A randomized phase II remote study to assess Bacopa for Gulf War Illness associated cognitive dysfunction: Design and methods of a national study

Abstract

Aims:

Gulf War Illness (GWI) is a chronic, debilitating, multi-symptom condition affecting as many as one-third of the nearly 700,000 U.S. troops deployed to the Middle East during the 1990–1991 Gulf War (GW). The treatment of GWI relies on symptom management. A common challenge in studying the efficacy of interventions for symptom management is participant recruitment related to factors such as the burden of travelling to study sites and the widespread dispersion of Veterans with GWI. The goal of this study is to assess the efficacy of a novel low-risk therapeutic agent, Bacopa monnieri, for cognitive function in Veterans with GWI and to evaluate the utility of a remote patient-centric study design developed to promote recruitment and minimize participant burden.

Main Methods:

To promote effective participant recruitment, we developed a remote patient-centric study design. Participants will be recruited online through social media and through a web-based research volunteer list of GW Veterans. An online assessment platform will be used, and laboratory blood draws will be performed at clinical laboratory sites that are local to participants. Furthermore, the assigned intervention will be mailed to each participant.

Significance:

These study design adaptations will open participation to Veterans nearly nationwide and reduce administrative costs while maintaining methodologic rigor and participant safety in a randomized, placebo-controlled phase II clinical trial.

1. Introduction

Gulf War Illness (GWI) is a chronic, debilitating, multi-symptom condition affecting as many as one-third of the nearly 700,000 U.S. troops deployed to the Middle East during the 1990–1991 Gulf War (GW) [1,2]. Symptoms associated with the illness include joint and muscle pain, fatigue, gastrointestinal disturbances, headaches, sleep difficulties, neurologic and neuropsychological symptoms, respiratory issues, and cardiovascular problems [2]. Researchers have identified exposures during the GW, including nerve agents, pyridostigmine bromide tablets, and other chemical agents (e.g., smoke from oil well fires, pesticides, and solvents and corrosive liquids used during repair and maintenance), combined with genetic factors, that are associated with the illness [1,2]. While the underlying pathophysiological mechanisms of GWI have yet to be fully elucidated, potential contributions to disease activity (including immune and neurological dysfunction) have been identified through epidemiologic, clinical, and basic science studies [3–5]. However, to date, treatment has remained focused on alleviating symptom burden.

Investigative and clinical research studies seeking to understand the underlying mechanisms of GWI and evaluate targeted treatments have met with limited success. One of the critical difficulties has been recruitment, which has been attributed to several factors, particularly the distance between study locations and residence locations of the afflicted Veterans who tend to live dispersed nationwide. Also, many Veterans from the GW are currently employed and unable to take time for travel. Furthermore, travel to attend multiple study visits can be very difficult for nearby Veterans with GWI who are burdened by chronic unrelenting symptoms, increased risk of infection, and cardiovascular and respiratory complications. Many GW Veterans affected by this illness do not reside near institutions with research expertise and must travel to take part in studies. Additional complexities arise when GWI patients live far from recruitment sites, as the expense to engage these patients increases due to increased participation needs such as long-distance travel, hotel/lodging, caregiver travel, etc. The inability to include individuals due to these challenges may introduce bias and reduce generalizability of findings, even if recruitment goals are met. The recent COVID-19 pandemic has exacerbated these and related issues, emphasizing the need to find new ways to engage patients, while minimizing the risks associated with their study participation.

To address these recruitment challenges, our research team developed a novel remote patient-centric intervention study design for Veterans with GWI. This study is supported by the multi-investigator, multi-site Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC) funded by the Congressionally Directed Medical Research Programs (CDMRP). The goal of the GWICTIC is to focus on phase I and phase II clinical trials in a collaborative research network that engages many of the clinical and preclinical experts in the field in partnership with an advocacy coalition. The members of the Veterans’ Advocacy Committee advise the investigators on the challenges faced by the Veterans and provide invaluable input for the study design and implementation.

This paper reports the design of a remote phase II randomized trial with elements and approaches intended to support the inclusion of GWVs with GWI from across the United States to evaluate the efficacy of a low-risk botanical intervention (Bacopa monnieri) for central nervous system (CNS)-related symptom management compared to placebo.

