for its effects on overall tissue metabolism 
and inflammation. (Groneberg et al., 2005; Schmeizer et al., 2008). This is relevant, considering the observation of a 
reduced cardiac output in GWI subjects a finding more severe in those with comorbid PTSD (Peckerman et al., 2003). 
 
Pharmacokinetics of CoQ10 
A pharmacokinetic study showed oral administration of CoQ10 30 mg in healthy subjects can significantly increase 
the mean peak blood level to about 1 µg/ml within an average of 6 hours, with a second peak occurring again at 24 
hours after dosing (Lucker, 1984). These findings corroborate those of studies in the existing pharmacokinetic 
literature that examined higher dose (Tomono, et al., 1986; Yuzuhiro, et al., 1983). The increase observed in plasma 
CoQ10 levels 24 hours after dosing may suggest enterohepatic recycling (Tomono et al., 1986). Maximum 
concentrations achieved from the administration of 30-mg doses either as a meal or capsule in healthy subjects did 
not differ significantly (Lucker, 1984). Administration of 100 mg 3 times/day achieved a mean steady-state level that 
was estimated at 5.4 µg/mL, which may be up to 7 times higher than endogenous levels of CoQ10 (Murray,1996). 
The plasma half-life is approximately 34 hours and is indicative of the low clearance rate from plasma and would 
support once a day dosing strategies (Overvad, 1999; Greenberg, 1990). 
On deposition in the liver, exogenous CoQ10 is packaged into low-density lipoprotein and very low-density 
lipoprotein fractions of cholesterol and highly concentrates in tissues of the heart, liver, and kidneys (Weis, 1994). 
The slow absorption of CoQ10 from the gastrointestinal tract can be attributed to the coenzyme's high molecular 
weight and low water solubility. Coenzyme Q10 is a lipophilic molecule and therefore can display variability in 
absorption depending on the formulation. In a trial comparing different formulations that included combinations of 
polysorbate, lecithin, or soybean oil, results indicated highest bioavailability with the soybean oil-only formulation 
(Weis, 1994). Preparations of CoQ10 that contain lipid vehicles, such as vegetable oil and vitamin E, increase 
solubility and yield more efficient absorption rates than that of the purified coenzyme alone (Chopra, 1995). The 
extent of hepatic metabolism is unknown, and the excretion of CoQ10 is mainly through the biliary tract, with over 
60% of an oral dose recovered unchanged in the feces (Greenberg, 1994). 
The available information would argue for an oil based CoQ10 supplement, in either the reduced form 
(ubiquinol) or precursor (ubiquinone). Because Dr. Golomb’s study of CoQ10 in higher doses (300 mg bid) saw a 
loss of efficacy with bid dosing, thought to be a result of increased evening energy and reduced sleep (personal 
communication), and because they saw the best responses in those with the biggest change from baseline CoQ10 
plasma levels, we would propose a daily morning dosing strategy with the more highly bioavailable formulation, 
ubiquinol, in a dose substantial enough to have proven health impact in other conditions of low cellular energy and 
chronic oxidative stress. 


3 
 
The role of CoQ10 in chronic illnesses and symptom management: The role of CoQ10 can be rationalized in 
numerous conditions based on its involvement in the mitochondrial electron transport chain leading to synthesis of 
adenosine 5´-triphosphate (ATP) and on its possession of antioxidant and membrane-stabilizing properties The 
health benefits of CoQ10 have been recognized in the medical literature to ameliorate symptoms experienced by 
Gulf War veterans with GWI such as headaches, muscle pain, or weakness and cognitive symptoms. CoQ10 has 
shown benefits for medical conditions such as congestive heart failure, essential hypertension, stable angina, 
doxorubicin cardiotoxicity, ventricular arrhythmias, cardiomyopathy, breast cancer, acquired immunodeficiency 
syndrome, diabetes, muscular dystrophy, and periodontal disease and as prophylaxis for heart surgery, with differing 
degrees of efficacy (Jellin et al., 1993). Furthermore, the existence of deficient endogenous levels of CoQ10 is 
associated with a variety of these disorders and is particularly well documented in heart failure. A deficiency of 
CoQ10 appears to be directly related to severity of symptoms and disease (Mortenson, 1993). Either an increased 
requirement or a decreased production of CoQ10 with advancing age contributes to a reduction of the endogenous 
level of this pro-vitamin. Low endogenous levels of CoQ10 can also be the result of inadequate nutritional intake, a 
genetic defect in biosynthesis, or a depletion of vitamins, trace elements, or other precursors necessary for CoQ10 
biosynthesis (Murray, 1996; Greenberg, 1990). The CoQ10 levels in GWI have not been reported except in the 
Golomb study, which showed highly variable baseline levels. While an analysis was not provided on response as it 
related to baseline levels, degree of change from baseline seemed predictive of best responders (personal 
communication). 
Migraines are a common feature of GWI, and there is some evidence that migraines may be a 
mitochondrial disorder (Markley, 2012). Supplementation of CoQ10 appears to give relief from 
migraines, as suggested by a study where patients who experience migraines took 150 mg CoQ10 
daily for three months and demonstrated a 50-percent reduction in number of days with migraine headache. 
(Rozen et al., 2002). Coenzyme Q10 was superior to placebo for attack-frequency, headache-days and days 
with nausea in another randomized controlled trial (Sandor et al., 2005). A study of patients with 
cardiovascular disease highlighted the anti-inflammatory and antioxidant properties of CoQ10. In a 
randomized, placebo-controlled trial of coronary artery disease patients, study results revealed that following 
use of CoQ10, antioxidant enzymes activities were significantly higher, and markers of inflammation were 
significantly lower (Lee et al., 2013). 
In another study, patients with fibromyalgia participated in a Phase II randomized, double-blind, placebo- 
controlled trial where CoQ10 supplementation induced a recovery of inflammation, antioxidant 
enzymes, mitochondrial biogenesis and AMPK (5' adenosine monophosphate-activated protein kinase) gene 
expression levels. The study participants demonstrated a reduction in pain, tender points, fatigue, 
and morning tiredness. The investigators concluded that CoQ10 may have a potential therapeutic effect in fibromyalgia 
and may indicate new potential molecular targets for the therapy of this disease (Cordero et al., 2013). Further support 
of CoQ10 supplementation to increase antioxidant enzyme activity, reduce oxidative stress, and improve symptoms of 
fatigue and depression was demonstrated in a study of patients diagnosed with multiple sclerosis (Sanoobar et al., 
2013). 
The use of CoQ10 on the treatment of neurodegenerative diseases such as Parkinson’s and Huntington’s 
that focus on symptoms reveal disappointing results in recent studies (Lin and W ang,2014). Clinical trials of 
CoQ10 for Huntington’s disease and ALS patients did not show positive results (Kaufman et al., 2009; Mestre et 
al., 2009) A large multicenter study of escalating high dose up to 2400 mg CoQ10 for patients with Parkinson’s 
disease saw no difference in their progression rates symptom or scores, although the treatment was well 
tolerated without significant side effects. (Parkinson’s Study Group QE3 Investigators, 2014). In terms of the 
effects of CoQ10 on cognitive performance, several recent animal studies indicate benefits that encourage 
further research on human subjects. The beneficial effects of CoQ10 were demonstrated in a recent study of rats 
against organophosphate-induced cognitive impairments and hippocampal neuronal degeneration (Binukumar et 
al., 2012), in a GWI animal model. In another study of mice to evaluate the effect of CoQ10 on the role of 
mitochondrial functions in cognitive impairment, the study results indicate that CoQ10 improves cognitive decline 
in post-menopausal state by modulating mitochondrial functions and oxidative stress (Sandhir et al., 2014). 
Improvements in cognitive performance were indicated in a mouse model of Alzheimer’s disease that showed 
that CoQ10 also reduces oxidative stress and amyloid pathology (Dumont et al., 2011). Poorer cognition was 
correlated with lower levels of CoQ10 in the parietal cortex in a study of aged dogs (Martin et al., 2011). 


4 
 
Recognizing the antioxidant properties of CoQ10 and its role in proper mitochondrial function, these studies 
support further research of CoQ10’s role in cognitive health. 
 
Safety and Tolerability and Dosage 
Excellent safety and tolerability is a common feature of CoQ10 clinical trials results across multiple disease states, 
formulations, and dose ranges from 50 to 3600 mg daily. The most common adverse effects are gastrointestinal in 
nature and can include nausea, epigastric pain, diarrhea, heartburn, and appetite suppression. However, the 
prevalence of these adverse effects was less than 1% in reported studies (Jelin, 1999). Gastrointestinal effects of 
CoQ10 may be lessened with a dosage reduction or may subside with continued therapy. Asymptomatic elevations in 
serum lactate dehydrogenase and hepatic enzymes were observed and may occur with oral dosages of CoQ10 in 
excess of 300 mg/day; however, cases of serious hepatotoxicity have not been reported (Greenberg, 1990; 
Micromedix, 2014). In congestive heart failure studies, clinical relapse was noted on withdrawal of CoQ10, whereas 
reinstatement of therapy resulted in improvement (Mortenson, 1990; Mortenson, 1985). We selected a formulation 
that has been used in prior clinical trials in other disease states and have published safety data, bioavailability data as 
well as efficacy data (Chandran et al., 2012; Sanmukhani et al., 2014; Kizhakkedath et al., 2013; Kern, 2011). Based 
on the literature review of treatment responses in other illnesses and Dr. Golomb’s experience we will use ubiquinol 
200 mg (the equivalent of ubiquinone 600mg) as a morning dose, to avoid evening side effects of sleeplessness and 
to optimize its bioavailability, after a 2 month loading dose of 400 mg to restore any deficiency states. 
 
