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

• ClinicalTrials.gov Identifier: NCT04542161
• Recruitment Status: Recruiting
• First Posted: September 9, 2020
• Last Update Posted: June 9, 2021
• Sponsor: Weill Medical College of Cornell University
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Fatigue Syndrome; Myalgic Encephalomyelitis	Drug: NAC 900mg/day; Drug: NAC 3600mg/day; Drug: NAC 0mg/day (Placebo)	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 95 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: Mechanistic Assessment of N-Acetylcysteine as an Antioxidant Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Through Dose Response and Treatment Target Engagement
• Actual Study Start Date: September 1, 2020
• Estimated Primary Completion Date: April 30, 2025
• Estimated Study Completion Date: April 30, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in GSH levels of treatment response [ Time Frame: pre/post 4 weeks of NAC supplementation ]
   Levels of striatal and occipital cortex GSH, as measured in vivo with 1H MRS,

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Jihyun Lee, MPH; 2127462481; jil4015@med.cornell.edu

Contact: Xiangling Mao, MS; 2127462632; xim2004@med.cornell.edu

Locations

United States, New York

Weill Cornell Medicine; Recruiting

New York, New York, United States, 10021

Principal Investigator: Dikoma C. Shungu, Ph.D.

Sub-Investigator: Xiangling Mao, MS

Sub-Investigator: Elizabeth Sweeney, Ph.D.

Sponsors and Collaborators

Weill Medical College of Cornell University

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Dikoma Shungu, Ph.D.; Weill Medical College of Cornell University

More Information

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT04542161
• Other Study ID Numbers: 20-01021280; R01NS116887 ( U.S. NIH Grant/Contract )
• First Posted: September 9, 2020
• Last Update Posted: June 9, 2021
• Last Verified: June 2021

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

Additional relevant MeSH terms:

Fatigue Syndrome, Chronic; Syndrome; Fatigue; Encephalomyelitis; Myalgia; Disease; Pathologic Processes; Virus Diseases; Infections; Muscular Diseases; Musculoskeletal Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Central Nervous System Infections; Musculoskeletal Pain; Pain; Neurologic Manifestations