2. Materials and methods

2.1. Study rationale

Increasing evidence suggests concomitant exposure of Veterans to acetylcholinesterase (AChE) inhibitors in war-related chemicals (e.g., sarin nerve gas) and the prophylactic anti-nerve agent pyridostigmine bromide (PB) caused neurological dysfunction likely tied to GWI [6,7]. A combination of neurotoxicant-triggered neuroinflammation and physical and mental stressors is a putative cause of the neuro-immune abnormalities observed in GWI [8–13]. The hypothesis has spiked interest in chronic glial cell inflammatory activation being a contributor to GWI symptoms due to accompaniment by sickness behavior [6,12,14–16]. In addition to overlap of clinical presentation of GWI with fibromyalgia, the pattern of neuroinflammatory biomarkers in GWI also showed similarity with fibromyalgia [8,9]. In addition, a study reported significant elevations in surrogate markers of neuroinflammation with microglial or astrocytic contributions, but not the marker with mainly astrocytic contributions [8], which highlights the potential of microglial inflammatory activation modulation as a potential therapeutic target for GWI-associated neuroinflammation [17].

We aim to evaluate a therapeutic agent, Bacopa monnieri (Bacopa), that is known to target some of the underpinnings of GWI such as neuro-immune function [18] and inflammation [19–21]. A review of the clinical and preclinical literature on Bacopa reveals age-independent benefits on cognitive function and other parameters such as mood, alertness, anxiety, depression, and overall sense of well-being [22,23]. In addition, bacosides isolated from Bacopa have been shown to improve neuron transport, regenerate synapses, and repair damaged neurons, enhancing cognitive function [24] while stimulating the cholinergic system and activating neuroprotective agents [25–27].

2.2. Dosing and duration

Many Ayurvedic rasana (preparations) include consistent use of Bacopa for cognitive dysfunction. Stough and colleagues conducted a randomized, double-blinded, placebo-controlled study assessing effects of 300 mg/day of Bacopa for 12 weeks on cognitive function in healthy human participants [28]. The visual information processing speed, rate of learning, memory consolidation, and anxiety were significantly improved in those who took Bacopa for 12 weeks as compared to placebo [28]. Roodendrys and colleagues, and Morgan and Stevens found similar cognition-enhancing effects of 12 weeks of 300 to 450 mg of Bacopa in healthy individuals [29,30]. Goswami and colleagues reported improvement of cognitive functions in 39 geriatric patients suffering from Alzheimer’s disease after taking 300 mg twice a day for six months [31]. Neale and colleagues reported comparable effect sizes among the pharmaceutical modafinil (0.77), Bacopa (0.95) and ginseng (0.86) on cognitive function in a meta-analysis of eight clinical trials in adults [32]. These studies administered Bacopa at 300 to 450 mg, modafinil at 100 to 300 mg, and ginseng at 200 to 600 mg dosages [32]. Based on the published evidence, Bacopa monnieri standardized extract will be administered at the dose of 300 mg daily for 12 weeks in this study.

2.3. Safety and tolerability of Bacopa

The choice of therapeutic agent is important in GWI, considering the high chemical sensitivity seen in this participant population. This clinical trial will use BacoMind® Bacopa monnieri standardized extract (Natural Remedies Private Limited), which has been extensively studied in clinical and pre-clinical research, and for which safety and tolerability data are available for the general and geriatric populations [29,31,33–35]. BacoMind® has met the requirements of self-affirmed Generally Recognized as Safe (GRAS) status based on the evaluation of toxicology and safety data conducted by Soni and Associates, Inc. for daily dosage of up to 319 mg in accordance with Section 201(s) of the Federal Food, Drug, and Cosmetic Act of the United States.