FDA Approvals 
We requested a pre-IND meeting with the FDA. As we anticipated the FDA waived the need for a full IND review. 
The nutraceutical CoQ10 is widely used, and the target of treatment focuses on a reduction in symptom severity. 
CoQ10 is a nutraceutical that has been evaluated by the United States Food and Drug Administration and approved 
as being classified as “GRAS” (generally recognized as safe), available in this country without prescription at the 
doses being studied. 
 
Study Objectives and Specific Aims 
In this study, we will assess the clinical efficacy and safety of CoQ10 (ubiquinol) in 200 veterans with GWI, in a classic 
double-blind, randomized, placebo-controlled trial, with 100 participants per treatment arm of the study. Subjects will 
be recruited at four geographically different sites. 
 
Objectives: 
1. To determine the efficacy of CoQ10 in GWI related symptom control; 
2. To evaluate putative biomarkers for their ability to predict severity and response to therapy; 
3. To test the utility of measures of illness severity and function as outcome variables in GWI. 
 
Specific Aims: 
1. Perform a randomized, double blind, placebo control, Phase III study comparing CoQ10 (ubiquinol) (200 mg q 
am) to placebo, with a 6 month intervention and assessment of safety, efficacy and biomarker response to therapy; 
2. Perform biomarker studies before and after 2, 4, and 6 months of therapy, with blood and saliva collections and 
laboratory assessments of oxidative stress and mitochondrial function, CoQ10 levels, cytokine, neuropeptide, 
hormone and cell population studies; 
3. Assess the domains of illness and illness severity and evaluate the utility of the selected instruments for future 
clinical trials use in GWI. 
 
The primary objective is to assess efficacy. The primary endpoint will be the SF36 physical subscore, selected for 
its sensitivity to the impact of this illness. We will assess a number of secondary outcome variables, as there are few 
large longitudinal studies in GWI and this study can provide data on the best instruments to utilize in the clinical trials 
setting, covering the key domains of the illness. Therefore, the secondary endpoint instruments will include 
objective measures of activity and cognitive function, the Conners CPT-3, Brief Visual Memory Test, and the 
California Verbal Learning Test-I, as well as self-report instruments to include the SF36 mental and total scores, the 
Health Symptom Checklist (HSC) adapted for severity and frequency scoring, the Multidimensional Fatigue 


5 
 
Inventory, Checklist Individual Strength (CIS), Cognitive Difficulties Scale, Pittsburgh Sleep Inventory, and Brief Pain 
Inventory. Each of these instruments are well established assessment tools that are validated in complex medical 
illnesses. The HSC is unique to GWI but is quite similar to the instrument validated in ME/CFS, the DePaul 
Symptom Survey (Jason et al 2010). The HSC is a list of 34 frequently reported health and mental health symptoms 
rated as how often in the past 30 days the symptoms were experienced. Symptoms from 9 body systems are 
assessed (cardiac, pulmonary, dermatological, gastrointestinal, genitourinary, musculoskeletal, neurological, and 
psychological). The HSC classification method was developed by VA Boston investigators and has been used in the 
longitudinally following 2,949 member Ft. Devens, MA Gulf War veteran cohort to assess self-reported health 
symptoms incrementally over the past 24 years (Proctor et al., 1998; Wolfe et al., 1998). It was originally adapted 
from the 20-item health symptom checklist of Bartone et al., (1989). Biomarkers, identified in our earlier GWI 
studies, will also serve as secondary outcome variables to better design future clinical trials with surrogate markers 
(Whistler et al., 2009; Broderick et al.; 2011; Broderick, et al., 2012; Broderick, et al., 2013). We have reported that 
SF36 measures for physical function, physical limit, pain, and vitality cluster together and were linked to IL-1α, IL-2 
and IL-5 levels. MFI indicators were more diffuse in their association with reduced motivation, for example, standing 
apart and correlating positively with changes in IL-4, 12 and IL-10. SF36 general score also stood apart and 
correlated negatively with levels of IL-10. Of the 6 cytokines that remained in the sub-network, IL-10 had the 
broadest effects on severity with direct connections to 6 symptom constructs including SF36 social function which 
itself supported a cluster of 10 symptoms. We propose to include a cytokine multiplex assay to assess pro- 
inflammatory, TH1, Th2, Th17 and anti-inflammatory cytokines as putative biomarkers in GWI. We will also assay 
CoQ10 levels, oxidative stress and other mitochondrial measures. Two other objective domains of illness will be 
assessed. Activity measurement using the FitBit will be utilized as an objective marker of activity and an indirect 
measure of sleep efficiency. This measurement can also be used to assess relapse after activity rates by looking for 
rest pattern responses after bursts of sustained activity. Secondary outcomes will include measures from a 
previously validated assessment of cognitive function in GW veterans (Sullivan et al., 2003). 
 
Research Design and Methods 
 
Study Design and Population. The proposed project utilizes a multi-site, Phase III double blind, placebo controlled 
design of CoQ10 in a total of 200 1991 Gulf War veterans at four VA clinical study sites: Miami (n=50 veterans), 
Boston (n=50 veterans), Bronx (n=50 veterans), and Minneapolis (n=50 veterans) recruited from among veterans 
attending VA GW clinics The study includes a large number of GWI cases to enhance the study’s power to evaluate 
GWI subgroups of potential importance (e.g. subgroups associated with illness severity, exposure history, and 
gender). The Phase III placebo control clinical trial will be designed as a 6-month intervention in a group A to group 
up B comparison. With this study design we will compare groups A and B, in addition response rate across 3 
assessment times and/or recovery from any adverse events will be studied. Dosing will reflect the standard dosing 
used in illnesses that presume mitochondrial dysfunction or oxidative stress mechanisms for relevant and 
associated conditions we are using a nutraceuticals (ubiquinol) w i t h established safety profiles at doses that 
exceed the proposed treatment range, and efficacy profiles established in other diseases. 
 
Study Surveys and Questionnaires 
The Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I) (First, et al., 1996): Computer 
driven interview format assessment to diagnose current and lifetime DSM-IV Axis 1 psychiatric disorders. These 
include mood, anxiety, psychotic, substance abuse, eating and somatoform disorders. (Staff administered, staff 
trained by Dr. Krengel and Sullivan’s group, Boston VAMC/BU) In this Phase III study, there will be a broad panel 
of variables measured. These will include the GWI Health Symptom Checklist (HSC), a list of the domains 
noted in the GWI case definitions (previously determined by factor analysis), with a visual analog severity scale, 
including current, worst day and best day scales which we have further adapted to include frequency of symptom. 
Further emphasis on the domains of GWI will include measures of biomarker studies. Multidimensional Fatigue 
Inventory (MFI) (Smets, et al, 1995). The Pittsburgh sleep inventory (short form) measuring quality of sleep, 
patient assessment of Pain (by a 10-cm visual analog scale, in which 0 = no pain and 10 = the worst pain 
possible), (Note that the PE also includes a quantitative tender point evaluation), Medical Outcomes Study 36- 
item short-form health survey (SF-36) (Ware and Sherborne, 1992): This instrument is a general indicator of 


6 
 
health status (function and well-being) with physical and emotional subscales. The SF-36 assesses health-related 
quality of life in 8 areas: 1.) Limitations in physical activities because of health problems; 2.) Limitations in social 
activities because of physical problems; 3.) Limitations in usual role activities because of physical health 
problems; 4.) Bodily pain; 5.) General mental health; 6.) Limitations in usual role activities because of emotional 
problems; 7.) Vitality (energy and fatigue); and 8.) General health perceptions. For the Gynecologic 
Questionnaire, female subjects are asked to complete this questionnaire to assess routine gynecologic 
parameters and time of assessment as it relates to menstrual cycle. In our operationalization, we sync the first on 
site (T0) assessment with estrous phase in menstruating subjects. Ham-D, Ham-A (Hamilton, 1959) measuring 
depression and anxiety; Davidson Trauma Scale (Davidson et al, 1997) is designed to assess symptoms of 
PTSD in three clusters: intrusion, avoidance, and hyperarousal. While not exclusion criteria unless hospitalized for 
PTSD in the prior 3 years, this information is collected to establish subpopulations and inform the understanding of 
results. Gulf War Exposures Questionnaire includes questions regarding military service and career and 
experiences in the Persian Gulf region. Cognitive function will be assessed, as described in Table 2. Another 
objective measure, the activity monitor, Fitbit counts steps, stairs, heart rate, periods of inactivity, that can 
tabulate this indirect measure of hours of sleep, restless periods of sleep, awake periods during sleep, and naps. 
For the purpose of this study, it will be worn on the wrist continuously for 28 weeks. It does not need to be 
removed during water exposure (swimming, showering, etc.), and will be given to the participant as a gift for 
participating in the study. In earlier studies using actigraph, non-adherence due to forgetfulness after bathing 
compromisted the results. The Fitbit data has near 100% compliance in current studies (Klimas, personal 
communication) and has the advantage of continuously updating the data in Wi-Fi environments, reducing the risk 
of lost data due to lost devices. Participants will also keep a sleep and activity diary as a validation step. 
Autonomic nervous system measures include measurement of blood pressure and heart rate in laying and 
standing positions. Subjects are recumbent for 30 minutes and stand for five minutes and ten minutes. Blood 
pressure and heart rate are measured at lying and after five and ten minutes of standing. For the virtual platform, 
autonomic measures, pressure point, lymph node and physical exam will not be performed and laboratory tests will 
be combined for the screening and baseline visits. During the screening visit, (after signed consent is received), the 
tests will include all baseline tests and the exclusion tests. The Coordinator will instruct the virtual participant on 
use of a personal blood pressure monitor. 
 
