Coenzyme Q10 Phase III Trial in Gulf War Illness

• ClinicalTrials.gov Identifier: NCT02865460
• Recruitment Status: Completed
• First Posted: August 12, 2016
• Results First Posted: February 15, 2023
• Last Update Posted: February 15, 2023
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Gulf War Illness; Chronic Fatigue; Ubiquinol; Coenzyme Q10	Drug: Ubiquinol; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind Placebo-controlled Phase III Trial of Coenzyme Q10 in Gulf War Illness
• Actual Study Start Date: July 24, 2017
• Actual Primary Completion Date: October 7, 2020
• Actual Study Completion Date: December 31, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ubiquinol; Take oral tablets as directed (2x200 mg for 2 months; 1x200 mg for 4 months) with food each morning- upon waking	Drug: Ubiquinol; Take oral tablets as directed (2x200 mg for 2 months; 1x200 mg for 4 months) with food each morning- upon waking; Other Name: Coenzyme Q10, CoQ10
Placebo Comparator: Placebo; Take oral tablets as directed (2x200 mg for 2 months; 1x 200 mg for 4 months) with food each morning-upon waking	Drug: Placebo; Take oral tablets as directed (2x200 mg for 2 months; 1x200 mg for 4 months) with food each morning- upon waking; Other Name: Sugar pill, inactive substance

Outcome Measures

Primary Outcome Measures :

1. Veterans Short Form 36-Item Health Survey Physical Component Summary [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 24 ]
   Veterans Health Survey contains 36 items to measure health functioning from the patient's point of view. The scale is 0-100. The higher value indicates better physical health.

Secondary Outcome Measures :