Several human subject studies have investigated the safety and tolerability of Bacopa. A double-blinded, placebo-controlled study showed that 300 mg of Bacopa for 12 weeks improved early information processing, verbal learning, and memory consolidation with no serious adverse events [28]. A pilot study was conducted to evaluate the safety and tolerability of BacoMind® in elderly volunteers receiving 300 mg Bacopa for 14 days, followed by 450 mg for the next 14 days, as a single daily dose. No abnormalities were reported in clinical examination, routine hematology, serum biochemistry, urinalysis, or neurological measures [34]. Calabrese and colleagues studied the effect of Bacopa on cognitive function in elderly participants (mean age 73.5 years) and found no difference in adverse events between placebo and Bacopa groups [36]. The most commonly reported side effects of Bacopa include nausea, gastrointestinal upset, and gastrointestinal hypermotility due to its cholinergic action. The studies to date indicate that Bacopa has a high therapeutic index, which accounts for its safety during long term use without any serious adverse events.

2.4. Study design

Eligible participants (n = 264) will be randomized to receive 12 weeks of Bacopa (300 mg once per day) or placebo that is identical in size, shape, and color to the active treatment capsules, and without a characteristic smell, to preserve blinding. Participants will be instructed to take their randomly assigned treatment orally with water after their morning meal. If a dose is missed, the participants are to discard the missed dose and proceed with the treatment regimen the following day.

Participants will undergo assessments at screening, baseline, and 6 weeks, 12 weeks (assessment of primary endpoint), and 16 weeks (assessment of duration of effect) after baseline (Fig. 1). Participants will also receive biweekly phone calls during the intervention period to monitor their adherence, adverse event occurrence, COVID-19 status, and characteristics related to continued study eligibility. The total participation time is estimated to be approximately 18–20 weeks. To address recruitment and logistical challenges that are common to GWI research, this study adopts several design approaches that are novel in this domain:

1. Participants will be recruited online (through social media) and through an Institutional Review Board (IRB)-approved web-based research volunteer list of Veterans who served in the GW. Participants in this volunteer list gave permission to be contacted via their preferred mode of communication (phone, email, or postal mail) regarding future research studies.

2. An online assessment platform will permit participants to complete nearly all self-reported assessments using a participant-facing electronic data capture (EDC) system. This removes the need for travel to recruitment sites, allowing Veterans who are outside of the traditional GW Veteran catchment areas to participate and reducing the administrative costs of the study. This approach was successfully pilot-tested in a clinical trial where clinical response to over-the-counter oral L-Methylfolate was assessed in participants with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and heterozygous C677T MTHFR alleles (personal communication).

3. Partnership with nationwide laboratories will allow participants to complete study blood draws at a laboratory that is local to them, further reducing their burden of participation and increasing geographic access to the study. Participants will be mailed all materials needed for completion of the blood draw including labeled tubes and shipping materials. Their local clinical laboratory will perform screening labs and return the remaining biospecimens to the coordinating site for further analysis and storage.

4. For participants who are determined to be eligible after screening, baseline laboratory assessments will be performed using the biospecimens remaining from their screening labs. This reuse removes the need for an additional visit to the laboratory, reducing the burden on participants.

5. Participants will be mailed their assigned blinded intervention, removing the need to visit their research site to obtain the study product. This mailing further reduces the burden on participants and improves access to the study.

6. Participant randomization will be stratified according to sex and whether they are willing to commit to providing an additional blood draw 12 weeks after initiation of the intervention. This aims to balance the treatment arms in terms of participant dropout for biomarker-based secondary outcomes. In formally accounting for this strong predictor of missing data, the stratified design strengthens the statistical inference regarding treatment effects. Furthermore, the stratified design will improve the study’s efficiency by minimizing wasted materials.

Fig. 1.

Schematic of Bacopa phase II trial design.

2.5. Screening and eligibility

Potential participants will undergo a three-step screening process. First, Veterans from an existing GWI research volunteer list will be contacted via their preferred mode of communication. If they respond with an expression of interest in the study, research staff will schedule a time for a phone conversation. During this phone conversation, if verbal consent is provided, they will be given information about the study and an opportunity to ask questions. This study will require that all prospective participants discuss verbally the study details, expectations, and risks. Research staff will describe the assessment platform and allow prospective participants to read the approved informed consent form. Once the study coordinator determines that the prospective participant understands the implications of participating in the study, the prospective participant will be asked to give consent to participate in the study by signing the informed consent form through the EDC. Prospective participants will then complete their screening labs at their local clinical laboratory as discussed in the study design.

