Challenges Addressed: (1) Revolutionize treatment and minimize negative side effects with a highly safe treatment that surpassed virtually all others in a survey of treatments tried by Veterans with Gulf War Illness (GWI). (2) Slash the health consequences associated with GWI, with a treatment that has already been shown to reduce conditions and events to which Veterans are at heightened risk – hypertension, cardiovascular events and death – and to reduce mechanisms relevant to other conditions experienced by those with GWI.

Objective: In a nationwide study of coenzyme Q10 (coQ10) vs. placebo in Veterans with GWI, using the previously tested Pharma Nord coQ10 product, now available over the counter in the US, to confirm benefits of coQ10 to symptoms and function in GWI – via a true replication study (see below).

Rationale: In our prior study, coQ10 compared to placebo significantly reduced GWI symptoms; improved objectively measured physical function; and in men with GWI, improved perceived general health. Size of benefit related to size of coQ10 increase. CoQ10 has shown benefit to symptoms and function in others, including patients with GWI-relevant fibromyalgia and chronic fatigue. Moreover, trials have shown that coQ10 (vs. placebo) reduces hypertension and heart attacks, for which Gulf War Veterans are at heightened risk. It reduced cardiovascular death and death from all causes in heart patients. CoQ10 reduces mitochondrial impairment, oxidative stress, inflammation, and cell death – mechanisms implicated in GWI that may place Veterans with GWI at risk of many other outcomes. Therefore, coQ10 may in future be shown to reduce many additional conditions to which Veterans may be subject. There is need for a true replication, using the same product and outcomes. CoQ10 is sold in two forms, “ubiquinone” and “ubiquinol.” Each partly turns to the other in the body. We used and will use ubiquinone, the form used in most studies that have shown benefit with coQ10. Some think that ubiquinol should be better (others give reasons it is not), so it was chosen for a Department of Veterans Affairs (VA) study in GWI. But in fact, some Veterans with GWI (and others with GWI-relevant symptoms and exposures) state that while ubiquinone made them better, ubiquinol made them worse. These reports underscore the need for a true replication, with the ubiquinone form. (Also, the Pharma Nord ubiquinone we will use is the form, and high-quality brand, that in recent trials of heart patients and elderly patients, slashed cardiovascular morbidity and mortality, and all-cause mortality: benefits to Veterans beyond GWI symptoms and function are possible.) Clearly a true replication – with the same high-quality product and brand and assessing the same validated and important outcomes – is needed.

Treatment Duration: The main placebo-controlled study time point is 3.5 months. This is followed by a further 3.5-month “extension” phase in which all participants receive active treatment, i.e., coQ10. Veterans will not know their original assignment. Thus, some will receive coQ10 for 7 months, some for 3.5 months, and neither staff nor participants will know who received which duration of treatment. This has three benefits: (1) All participants have the chance to receive active treatment. (2) Knowing that they will for sure receive active treatment may boost interest in the study and knowing this comes in the second half may aid participant retention through the main time point. (3) We can assess if longer treatment confers greater benefit – comparing those who had 7 months vs. 3.5 months of treatment, in participants all of whom are the same 7 months from baseline (so they have the same opportunity for time and other factors to lead to changes in symptoms).

Clinical Applications, Benefits and Risks for Veterans with GWI: Risks of the ubiquinone form of coQ10 are very low. “Activation insomnia” can occur with coQ10 taken near bedtime – due to revving up of cell energy production. But this is usually avoided just by advising participants not to take their treatment near bedtime – as we will advise for all participants. Potential benefits are considerable. In the earlier study it was found coQ10 mitigated symptoms and improved function and health (men) in Veterans with GWI. Additional benefits have been shown outside of GWI populations: coQ10 has reduced high blood pressure, heart disease, heart attacks, and Pharma Nord coQ10 specifically has reduced major adverse cardiovascular events and deaths, and markedly cut death from all-causes in heart patients – important for Gulf War Veterans who are known to have elevated rates of hypertension and heart disease. Pharma Nord CoQ10 (adding selenium) also markedly cut cardiovascular deaths in healthy elderly. Use during the study continued to cut these deaths in the decade afterward. Based on its documented benefits to energy, oxidative stress, inflammation, and cell death, coQ10 is expected to reduce many other aging-related conditions. Thus, coQ10 is a treatment that may not only alleviate suffering and improve function for many Veterans in the present – but may produce benefits that may be cumulative, and lifesaving, as these Veterans passage into older age.

Projected Time to a Patient-Related Outcome: We expect symptoms and function to show benefit by 3.5 months. (Longer term study might begin to show reduced healthcare visits, morbidity and mortality.)