 
Table 1. Assessment Platform and Timeline 
 
Laboratory 
Variables 
Screening 
on-site 
T0 
on-site 
4 wk 
on-line 
8 wk 
on-site 
12 wk 
on-line 
16 wk 
on-site 
20 wk 
on-line 
24 wk 
on-site 
28 wk 
on- 
line 
CBC with diff 
 
 
 
 
CMP 
 
 
 
 
U/A 
 
 
 
 
Cortisol series 
 
 
 
 
 
measures 
 
 
 
HPG axis 
 
 
 
HPT axis 
 
 
 
CoQ10 
 
 
 
 
Exclusion HIV, Hep 
B, C, RA, CBC, RF, 
LFTS, CRP, HbA1c 
 
Stored sample for 
biomarker studies 
 
 
 
 
 


7 
 
 
Self-Report Variables 
on- 
site 
on- 
site 
on- 
line 
on- 
site 
on- 
line 
on- 
site 
on- 
line 
on- 
site 
on- 
line 
MFI 
 
 
 
 
 
 
 
 
 
Sx checklist 
 
 
 
 
 
 
 
 
 
Pain 
 
 
 
 
 
 
 
 
 
Pittsburgh Sleep 
 
 
 
 
 
 
 
 
 
SF 36 
 
 
 
 
 
 
 
 
 
HAM A 
 
 
 
 
 
 
 
 
HAM D 
 
 
 
 
 
 
 
 
Davidson Trauma 
 
 
 
 
SCID 
 
Gyn Questionnaire 
 
 
 
 
 
 
 
Objective Clinical 
Measures 
on- 
site 
on- 
site 
on 
- 
on- 
site 
on- 
lin 
on- 
site 
on- 
line 
on 
- 
on- 
line 
Cognitive Testing 
 
 
 
 
Fitbit Activity 
measurement 
 
 
 
 
 
 
 
 
 
 
The cognitive test battery to be used assesses the functional domains of sustained attention, 
psychomotor function, visual memory and verbal memory. The battery includes tests shown to have 
high specificity and sensitivity for detecting changes in cognitive function between veterans with and 
without Gulf War Illness. Sustained attention is measured by the number of errors on a test of 
continuous performance (CPT), a computer-assisted test from Conners et al., 2013. This instrument is 
widely used in the field of occupational health, and represents adaptations of traditional cognitive 
instruments for computerized stimulus presentation and recording of responses. The Conners CPT-3 
has reliable psychometric properties and has demonstrated validity in epidemiological and laboratory 
studies. Psychomotor functioning is assessed by reaction time on the CPT test. Previous studies of Gulf 
War veterans have documented changes in perceptual motor functions and motor speed (Proctor et al., 
2006; Toomey et al., 2009; Chao et al., 2010). 
Treatment-seeking GWVs have had difficulty in the areas of acquisition and retrieval (Sullivan et al., 
2003). Therefore, we will examine verbal and nonverbal memory with the use of the Brief Visual Memory 
Test (BVMT; Benedict, 1996) and the California Verbal Learning Test-II (CVLT-II) and an alternate version 
(Delis et al., 2000) that measures total recall trials 1 to 5 (raw score) and long-delay free recall (raw score). 
For the virtual platform, the BVMT will not be performed, as it must be administered in person. 
The advantage of these memory tests is that they have multiple alternate but psychometrically 
comparable versions that can be used during the different follow-up sessions, thus reducing practice 
effects. Differences in cognitive measures will be considered secondary outcome measures in this 
CoQ10 treatment trial. A description of the cognitive domains, the complete cognitive test battery, and 
the study instruments and procedures is presented in Table 2. 


8 
 
Table 2. Cognitive Test Battery 
Test Name 
Description 
Outcome 
I. Tests of Attention, Vigilance and Tracking 
Conners Continuous Performance 
Test (CPT-3; Conners et al., 2013) 
Target letter embedded in series of 
distractors; to assess sustained 
attention and reaction time. 
Reaction 
Time 
Total 
Omission 
II. Tests of Verbal and Visual Memory 
California Verbal Learning Test 
(CVLT-II; Delis et al., 2000) 
List of 16 nouns from 4 categories 
presented over multiple learning trials 
with recall after interference; assesses 
memory and learning strategies. 
Total Trials 
1-5 Long 
Delay 
Brief Visual Memory Test 
(Benedict, 1996) 
Drawing test of 6 geometric figures; 
measures visual memory recall. 
Total recall 
and 
placement 
score. 
 
Selection of CoQ10 product study medication and composition of placebo 
The decision to use the reduced form of CoQ10 (ubiquinol) over the oxidized form (ubiquinone) was 
based on the following factors: (1) Ubiquinol accounts for approximately 95% of the total CoQ10 
plasma concentration; (2) Ubiquinol is responsible for the antioxidant activity in the mitochondria and 
lipid membranes; (3) Ubiquinol has a higher oral bioavailability than ubiquinone resulting in higher 
plasma concentrations. The active formulation will be soft gelatin capsules containing 200 mg of 
CoQ10 (ubiquinol) emulsified with diglycerol monooleate, rapeseed oil, soy lecithin, and beeswax 
and the matching placebo formulation will be soft gelatin capsules containing all the above 
ingredients excluding CoQ10. We will be administering one 400 mg ubiquinol capsules for 2 months 
followed by 200 mg per day for the remaining 4 months of the clinical trial. The active and placebo soft 
gelatin capsules will l be provided by Kaneka Nutrients, an FDA registered, NSF International and 
Natural Products Association (NPA) Good Manufacturing Practices (GMP) certified facility that 
manufactures United States Pharmacopeia (USP) compliant supplements. The purity and stability of 
the CoQ10 soft gelatin capsules will be monitored by the VA CSP CRPCC Laboratory following USP 
standards. 
 
Pre-Enrollment Screening: Case definition: In our prior work and in Beatrice Golomb’ s work using 
CoQ10 in GWI, we have used concurrent CDC and Kansas case definitions (Steele, 2000; Fukuda et 
al., 1998). The more rigorous Kansas case definition captures at least a third of the deployed 
veterans from the first Gulf War (Research Advisory Committee Report, 2014, page 18), and the 
CDC captures about 10% more. The key difference between the two is the factor analysis based 
Kansas definition weighted severity and frequency of symptoms. The Kansas definition requires 
deployment to the theater of operations between August 8, 1990 and July 31, 1991 with multiple and 
moderately severe symptoms (> 6 months) in at least 3 of 6 symptom domains; excluding serious 
medical/psychiatric diagnoses that account for symptoms or preclude accurate symptom reporting. 
The 6 domains are fatigue/sleep problems; somatic pain symptoms; neuro/cognitive/mood 
symptoms; gastrointestinal symptoms; respiratory symptoms, and skin symptoms. The exclusion 
criteria as modified by Steele in 2014 allow for common comorbid conditions. 
 
Due to the aging of the Gulf War I cohort, we will adjust the restrictions of the exclusion criteria 
imposed by the Kansas case definition to allow for recruitment of veterans who are diagnosed with 
specific well-controlled, chronic conditions that may be typical of an aging population. We will defer to 
the clinician at each site to decide whether the conditions meet the relaxed Kansas exclusions, 


9 
 
according to specific guidelines. This change follows the principles recommended by experts and 
funded Investigators in Gulf War Illness research. 
 
The relaxed Kansas exclusions include the following: 
1) Allowance for normal illnesses of aging, if the conditions are treated and are in demonstrable 
stable and normal ranges at the time of screening and assessment. 
2) Allowance of stable comorbid conditions include PTSD, MDD, and mild TBI that have 
not required hospitalization in the 2 years prior to recruitment. Severe TBI is excluded. 
 
The changes to the entry criteria include:1) Diabetes—include if blood sugar controlled over the past 
2 years; 2) Heart disease (stable hypertension is acceptable)—if not had condition in the past 2 
years; 3) Arthritis—depending on type: include for osteoarthritis and exclude for rheumatoid 
arthritis;4)Seizure disorder—include if not treated or not had any seizures in the past 2 years; 5) 
Cancer—include if not treated in the past 3 years; 6) Skin cancer—include if Stage 1 or treated by 
excision only; 7) Liver disease—include if not had condition in the past 2 years; 8) Kidney disease— 
include if not had this condition in the past 2 years. 
 
