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Subjective Cognitive DeclinePhase 2NCT06588946

Β-OHB Supplementation and Brain Health in Older Adults

A Phase 2 study testing Ketone monoester (KME) supplement in people with Subjective Cognitive Decline, run by McMaster University at 1 site in Canada.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
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Trial summary

The goal of this randomized placebo controlled crossover trial is investigate the effects of short-term ketone monoester (KME) supplementation to brain function in older adults with subjective cognitive decline. Read more about this study

Who is it for?
Ages 55 to 75 years
Conditions the study is for
Subjective Cognitive Decline
What is being tested?
Ketone monoester (KME) supplement
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
48 participants
Where
1 siteCanada
Study dates
Mar 2025to Aug 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 55 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Being objectively cognitively normal as determined by a Montreal Cognitive Assessment (MoCA) score ≥26 with independent living and ambulating
  • SCD will be determined using the Prospective-Retrospective Memory Questionnaire (PRMQ) following the SCD Initiative Working Group framework

Who cannot join

  • A diagnosis of mild cognitive impairment, dementia, or psychiatric and/or mood disorders (e.g., major depression)
  • MoCA score <26
  • Diagnosis of cardiometabolic disease (e.g., hypertension, type 2 diabetes)
  • Obesity (BMI >30 kg/m2)
  • History of heart attack or stroke
  • History of smoking
Show all 9Show fewer
  • Currently following a ketogenic diet or taking ketogenic supplements
  • Having MRI contraindications
  • Participants with literacy, visual, hearing, and/or speech issues, as well as individuals who are not proficient in English will not be eligible for this trial

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Walsh contact

(905) 525-9140

walshj18@mcmaster.ca

Canada1 site

  • McMaster University

    Hamilton, Ontario, L8S 4K1

Other trials in Canada

About this study

Official title: The Effect of Exogenous Β-OHB Supplementation on Cerebral Blood Flow and Functional Brain Characteristics in Adults with Subjective Cognitive Decline

The goal of this randomized placebo controlled crossover trial is investigate the effects of short-term ketone monoester (KME) supplementation to brain function in older adults with subjective cognitive decline. We will test the hypothesis that KME supplementation will increase cerebral blood flow and improve resting-state functional connectivity in the brain compared to placebo supplementation in older adults with subjective cognitive decline.

Participants will be randomly assigned to either placebo of KME supplementation for 14 days. Following a washout period, participants will complete the alternate condition for 14 days. Outcome measures will be assessed before and after each intervention period.

Read the detailed description

In this randomized placebo-controlled crossover double-blind designed clinical trial, 48 adults with SCD (50% female; aged 55 to 75 years old) will be allocated to a ketone monoester (KME) or placebo condition in random order (e.g., A-B or B-A), stratified by sex. Participants will be recruited from the local community through McMaster University, the local Alzheimer Society, and community outreach.

In total, participants will be asked to complete 5 visits. Data will be collected at a single site in Hamilton, Ontario associated with McMaster University. All interested individuals will complete an eligibility screening study visit (Visit 1) to establish inclusion/exclusion. Written, informed consent will be obtained before data collection. Demographic information and medical history will be collected at the beginning of Visit 1 to obtain information regarding medication use, medical history, age, years of education, and sex and gender-based variables. This information will be collected using a participant history questionnaire and the GENESIS-PRAXY questionnaire. Participants will also be introduced to the lab and the different tests that we will run during the experimental visits. Data will be collected at two time points for each condition: 1) Pre-intervention (Visits 2 \& 4: baseline); and post-intervention (Visits 3 \& 5: following 14-day intervention). In a randomized crossover design, participants will be randomly allocated to a condition (placebo or KME) for a 14-day intervention. Participants will then undergo a washout period, afterwhich participants will be complete the alternate condition including baseline data collection (Visit 4) and post-intervention visit (Visit 5) after the second 14-day intervention period.

