Background: Gulf War Veterans (GWV) with Gulf War Illness (GWI) have shown evidence of dysfunction of the energy producing elements of cells, called "mitochondria." Evidence supports benefit from coenzyme Q10 (coQ10) supplementation to physical function and symptoms in GWI10. CoQ10 benefits mitochondrial (mt) function and antioxidation. But it is just one part of a "mt cocktail," comprising a number of nutrients chosen to support cell energy and defend against oxidative stress, now considered to be "standard of care" for mt conditions. Dr. Richard Kelley, a mt expert, has experience caring for patients with apparently environmentally triggered mt dysfunction associated with developing the regressive form of autism spectrum disorder (rASD). rASD and GWI share many features: in both, a prior healthy state is followed by deterioration. Common exposures are linked to both, include pesticides, and genetic variants of an enzyme that detoxifies organophosphates called paraoxonase. Both often have multiple symptoms spanning fatigue, muscle, gastrointestinal, sleep, and respiratory problems. They share common objective abnormalities, such as elevation in autoimmune markers, reduced natural killer cell function, and presence of autonomic insufficiency. (The developmental period of exposure/illness onset may underlie the distinctive social aspects of rASD.) A mt cocktail designed to support cell energy and defend against oxidative stress, which also addresses abnormalities in amino acids (AAs) (protein building blocks) important to the "citric acid cycle" (CAC) that generates energy in mitochondria, has effectively treated this mt-affected population sharing exposure relations, symptoms, and objective markers -- often normalizing function. GWI, with its many parallels, has strong prospects to achieve similar benefit.

Our aim is to secure information to affirm that a full trial of this mt cocktail is justified in GWI and to develop the critical information to ensure a successful large-scale trial, e.g., to select outcomes, duration, and sample size. To do this, 32 GWV meeting Kansas and Centers for Disease Control and Prevention criteria for GWI will be randomly allocated to either a mt cocktail with individualized CAC/AA treatment or a sham treatment in identical capsules.

Treatment will occur in double blind fashion for 6 months. After 6 months, each group will receive active treatment for an additional 6 months in "open label" fashion (now, knowing they are receiving treatment) to allow the sham-allocated group to also have the opportunity to receive treatment and to assess the impact of treatment duration, comparing, at the end, those who have been on treatment for 1 year vs. 6 months. The treatment comprises nutrients important for mt energy production and protection against oxidative stress, including vitamins C, E, coQ10, alpha lipoic acid, selected B-complex vitamins, carnitine, and omega-3s. Each Veteran's laboratory tests will be examined to individualize protocols for AA/CAC correction. The cocktail elements will be put together into capsules by a pharmacy; those receiving the sham treatment will receive identical capsules. Each participant will take, with meals, four capsules three times a day of the main cocktail or identical sham, plus 1 capsule three times a day of fish-based omega-3 product or matched sham plus six capsules three times a day of AAs (actually, six, six, and five capsules). At 3 months, nutrient levels will be retested to test if target levels are achieved. If not, dosing will be modified by Dr. Kelley and communicated to the pharmacist (preserving blinding and the same capsule number). Outcomes will assess correction of CAC and AA, as well as fatigue, cognition, muscle function, quality of life/general health, pain, and symptoms. The data will be used to affirm whether the mt cocktail is promising for GWI, as we think it will be; to determine how large the apparent effects are relative to the variability; to guide the number of people required for a full clinical trial; to learn which outcomes most cost-efficiently capture the benefits; and to see how duration of treatment affects outcomes (to guide treatment duration for a future study).

There are strong prospects for benefit. The protocol has successfully normalized function in many who, like GWI, have had apparently environmentally triggered mt dysfunction, with symptom profiles and objective markers that share close similarities with GWI. Evidence already supports benefit with coQ10 vs. placebo in GWI, one element of the protocol. But experience dictates that the full mt cocktail is important to achieving more complete and progressive benefit. There is cause to expect that ongoing cellular damage and loss will be minimized, that key facets of physiology will shift toward normal, that symptoms and function will improve, and that oxidative contribution to many conditions will diminish (from cancer to heart disease to autoimmune disease). This treatment is expected to reduce energetic vulnerability, and thus improve outcomes, in settings of illness, injury, and surgery. It is also expected to reduce risk of progressing to an oxidative-mitochondrial vicious cycle contributing to neurodegenerative conditions, like amyotrophic lateral sclerosis or Alzheimer's disease, going forward.