Investigating the Efficacy of Ergothioneine to Delay Cognitive Decline (Pilot)

June 5, 2025 updated by: National University Hospital, Singapore

Pilot Study to Investigate the Efficacy of Ergothioneine to Delay Cognitive Decline in Mild Cognitively Impaired Subjects

With the growing burden of dementia (including Alzheimer's disease), and the lack of efficacious therapies, there is an urgent need to identify new therapeutics.

Ergothioneine (ET) is a naturally occurring thiol derivative of histidine, obtained solely through diet and is able to accumulate in the body and brain, through the action of a specific transporter, OCTN1. In addition to a wide variety of in vitro and in vivo (animal) studies demonstrating the antioxidant, anti-inflammatory properties of ET, several studies have demonstrated the neuroprotective potential of ET in various cell and animal models.

Based on the ability of ET to counteract the underlying pathology of AD dementia, it is hypothesize that ET supplementation may prevent cognitive decline, especially in individuals at risk of cognitive impairment. This will be assessed using a randomized, double blinded, placebo-controlled, intervention study to test the ability of ET to delay or reverse cognitive impairment in elderly individuals with mild cognitive impairment.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Ergothioneine (ET) is a naturally occurring thiol/thione obtained in humans solely through diet. It is able to accumulate in specific cells and tissues (including the brain), via a specific transporter, OCTN1, at high levels. Although the exact physiological function(s) of ET have yet to be elucidated, numerous reports have demonstrated that this compound can scavenge reactive oxygen species (such as hydroxyl radicals, hypochlorous acid, and peroxynitrite), modulate inflammation, and chelate divalent metal ions. These processes are all implicated in the pathology of dementia. Various studies in cell and animal models have also highlighted the potential neuroprotective capabilities of ET following insult by various neurotoxic agents such as cisplatin and amyloid beta peptide.

Studies demonstrated that ET dose-dependently protected PC12 cells against beta amyloid-induced apoptotic death, and later was shown to protect against neuronal injury caused by direct administration of amyloid beta into the mouse hippocampus, thereby increasing scores in active avoidance and water maze tests. ET also dose-dependently extend lifespan of a transgenic Caenorhabditis elegans model of AD by reducing amyloid oligomer formation. Other studies also demonstrated that ET is also able to attenuate oxidative stress and prevents cognitive deficits in a D-galactose-induced dementia mouse model; protect against N-methyl-D-aspartate-induced cytotoxicity in rat retinal neurons; and prevent cisplatin-induced neuronal damage in cell cultures and mice.

To date no studies have evaluated the therapeutic ability of ET, clinically, to delay or halt cognitive decline. Prior studies administering pure ET to humans provide insights into the pharmacokinetics and demonstrate the safety of this compound, laying the foundations for this clinical study. The present proposal will shed light onto a relatively lesser known natural compound and the therapeutic capabilities it possesses, which has the potential to significantly impact the economic and societal burdens of dementia.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
19

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Singapore
      • Singapore, Singapore, 119074
        • National University Cancer Institute, Singapore

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

60 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Elderly individuals 60 - 90 years of age
  • Chinese ethnicity (from other local cohort studies)
  • Demonstrate amnestic mild cognitive impairment (assessed by panel of psychiatrists)
  • Independent and able to travel to study site without assistance
  • No other severe underlying conditions or terminal illnesses
  • Capable of understanding the study and requirements and able to provide informed consent to participate
  • Willing to commit to the year-long study, comply with study administration and periodic blood and urine sampling

Exclusion Criteria:

  • Inability to understand the risks and requirements of the study for any reason
  • Any intolerance to lactose, and/or allergies to mushrooms
  • History of cardiovascular complications, diabetes, hypertension or hypercholesterolemia, or other pre-existing condition that may prevent them from completing the study
  • Evidence of anaemia or other significant haematological conditions
  • History or mental illness, depression or other underlying psychiatric illnesses
  • History of drug or alcohol abuse
  • Involvement in another study requiring administration of an investigational compound in the past 30 days
  • Subjects whose blood analysis reveal and extremes of liver or kidney function markers (from baseline screening)
  • Deemed unfit for any reason as determined by the principal/co-investigator