The eligibility criteria for this study are listed in Table 1.

Table 1.

Inclusion and exclusion criteria and prohibited concomitant and prior therapies.

Inclusion criteria  An individual is eligible for inclusion if all of these apply:	Age 47 to 75 years Served in the Gulf War theater for any period between August 1990 and July 1991 Meets modified Kansas case definition criteria and CDC case definition for Gulf War Illness. The modified Kansas definition, which includes the CDC criteria, includes: Allowance for normal illnesses of aging, such as hypertension and diabetes, if the conditions are treated and are in demonstrable stable and normal ranges at the time of screening and assessment. Allowance of stable comorbid conditions such as post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and traumatic brain injury (TBI) that have not required hospitalization in the 5 years prior to recruitment. Severe TBI is excluded. Able to provide consent to study Participants of childbearing potential must practice effective contraception during the study so that, in the opinion of the Investigator, they will be compliant with birth control measures during the study. Agrees to participate in follow-up visits
Exclusion criteria  An individual is ineligible to participate if any of these apply:	Scheduled for surgery within 20 weeks after study enrollment Current treated or untreated major depression with psychotic or melancholic features, schizophrenia, bipolar disorder, delusional disorders, dementias of any type, and alcoholism or drug abuse (as determined by self-report and the web-based Structured Clinical Interview for DSM-5 (NetSCID-5)), or a history of CNS disorders that may affect cognitive function (e.g., epilepsy, stroke, brain tumor, multiple sclerosis, Parkinson’s Disease, Alzheimer’s disease) Chronic active infections such as HIV, hepatitis B, or hepatitis C (as determined by antibody tests) Current primary sleep disorders (self-report) Any serious allergic disease (self-report) possibly resulting in anaphylaxis, such as food/drug allergies, including gelatin, and allergic asthma Use of medications that could affect immune function (e.g., steroids, immunosuppressants) (self-report) Renal insufficiency with serum creatinine >2.0 mg/dL Hepatic insufficiency (bilirubin >2.5 mg/dL or transaminases >3× the upper limit of normal (ULN)). Participants with Gilberts syndrome are eligible for the study if other liver function tests are normal, regardless of bilirubin level. Pregnancy Current exclusionary diagnosis that could reasonably explain the symptoms of their fatiguing illness and their severity, using the exclusion criteria best described in the Ambiguities in Case Definition for Chronic Fatigue Syndrome (CFS) (Reeves et al., 2003), which clarifies exclusionary conditions. Current heavy alcohol or tobacco use (self-report). Alcohol consumption not to exceed approximately 15 drinks per week (with a drink defined as 12 oz. beer, 5 oz. wine, or 1.5 oz. distilled spirits) and tobacco use not to exceed 20 cigarettes (or equivalent) per day. Diagnosis of CNS demyelinating disease (e.g., multiple sclerosis, neuromyelitis optica spectrum disorder)
Prohibited concomitant or prior therapies	Use of Bacopa within 6 months prior to enrollment in this study Currently on dialysis Participating in another interventional clinical trial of an investigational therapy within 8 weeks prior to consent to participate in this study, or planning to participate in another interventional clinical trial of an investigational therapy within 20 weeks after consent to participate in this study Current use of drugs that impact cognitive function or oxidative stress, as deemed by the research pharmacist, such as carbamazepine, valproate, lamotrigine, AChE inhibitors, or cholinergic drugs.

2.6. Randomization

Once the enrolled participant completes the baseline assessment (including the California Verbal Learning Test (CVLT-II)), they will be randomly assigned in parallel in a 1:1 ratio to receive either 300 mg of Bacopa monnieri standardized extract or placebo once a day for 12 weeks. Randomization will be stratified by consent to participate in the blood draw at the end of intervention and by sex and will be generated by the study biostatistician using a stratified permuted block design with randomly-ordered differing block sizes.