Entry Criteria 
We will study 200 veterans with GWI, 100 in each group (intervention or placebo). The inclusion 
criteria will follow the case definition by Steele (Kansas Case Definition described) but will be 
expanded to accept veterans as eligible participants who possess specific, well-controlled chronic 
conditions. All subjects will be between 35 and 70 years old, in good health by medical history prior 
to 1990, and currently have no exclusionary diagnoses that could reasonably explain the symptoms 
of their fatiguing illness and their severity, using the exclusion criteria best described in the paper 
by Reeves et al. 2003, which clarifies exclusionary conditions for complex multisymptom illness 
and agrees with Steele’s recent unpublished modification. This includes exclusion of major 
depression with psychotic or melancholic features, schizophrenia, bipolar disorder, delusional 
disorders, dementias of any type and no hospitalization in the past 2 years for alcoholism or drug 
abuse. Medical conditions excluded include organ failure, defined rheumatologic inflammatory 
disorders, chronic active infections such as HIV, hepatitis B and C, transplant, and primary sleep 
disorders. Medications that could potentially impact immune function will be excluded (e.g., 
steroids, immunosuppressives; as well as nutraceuticals that are formulated to impact 
mitochondrial function or oxidative stress). Morphine derivatives that are used daily will be 
disqualifiers in in this study. PRN use of less strong pain medications is one of the variables that 
can be studied, thus medications such as tramadol or codeine can be monitored for frequency of 
use as an indication of CoQ10’s impact on chronic pain. Common multivitamin preparations will 
be allowed if taken without change throughout the protocol. Known allergy to CoQ10 and/or 
inactive ingredients of active and placebo soft gelatin capsules or current use of Coumadin (given 
the vitamin K structural similarity of CoQ10) will also be excluded. In the event a subject tests 
positive for an infectious disease or medical condition at the screening visit, he/she will be 
counseled and referred to the appropriate service within the Veterans Administration Medical 
Center (VAMC) or to their primary health care provider. All reportable diseases will be reported as 
required by hospital and state guidelines. If our psychological exams indicate that the participant 
is at risk from a mental health perspective, the individual will be referred for further care. Subjects 
need to not take the supplement CoQ10 (ubiquinone or ubiquinol) for at least 3 months before 
study entry; as well as other nutraceuticals formulated to impact mitochondrial function. They 
agree to leave any other supplements unchanged in their regimen throughout the course of the 6 
month intervention. 
 
The clinical and laboratory testing is performed without knowledge of the subjects’ group 
membership, the group A vs B true condition will remain blinded throughout the study until its 
conclusion. There are two treatment conditions: CoQ10 (ubiquinol) 400mg for 2 months followed 


10 
 
by 200mg maintenance for 4 months and placebo taken once a day in the morning with food. The 
subject schedule includes 5 on-site assessments. On-site assessments include the screening visit 
with informed consent, the drug initiation visit, an 8 week visit and the 16 and 24-week visits. In 
addition, there is a web based self-report assessment given every 4 weeks throughout the 
treatment period and at 4 weeks after completion of the study drug. A member of the research team 
may contact the participant by phone to remind him or her to complete the surveys on the 
computer. Subjects will also utilize an activity monitor (FitBit) device to assess activity and sleep 
throughout the study period through 7 months. (Assessments, see Table 1.) 
 
The CSR&D Data Monitoring Committee (DMC) and the local VA pharmacist will have the authority 
to break the blind and recommend stopping the study should one group have evidence of adverse 
effects or significant efficacy in group A or B that would ethically require the blind to be broken. 
Further details regarding the interim efficacy analysis and formal efficacy stopping rules are provided 
in the statistical section below. There will be no formal stopping rules for safety; the DMC may 
recommend stopping the study for any concerns they feel jeopardize the safety of patients in the trial 
regardless of resulting p-values. The research pharmacist will also have access to an electronic 
emergency unblinding system developed by the CSP Pharmacy Center should an individual subject 
event require the blind be broken to access appropriate care (e.g., a toxic reaction to a product 
requiring treatment). This decision would follow institutional guidelines, following a discussion with 
the treating clinician. All subjects will have a physical examination, medical history, and will be given 
a battery of psychometric questionnaires. 
 
Recruitment Process and Informed Consent 
Gulf War veterans will be recruited at all four VA clinical sites: Miami, Boston, Bronx, and 
Minneapolis. Miami VA study staff also will recruit participants using a virtual platform. Subject 
recruitment will be the responsibility of the clinical research staff and each VA site investigator. 
Subjects are recruited by several methods: discussions with their physician in the GWI clinic,; in 
response to brochures that are handed out by study staff at veteran events in the community; 
directed to our research personnel by their primary care providers who are made aware of our work 
in CME lectures or seminars; through the use of social media as described by Dr. 
Golomb’ s group in a recent paper (Erickson 2013); and through direct contact with veterans who 
have been assessed through the VA registry, using a phone screen (scripted) contact. Prior to 
enrollment in the study, all subjects will be fully informed about the nature of the study and sign 
an informed consent document. The initial contact will include a description of the study protocol 
including surveys, cognitive assessments, blood draws (approximately ½ cup), time required, and 
reimbursement for their time and effort. 
 
Informed consent will be obtained by the study investigator or by an IRB-approved delegate after a 
screening interview, but prior to the initiation of any study procedures. Subjects will be given a local 
telephone number and will have an opportunity to ask questions about the procedures. They will be 
informed that their decision to or not to participate will have no bearing on their medical care and 
that, if they choose to participate, they may withdraw at any time without loss of VA benefits to 
which they are entitled. There is no coercion; potential subjects are given the opportunity to ask 
questions, take home materials that accurately reflect the study protocol, and volunteer or not 
without impacting their relationship with providers. For the virtual platform, Miami VA research staff 
will mail 2 copies of the informed consent to the prospective participant. Once the signed copy is 
received, the Miami VA research staff will contact the participant to initiate study procedures. A 
consent form will be mailed to a potential participant only if he/she is interested in the study. If the 
individual does not return a signed consent form to the Coordinator, the individual will demonstrate 
that he/she has opted to not participate in the study. Subjects are compensated for their travel and 
effort in small part. 


11 
 
After a screening visit, they are compensated $125 for assessment at Baseline and 3 follow-up 
visits that involve relatively lengthy self-report instruments, a physical exam, a cognitive 
assessment fitting, given an activity meter with instructions and a blood draw. This initial visit 
requires 3-4 hours to complete. They return for additional visits that focus on cognitive testing and 
a brief physical exam at month 2, 4, and 6. For the virtual platform, Miami VA research staff will ask 
the participant to complete the cognitive testing online at baseline, 2, 4, and 6. At these visits, the 
Miami VA Nurse Coordinator will ask the same health status and medication questions via 
telephone, in place of the physical exam procedures. At the 6-month visit, the Nurse Coordinator 
will complete the end of study procedures and ask the participant to return any unused medications 
to the Miami VA via mail. 
 
During the consent procedure, subjects will be informed that genetic testing will be performed and 
that samples of blood will be stored at the Miami VAMC research laboratory for later analyses. We 
will notify subjects that names and addresses will be kept and can be linked to their identification 
numbers for later contact and to allow subjects access to laboratory data that may be useful in their 
clinical care. On completion of the study, samples and clinical data will be de-identified and 
biorepository samples to be used in future studies requiring informed consent will include genetic 
testing. Informed consent documents will be submitted to the individual VAMC IRB for approval and 
oversight. After giving informed consent, subjects will be scheduled for clinical assessment at the 
participating VAMC or via telephone interview with the Miami VA research team using the virtual 
platform. Those meeting the study requirements will then be randomized in a 1:1 manner to the 
treatment or control (placebo) condition; randomization will be stratified by study center and gender. 
The CSP Pharmacy Center will use an electronic randomization and drug assignment system similar 
to the system used for most CSP studies, based on the program developed by this study’s statistician. 
The research pharmacy will work with the local study coordinators to dispense study drug and 
placebos. In order to reduce variation in the data, all laboratory testing will be done at the Miami VAMC. 
Samples will be sent via overnight express. For the virtual platform, samples will be drawn and 
packed by phlebotomists at Quest Laboratories in the participant’s local area and shipped via 
overnight express for analysis at the Miami VAMC. 
 
Gulf War Registry recruitment 
It is critical that the recruitment projected in this study be on timeline, in order to complete the study 
in the 3 year timeframe. Prior clinical trials studies have suffered from difficulties with recruitment, 
often because the per site recruitment targets were ambitious, access to the study population 
limited, or studies were understaffed. For that reason, we have paid attention to all of these issues, 
performing this study across 4 sites with established track records of successful recruitment. In 
addition, we have included a national recruiter working from the national and regional registry, 
contacting potential subjects and performing scripted screening interviews to refer to the study. A 
similar strategy was recently employed by the Synergy trial, fully recruiting and completing a similarly 
powered (number of subjects)/number of sites study in just 18 months. Thus, the study population 
will be drawn from established GWI populations from 4 VAs with a track record of successful 
recruitment for clinical studies. 
 
The PI, Dr. Klimas, will seek a DUA to access the national Gulf War Registry list. After gaining 
access, the Registry Recruiter will mail an introductory letter to the GW veteran. Upon response, 
the Registry Recruiter will call the veteran by telephone to discuss the study eligibility and then will 
mail eligible veterans a study packet containing information about the study and directions to the 
study site. The Registry Recruiter will coordinate scheduling an appointment and travel 
arrangements, if necessary. After reporting to the clinic site, veterans will be asked for consent to 
participate, after being fully informed about the study, including risks and human subjects’ 
protections. 


