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

Mitochondrial Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05241262
• Other study ID #: AAAT7415
• Secondary ID: PR 190511
• Status: Recruiting
• Phase: Phase 1
• Start date: April 2023
• Est. completion date: June 2024

Study information

• Verified date: March 2023
• Source: Columbia University
• Contact: Kris Engelstad, MS, CGC
• Phone: 212-342-5767
• Email: ke4[@]cumc.columbia.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Mitochondrial Disease
• Mitochondrial Diseases

Intervention

Drug:
• N-Acetylcysteine
1800, 3600 or 5400 mg NAC per day (divided into 3 daily doses) depending on dose toxicity plan

Locations

Country	Name	City	State
United States	Columbia University Irving Medical Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Michio Hirano, MD	United States Department of Defense

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in Brain glutathione (GSH) level	As measured by brain Magnetic resonance Imaging and Magnetic resonance spectroscopy.	4 months