2.7. Assessments

All enrolled participants will be asked to provide information at baseline including demographic characteristics, a history of their GW exposures, and information related to inclusion/exclusion criteria and potential confounders, such as medical history, smoking and alcohol use, and personal COVID-19 status. The participants will be followed up biweekly via phone call to collect information on changes in characteristics pertinent to safety, adherence, and continued eligibility, including health, medication use, adherence to intervention, smoking and alcohol use, and COVID-19 status.

The instruments selected for this study are drawn from GWI Common Data Elements developed through a joint effort of the U.S. Department of Veterans Affairs and the Department of Defense (DoD) CDRMP to support collaboration with the National Institutes of Health, the Centers for Disease Control and Prevention (CDC), and the GWI research community [37].

The primary objective is to evaluate the efficacy of Bacopa for central nervous system (CNS)-related symptom management in GWI using the CVLT-II [38] as the primary outcome to measure cognitive function. The CVLT-II is a commonly used metric of adult cognitive function that assesses multiple aspects of verbal learning and memory recall. Several studies have reported cognitive problems to be among the most prevalent symptoms reported by GW Veterans [39–41]. Furthermore, multiple studies have reported that Veterans with GWI demonstrate measurable cognitive decrements on the CVLT-II [39–43]. The CVLT-II will be administered at baseline and an alternate version will be administered at the 12-week assessment to reduce practice effects.

Secondary outcomes for this study include biological response and physical health. There is a lack of known blood biomarkers available for cognitive impairment. However, certain molecules are substantially linked with neuro-inflammatory diseases, such as brain-derived neurotrophic factor (BDNF) and neurofilament light chain (NfL). BDNF is associated with promoting neuron survival, maintenance, and regulating synapses, and deficits in BDNF signaling have been linked with cognitive decline associated with depression and Alzheimer’s disease [44–49]. NfL is essential for structural integrity of neurons, and axonal damage and leaky blood-brain barrier attributed to neuroinflammatory diseases can lead to a release of NfL, which is measurable in plasma [50,51]. In addition to BDNF and NfL, quantifications of neuroinflammation and immune signaling will be measured using an 18-plex cytokine panel and glutamate assay, respectively [52–54]. The objective assessments of neuron health and structural integrity, neuroinflammation, and immune signaling will be measured from blood draws taken prior to randomization and at the end of the 12-week intervention.

The Veterans RAND-36 (VR-36) [55] physical component score (PCS) will be used as the secondary endpoint related to physical health. The VR-36 is one of the most widely used generic measures of health-related quality of life (HRQoL) for Veterans. The VR-36 will be administered at baseline and at 6 weeks, 12 weeks, and 16 weeks post-baseline, with all analyses performed on the norm-based scores. Specifically, the PCS draws from questions on the VR-36 aiming to assess overall physical health through the domains of general health, physical function, role limitations due to physical difficulties, and bodily pain.

Safety will be assessed by documenting the frequency and severity of adverse events. Assessments will be performed at baseline and every two weeks during the intervention period.

Exploratory endpoints will be assessed at baseline and at 6 weeks, 12 weeks, and 16 weeks thereafter by the VR-36 physical subscale score, VR-36 vitality subscale score, Pittsburgh Sleep Quality Index (PSQI) [56], Brief Pain Inventory (BPI) pain severity subscale for pain severity and interference [57], and DePaul Symptom Questionnaire (DSQ) for GWI symptoms [58].

Dietary factors that influence cognitive function have not yet been systematically defined, nor are their relationships with proteins normally found in the brain. However, it is reported that deficiencies of some of these nutrients affect the rate at which the brain atrophies or can respond to cognitive treatment [59–61]. Therefore, self-reported dietary intake (Willett’s Food Frequency Questionnaire [62]) and carefully selected nutritional biomarkers will be assayed at baseline to document nutritional status. These data will be used in post-hoc analyses of the potential heterogeneity of treatment effects of Bacopa.