12 
 
Screening and assessment procedures 
Prior to enrollment in the study, subjects will undergo a screening visit. Subjects will be consented 
and screened for exclusion criteria and symptoms. For the virtual platform, the Nurse Coordinator 
will conduct the screening via telephone. 
 
Procedure if Psychiatric Problem is Discovered During Assessment 
1. If the Research Coordinator or Principal Investigator assesses a risk to the participant, she 
will walk with the participant to the Miami VA ER for evaluation of suicidal ideation. The 
research team will follow the plan submitted with the original amendment (see attached). 
If the Research Coordinator or PI assesses a risk during the telephone interview on the 
virtual platform, the call will be transferred to the VA Suicide Prevention hotline according to 
procedures outlined in the Psychological Safety Plan. 
2. In the case where a participant displays a psychiatric problem that is known to his or her 
clinician as noted in CPRS, then the research coordinator will place a note in the study 
file specifying that the patient was excluded from this research study. 
3. If the test results indicate a psychiatric problem that is not noted in CPRS, the research 
coordinator will assess the urgency of the situation while the potential participant is in the 
clinic. 
a. If the patient’s behavior/mental health status is deemed to be emergent or urgent, the 
research coordinator will walk the patient to the ER at the Miami VA for immediate 
treatment and will stay with the patient until services are rendered. The Miami VA ER 
and/or After-Hours Mental Health Staff will conduct an assessment and management of 
distressed veterans who need assistance during the assessment or call after hours. 
b. If the psychiatric problem is non-urgent, the research coordinator will make a note in 
the research study file and will place a note in CPRS indicating a referral for follow-up 
with the patient’s primary care physician at the VA. If the patient does not have a 
primary care physician at the VA, the research team member will arrange for one to be 
assigned. The Research Coordinator will be responsible to follow up with the patient 
in order to provide continuity of care as needed and to confirm that the patient follows 
up with the primary care physician. 
 
Screening labs 
Screening labs as outlined will be shipped to the Miami lab. This will include a history and physical 
exam; blood tests directed at detecting conditions, which would explain the severity of the illness 
and thus be exclusionary (e.g. untreated hypothyroidism, severe liver disease, anemia etc.). 
Additional blood tests that are being evaluated to better understand the illness or develop the data 
needed to prove their utility as surrogates for severity of illness. Blood volume at any one visit will 
not exceed 120 ml (8 tablespoons). Risk of blood draw includes local bruising and vasovagal 
responses to phlebotomy (fainting). In the on-site initiation visit as well as the week 8,16, and 24 
week visits, the subject will have a brief physical exam emphasizing vital signs, autonomic function 
(lying and 10 minute stand BP and P), and trigger point assessment. For the virtual platform, the 
subject will not have this brief physical exam. 
 
For the virtual platform, the Miami VA research team will ship collection boxes directly to the 
participant. Laboratory tests will be combined for the screening and baseline visits. During the 
screening visit, (after signed consent is received), the tests will include all baseline tests and 
the exclusion tests. Samples will be drawn and packed by phlebotomists at Quest 
Laboratories in the participant’s local area and shipped via overnight express to Miami VA. 
 
The subject will be given a web link to the REDCap platform of self-administered questionnaires to 
be completed within 48 hours prior to the drug initiation visit. Scoring will follow standardized scales. 


13 
 
During the screening visit, the subject will be taught the proper technique for using the activity 
monitor, assign and practice the web login for the REDCap based platform by performing the core 
assessments on the computer in the office, assisted by research staff as needed, and perform the 
studies that require a face-to-face interaction (SCID). The SCID will be performed by telephone for 
the virtual platform. They also complete the following standardized scales either at home on a 
weblink within 4 days of each scheduled assessment or on site (cognitive testing is always on site). 
All subjects wear an activity monitor from the first assessment throughout the 6-month period, which 
links in any wireless environment to update the activity / sleep data files. For the virtual platform, all 
assessments will be completed via the telephone interview format or via online surveys in the 
REDCap platform. The research staff will mail the Fitbit directly to the subject’s home, after the 
screening interview and satisfactory completion of the laboratory tests and assessment forms that 
confirm eligibility. 
 
Medication review: review for exclusionary meds, document all medications and over the 
counter supplements. 
 
Screening blood draw: TSH, ANA, RF, CMP, CBC, ESR, HIV serology, Hep and Hep C, CRP, 
Hemoglobin A1c for screening purposes. Females will also have a pregnancy test. The focus is 
on exclusionary conditions. A sample also will be drawn for the biorepository. 
 
Informed Consent for Screening 
The research staff members who conduct the screening will administer informed consent prior to 
the initiation of testing. An introductory informed consent script that informs study participants 
about the study, their rights, the randomization of groups to receive the study medication or the 
placebo, study-related laboratory tests, cognitive test procedures, and the surveys on the REDCap 
database. This document will be read to participants before beginning the screening tests. A 
separate document will be recorded for each potential participant. After guiding the potential 
participant through the informed consent topics, the interviewer will ask the participant to sign the 
written consent and will give a copy to the participant. For the virtual platform, Miami VA research 
staff will mail 2 copies of the informed consent to the prospective participant. Once the signed 
copy is received, the Miami VA research staff will contact the participant to initiate study 
procedures. A consent form will be mailed to a potential participant only if he/she is interested in the 
study. If the individual does not return a signed consent form to the Coordinator, the individual will 
demonstrate that he/she has opted to not participate in the study. 
 
After the informed consent process, it will be verified and documented whether the participant 
meets the inclusion/exclusion criteria for the study. The interview will terminate if it is determined 
that the participant is ineligible. Only once informed consent has been obtained from the study 
subject will the subject be considered to be enrolled in the study. The list of subjects will reside on 
the respective VA medical center network drive and will be secured in compliance with all VA 
confidentiality and information security requirements in the investigator’s file for each study. For 
the virtual platform, no data, except that which is necessary for scheduling will be collected prior 
to receiving the signed informed consent.at the Miami VA. This information will include that the 
prospective participant has a primary care clinician and receives services at a specific VA medical 
center. The Coordinator will document this information during the prescreen telephone contact and 
will not mail an informed consent to a veteran who does not have a primary care clinician. All 
participants will be required to be enrolled at the VA, regardless of whether they are recruited to 
participate in on-site visits or in telephone visits using the virtual platform. Should the veteran 
experience psychological distress during the study visits, he or she will be referred for services at 
the VA medical center. 


14 
 
Enrollment 
Potential participants will be considered to be enrolled in the study upon meeting eligibility 
criteria, completion of written informed consent, satisfactory completion of screening laboratory 
tests. No data, except that which is necessary for scheduling will be collected prior to informed 
consent. 
 
Laboratory Specimens and Evaluations 
During the course of this study, clinical laboratory specimens will be collected for research 
purposes. In order to determine eligibility for study participation, the subject will be consented and 
a screening lab test will be performed to make a diagnostic determination regarding GWI status 
and to evaluate the presence or absence of exclusionary medical conditions. For the virtual 
platform, the Miami VA research team will ship collection boxes directly to the participant. Samples 
will be drawn and packed by phlebotomists at Quest Laboratories in the participant’s local area 
and shipped via overnight express for analysis at the Miami VAMC. The health assessment also 
will consist of a medical history, physical examination, and laboratory testing listed in Table 1. 
 
Protocol for Blood Samples. At each of the clinical sites, blood samples will be obtained from 
each subject for the tests shown in Table 1 as well as the study sample storage for batched 
assays. 
 
Appropriate samples for CBC, CMP, and U/A are sent to the Miami Lab. Whole blood samples are 
collected from the patients, according to the outline shown in Table 3. The blood samples are to 
be collected in afternoon and shipped by overnight carrier to the lab at the Miami VA Medical 
Center. Salivary samples will be collected 4 times over 24 hours and stored frozen at the sites, to 
be shipped on dry ice in batches to Miami VA. 
 
Table 3. Blood Samples each onsite visit 
Serum 
Plasma 
PBMC 
Tubes 
Total: 64 ml 
one 10 ml red top 
(siliconized) 
two 7 ml purple top 
EDTA 
four10 ml green 
tops (sodium 
 
Types of samples and storage requirements 
1. 
Peripheral blood mononuclear cells are separated from blood and cryopreserved according 
required protocol. Viability and cell count is determined and aliquots are placed in freezer 
vials and stored in liquid nitrogen or at -800C as required by protocol. 
2. 
Plasma is separated from the cellular component of blood by centrifugation and stored 
in required aliquots at -800C. 
3. 
Serum is separated from the clot by centrifugation and stored in required aliquots at -400C. 
 
Monitoring of freezers All mechanical freezers are connected to emergency outlets. If a freezer 
goes down, an alarm goes off in the building engineering section and lab personnel are 
immediately notified. In addition, the lab personnel check the interior temperature each day and 
record it on a chart attached to the freezer door. If the building power is disrupted, the freezers are 
automatically connected to the emergency generator system. Liquid nitrogen freezers are 
checked each day. The level of liquid nitrogen is measured and adjusted if needed. A liquid 
nitrogen storage tank is available in the freezer room. The storage tank is replaced each month. 
 
