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Trial registered on ANZCTR


Registration number
ACTRN12621001607864
Ethics application status
Approved
Date submitted
21/09/2021
Date registered
25/11/2021
Date last updated
2/06/2023
Date data sharing statement initially provided
25/11/2021
Date results provided
13/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised study with placebo control to assess the effects of Ergothioneine (ERG-001) on Cognition, Mood and Sleep in both adult men and woman aged between 55 and 79 years of age.
Scientific title
A Placebo-controlled, Randomized, Double-blind Trial to Assess the Effects of Ergothioneine (ERG-001) on Cognition, Mood, and Sleep in Adult Men and Women at 4 and 16 weeks.
Secondary ID [1] 305542 0
Not applicable
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cognitive Decline 323570 0
Condition category
Condition code
Mental Health 321119 321119 0 0
Studies of normal psychology, cognitive function and behaviour
Diet and Nutrition 321672 321672 0 0
Other diet and nutrition disorders
Neurological 321673 321673 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ergothionenine is the name of the investigational product.

Participants will be assigned to receive one of three arms:
ARM 1: 25mg Ergothioneine, one oral capsule, per day for 112 days
ARM 2: 10mg of Ergothioneine, one oral capsule, per day for 112 days
ARM 3: 0mg placebo control, one oral capsule, per day for 112 days

All participants will be required to take 1 capsule, orally at the same time every day for 112 days. Bottles will be returned by the patient to the site for accountability in every instance. The patient will also be queried about their adherence to the regime in addition to completing a daily intake log via a compliance monitoring application.

The impact of the intervention will be assessed at +16 weeks (+112 days), with some interim measures completed at +4 weeks (+28 days).
Intervention code [1] 321675 0
Behaviour
Comparator / control treatment
ARM 3: Placebo control (0mg), one oral capsule, per day for 112 days.

The placebo is the same formulation as the investigational product but without the active ingredient. It is a vegetarian capsule.
Control group
Placebo

Outcomes
Primary outcome [1] 328894 0
Neuropsychological function, as measured by the CNS Vital Signs Cognitive Assessment Battery. This assessment includes composite memory, verbal memory, visual memory, processing speed, executive function, psychomotor speed, reaction time, complex attention, simple attention, motor speed, and cognitive flexibility.
Timepoint [1] 328894 0
Twice at screening, Baseline, then 4 weeks (28 days) and 16 weeks (112 days) (primary timepoint) after the first dose of treatment on Day 1.

Out of Range (OOR) Vital signs will be assessed up to 3 times (2 unscheduled readings), with a rest of 5-15 minutes between each assessment. If any vital signs remain out of range after the third measure, the participant cannot continue in the study.
Primary outcome [2] 330584 0
Neuropsychological function, as measured by Computerised Mental Performance Assessment System (COMPASS). This assessment includes an assessment battery known to be sensitive to nutritional intervention, will be used to obtain estimates of Cognitive Efficiency . This construct encompasses an individual’s capacity to process and problem solve information under timed conditions. Computerised assessments enable the determination of the speed with which an individual is able to undertake mental operations and is a proxy measure of neural efficiency. The COMPASS is an automated battery that will be completed by participants under supervised conditions and will take approximately 30-minutes to complete. The following will be assessed:
- Reaction Time – Choice Reaction Time, Four choice reaction time
- Sustained Attention – Digit Vigilance
- Working Memory - Corsi Blocks, Numeric Working Memory
- Secondary Memory – Object Recall, Face Recall
The test battery will be completed immediately following the CNS-Vital Signs Cognitive Assessment Battery.
Timepoint [2] 330584 0
Once at screening, Baseline, then 4 weeks (28 days) and 16 weeks (112 days) (primary timepoint) after the first dose of treatment on Day
Secondary outcome [1] 400819 0
Safety and tolerability of the treatment is measured via Adverse Events, including assessment of AEs, vital signs (blood pressure and heart rate), and chemistry blood panel.
Timepoint [1] 400819 0
The secondary outcomes are compared to that of baseline and then post treatment initiation at 28 days (4 weeks) and 112 days (16 weeks).
Secondary outcome [2] 401891 0
- Cognitive Impairment assessed by a Montreal Cognitive Assessment (MoCA).

