Assessment of N-Acetylcysteine as Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (NAC ME/CFS)

Mechanistic Assessment of N-Acetylcysteine as an Antioxidant Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Through Dose Response and Treatment Target Engagement

Chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS) is an unexplained multisymptom/multisystem disorder for which there are currently no validated treatments. The present exploratory clinical trial aims to advance our understand of the mechanisms of in situ GSH synthesis control through assessment of the response of brain GSH and plasma markers of oxidative stress to different doses of NAC in comparison to placebo, as a potential treatment for ME/CFS that would provide neuroprotection against oxidative stress by restoring cortical GSH reserves. If successful, this exploratory clinical trial would address a significant public health concern by shedding new light onto the mechanisms of action of NAC in brain GSH restoration, which could open a new avenue for the development of potentially effective treatments for a disorder, ME/CFS, that currently has none.

Study Overview

• Status: Recruiting
• Conditions: Chronic Fatigue Syndrome; Myalgic Encephalomyelitis
• Intervention / Treatment: Drug: NAC 900mg/day; Drug: NAC 3600mg/day; Drug: NAC 0mg/day (Placebo)

Detailed Description

This phase two, single-site study will utilize a double-blind, placebo-controlled, randomized, pre-/post-treatment design to investigate the effect of NAC dosing on brain GSH levels and measure temporally concordant plasma levels of several established circulating markers of oxidative stress. Three study groups, of 20 subjects each (for a total of 60 who completed all components of the study), will each be administered a different dose (0 mg/day, 900mg/day, 3600mg/day) of the study intervention over a four week period; N-acetylcysteine (NAC) treatment. Subjects receiving 0 mg/day dose will be administered a placebo. Baseline visit assessments will include blood collection, survey questionnaires, MRI and MRS imaging. Subjects whose initial screening confirms low GSH level at baseline will be provided with a 4-week supplement of anonymized NAC or placebo caplets. After 4 weeks, subjects will then undergo a follow-up visit to repeat the baseline assessments.

• Study Type: Interventional
• Enrollment (Estimated): 95
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xiangling Mao, MS; Phone Number: 2127462632; Email: xim2004@med.cornell.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Recruiting
      • Weill Cornell Medicine
      • Principal Investigator: Dikoma C. Shungu, Ph.D.
      • Sub-Investigator: Tracy A. Butler, M.D.
      • Sub-Investigator: Xiangling Mao, M.S.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males or females, ages 21 to 60 years (inclusive).
• Baseline GSH levels at or less than a predefined cutoff value.
• Primary diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
• Willing and capable of providing informed consent.

Exclusion Criteria:

• Significant and/or comorbid axis I (especially mood and anxiety) and axis II disorders.
• Any significant neurological illness or impairment.
• Other unstable medical conditions (asthma, hypertension, endocrine or metabolic disease, etc).
• History alcohol abuse.
• Positive urine toxicology at screening and on days of assessments.
• Positive pregnancy test at screening or on days of assessments.
• Contra-indication for clinical MRI scan (e.g., pacemaker, metallic prosthesis).
• Baseline GSH levels higher than a predefined cutoff value.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: NAC 900mg/day; Subjects who pass screening may be randomly assigned to this arm where they will self administer NAC 900mg/day caplets for a four week period	Drug: NAC 900mg/day; self administer NAC 900mg/day caplets for a four week period
Active Comparator: NAC 3600mg/day; Subjects who pass screening may be randomly assigned to this arm where they will self administer NAC 3600mg/day caplets for a four week period	Drug: NAC 3600mg/day; self administer NAC 3600mg/day caplets for a four week period
Placebo Comparator: NAC 0mg/day (Placebo); Subjects who pass screening may be randomly assigned to this arm where they will self administer NAC 0mg/day (placebo) caplets for a four week period	Drug: NAC 0mg/day (Placebo); self administer NAC 0mg/day (placebo) caplets for a four week period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in GSH levels of treatment response: measure 1	Levels of occipital cortex GSH, as measured in vivo with 1H MRS	pre/post 4 weeks of NAC supplementation
Change in GSH levels of treatment response: measure 2	Levels of striatal GSH, as measured in vivo with 1H MRS	pre/post 4 weeks of NAC supplementation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Oxidative stress levels of treatment response: measure 1	Level of F2-isoprostanes, a marker of oxidative stress, in plasma samples obtained	pre/post 4 weeks of NAC supplementation
Change of levels of ventricular CSF lactate of treatment response	Levels of ventricular CSF lactate, as measured in vivo with 1H MRS	pre/post 4 weeks of NAC supplementation
Change of regional cerebral blood flow (rCBF) of treatment response	Regional cerebral blood flow (rCBF), as measured in vivo with perfusion MRI	pre/post 4 weeks of NAC supplementation
Change in Oxidative stress levels of treatment response: measure 2	Level of 8-hydroxy-2-deoxy guanosine (8-OH-2dG), a DNA damage marker, in plasma samples obtained	pre/post 4 weeks of NAC supplementation
Change in Oxidative stress levels of treatment response: measure 3	Level of reduced (GSH) glutathione, an antioxidant capacity and redox state marker, in plasma obtained	pre/post 4 weeks of NAC supplementation
Change in Oxidative stress levels of treatment response: measure 4	Level of oxidized (GSSG) glutathione, an antioxidant capacity and redox state marker, in plasma obtained	pre/post 4 weeks of NAC supplementation
Change in Oxidative stress levels of treatment response: measure 5	Level of GSH peroxidase, an antioxidant enzyme activity marker, in plasma obtained	pre/post 4 weeks of NAC supplementation
Change in Oxidative stress levels of treatment response: measure 6	Level of protein carbonyls, a protein damage marker, in plasma obtained	pre/post 4 weeks of NAC supplementation

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Dikoma C. Shungu, Ph.D., Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Estimated): April 30, 2025
• Study Completion (Estimated): April 30, 2025

Study Registration Dates

• First Submitted: August 28, 2020
• First Submitted That Met QC Criteria: September 3, 2020
• First Posted (Actual): September 9, 2020

Study Record Updates

• Last Update Posted (Actual): June 26, 2023
• Last Update Submitted That Met QC Criteria: June 22, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Infections; Pain; Neurologic Manifestations; Disease; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Musculoskeletal Pain; Central Nervous System Infections; Neuroinflammatory Diseases; Syndrome; Fatigue; Myalgia; Fatigue Syndrome, Chronic; Encephalomyelitis
• Other Study ID Numbers: 20-01021280; R01NS116887 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No