Laboratory Measurements (Measured at T0, 16w, and T24 w) 
1. CoQ10 in plasma: The method of Tang and Miles (2012) will be used to measure reduced 
(ubiquinol) and oxidized (ubiquinone) CoQ10. Plasma is extracted with 1-propanol. After 
centrifugation, the 1-propanol supernatant is directly injected into HPLC and monitored at a dual- 


15 
 
electrode. This method meets regulatory requirements for clinical laboratories, and has been 
proven reliable for analysis of clinical and research samples for clinical trials. CoQ10 screening 
will take place at the 8 week visit. 
2. Hormone studies: Hypothalamic-pituitary-thyroid (HPT) axis. Thyroid status is assessed 
using a chemiluminescent method (TSH, free T3, free T4), Hypothalamic Pituitary Gonadal axis 
will be measured using ELISA methods measuring testosterone (free), FSH, LH and estrogen. 
Cortisol will be measured using a 24 hour salivary collection with 4 time points to assess circadian 
rhythm. The measures will be evaluated at baseline and to evaluate response to treatment. 
3. Safety and screening labs: CBC, CMP and urinalysis will be performed at every time point as a 
safety screen: HIV, Hep B, C, Rheumatoid factor, Antinuclear antibody, CBC, CRP, and HbA1c, and 
LFTS will be drawn at screening to rule out exclusionary illnesses. 
 
Laboratories Performing Evaluations 
The clinical laboratories under the direction of Dr. Mary Ann Fletcher and Dr. Nancy Klimas at the 
Miami VA will be used for medical laboratory testing. Local VA laboratories will pack, and ship blood 
and saliva tests and will discard any residual samples. All research specimens will be processed at 
the Miami VA. 
 
Laboratory Storage 
Biological samples and laboratory data will be stored at the Miami VA Healthcare System, (Miami, 
FL) and related clinical data will be stored on a secure server. All samples will be processed and 
maintained according to documented SOPs that follow generally accepted good laboratory practices 
in order to assure sample quality, integrity and long-term stability. 
 
All clinical data for consenting subjects will be stored indefinitely under conditions protecting PHI. In 
the event that a subject withdraws consent, Dr. Klimas will be informed of their Subject ID and their 
clinical information will be expunged from the database, and biological samples will be destroyed. 
 
Data Analysis Plan 
Statistical considerations 
General Statistical Approach: Patients will be randomized in a 1:1 manner to Coq10 or placebo; 
randomization will be stratified by study center and gender. This study includes a comprehensive 
survey of patient status using a broad set of clinical assessments and laboratory assays designed 
to assess the response to treatment Unless otherwise specified, two-sided P < 0.05 will be 
considered statistically significant. Statistical analyses will be carried out using SAS Version 9.4 or 
higher. 
a) Baseline: Differences in continuous baseline variables will be compared by a two-sample t 
test. The Mann-Whitney U test will be used in the case of non-normal distribution. For baseline 
categorical variables, Fisher's exact test will be used. 
b) Evaluating the efficacy of CoQ10 in GWI: The primary analysis is to compare treatment groups 
on change from baseline SF-36 physical function score over time (6 monthly time points from 
Week 4 to W eek 24) in a repeated measures setting using a final two-sided 0.049 level of 
significance (a 0.049 level is being used at the end of the study instead of 0.05 to account for the 
interim analysis further described below). This will be carried out using a mixed model (MM) 
analysis of variance (ANOVA) with effects for treatment, time, baseline physical function score and 
the randomization strata of study center and gender. The within-patient correlation structure will be 
assumed to be unstructured. If this analysis shows a significant treatment difference across time or 
a significant treatment-by-time interaction, comparisons across treatment conditions also will be 
carried out separately at each time point using a Bonferroni alpha-adjustment (significance level at 
each time point = 0.049 divided by 6, the number of planned post-baseline time points) to account 
for the multiple comparisons. Data will be analyzed as an intention-to-treat model; i.e., all 


16 
 
randomized subjects will be included using available data (i.e., a patient does not have to provide 
data through the end of the study to be included in the analysis; this is the strength of the MM 
ANOVA approach). A secondary supportive analyses will be carried out where missing physical 
function data at each time point are first imputed via monotone multiple linear regression 
imputation, under the assumption the missing data mechanism is missing at random prior to 
carrying out the mixed model analysis. The imputation regression model at each time point will 
include randomized treatment, measures of the primary outcome at earlier time points and 
baseline covariates that will be specified in the final detailed statistical plan. Fifty imputed datasets 
will be created, and the MM ANOVA will be run on each data set; the 50 MM ANOVA results will 
then be combined across the data sets using PROC MIANALYZE in SAS to obtain one overall 
assessment of treatment difference on the imputed data. 
c) Sample size justification and power analysis: In this study population, we rely on the literature 
of Phase III studies of other inflammatory states to determine assumptions required for sample size 
calculations. Our primary clinical outcome variable is physical function of the SF36 measured over 
time (approximately monthly from week 4 through week 24; i.e., 6 measurements over time). Our 
current data suggests a coefficient of variation (CV) of approximately 0.40 for physical function at a 
given time point. Assuming this and assuming a relative increase in SF36 of at least 21% for Coq10 
over placebo at each time point, then there is a 0.525 treatment effect size at each time point. 
Under this effect size, power is at least 95% to detect a treatment difference over time using an 
evaluable group sample size of n=90 subjects at a two-sided 0.049 level of significance regardless 
of the within- patient correlation between time points. To account for approximately 10% attrition, 
100 subjects per group will be randomized. Such an evaluable sample size will also allow at least 
80% power to detect a relative increase t of 21% separately at each time point after using a 
Bonferroni multiple comparison adjustment across the six time points. 
d) Subgroup analysis on the primary endpoint: Treatments will be compared within each gender. 
The purpose of this analysis is not to show a statistically significant Coq10 effect on the primary 
endpoint within each gender (due to potential lack of power; e.g., if there are 25 evaluable women in 
each treatment group, power ranges from approximately 50% to 95% depending on the within-patient 
correlation between time points under the effect size assumptions used in the primary power 
calculation), but rather to investigate consistency of treatment difference across genders. In addition, 
treatment-by-gender interaction will be assessed in a mixed model repeated measures model that 
includes the main effects in the primary analysis and a term for treatment-by-gender interaction; an 
interaction p-value <0.15 will be considered as possibility indicating lack of consistency in treatment 
effect across gender. Similar analyses will be conducted to assess consistency of results across study 
centers. 
e) Other clinical efficacy end points will look at each of the self-report assessment measures 
across the domains of fatigue, pain, sleep, and the SF36 subscales of function and severity. Objective 
measures include laboratory data that could reasonably be considered a surrogate for illness severity 
(e.g., measures of immune activation, inflammation, cell function, and NPY), a focus of several of 
our prior publications (Fletcher 2002, 2009, 2010; Maher 2007; Broderick 2009, 2010). Other 
objective measures include cognitive assessments and the activity monitor data which will be 
measured at each assessment point at the beginning of the study and on the 24th week of treatment. 
These will all be analyzed in a similar manner as the primary endpoint. We will also look at the effect 
of duration of study drug exposure on a case by case basis if there are individuals who fail to 
complete 24 weeks of study drug, and will also look at the change in CoQ10 levels as a predictor of 
response. These endpoints are considered exploratory and no adjustment of significance level for 
the multiple comparisons will be applied. 
f) Safety Endpoints: The primary safety variable is the incidence of treatment emergent adverse 
events (TEAEs). A TEAE is an event that emerges, or a pre-existing event that worsens, any time 
after initiation of first study treatment. Adverse events will be coded by using the most recent 
released version of MedDRA at the time of study start. The incidence of TEAEs will be presented 
overall and by MedDRA system organ class and preferred term. TEAEs will also be presented by 


17 
 
severity (mild, moderate, or severe). Patients experiencing more than one occurrence of the same 
preferred term or system organ class will be categorized under the maximum severity experienced 
for that preferred term or system organ class. Similar analyses of TEAEs will be conducted by 
relationship to drug. Patients experiencing more than one occurrence of the same preferred term or 
system organ class will be categorized under the most related category experienced for that 
preferred term or system organ class. This will be repeated for serious TEAEs. Descriptive 
statistics (sample size, mean and median, quartiles, minimum and maximum) of laboratory values will 
be presented for each visit in which they were collected. Similarly, descriptive statistics from the 
change from baseline to each visit will be presented. Box plots of the changes from baseline will be 
presented across visits. 
g) Evaluation of blinding: Each subject and investigator will be asked at the end of their 
follow-up to guess whether they believe the subject was randomized to active treatment or 
sham group. Frequencies of correct and incorrect responses will be provided separately 
for subjects and for investigators. 
 
Data and Safety Monitoring Plan 
Risk management and Emergency Response: 
This study has been assigned for administrative and scientific oversight to the Clinical Services 
Research and Development Data Monitoring Committee (DMC) to Dr. Domenic Reda and his staff 
based at the Hines VAMC. They will monitor the study for safety, efficacy, and progress. Study 
participants will be asked to self-monitor and report to study personnel any episodes of symptoms. 
Adverse reactions will be reported to the Project Manager (Ms. Cohen) who will communicate with 
Dr. Klimas, the local IRB, and the DMC. While other trials have not seen serious adverse reactions, 
standard protocols are in place, with moderate to severe reactions r e p o r t ed to both the IRB and 
the DMC All unanticipated problems involving risk to subjects or others, serious adverse events, 
and all subject deaths associated with the protocol will be reported. Comments will be recorded on 
the outcomes of the event or problem. In the case of a serious adverse event, an assessment will 
be made on the relationship to the participation in the study. All reports determined by the 
investigators or DMC to be possibly or definitely related to study participation and reports of 
events resulting in serious adverse events will be promptly forwarded to the VACO ORD. 
 