2.8. Overview of statistical analysis plan

The primary efficacy analysis will be based on the intention-to-treat (ITT) principle, with data from all participants analyzed according to the arm to which they were randomized, irrespective of treatment received. The primary analysis will assess the primary endpoint by comparing the mean raw CVLT-II long-delay free recall scores [42,43,63] for the two study arms measured at the end of the 12-week intervention using an analysis of covariance (ANCOVA) model including baseline CVLT-II score and study arm as explanatory variables. This model will be used to generate point and interval estimates and to test the difference in mean cognitive function between the two comparison groups at 12 weeks, assuming a two-sided type I error of α = 0.05.

A secondary analysis for the primary endpoint will be performed on an “as treated” basis to examine treatment effects with explicit consideration of duration of intervention. Exploratory analyses to assess heterogeneity of the intervention effect for the primary endpoint with regard to environmental exposures during the GW and baseline nutritional biomarkers and dietary status will also be considered.

For the secondary endpoints of 18-plex cytokines, glutamate, BDNF, and NfL, descriptive analyses of their change over time will be performed. Furthermore, for each measure, mean blood concentrations from the blood draw taken at the end of intervention will be compared between the two study arms using ANCOVA methods adjusted for baseline concentrations. Exploratory analyses to assess the presence of heterogeneity of the intervention effect on biological response measures with regard to environmental exposures during the GW and baseline nutritional biomarkers and dietary status will also be considered.

Several subjective measures of participant status are repeatedly measured in this phase II study (baseline, 6 weeks, 12 weeks, and 16 weeks post-baseline) as exploratory endpoints, including the VR-36 physical subscale score, VR-36 vitality subscale score, PSQI, BPI, and DSQ. Descriptive analyses of these measures will be performed to better understand their distributional characteristics, including aspects of change over time and within-participant correlation of repeated measures.

Correction for multiple testing will not be necessary for this study due to the single endpoint for the primary analysis, absence of formal interim analyses, and hypothesis generating nature of the analyses of safety, secondary, and exploratory endpoints.

2.9. Sample size determination

The CVLT-II long-delay free recall score is measured over a range of 0 to 16, with an expected mean of 11.2 and standard deviation of 3.2 in GW Veterans with GWI [43,64–66]. Test-retest reliability for the CVLT-II long-delay free recall score has been documented with a correlation of 0.69 for both short and long periods between test and retest [38,67]. With a sample size of 264 participants (effective sample size 105 participants per arm after 20% attrition) and assuming a standard deviation of 3.2 and correlation between baseline and post-intervention CVLT-II long-delay free recall scores of 0.60, a difference of 1.0 point in the CVLT-II scores can be detected between the study arms with 80% power. The associated effect size is then d = 0.31, which is considered a relatively small effect size [68]. At least 80% power is maintained to detect a difference in CVLT-II scores of 1.1 points between the study arms if the correlation is as low as 0.50 with a standard deviation of 3.2 (d= 0.34), or if the correlation remains 0.60 with a higher standard deviation of 3.4 (d= 0.32). Alternatively, a difference in CVLT-II scores of 1.2 points can be detected with close to 80% power if the correlation is as low as 0.30 (with SD = 3.2, d= 0.38) or if the standard deviation is as large as 3.8 (with correlation = 0.60, d= 0.32), with variability and correlation values ranging in the intermediary.

For analysis of the secondary endpoint of the VR-36 PCS, the sample size of 264 participants provides approximately 95% power to detect a difference of 5.0 points in the VR-36 PCS at the end of the treatment period (12 weeks). Five points is the minimal clinically important difference for the normed VR-36 PCS as indicated by the half-standard deviation criterion for HRQoL measures presented by Norman and colleagues [69]. This difference between groups is further supported by Goldberg and colleagues [70] who observed an effect size of 0.52 (corresponding to 5.2 points) for the VR-36 PCS when comparing Vietnam Veteran twins who served in the Vietnam theater, where one twin was diagnosed with full post-traumatic stress disorder (PTSD) and the other twin was not diagnosed with PTSD.