1. Multidimensional Fatigue Inventory (MFI) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 24 ]
   MFI asks questions about general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. The Multidimensional Fatigue Inventory score is 0-100. The higher value indicates more fatigue.
2. Gulf War Illness Health Symptom Checklist [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, and 28 ]
   The Gulf War Illness Health Symptoms Checklist asks questions about symptoms related to Gulf War Illness. The linear scale is 0-42. The higher value indicates more symptoms.
3. Brief Pain Inventory [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 24 ]
   The Brief Pain Inventory is a linear scale of pain. The scale is 0-10. The higher value indicates more pain.
4. Pittsburgh Sleep Quality Index [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 24 ]
   The PSQI measures quality and patterns of sleep and wake cycles and is completed by the participant. The Pittsburgh Sleep Quality Index scale is 0-21. The higher value indicates more sleep disturbance.
5. Hamilton Anxiety Scale (HAM-A) [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
   This measure allows the participant to rate levels of anxiety. The Hamilton Anxiety Scale is 0-56. The higher value indicates more anxiety.
6. Hamilton Depression Scale (HAM-D) [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
   This measure allows the participant to rate level of depression. The Hamilton Depression Scale is a linear scale 0-62. The higher value indicates more depression.
7. Veterans Short Form 36-Item Health Survey: Mental Component Score (MCS) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 24 ]
   Veterans Health Survey contains 36 items to measure health functioning from the patient's point of view. The Veterans Short Form 36-item Health Survey Mental Component Score scale is 0-100. The higher value indicates more favorable mental health.
8. Connors Continuous Performance Test (CPT-3): Hit Reaction Time [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
   CPT-3 asks questions about cognitive symptoms related to attention and reaction time. The Connors Continuous Performance Test Hit Reaction Time scale is 0-No limit. The higher score indicates poorer outcomes.
9. Connors Continuous Performance Test (CPT-3):Omissions T-score [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
   CPT-3 asks questions about cognitive symptoms related to attention and reaction time. The Connors Continuous Performance Test Omissions score is 0-100. 50 indicates the population mean with a standard deviation of 10. The higher T-score indicates poorer outcomes.
10. Connors Continuous Performance Test (CPT-3):Commissions T-score [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    CPT-3 asks questions about cognitive symptoms related to attention and reaction time. The Connors Continuous Performance Test Commissions T-score scale is 0-100. 50 indicates the population mean with a standard deviation of 10. The higher score indicates poorer outcomes.
11. Brief Visual Memory Test (BVMT): Delayed Recall [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    BVMT asks questions about cognitive symptoms related to visual memory. The Brief Visual Memory Test Delayed Recall scale is 0-12. The higher value indicates better performance.
12. Brief Visual Memory Test (BVMT): Percent Retained [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    BVMT asks questions about cognitive symptoms related to visual memory. The Brief Visual Memory Test Percent Retained score is 0-100. The higher value indicates better performance.
13. California Verbal Learning Test (CVLT-II): Correct Trials # 1-5 [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    CVLT-II asks questions about cognitive symptoms related to recall and memory. The California Verbal Learning Test (CVLT-II) Correct Trials #1-5 score is 0-80. The higher score indicates better performance.
14. California Verbal Learning Test (CVLT-II): Short Delay [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    CVLT-II asks questions about cognitive symptoms related to recall and memory. The California Verbal Learning Test (CVLT-II) Short Delay Test scale is 0-16. The higher score indicates better performance.
15. California Verbal Learning Test (CVLT-II): Long Delay Test [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    CVLT-II asks questions about cognitive symptoms related to recall and memory. The California Verbal Learning Test (CVLT-II) Long Delay Test scale is 0-16. The higher score indicates better performance.
16. Davidson Trauma Scale [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Davidson Trauma Scale asks questions about stress, arousal, and avoidance. The scale is 0 - 136. The higher value indicates worse outcome.
17. FitBit Sleep Measurement - Total Sleep [ Time Frame: Baseline to 8 weeks, 8 weeks to 16 weeks, 16 weeks to 24 weeks ]
    FitBit measures the duration of sleep daily via a bracelet-type instrument worn on the participant's wrist throughout the study. No normative data for FitBit Sleep was available.
18. FitBit Sleep Measurement - Types of Sleep [ Time Frame: Baseline to 8 weeks, 8 weeks to 16 weeks, 16 weeks to 24 weeks ]
    FitBit measures the time spent in each type of sleep (Light, Deep, Rapid Eye Movement (REM)) daily via a bracelet-type instrument worn on the participant's wrist throughout the study. No normative data for FitBit Sleep was available.
19. Response to Therapy of Gulf War Illness-associated Peripheral Blood Biomarkers - Complete Blood Count (CBC) White Blood Cell Counts and Platelets [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Peripheral blood biomarker levels are quantified by complete blood count (CBC) analyses: white blood cell (WBC) counts and platelets. Average values fell within the normal range for this type of assay.
20. Response to Therapy of Gulf War Illness-associated Peripheral Blood Biomarkers - Complete Blood Count (CBC) Red Blood Cell (RBC) Counts [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Peripheral blood biomarker levels are quantified by complete blood count (CBC) analyses: red blood cell counts. Average values fell within the normal range for this type of assay.
21. Response to Therapy of Gulf War Illness-associated Peripheral Blood Biomarkers - Complete Blood Count (CBC) White Blood Cell Percentages [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Peripheral blood biomarker levels are quantified by complete blood count (CBC) analyses: percentages of white blood cells. Average values fell within the normal range for this type of assay.
22. Response to Therapy of Gulf War Illness-associated Peripheral Blood Biomarkers - Complete Blood Count (CBC) Hemoglobin [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Peripheral blood biomarker levels are quantified by complete blood count (CBC) analyses: hemoglobin. Average values fell within the normal range for this type of assay.
23. Response to Therapy of Gulf War Illness-associated Peripheral Blood Biomarkers - Complete Blood Count (CBC) Hematocrit [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Peripheral blood biomarker levels are quantified by complete blood count (CBC) analyses: percentages of hematocrit in blood. Average values fell within the normal range for this type of assay.
24. Response to Therapy on Hypothalamic-Pituitary-Thyroid (HPT) Axis: TSH [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Thyroid status is assessed using a chemiluminescent method: thyroid stimulating hormone (TSH). Average values fell within the normal range for this type of assay.
25. Response to Therapy on Hypothalamic-Pituitary-Thyroid (HPT) Axis: FT3 [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Thyroid status is assessed using a chemiluminescent method: Free triiodothyronine (FT3). Average values fell within the normal range for this type of assay.
26. Response to Therapy on Hypothalamic-Pituitary-Thyroid (HPT) Axis: FT4 [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    Thyroid status is assessed using a chemiluminescent method: Free thyroxine (FT4). Average values fell within the normal range for this type of assay.
27. Response to Therapy on Cortisol Levels [ Time Frame: Baseline, Weeks 8, 16, and 24 upon waking, mid-morning, evening, and sleep for each. ]
    Cortisol will be measured using a 24-hour salivary collection to assess circadian rhythm.
28. Response to Therapy on Hypothalamic-Pituitary-Gonadal (HPG) Axis: Testosterone [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    HPG will measure testosterone. Average values fell within the normal range for this type of assay.
29. Response to Therapy on Hypothalamic-Pituitary-Gonadal (HPG) Axis: Progesterone [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    HPG will measure progesterone. Average values fell within the normal range for this type of assay.
30. Response to Therapy on Hypothalamic-Pituitary-Gonadal (HPG) Axis: Estradiol [ Time Frame: Baseline, Weeks 8, 16, and 24 ]
    HPG will measure estradiol. Average values fell within the normal range for this type of assay.

