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

NCT03641404 | Completed Phase 1 DMC

• 2 other identifiers: 2017/009821823117J (Clinical Trial No.)
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Mild Cognitive Impairment

Keywords

ergothioneine; mild cognitive impairment; dementia; dietary antioxidant

Outcome Measures

Primary Outcomes (4)

• Demonstrating uptake of ergothioneine following dietary supplementation

  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

  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

  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

  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 Outcomes (11)

• Assessment of plasma neurofilament light chain (NfL) protein levels

  12 months (assessed at baseline and every 3 months)

• Evaluation of cognition using the Singapore Modified - Mini Mental State Examination Scores (Cognitive function assessment)

  12 months (assessed baseline, 6 months and 12 months)

• Evaluation of dementia stage using the Clinical Dementia Rating Scale (CDR).

  12 months (assessed baseline, 6 months and 12 months)

• Neuropsychological test battery: Rey Auditory Verbal Learning Test (Cognitive function assessment)

  12 months (assessed baseline, 6 months and 12 months)

• Neuropsychological assessment battery: Digit Span test (Cognitive function assessments)

  12 months (assessed baseline, 6 months and 12 months)

Study Arms (2)

Ergothioneine

ACTIVE COMPARATOR

Subjects will consume 25mg ergothioneine (capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks.

Drug: L-ergothioneine

Placebo

PLACEBO COMPARATOR

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

Interventions

L-ergothioneine DRUG

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.

Ergothioneine

Placebo DRUG

Placebo. Study control (99% microcrystalline cellulose, 1% magnesium stearate)

Placebo

Eligibility Criteria

• Age: 60 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• National University of Singapore: collaborator
• National University Health System, Singapore: collaborator

Study Sites (1)

National University Cancer Institute, Singapore

Singapore, Singapore, 119074, Singapore

Location

Related Publications (14)

• Halliwell B, Cheah IK, Tang RMY. Ergothioneine - a diet-derived antioxidant with therapeutic potential. FEBS Lett. 2018 Oct;592(20):3357-3366. doi: 10.1002/1873-3468.13123. Epub 2018 Jun 15.

  PMID: 29851075 BACKGROUND

• Cheah IK, Halliwell B. Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim Biophys Acta. 2012 May;1822(5):784-93. doi: 10.1016/j.bbadis.2011.09.017. Epub 2011 Oct 4.

  PMID: 22001064 BACKGROUND

• Halliwell B, Cheah IK, Drum CL. Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis. Biochem Biophys Res Commun. 2016 Feb 5;470(2):245-250. doi: 10.1016/j.bbrc.2015.12.124. Epub 2016 Jan 6.

  PMID: 26772879 BACKGROUND

• Cheah IK, Feng L, Tang RMY, Lim KHC, Halliwell B. Ergothioneine levels in an elderly population decrease with age and incidence of cognitive decline; a risk factor for neurodegeneration? Biochem Biophys Res Commun. 2016 Sep 9;478(1):162-167. doi: 10.1016/j.bbrc.2016.07.074. Epub 2016 Jul 19.

  PMID: 27444382 BACKGROUND

• Cheah IK, Tang RM, Yew TS, Lim KH, Halliwell B. Administration of Pure Ergothioneine to Healthy Human Subjects: Uptake, Metabolism, and Effects on Biomarkers of Oxidative Damage and Inflammation. Antioxid Redox Signal. 2017 Feb 10;26(5):193-206. doi: 10.1089/ars.2016.6778. Epub 2016 Sep 7.

  PMID: 27488221 BACKGROUND

• Tang RMY, Cheah IK, Yew TSK, Halliwell B. Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues. Sci Rep. 2018 Jan 25;8(1):1601. doi: 10.1038/s41598-018-20021-z.

  PMID: 29371632 BACKGROUND

• Gruber J, Fong S, Chen CB, Yoong S, Pastorin G, Schaffer S, Cheah I, Halliwell B. Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnol Adv. 2013 Sep-Oct;31(5):563-92. doi: 10.1016/j.biotechadv.2012.09.005. Epub 2012 Sep 27.

  PMID: 23022622 BACKGROUND

• Halliwell B, Cheah I. Are age-related neurodegenerative diseases caused by a lack of the diet-derived compound ergothioneine? Free Radic Biol Med. 2024 May 1;217:60-67. doi: 10.1016/j.freeradbiomed.2024.03.009. Epub 2024 Mar 14.

  PMID: 38492784 BACKGROUND

• Halliwell B, Tang RMY, Cheah IK. Diet-Derived Antioxidants: The Special Case of Ergothioneine. Annu Rev Food Sci Technol. 2023 Mar 27;14:323-345. doi: 10.1146/annurev-food-060822-122236. Epub 2023 Jan 9.

  PMID: 36623925 BACKGROUND

• Wu LY, Cheah IK, Chong JR, Chai YL, Tan JY, Hilal S, Vrooman H, Chen CP, Halliwell B, Lai MKP. Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia. Free Radic Biol Med. 2021 Dec;177:201-211. doi: 10.1016/j.freeradbiomed.2021.10.019. Epub 2021 Oct 19.

  PMID: 34673145 BACKGROUND

• Cheah IK, Ng LT, Ng LF, Lam VY, Gruber J, Huang CYW, Goh FQ, Lim KHC, Halliwell B. Inhibition of amyloid-induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model. FEBS Lett. 2019 Aug;593(16):2139-2150. doi: 10.1002/1873-3468.13497. Epub 2019 Jun 30.

  PMID: 31211853 BACKGROUND

• Wu LY, Kan CN, Cheah IK, Chong JR, Xu X, Vrooman H, Hilal S, Venketasubramanian N, Chen CP, Halliwell B, Lai MKP. Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics. Antioxidants (Basel). 2022 Aug 30;11(9):1717. doi: 10.3390/antiox11091717.

  PMID: 36139790 BACKGROUND

• Cheah IK, Halliwell B. Ergothioneine, recent developments. Redox Biol. 2021 Jun;42:101868. doi: 10.1016/j.redox.2021.101868. Epub 2021 Jan 26.

  PMID: 33558182 BACKGROUND

• Yau YF, Cheah IK, Mahendran R, Tang RM, Chua RY, Goh RE, Feng L, Li J, Kua EH, Chen C, Halliwell B. Investigating the efficacy of ergothioneine to delay cognitive decline in mild cognitively impaired subjects: A pilot study. J Alzheimers Dis. 2024 Dec;102(3):841-854. doi: 10.1177/13872877241291253. Epub 2024 Nov 15.

  PMID: 39544014 DERIVED

MeSH Terms

Conditions

Cognitive Dysfunction; Dementia

Interventions

Ergothioneine

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Sulfhydryl Compounds; Sulfur Compounds; Organic Chemicals; Histidine; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Rathi Mahendran

  National University of Singapore

  PRINCIPAL INVESTIGATOR

• Barry Halliwell

  National University of Singapore

  PRINCIPAL INVESTIGATOR

• Christopher Chen

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Investigational compound and placebo coded by manufacturer. Codes provided in envelope will only be unsealed at the end of the study (data assessment) or in case of emergency.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, double-blinded, placebo-controlled study

Study Record Dates

• First Submitted: July 16, 2018
• First Posted: August 22, 2018
• Study Start: August 1, 2019
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: June 11, 2025

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1)