Assessment of N-Acetylcysteine as Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Chronic Fatigue Syndrome, Myalgic Encephalomyelitis

Intervention / Treatment
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* Drug: NAC 900mg/day
* Drug: NAC 3600mg/day
* Drug: NAC 0mg/day (Placebo)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NAC 900mg/day<br>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<br>* self administer NAC 900mg/day caplets for a four week period<br>|
| Active Comparator: NAC 3600mg/day<br>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<br>* self administer NAC 3600mg/day caplets for a four week period<br>|
| Placebo Comparator: NAC 0mg/day (Placebo)<br>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)<br>* self administer NAC 0mg/day (placebo) caplets for a four week period<br>|

What is the study measuring?
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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 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 1 | Level of F2-isoprostanes, a marker of oxidative stress, in plasma samples obtained | 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 |