Should a systemic allergic reaction occur, subjects are advised to call 911, and take an 
antihistamine while awaiting response. The most common complaint with ubiquinol is GI 
upset and diarrhea. This is handled by taking the medication with food and if necessary with 
dose adjustment to 50%. All of the VA medical centers have a VA Emergency room that is 
available 24/7 if for some reason the study physician or back up is not available. 
 
Veterans are the study population and are cared for by the VA health care system, which will assume 
the costs of study related injuries. Women of childbearing years are asked to take measures to avoid 
pregnancy during the study. Barrier methods or better are sufficient. 
 
Psychological Safety Plan 
We aim to ensure the safety of psychological study participants. Specific objectives of this safety 
plan are to ensure that: 
 
1. Participants requesting assistance receive prompt response from mental health 
professionals who are knowledgeable safety risk assessment 
2. The study team responds when participant’s affect or behavior raises concerns (e.g., 
expressions of extreme distress), even if the participant him or herself does not request 
help. 


18 
 
The study team will check the on-line questionnaire HAM-D Question #3 regarding suicidality and 
will alert Dr. Klimas. Dr. Klimas will call the participant by telephone to assess the situation. If 
necessary, she will transfer the participant to the national VA Suicide Prevention Hotline. She will 
give the veteran the toll free number for the national VA Suicide Prevention Hotline (1-800-273- 
TALK (8255)) so that veterans, regardless of proximity to the Miami VA Healthcare System, can 
receive assistance in case of emergency. The hotline directs veterans to a VA professional who can 
immediately address their crisis situation. The local Suicide Prevention Coordinator then provides 
follow-up and assurance that these veterans in crisis receive on-going care. The study team will 
record and report to the IRB any incidents they are made aware of in which a participant calls the 
suicide prevention hotline. During the on-site assessment, if the Research Coordinator or Principal 
Investigator assesses a risk to the participant, she will walk with the participant to the Miami VA ER. 
 
Because the study is based at the Miami VA, the study team will take additional measures to 
inform the Miami VA mental health after-hours and ER staff about this study. Specifically, we will 
distribute an information letter describing the study and listing the contact information for the study 
PI and Research Coordinator. 
 
Risk Assessment Personnel 
Professionals assessing potential risk in participants include Research Coordinator, Principal 
Investigator, VA Suicide Prevention Hotline staff, Miami VA ER and after-hours mental health staff. 
The Research Coordinator and Principal Investigator will assess risk in participants during 
administration of the structured clinical interview, completion of questionnaires or when 
participants request that a member of the study team contact them during regular business hours 
because of distress. The Principal Investigator will assess risk in participants in situations where 
the Research Coordinator identifies a potential need for intervention. The VA Suicide Prevention 
Hotline will conduct assessments among veterans who call the hotline. The Miami VA ER and 
After-Hours Mental Health Staff will conduct assessment and management of distressed veterans 
who call after hours. The Research Coordinator will be responsible for managing communication 
among these professionals to provide continuity of care as needed and report any adverse events 
among participants to the IRB. 
 
Safety 
Coenzyme Q10, (ubiquinol) is widely used as an overly the counter supplement and is considered 
to be safe by the FDA, with rare reports of side effects. We will be monitoring for symptoms that 
suggest allergic reactions (rash, stomach upset) or any other medication related side effect. It is 
hoped that the medications will improve your energy levels. Should this happen, there is a 
possibility that it will interfere with sleep. If this occurs, we will assess the benefit of reducing the 
dose. Dosing schedules will be reviewed at the investigators meeting before study initiation, and 
standard operating procedures to handle any perceived drug intolerance such as GI side effects will 
be addressed by the clinicians. Typically, a dose modification, reducing the dose by half for a week 
then increasing back to the target range over 2 weeks can be employed to determine if the 
presumptive associated side effect recurs. In the final analysis, we will review blood levels to 
determine if drug levels predict response or adverse reaction. 
 
Adverse reactions of drug intolerance will be categorized by severity, body system, and number of 
events per individual studied. Serious reactions will be reported promptly to the IRB and CSR&D 
Data Monitoring Committee (DMC). Study personnel, including the PI, who also is the Director of 
the GWI clinic, will be available by telephone 24/7 and in clinic during routine hours. The Miami 
VAMC Emergency Department will serve as back up should a serious adverse reaction occur when 
personnel are not available. 


19 
 
Risks/ Benefits Assessments for Ubiquinol 
Both ubiquinone and ubiquinol have been used extensively in clinical trials and in clinical settings. 
Whether efficacious or not, one remarkable observation is the reassuring safety profile of both 
preparations. Ubiquinone has been used in dosages up to 4,500 mg per day in frail populations 
(Parkinson’s) and has seen positive results at the dosages proposed in this study in congestive 
heart failure and in illnesses known to be secondary to mitochondrial disorders (reviewed in Kern 
2011, Kizhahkkedath 2013). 
The most common adverse effects are gastrointestinal in nature and can include nausea, epigastric 
pain, diarrhea, heartburn, and appetite suppression. However, the prevalence of these adverse 
effects was less than 1% in reported studies (Jelin, 1999). Gastrointestinal effects of CoQ10 may be 
lessened with a dosage reduction or may subside with continued therapy. Asymptomatic elevations in 
s er um lactate dehydrogenase and hepatic enzymes were observed and may occur with oral 
dosages of CoQ10 in excess of 300 mg/day; however, cases of serious hepatotoxicity have not been 
reported (Greenberg, 1990; Micromedix, 2014). If female veterans are pregnant, are breastfeeding, or 
become pregnant, ubiquinol might involve risks to the embryo or fetus, which are currently 
unforeseeable. For this reason, you will be required to take a pregnancy test in the beginning of the 
study and use adequate protection to prevent pregnancy. There is the possibility that ubiquinol may 
interfere with sleep and may lower blood pressure. For participants who commonly have very low 
blood pressure, they should check blood pressure carefully. For the virtual platform, if the clinician 
learns that the potential participant has a history of low blood pressure, then the participant will be 
excluded from the virtual study option. In congestive heart failure studies, clinical relapse was noted 
on withdrawal of CoQ10, whereas reinstatement of therapy resulted in improvement (Mortenson, 
1990; Mortenson, 1985). We selected a formulation that has been used in prior clinical trials in other 
disease states and have safety data, bioavailability data as well as efficacy data published (Chandran 
et al., 2012; Sanmukhani et al., 2014; Kizhakkedath et al., 2013; Kern, 2011). Based on the literature 
review of treatment responses in other illnesses and Dr. Golomb’ s experience, and conversations 
with Kaneka Nutrients (the primary source of ubiquinol in the USA) we will use ubiquinol 200 mg (the 
equivalent of ubiquinone 600mg) after a 2 month “loading” of 400 mg to correct deficiency states. It 
will be given as a morning dose, with food, to avoid evening side effects of sleeplessness and to 
optimize its bioavailability. 
Adequacy of Protection Against Risk 
Minimal risk is expected to be incurred by research participants, according to the safety records of 
the selected compound, an oil-based Ubiquinol soft gel. Ubiquinol has established safety profiles at 
doses that exceed the proposed treatment range and efficacy profiles established in other diseases. 
The blood draws in the study pose the risk of fainting from vaso-vagal reactions, local bruising, and 
discomfort. Minimization of risk includes having blood drawn only by experienced Registered Nurse 
or MD personnel. 
 
Although the risks to the study participants are no greater than daily activity, the cognitive tests may 
cause discomfort. However, interviewers will be instructed and trained to identify potential problems 
and to tailor the testing as appropriate so as to minimize that risk. Throughout the testing, the 
research staff will remind participants of the goal of the testing, allowing short breaks when 
necessary. For the survey component, the risks are no greater than daily activity. Psychological risk 
associated with self-disclosure is handled by having interviewers who are trained psychologically in 
order to provide appropriate interaction and counseling. If any adverse reactions occur during the 
interview, Dr. Klimas will be available. For this study, there is a risk of loss of confidentiality. For the 
survey component, the data that will be accessed through the REDCap platform will be de-identified, 
with the identifiers remaining embedded in the database system. Unique participant ID numbers will 
be assigned to survey data and will be inputted into the database on a secure, password-protected, 


20 
 
encrypted computer and entered into a secure database. 
Potential benefits: 
It is our hope the subjects in the proposed clinical interventions will see clinical benefit. As this is 
the first time these treatments have been used in so large a GWI population, it is not assumed, and 
the duration of benefit is also not predictable. Subjects in both arms of the study have the benefit of 
a thorough evaluation, careful management, access to lab results not normally performed in the 
course of routine care (cytokines, immune studies and genomic studies), and will gain a better 
understanding of their illness. Ubiquinol is also associated with a reduction of the oxidized form of 
cholesterol (LDL) which will be measured, another potential benefit. in the experience of our team 
study volunteers have a sense of satisfaction in helping others through their participation, an 
intangible, but a benefit. 
 
