GWICTIC: NAC Mechanistic Study in Gulf War Veterans (NAC)

Mechanisms of Oxidative Stress During N-Acetyl Cysteine (NAC) Supplementation in Veterans With Gulf War Illness (GWI)

This mechanistic study will test if NAC affects chronic oxidative stress and depletion of antioxidants in GWI participants. Blood specimen collection and neuroimaging will be used to determine whether NAC affects serum glutathione (GSH) concentration and oxidative stress in the CNS when compared to placebo.

Study Overview

• Status: Recruiting
• Conditions: Gulf War Syndrome
• Intervention / Treatment: Drug: N-Acetyl Cysteine; Drug: Placebo

Detailed Description

During the 1990-91 Gulf War (GW), military personnel were exposed to numerous chemical and environmental agents during deployment including spraying of pesticides, petroleum combustion products, and nerve gas. Exposure to these chemical and environmental agents can damage cell function and more specifically, mitochondrial function, which negatively affects energy production and can lead to oxidative stress and neuroinflammation. Animal models using similar exposures have documented this in the central nervous system (CNS) compartment. This disruption in mitochondrial function and energy production is likely tied to resulting symptoms of Gulf War Illness (GWI) including fatigue, headaches, joint and muscle pain, gastrointestinal and sleep disturbances, neurologic and neuropsychological symptoms, respiratory issues, and cardiovascular problems.

The Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC) plans to evaluate N-Acetyl Cysteine (NAC) as a promising approach to help the CNS recover from chronic oxidative stress and depletion of antioxidants. The Congressionally Directed Medical Research Program's (CDMRP's) two Gulf War Illness Consortiums (GWICs) and others have added to the growing evidence of the role of CNS oxidative stress and neuroinflammation in symptoms of GWI, yet there is little definitive work on the delivery of antioxidants to the CNS environment. In this mechanistic study, we aim to determine if NAC has the ability to target mitochondrial dysfunction and reverse oxidative stress in the CNS. Based on our early experiences with antioxidants in GWI and other complex disease states along with the proven record of NAC in reducing glutathione (GSH) deficits, it is possible that this antioxidant will help to restore mitochondrial function and provide a more targeted approach to improve outcomes in Veterans with GWI.

• Study Type: Interventional
• Enrollment (Estimated): 170
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Nancy Klimas, MD; Phone Number: 9542622855; Email: nklimas@nova.edu
• Study Contact Backup: Name: Karen Kesler, PhD; Email: kkelser@rti.org

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Recruiting
      • VA Palo Alto Health Care System War Related Illness and Injury Study Center
      • Contact: Wes Ashford, MD; Phone Number: 650-852-3316; Email: wes.ashford@va.gov
      • Principal Investigator: Wes Ashford, MD
  • Florida
    • Fort Lauderdale, Florida, United States, 33314
      • Recruiting
      • Nova Southeastern University
      • Principal Investigator: Nancy Klimas, MD
      • Contact: Nancy Klimas, MD; Email: nklimas@nova.edu
      • Contact: Amaanpreet Cheema, PhD; Email: acheema@nova.edu
      • Sub-Investigator: Amaanpreet Cheema, PhD
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Boston University Medical School
      • Contact: Kimberly Sullivan, PhD; Phone Number: 617-358-2168; Email: tty@bu.edu
      • Principal Investigator: Kimberly Sullivan, PhD
      • Sub-Investigator: Anna Cervantes-Arslanian, MD
      • Sub-Investigator: Bang-bon Koo, PhD
      • Sub-Investigator: Maxine Krengel, PhD
  • New Jersey
    • East Orange, New Jersey, United States, 07018
      • Recruiting
      • VA New Jersey Health Care System War Related Illness and Injury Study Center
      • Contact: Helena Chandler, PhD; Phone Number: 973-676-3580; Email: Helena.Chandler@va.gov
      • Principal Investigator: Helena Chandler, PhD
  • New York
    • New York, New York, United States, 10021
      • Active, not recruiting
      • Weill Cornell Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27709
      • Active, not recruiting
      • RTI International
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Michael E. DeBakey VA Medical Center
      • Contact: Drew Helmer, MD; Phone Number: 713-440-4452; Email: Drew.Helmer@va.gov
      • Principal Investigator: Drew Helmer, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 47 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 47 to 70 years
• Served in the Gulf War Theater for any period between August 1990 and July 1991.