2.10. Ethics

This study was developed as a part of a larger CDMRP Gulf War Illness Research Program (GWIRP)-funded infrastructure for conducting innovative clinical trials (the GWICTIC) and was approved by the participating institutions’ IRBs. The study was also reviewed and approved by the GWICTIC External Peer Review panel, External Advisory Board, Data and Safety Monitoring Board (DSMB), and DoD Human Research Protections Office. The DSMB will review study progress and safety events on a quarterly basis as generated by an unblinded member of the Data Coordinating Center. Additionally, adverse events that are at least possibly related to study treatment, unexpected, and serious will be reported to the IRB, DSMB, and GWICTIC director within seven days. Documentation of all IRB approvals, including the already IRB-approved protocol, and of the IRB compliance with International Council on Harmonisation Guideline E6 will be maintained by the site and will be available for review by the sponsor or its designee. This study has been registered with ClinicalTrials.gov as NCT04927338.

3. Discussion

This study is unique in several aspects. Despite over half a billion dollars of investment in GWI research in the last three decades, the efforts of the research and clinical community have not yet yielded any condition-specific effective treatment. However, these decades of research have substantially enhanced the understanding of GWI symptoms, many of which have well understood pathophysiological mechanisms, enabling identification of therapeutic targets and potentially effective treatments. Bacopa is one such candidate intervention with modes of action overlapping with the molecular markers of disease symptomology, as identified by computational modeling [71,72]. The evidence from research studies elucidating its direct pro-cholinergic effect [27], antioxidant and anti-inflammatory activity highlights the potential for Bacopa to inhibit neuroinflammation and positively affect CNS function. This indicates its promising therapeutic potential for treating Veterans with GWI, especially when a large proportion report cognitive problems [39–42]. While Bacopa has not been previously studied in GWI, Bacopa is well tolerated in other populations [29,31,33–35], and its low toxicity profile adds to its appeal in this population for which chemical sensitivities are common. If found to be safe and effective in symptom management, Bacopa could serve as an easily accessible botanical component of treatment plans for GWI.

This study presents design adaptations that are novel to interventional trials in GWI, striving for a patient-centric approach that is cost-effective and feasible for nationwide implementation. These include recruitment through social media and an IRB-approved web-based research volunteer list, use of an online EDC platform, mailed interventions, and a small number of local blood draws. These adaptations will permit participants to complete their study participation without travelling to hospital-based recruitment sites, minimizing participant burden, opening participation to Veterans nearly nationwide, and reducing administrative costs, while maintaining methodologic rigor and participant safety. Design adaptations such as these may be applicable to future clinical trials of low-risk interventions in GWI, accelerating the pace at which candidate interventions can be evaluated for safety and early indications of efficacy.

4. Conclusion

Bacopa is a promising botanical supplement to address cognitive problems in Veterans with GWI. Its established low risk of adverse effects facilitates the use of an innovative remote randomized placebo-controlled trial of its efficacy. This promotes broader opportunity for GWV engagement in the clinical trial and should enhance recruitment, retention, and generalizable findings. This combination of carefully selected interventions and thoughtful and respectful design reflect a trailblazing strategy that, if successful, may dramatically accelerate research of low-risk interventions for GWI and improve the portfolio of candidate treatments.

Abbreviations:

AChE

acetylcholinesterase

ANCOVA

analysis of covariance

BDNF

brain-derived neurotrophic factor

BPI

Brief Pain Inventory

CDC

Centers for Disease Control and Prevention

CDMRP

Congressionally Directed Medical Research Programs

CNS

central nervous system

CVLT-II

California Verbal Learning Test-II

DoD

Department of Defense

DSMB

Data and Safety Monitoring Board

DSQ

DePaul Symptom Questionnaire

EDC

electronic data capture

GRAS

generally recognized as safe

GW

Gulf War

GWI

Gulf War Illness

GWICTIC

Gulf War Illness Clinical Trials and Interventions Consortium

GWIRP

Gulf War Illness Research Program

HRQoL

health-related quality of life

IRB

Institutional Review Board

ITT

intention-to-treat

MDD

major depressive disorder

ME/CFS

myalgic encephalomyelitis/chronic fatigue syndrome

NfL

neurofilament light chain

PB

pyridostigmine bromide

PCS

physical component score

PSQI

Pittsburgh Sleep Quality Index

PTSD

post-traumatic stress disorder

TBI

traumatic brain injury

VR-36

Veterans RAND-36