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Placebo Comparator: Placebo
Subjects will be given placebo (99% microcrystalline cellulose, 1% magnesium stearate; capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks.
Drug: Placebo
Placebo. Study control (99% microcrystalline cellulose, 1% magnesium stearate)
Active Comparator: Ergothioneine
Subjects will consume 25mg ergothioneine (capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks.
Drug: L-ergothioneine
Ergothioneine is naturally occurring thiol compound obtained solely from diet in humans. Ergothioneine is widely reported to be a natural antioxidant and anti-inflammatory compound. In addition we hypothesize that this compound will be beneficial in improving cognition.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Demonstrating uptake of ergothioneine following dietary supplementation
Time Frame: 12 months
This pilot study will evaluate the ability of oral ergothioneine supplementation to raise levels of ergothioneine in the body (blood measurements) over the one year period
12 months
Demonstrate safety of oral ergothioneine supplementation
Time Frame: 12 months
This study will evaluate the safety oral ergothioneine supplementation over a period of 12 months. Safety is monitored through monthly visits (assessment and feedback on adverse reactions) and quarterly blood assessment (blood counts, liver and renal function).
12 months
Evaluating the impact of ergothioneine supplementation to modulate oxidative damage
Time Frame: Over 12 months
The ability of oral ergothioneine supplementation to modulate oxidative stress in the subjects will be assessed through changes in plasma and urinary oxidative damage biomarkers collected at baseline and quarterly (every 3 months) over the 12-month study duration.
Over 12 months
Evaluate the impact of ergothioneine supplementation to modulate inflammation
Time Frame: Over 12 months
The ability of oral ergothioneine supplementation to modulate inflammatory status in the subjects will be assessed through measurement of inflammatory cytokines in the plasma at baseline and quarterly (every 3 months) over the 12-month study duration.
Over 12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Assessment of plasma neurofilament light chain (NfL) protein levels
Time Frame: 12 months (assessed at baseline and every 3 months)
Elevated levels of NfL are suggested to be a biomarker of neurodegeneration and hence changes in this biomarker could reflect pathological changes. Increasing levels of NfL suggest progression or increasing severity of neurodegeneration and cognitive impairment whereas unchanged or decreasing levels of NfL may indicate a stabilisation or mitigation of neurodegeneration.
12 months (assessed at baseline and every 3 months)
Evaluation of cognition using the Singapore Modified - Mini Mental State Examination Scores (Cognitive function assessment)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
30 point questionnaire to assess for cognitive function and memory recall, with a minimum score of 0 and maximum of 30; where higher is better. A score of less than 7 may be indicative of cognitive impairment.
12 months (assessed baseline, 6 months and 12 months)
Evaluation of dementia stage using the Clinical Dementia Rating Scale (CDR).
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
CDR evaluates multiple domains including memory, orientation, judgement and problem solving, home and hobbies, community and personal care using a 5-point scale (0, 0.5, 1, 2, 3, where higher score indicates increasing severity of dementia) from 0 (no dementia) to a maximum of 3 (severe dementia). A 0.5-1 score indicates possible to mild cognitive impairment.
12 months (assessed baseline, 6 months and 12 months)
Neuropsychological test battery: Rey Auditory Verbal Learning Test (Cognitive function assessment)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
The Rey Auditory Verbal Learning Test (RAVLT) evaluates short-term auditory-verbal memory, rate of learning, learning strategies, retroactive, and proactive interference, presence of confabulation of confusion in memory processes, retention of information, and differences between learning and retrieval. Participants are given a list of 15 unrelated words repeated over five different trials and are asked to repeat the words. Another list of 15 unrelated words are given and the client must again repeat the original list of 15 words and then again after 30 minutes. A score out of 75 for immediate recall and 30 for secondary and delayed recall, whereby higher indicates better verbal learning and memory.
12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Digit Span test (Cognitive function assessments)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
The digit span task is a measure of working memory, based on a person's ability to recall a sequence of numerical digits evaluating short-term and working memory. A maximum score of 16 for forward and 14 for backward where higher indicates score indicates better short-term and working memory and cognitive control.
12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Block Design Test (Cognitive function assessment)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
The block design test examines the spatial visualisation ability and motor skills of an individual where the subject is asked to replicate a different design patterns using cubes. Scoring as based on timing and correct pattern with a maximum score of 68 with higher indicating better spatial visualisation.
12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Symbol Digit Modality Test scores (Cognitive function assessment)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
The symbol digit modality is a cognitive assessment test for evaluating information processing speed and attention. Increased written and oral symbol score (1 point per correct answer, minimum of 0 and maximum of 100 limited by the test form) over 90 seconds indicates better processing speed.
12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Semantic Verbal Fluency Test (Cognitive function assessment)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
The Semantic Verbal Task involves asking the subject to name as many animals (part 1) and fruits (part 2) as they can in 60 seconds, which each correct answer adding one point. Scores are tallied from parts 1 and 2, with higher scores (no limit, only based on time) indicating better language, semantic memory, and processing ability.
12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Colour Trials Test (Cognitive function assessments)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
The colour trails test assesses sustained and dividend attention, and executive function involving parts 1 - connecting numbered circles in sequence and part 2 - requires alternating between circles of different colours (pink and yellow) while connecting them in numerical order. The time taken to complete parts 1 and 2 are recorded (as well as errors) with faster time indicating better attention and cognitive flexibility.
12 months (assessed baseline, 6 months and 12 months)
Evaluation of Geriatric Anxiety Inventory (Neuropsycological assessment)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
The geriatric anxiety inventory is a self-reported assessment to identify anxiety syndromes in elderly individuals, through a series of 20 questions (with minimum of 0 and maximum score of 20) with a higher score indicating the possibility of underlying anxiety and greater than 9 indicating the possibility of an underlying anxiety disorder. At the conclusion of the study a reduction or absence of change is expected in the geriatric anxiety score.
12 months (assessed baseline, 6 months and 12 months)
Evaluation of Geriatric Depression Scale (Neuropsycological assessment)
Time Frame: 12 months (assessed baseline, 6 months and 12 months)
The geriatric depression scale is a self-reported assessment to identify depressive symptoms in elderly individuals, through a series of 15 guided questions (with minimum of 0 and maximum score of 15) with a higher score indicating greater severity and greater than 5 indicating the possibility of an underlying depressive syndromes. At the conclusion of the study a reduction or absence of change is expected in the geriatric depression scale.
12 months (assessed baseline, 6 months and 12 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
National University Hospital, Singapore

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National University Health System, Singapore
National University of Singapore

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Rathi Mahendran, National University of Singapore
  • Principal Investigator: Barry Halliwell, National University of Singapore
  • Principal Investigator: Christopher Chen, National University Hospital, Singapore

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 1, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 16, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 19, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 22, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 11, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 5, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2017/00982
  • 1823117J (Clinical Trial No.) (Other Identifier: Health Science Authority (Singapore))

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

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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