30-point screening tool for cognitive impairment assessing attention, orientation, language, verbal memory, visuospatial and executive function. This assessment takes approximately 10 minutes to administer,

The short-term memory recall task (5 points) involves two learning trials of five nouns and
delayed recall after approximately 5 minutes. Visuospatial abilities are assessed using a clock-drawing task (3 points) and a three-dimensional cube copy (1 point).
Multiple aspects of executive functions are assessed using an alternation task adapted from the Trail Making B task (1 point), a phonemic fluency task (1 point), and a two-item verbal abstraction task (2 points). Attention, concentration, and working memory are
evaluated using a sustained attention task (target detection using tapping; 1 point), a serial subtraction task (3 points), and digits forward and backward (1 point each).
Language is assessed using a three-item confrontation naming task with low-familiarity animals (lion, camel, rhinoceros; 3 points), repetition of two syntactically complex sentences (2 points), and the aforementioned fluency task. Finally, orientation to time and place is evaluated (6 points). The MoCA score is the sum of all items representing degree of
impairment (lower scores = more impairment). Individuals with scores equal to 22 on the MoCA will be excluded because of the high probability of underlying dementia or Mild Cognitive Impairment.
Timepoint [2] 401891 0
Baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [3] 401893 0
- Subjective memory complaints, assessed by a Prospective Retrospective Memory Questionnaire (PRMQ).

The PRMQ is self-administered with a completion time of approximately five minutes. It is a standardised measure that assesses the frequency of different types of memory failures. In addition, the scale assesses the level of “frustration” (in the informant) caused by the memory failures to gauge the extent to which they are impacting on one’s daily activities. The 16-item PRMQ contains 2 items representing each of 8 categories: 4 items for prospective memory (both short-term and long term, self-cued and environmentally cued). An additional 4 items comprise the informant-rated “frustration” component of the PRMQ. Items are rated on a 5-point scale: 1 (never), 2 (rarely), 3 (sometimes), 4 (quite often), 5 (very often).
Results can be derived for prospective or retrospective, short-term or long-term, self-cued
or environmentally cued domains. Higher scores represent greater frequency of self-reported memory failures.
Timepoint [3] 401893 0
Baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [4] 401894 0
- Psychological health, assessed by Profile of Mood States-Short Form (POMS)

35-item test that measures psychological health as defined by questions assessing the participants' usual mood. The participant should rate how they have been feeling in the past week with regard to each adjective item on a scale from 0 (not at all) to 4 (extremely)
.
The questionnaire covers seven domains:
- Tension-Anxiety,
- Depression-Dejection,
- Anger-Hostility,
- Vigor-Activity,
- Fatigue-Inertia,
- Confusion-Bewilderment
- Friendliness
Timepoint [4] 401894 0
Baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [5] 401895 0
- Sleep quality, assessed by Leeds Sleep Evaluation Questionnaire (LSEQ)

10 x visual analogue scales that request the self-reporting answers from the respondent on the ease of getting to sleep, quality of sleep, awakening from sleep and behaviour following wakefulness.
Timepoint [5] 401895 0
Baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [6] 401896 0
- Serum inflammatory measures (IFN-gamma, TNFa, IL-1b, IL-6 and IL-10).
Timepoint [6] 401896 0
Screening, baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [7] 401897 0
- Measure Ergothioneine levels by blood sample.
Timepoint [7] 401897 0
Baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [8] 401898 0
Assess telomere length, analysed in lymphocytes using a validated, published flow cytometric method.
Timepoint [8] 401898 0
Baseline prior to treatment initiation and at 112 days (16 weeks) after the first dose of treatment on Day 1.
Secondary outcome [9] 401899 0
Measure HS-CRP, Biochemistry and Haematology levels via blood test - these are considered exploratory health biomarkers.
Timepoint [9] 401899 0
Screening baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [10] 401900 0
- Resting blood pressure measured by a sphygmomanometer.