Eligibility Criteria

• Ages Eligible for Study: 35 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male and female Veterans who were deployed in 1990 -1991 Gulf War.
• Veterans who currently meet the Kansas Gulf War Study Case Definition for Gulf War Illness.
• Veterans who were in good health based on medical history prior to 1990.
• Veterans whose severity of illness is moderate to severe, evidenced by scoring less than 30 of 100 on the physical domain of SF36.

Exclusion Criteria:

• Veteran has a condition that may interfere with the ability to accurately report symptoms, such as:

  • severe psychiatric problems
  • schizophrenia
  • bipolar disorder
  • major depression with psychotic or melancholic features
  • delusional disorders alcohol or drug dependence requiring hospitalization, or regular illegal drug use or other psychiatric condition requiring inpatient stay in the 6 months prior to study entry.
  • Has dementias of any type
  • Currently does not have exclusionary conditions that could reasonably be responsible for the symptoms in multi-symptom disorders, as determined by Investigator (based on Reeves et al.2003).
  • Is pregnant or breastfeeding or plans to become pregnant within the next 6 months.

• Medical conditions excluded:

  • organ failure
  • defined rheumatologic inflammatory disorders
  • chronic active infections such as HIV, hepatitis B and C, or transplant
  • primary sleep disorders

• Medications that could potentially impact immune function excluded:

  • steroids
  • immune-suppressives
  • nutraceuticals that are formulated to impact mitochondrial function or oxidative stress
  • Biologic response modifiers within 3 months of study entry.
• Current use of Coumadin (given the vitamin K structural similarity of CoQ10)
• Known allergy to CoQ10 and/or inactive ingredients of active and placebo soft gelatin capsules
• Willingness to have 12 weeks of washout of current CoQ10, ubiquinol, or ubiquinone supplements will be required between the screening and baseline visits.
• Common multivitamin preparations will be allowed if taken without change throughout the protocol.

Contacts and Locations

Locations

United States, Florida

Miami VA Healthcare System, Miami, FL

Miami, Florida, United States, 33125

United States, Massachusetts

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Boston, Massachusetts, United States, 02130

United States, Minnesota

Minneapolis VA Health Care System, Minneapolis, MN

Minneapolis, Minnesota, United States, 55417

United States, New York

James J. Peters VA Medical Center, Bronx, NY

Bronx, New York, United States, 10468

Sponsors and Collaborators

VA Office of Research and Development

Investigators

• Principal Investigator: Nancy G Klimas, BS MD; Miami VA Healthcare System, Miami, FL

  Study Documents (Full-Text)

Documents provided by VA Office of Research and Development:

Study Protocol and Statistical Analysis Plan  [PDF] February 19, 2020

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02865460
• Other Study ID Numbers: SPLD-04-15F
• First Posted: August 12, 2016
• Results First Posted: February 15, 2023
• Last Update Posted: February 15, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:

Ubiquinol/ubiquinone; Gulf war illness; Chronic Pain; Cognitive Disorders; Inflammation; Neurologic manifestations; Dementia; Mental Disorders; Pathologic Processes; Nervous System Diseases; Hormones, Hormone Substitutes, and Hormone Antagon; Anti-Inflammatory Agents; Pharmacologic Actions; Therapeutic Uses; Physiological Effects of Drugs; Chronic fatigue

Additional relevant MeSH terms:

Fatigue; Coenzyme Q10; Micronutrients; Physiological Effects of Drugs; Vitamins