 
Monitoring Plan: 
A data safety and monitoring plan will be implemented to ensure that there are no changes in the 
benefit/risk ratio during the study and that confidentiality of research data is maintained. The Principal 
Investigator, Co-Investigators, and research staff will be responsible for data safety and monitoring. 
All data obtained in the course of the study will be confidential. All participants will be informed of 
their confidentiality rights at the time informed consent is administered. Data collection and 
management will be conducted in strict accordance with the policies and procedures set forth by the 
VA Research & Development Office Data Security and Privacy Policy. 
 
All study subjects will be assigned a study ID number by the research staff at their respective VA 
medical center at the time of enrollment in the study. Subjects will be identified by that number 
during the course of the study and data analysis. REDCap survey data will be entered as coded 
numerical values linked only to that subject’s study ID number. Windows integrated security will be 
used for all computer access by the research staff. At each VA medical center, all PCs, laptops, 
workstations and remote devices will be secured with a password-protected screensaver, wherever 
possible, and set to deactivate after being left unattended for 15 minutes or more, or by logging-off 
when the equipment will be unattended for an extended period. User and role permissions will be 
defined at the computer, file, directory, server and database level to ensure data security. All 
research records will be maintained in accordance with the Veterans Health Administration (VHA) 
Records Control Schedule. Paper records will be disposed of using methods deemed appropriate by 
the respective VA medical center Privacy Officer, and all electronic data will be sanitized using 
methods rendered appropriate by the VA ISO. 
 
The project team will meet weekly until the analysis commences to discuss the study (e.g., study 
goals, progress, modifications, documentation, recruitment, retention, and data analysis), and 
address any issues or concerns at the time. The discussion will include issues pertaining to data 
integrity, the assurance of patient confidentiality, and any needed changes will be instituted 
immediately to assure optimal subject protection. Breaches of confidentiality will be brought to the 
attention of the appropriate persons immediately as will any proposed changes to the data safety and 
monitoring plan. 
 
These meetings will be overseen by the site PI at each medical center. Minutes will be kept for these 
meetings and will be on file. In addition, the site PI and Dr. Klimas may review study documentation 
and/or consent forms to ensure that subject’s confidentiality is maintained. Any instances of protocol 
deviations, breaches of confidentiality, adverse events or other problems will be reported adverse 
effects will be reported immediately using the standard forms and/or procedures set forth by the IRB. 
Each VA site has an interim reporting requirement of all moderate to severe events to alert the site 
PI, with appropriate tracking logs and forms. All sites will be asked to share the VA Tracking Log for 


21 
 
Reportable and Non-Reportable Events and to follow the report of protocol deviations, violations, 
and/or Noncompliance with Dr. Klimas and the Project Manager, Devra Cohen, at the time of their 
scheduled IRB Continuing Review. In addition, all site PIs will report unanticipated serious adverse 
events (U-SAE), unanticipated problems (UAP) involving risks to participants and others to Dr. 
Klimas and Ms. Cohen in a timely manner. Research coordinators may review study documentation 
to ensure that subject’s confidentiality is maintained. 
 
Any paper notes on the forms will be collected and stored in a locked file cabinet in an office within 
the respective VA medical centers and staff will be responsible for their respondent confidentiality. 
The input from all individual surveys will be consolidated into an aggregated summary and no 
specific comments in the surveys will be attributed to an individual. Electronic data from the surveys 
will be kept on a secure, password-protected, encrypted VA computer and entered into a secure 
database behind VA firewalls. Unique participant ID numbers will be assigned to the survey data and 
will be inputted into the database. A crosswalk linking individual information to unique ID will be kept 
in a separate location in a password-protected file on a VA secure server, to which only investigators 
and analysts assigned to this project and listed on the research staff form will have access. A study 
investigator will review all files for consistency, accuracy and completeness and de- identification. 
Physical and electronic records will be kept according to the respective VA medical center’s 
guidelines. 
 
Data Handling 
Confidentiality and sharing of data from human subjects: All database functionality will be designed in 
strict compliance with Health Insurance Portability and Accountability Act (HIPAA) standards in the 
U.S. and the Privacy of Information Act in Canada. All data collected about participants will be treated 
as highly confidential. To protect study subjects from confidentiality risks, the data will be entered and 
stored on REDCap/ MySQL database hosted at Boston University servers with a comprehensive 
software security system to limit access of data to authorized personnel only. Access to specific data 
will be defined in each research personnel’s user profile and established based on that individual’s 
role in the project. All paper records containing identifying information (including the subject contact 
list and linking codes) will be kept in locked files in locked offices at the site VA. The study identifier 
(ID) number will be included on all records; these identification methods are consistent with HIPAA 
guidelines. Only de-identified data including genetic/genomic data will be sent to the Computation 
Science Core team. Current or future results from procedures described in this proposal could 
provide information about participant susceptibility to certain ailments or conditions. Should any 
results of immunological or standard screening tests performed in this study demonstrate clinically 
relevant abnormalities, that information will be communicated to the participant’s attending physician 
in accordance with local laws and the IRB medical ethics approvals in effect. Genetic/ genomic data 
will not be shared beyond authorized members of this research consortium. Results of the study will 
be shared with the participants but will be reported in such a manner that individual participants 
cannot be identified. 
 
Data infrastructure 
The core component of the project’s data management and data storage infrastructure is the 
Research Electronic Data Capture (REDCap) environment, an existing web- based relational 
database developed specifically by Vanderbilt University for clinical research and a v a i l a b l e to the 
general research community. REDCap is a secure, web-based application for building and 
managing online databases that are based on PHP webserver + JavaScript programming languages 
and uses a MySQL database engine for data storage and manipulation. The standard REDCap 
MySQL database is built around five components: i) a metadata table describing the database 
configuration (data field types and naming used for automatic creation of separate data storage 
table); ii) a data transaction log used to store all information about data changes and exports; iii) a 
document storage table used to store consent forms, and analysis code as well as analysis results 


22 
 
exported from applications such as SAS, SPSS, R, MatLab, Stata, Excel, and others; iv) a user 
privileges table containing details of access rights and expiration settings; and v) a set of flat data 
tables used to store all collected data (typically one record [row]) per sample with all associated data 
fields stored in columns). REDCap accomplishes key functions through the use of a single study 
metadata table referenced by presentation-level operational modules. This abstract meta-data 
programming model allows research teams to autonomously develop study-related databases in 
an efficient manner as an easily maintainable resource for multiple concurrent studies [Nadkarni et 
al., 2000]. The REDCap initiative is driven by a user consortium composed of 396 active 
institutional partners in 46 countries. Use of this environment is fully supported by a dedicated team 
of database architects located at Vanderbilt University. NSU is a full member of this software 
consortium. 
 
Data Identifiers 
Each study participant will be assigned a unique code number from which they can be identified. 
Personal identifiers such as name, address, and date of birth will not be used on any study collection 
sheets except for the study contact sheet. This identifiable information is collected for patient tracking 
and safety purposes. The electronic information from the contact sheet will be stored separately f r o 
m the main study database in a password-protected file at the site on a VA computer behind a VA 
firewall. Any paper versions of the contact sheet will be stored in locked file cabinets separate from 
other study data and accessible only by authorized study staff. In study databases, all data will be 
coded with the unique study identifier for each participant and stored in a de-identified manner. 
 
Data Collection and Quality Assurance 
The research coordinators at each study site will be responsible for managing the local study data. 
After a patient consents to participate in the study, the site clinical research assistant will create a 
patient casebook, which will contain the consent forms, all relevant source documents, and any 
other information pertinent to the study. The completed summary study forms will be uploaded 
electronically to REDCap for cleaning and processing into an electronic data document allowing for 
real-time data quality assurance and analysis. This will allow clinical research assistants to enter the 
source document data directly into a study database and thus manage their patient’s study activity, 
handle data clarifications, and correct patient data in real-time. The data will be entered by site 
research assistants remotely through electronic case report forms. Extensive data checks, including 
missing values, out-of-range entries, and consistency between variables, both within and across 
forms, will be built into the system developed for this project. There will be two levels of checking. 
The first level will be done at the time the data is entered into the case report form. These checks 
will automatically appear on the screen at the time of entry. After submission of the form into the 
database, second-level checks against other data already captured for that patient will be done. 
 
Data Confidentiality, Security, and Disposition 
The database will not contain information that can directly identify the study subject (such as name, 
address, etc.). Study participants will be identified by a code number and not their personal 
identifiers on all study collection sheets except the study contact sheet. The electronic information 
from the contact sheets is stored separately from the main study database in a password-protected 
file. Any paper versions of the contact sheets are stored in locked file cabinets separate from other 
study data and accessible only by authorized study staff. Contact form information will be entered 
into the electronic system as password-protected files. Study data will be coded with a unique study 
identifier for each participant and stored in a de-identified manner. Identifiable information will be 
collected for patient tracking and safety purposes. All private information will be kept on an 
encrypted, password-protected server to which a small number of people will have access. All staff 
involved in the research project will have completed the appropriate IRB trainings. Access to the 
Cross-walk file linking the participant's identifiers and their study data will be restricted to the clinical 
VA sites. While the study is on-going, the data capture systems will utilize state-of-the-art 


23 
 
technologies in order to protect the data during transmission through web upload. Data will be 
stored indefinitely after study completion. 
 
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