Brachial Blood pressure measurements will be calculated using the InBody BPB10750 clinical grade automated blood pressure machine (CSIRO). An initial mock measurement will be taken at the beginning of the consult, this measurement is not recorded.
After resting for 5mins in a quiet room the blood pressure measurement is taken.
If this is out of clinical range a subsequent measurement is taken after 5 to 15mins
rest. Up to two repeated measurements can be taken.
Timepoint [10] 401900 0
Baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [11] 402726 0
- Resting heart rate measured by a sphygmomanometer.

Heart rate measurements will be calculated using the InBody BPB10750 clinical grade automated blood pressure machine (CSIRO). An initial mock measurement will be taken at the beginning of the consult, this measurement is not recorded.
After resting for 5mins in a quiet room the heart rate measurement is taken.
If this is out of clinical range a subsequent measurement is taken after 5 to 15mins
rest. Up to two repeated measurements can be taken.
Timepoint [11] 402726 0
Baseline, then 4 weeks (28 days) and 16 weeks (112 days) after the first dose of treatment on Day 1.
Secondary outcome [12] 406785 0
Habitual food intake patterns will be assessed to capture any wider alterations to diet throughout the study and/or to consider any effects in the context of habitual dietary patterns. Habitual dietary intake will be assessed using the CSIRO Short Food Survey (Hendrie, Baird, Golley, & Noakes, 2017) which has been validated for use in child and adult populations.

Participant’s are required to recall average intakes of different food groups and beverages (in serves) that they consume within a self-selected time frame for each response (day, week, month). Responses are transformed to an average daily consumption in serves and scored against age and gender specific dietary guidelines providing an estimate of overall compliance with dietary guidelines expressed as a score ranging from 0 to 100.
Timepoint [12] 406785 0
The survey will be completed during the baseline and endpoint (week 16) visits only.

Eligibility
Key inclusion criteria
1. Males and females
2. Aged >=55 & <=79 years of age at Informed Consent
3. Scores >=25 on the subjective memory complaints questionnaire (MAC-Q)
4. BMI >=18.5 and <=35 at time of clinic screening
5. Willing and able to provide Informed Consent
6. Able to access own email address
Minimum age
55 Years
Maximum age
79 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Currently depressed (indicated by scores equal or greater to a score of 6 on GDS 15 questionnaire ).
2. Score of less or equal to 22 on the MoCA.
3. Self-reported Colour Blindness.
4. Aversion and/or intolerance/allergy to any of the following: Mushrooms, Microcrystalline cellulose, vegetarian capsules (hypromellose, purified water, titanium dioxide, carrageenan, pectin), magnesium stearate, or silicon dioxide.
5. Any condition or event, as confirmed by the trained Clinical Team Member, where cognitive impairment may occur, including but not limited to: head injury that required hospitalisation, brain surgery, transient ischemic attacks, stroke, coronary artery bypass surgery, other heart surgery, degenerative neurological disease, which in the opinion of the Investigator may affect the participant’s ability to participate in the study or the study results.
6. Previous diagnosis of Type 1 Diabetes.
7. HbA1c greater or equal to 6.5% for non-diabetics (equal to 48mmol/mol) or greater or equal to 7% (less or equal to 53mmol/mol) if diagnosed with Type 2 Diabetes and medically managed for at least 6 months, assessed at screening.
8. Untreated hypertension (Blood pressure equal to 155 mmHg and diastolic equal to 100 mmHg, obtained over three readings at the screening visit (unless applicant obtains a letter from medical professional indicating fit for inclusion)).
9. Current smoker (or history of smoking including within last 6 months).
10. History of Intellectual Disability or other developmental disorder (e.g., language disorder, ADHD, Autism).
11. Any mental health condition that is being actively treated either pharmacologically or by a licensed mental health professional .
12. Has undergone Chemotherapy or Radiotherapy treatment within preceding two years of screening.
13. Any of the following sleep disorders: Insomnia, Restless Legs Syndrome, Narcolepsy, Idiopathic Hypersomnia, Circadian Rhythm Disorders, Sleep Apnoea (unless actively treated by CPAP for at least the preceding 6-months).
14. Participation in a study utilising the same cognitive assessment measures within the previous 90 days of screening.
15. Self-reported regular use of sedatives (e.g., tranquillizers, Benzodiazepines,
antihistamines etc) to aid sleep defined as 3 or more nights per week over the four weeks preceding screening.
16. Self-reported alcohol intake exceeding 1 standard drink per day on average over the four weeks preceding screening in accordance with the Australian Government Guidelines.
17. Current or recent participation (within the last 60 days of screening) in any other clinical trial involving the administration of an active intervention for any purpose.
18. Consumption of more than one serve (approx. half a cup raw) of mushrooms per week on average over the 4 weeks preceding baseline assessment.
19. Consumption of greater than 400 mg/d intake of Caffeine per day averaged over the 4 weeks preceding screening.
20. Blood haematology and biochemistry test results outwith the normal reference range at screening, in the opinion of the treating doctor.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by internet using IWRS system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is the method used to create the random order for the allocation of subjects into different groups.
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation which is then loaded into the IVRS/randomisation system which randomly assigned the treatment arm to a participant ID number.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
This is a double blind study meaning that the study doctor, participant and Sponsor does not know which treatment arm has been assigned. This is protected by an Interactive Voice/Web Recognition System (IVRS) which has the ability to also unblind information in an emergency. This trial has key outcomes which are self-reported.
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical analyses will be conducted using IBM SPSS Statistics for Windows, Version 25 or higher (IBM Corp., Armonk, NY), or a suitable alternative statistical analysis package. Tests of significance, unless otherwise stated, will be performed using an alpha of 0.05, two-sided.

