Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels

A Multiple Ascending Phase 1 Dose Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels

N-Acetylcysteine (NAC), an anti-oxidant, will be studied to investigate the effects on brain glutathione levels, cognitive skills, motor skills, and quality of life.

A group of 18 participants will take either 1800, 3600 or 5400 mg per day of N-acetylcysteine (NAC) for 3 months in this dose escalation study. The investigators want to determine first if the 3600 mg dose per day is safe and might provide some efficacy. If the 3600 mg dose is safe, then additional participants will be treated with 5400 mg per day of NAC, for up to a total of 18 participants. If the 3600 mg per day dose is unsafe, then participants will be treated with the 1800 mg per day dose. Data from this pilot study will be used to determine the most safe and effective dose of NAC for a future clinical trial.

Study Overview

• Status: Recruiting
• Conditions: Mitochondrial Disease
• Intervention / Treatment: Drug: N-Acetylcysteine

Detailed Description

Patients with the m.3243A>G mitochondrial mutation often have low brain glutathione levels. These low levels can reduce the repair processes in the brain to fix toxic chemicals that result from a mitochondrial disorder. The investigators are aware of a potent anti-oxidant, called N-Acetylcysteine (NAC), that may improve the brain glutathione level when taken in sufficient quantity. In turn, cognitive and motor skill impairment may improve as these toxic levels are reduced. will be studied to investigate the effects on brain glutathione levels, cognitive skills, motor skills, and quality of life.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kris Engelstad, MS, CGC; Phone Number: 212-342-5767; Email: ke4@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Principal Investigator: Michio Hirano, MD
      • Contact: Kris Engelstad, MS, CGC; Phone Number: 212-342-5767; Email: ke4@cumc.columbia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ages 18-80 years
• Low brain glutathione (GSH) levels as determined by magnetic resonance spectroscopic imaging (MRSI)
• Individuals who carry, or are suspected of carrying the m.3243A>G mitochondrial mutation (genetic confirmation of mutation required prior to initiation of NAC)

Exclusion Criteria:

• Individuals with normal brain glutathione levels
• Pregnant or lactating individuals
• Medically unstable as determined by the Principal Investigator
• Allergy to NAC or other sulfur-containing drug
• Inability to adhere to study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active drug (NAC); Participants will receive NAC for 3 months.	Drug: N-Acetylcysteine; 1800, 3600 or 5400 mg NAC per day (divided into 3 daily doses) depending on dose toxicity plan; Other Names: NAC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) of NAC	Establish maximum tolerated dose of NAC by initiating dosing at one level, then increasing or decreasing dose based on toxicity. The MTD is defined as the dose associated with a target probability of dose limiting toxicity (DLT) of 0.10.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Columbia Neurological Score	The Columbia Neurological Score evaluates patients with cerebral energy failure syndromes and quantifies key neurological examination domains. The Columbia Neurological Score ranges from 0 to 76 with higher scores indicating less clinical severity.	4 months
Change in Global Neuropsychological Score	A composite global neuropsychological score is used to assess loss of cognitive function. The global neurological score is derived from measures across a standard neuropsychological battery. Test domains include: Memory, Orientation, Abstract reasoning, Dementia,Language,Word Association, and Naming. The scores range from 0 to 2 with higher scores indicating worsening cognitive function.	4 months
Change in Functional Exercise Capacity (6 minute walk test (6MWT))	The 6MWT is an objective evaluation of functional exercise capacity assessing the distance a person can walk in six minutes.	4 months
Change in Karnofsky Performance Scale (KPS) Score	KPS assesses functional activities of daily living (ADL). Scores range from 0 to 100 with a score of 0 defined as death and 100 defined as normal; no complaint; no evidence of disease (better outcome).	4 months
Change in Brain glutathione (GSH) level	As measured by brain Magnetic resonance Imaging and Magnetic resonance spectroscopy.	4 months

Collaborators and Investigators

• Sponsor: Michio Hirano, MD
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Michio Hirano, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2023
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: February 3, 2022
• First Submitted That Met QC Criteria: February 11, 2022
• First Posted (Actual): February 15, 2022

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 22, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: diabetes; MELAS; m.3243A>G; deafness
• Additional Relevant MeSH Terms: Neurologic Manifestations; Endocrine System Diseases; Musculoskeletal Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Neuromuscular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Glucose Metabolism Disorders; Otorhinolaryngologic Diseases; Sensation Disorders; Ear Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Hearing Loss; Hearing Disorders; Cerebral Small Vessel Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Diabetes Mellitus; Deafness; Mitochondrial Diseases; MELAS Syndrome; Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Amino Acids; Cysteine; Amino Acids, Sulfur; Acetylcysteine
• Other Study ID Numbers: AAAT7415; PR 190511 (Other Grant/Funding Number: Department of Defense)

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
• product manufactured in and exported from the U.S.: No