• Meets modified Kansas case definition criteria for Gulf War Illness. The modified Kansas definition includes the following:

  1. Allowance of normal illness 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.
  2. Allowance of stable comorbid conditions such as Post Traumatic Stress Disorder (PTSD), Major Depressive Disorder (MDD), and mild Traumatic Brain Injury (mTBI) that have not required hospitalization in the 2 years prior to recruitment. Severe TBI is excluded.
• Able to provide written consent to the study
• Agrees to participate in follow-up visits.

Exclusion Criteria:

• Self-report of current treated or untreated major depression with psychotic or melancholic features (as determined by self-report and Hamilton Depression Inventory (Ham-D)), schizophrenia, bipolar disorder, delusional disorders, dementias of any type, or a history of central nervous system (CNS) disorders that may affect cognitive function (e.g., epilepsy, stroke, brain tumor, multiple sclerosis, Parkinson's Disease, Alzheimer's disease), or alcoholism or drug abuse
• Severe claustrophobia or serious difficulty being in an MRI scanner or other enclosed space (MRS substudy only)
• Presence of ferrous implanted medical devices or metal fragments or objects that are embedded under the skin (MRS substudy only)
• 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.
• Chronic active infections such as HIV, Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) (self-report or antibody titer)
• Renal disease (self-report or laboratory results: renal insufficiency with serum creatinine > 2.0 mg/dL)
• Liver disease (self-report or laboratory results: hepatic insufficiency (bilirubin >2.5mg/dL or transaminases > 3 times the upper limits of normal)
• Uncontrolled diabetes (HgbA1c > 7.5) without adequate medical care. Individuals with HgbA1c > 7.5 will be reviewed and judged by the PI or delegate; if potential participant has adequate medical care to manage diabetes, enrollment is allowed; otherwise HgbA1c > 7.5 is exclusionary
• Diagnosed vascular disease (including congestive heart failure)
• Diagnosed bleeding disorders or use of blood-thinning medications
• Receipt of stavudine or didanosine for more than 7 days within 30 days prior to screening
• Currently have exclusionary diagnoses that could reasonably explain the symptoms of their fatiguing illness and their severity
• Are scheduled for a surgery during the period of study participation or had surgery within 6 weeks prior to screening
• Pregnant (women only)

Prohibited Concomitant or Prior Therapies

• Currently on dialysis
• Previous or current receipt of any antiviral medication, such as pegylated interferon, ribavirin, entecavir, tenofovir, or didanosine for more than 7 days within 30 days prior to screening
• Participating in another interventional (including social-behavioral therapy) clinical trial of an investigational therapy within 6 weeks prior to consent, or planning to participate in another interventional clinical trial of an investigational therapy during the course of this study
• Any herbal medicine within 30 days prior to consent and screening blood draw

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: N-Acetyl Cysteine (NAC); Participants who are randomized to the intervention arm will receive N-Acetyl-L-Cysteine (Free-Form/NAC) 900mg two times a day for 8 weeks after the initiation of the first dose of study drug.	Drug: N-Acetyl Cysteine; 900mg 2x daily; Other Names: NAC
Placebo Comparator: Placebo; Participants who are randomized to the placebo arm will take matching placebo two times a day for 8 weeks after the initiation of the first dose of study drug.	Drug: Placebo; Matching placebo bid; Other Names: NAC Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess glutathione levels	Change in glutathione levels after NAC supplementation compared to placebo in participants with gulf war illness (GWI)	Baseline to 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in glutathione levels	Measure the change of brain glutathione levels with magnetic resonance spectroscopy (MRS) in a subset of both arms of study at baseline and 8 weeks.	Baseline to 8 Weeks
Change in number of participants with treatment-related adverse events	Change in number of participants with treatment-related adverse events from baseline to 16 weeks during the intervention period as assessed by a safety questionnaire.	Baseline to 16 Weeks

Collaborators and Investigators

• Sponsor: Nova Southeastern University
• Collaborators: Boston University; Weill Medical College of Cornell University; RTI International
• Investigators: Principal Investigator: Nancy Klimas, MD, Nova Southeastern Univeristy

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2023
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: June 7, 2021
• First Submitted That Met QC Criteria: August 2, 2021
• First Posted (Actual): August 3, 2021

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Gulf War Illness; Placebo; CNS Recovery; N-Acetyl Cysteine (NAC)
• Additional Relevant MeSH Terms: Wounds and Injuries; Occupational Diseases; War-Related Injuries; Persian Gulf Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: GWICTIC-NAC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The plan is to release primary results from the study. Data are the property of Nova Southeastern University, but data and publication thereof will not be unduly withheld.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No