150 participants are expected in the sample size.

Descriptive statistics (number of subjects, mean, standard error of the mean (SEM), SD, median, IQR limits, minimum and maximum for continuous variables; counts and
percentages for categorical variables) will be presented for all outcomes by treatment group. Differences in changes from baseline to weeks 4 and 16 will be assessed using Generalised Linear Mixed Models will include baseline, week 4 and week 16 assessments.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
28/02/2022
Actual
16/03/2022
Date of last participant enrolment
Anticipated
26/09/2022
Actual
10/02/2023
Date of last data collection
Anticipated
30/06/2023
Actual
24/05/2023
Sample size
Target
150
Accrual to date
Final
147
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 20502 0
CSIRO Nutrition & Health Research Clinic - Adelaide
Recruitment postcode(s) [1] 35279 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 309643 0
Commercial sector/Industry
Name [1] 309643 0
Blue California Ingredients
Country [1] 309643 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Blue California Ingredients
Address
30111 Tomas Rd, Rancho Santa Margarita, California 92688.
Country
United States of America
Secondary sponsor category [1] 310661 0
Commercial sector/Industry
Name [1] 310661 0
SAPRO Consulting Pty Limited
Address [1] 310661 0
Suite 201/1 at 175b Stephen Street, Yarraville VIC 3013
Country [1] 310661 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309415 0
CSIRO Health and Medical Human Research Ethics Committee
Ethics committee address [1] 309415 0
Ethics committee country [1] 309415 0
Australia
Date submitted for ethics approval [1] 309415 0
05/02/2021
Approval date [1] 309415 0
10/05/2021
Ethics approval number [1] 309415 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114078 0
Dr Ian Zajac
Address 114078 0
CSIRO Nutrition & Health Research Clinic
SAHMRI North Terrace
Adelaide, South Australia 5000
Country 114078 0
Australia
Phone 114078 0
+61 8 8303 8875
Fax 114078 0
Email 114078 0
ian.zajac@csiro.au
Contact person for public queries
Name 114079 0
Naomi Kakoschke
Address 114079 0
CSIRO Nutrition & Health Research Clinic
SAHMRI North Terrace
Adelaide, South Australia 5000
Country 114079 0
Australia
Phone 114079 0
+61 8 8303 8982
Fax 114079 0
Email 114079 0
naomi.kakoschke@csiro.au
Contact person for scientific queries
Name 114080 0
Ian Zajac
Address 114080 0
CSIRO Nutrition & Health Research Clinic
SAHMRI North Terrace
Adelaide, South Australia 5000
Country 114080 0
Australia
Phone 114080 0
+61 8 8303 8875
Fax 114080 0
Email 114080 0
ian.zajac@csiro.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo The study results are not yet available.

Documents added automatically
No additional documents have been identified.