Being tested
Ketone monoester (KME) supplement, Placebo supplement
Keywords
early-stage dementia, ketone monoester supplementation, cerebral blood flow, cognition, resting state functional magnetic resonance imaging, placebo
Medical subject headings
Dementia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ketone monoester (KME) supplementDietary supplement

    Also called [R]-3-hydroxybutyl [R]-3-hydroxybutyrate (ΔG®, TDeltaS, Oxford, UK)

    15g of a KME supplement orally consumed 3x daily for 14 days. This dosing protocol raises plasma β-OHB consistently during the waking hours. Oral KME will be provided in opaque bottles labelled A or B to maintain condition blinding. Each bottle will contain a drink providing 15g of a KME supplement: [R]-3-hydroxybutyl [R]-3-hydroxybutyrate (ΔG®, TDeltaS, Oxford, UK).

  • Placebo supplementDietary supplement

    50mL taste-match inert calorie-free placebo drink orally consumed 3x daily for 14 days. Oral placebo will be provided in opaque bottles labelled A or B to maintain condition blinding.

Study groups in NCT06588946
Study groupRoleWhat they receive
Ketone monoester (KME) supplementExperimentalParticipants will be instructed to consume a ketone monoester (KME) supplement prior to each meal (3x/day) for 14 days.
Receives: Dietary Supplement: Ketone monoester (KME) supplement
Placebo supplementPlacebo comparatorParticipants will be instructed to consume a bottle of placebo supplement prior to each meal (3x/day) for 14 days.
Receives: Dietary Supplement: Placebo supplement

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Global cerebral blood flow (gCBF)

    Measured by magnetic resonance imaging (MRI) under resting, normocapnic conditions. Arterial flow measurement will be performed using a phase contrast flow sensitizing MRI pulse sequence. Cross-sectional areas and mean blood flow of the carotid and vertebral arteries will be measured, with total blood flow in all four vessels equaling global CBF.

    Measured: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions

  2. Resting-state functional connectivity

    A resting state functional magnetic resonance imaging (rsfMRI) scan will be performed eyes closed using a gradient echo EPI sequence. The temporal and regional co-activation of brain regions in the resting state provide a measure of functional connectivity in the brain. rsfMRI data will be analyzed to measure global whole-brain functional connectivity and within localized brain regions of interest.

    Measured: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions

Secondary outcomes (4)

  1. Cognitive testing

    A battery of computerized validated psychometric tests will be used, including: the Mnemonic similarities task (MST) to assess hippocampal-dependent learning and memory, the Stroop colour-word task to assess processing speed, working memory, attention, and inhibitory control, and a shortened version of the Odd-One-Out test to measure working memory and executive function. A non-computerized dual-task test will be performed to assess the multitasking ability of walking while performing another cognitive task.

    Measured: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions

  2. Microstructural white matter health

    Dual spin echo, echo-planar imaging (EPI) diffusion tensor imaging (DTI) sequence collected by magnetic resonance imaging (MRI) to assess brain white matter microstructural integrity.

    Measured: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions

  3. Cerebrovascular reactivity

    The phase contrast flow sensitizing MRI pulse and resting state functional MRI sequences will both be repeated while participants undergo an elevated CO2 breathing task. Cerebrovascular function will be calculated from the stimulus-response relationship between PaCO2 and (1) phase contrast: cross sectional areas of the internal carotid and vertebral arteries, and (2) rsfMRI: % change BOLD/mmHg.

    Measured: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions

  4. Blood-borne biomarkers

    A venous blood sample will be collected to assess circulating concentrations of various hormones and metabolites (e.g., brain-derived neurotrophic factor [BDNF]) that relate to brain health, metabolism, and inflammation.

    Measured: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Sep 2024
  2. Study startMar 2025 (estimated)
  3. Primary completionAug 2027 (estimated)
  4. Study completionAug 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Model description
placebo-controlled
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
48 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06588946
Sponsor's protocol ID
05992572
Status last verified
Feb 2025
First submitted
5 Sep 2024
Last updated
26 Feb 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: The investigators will share individual patient data (de-identified) with researchers upon request.

Publications

  • 2023 Alzheimer's disease facts and figures. Alzheimers Dement. 2023 Apr;19(4):1598-1695. doi: 10.1002/alz.13016. Epub 2023 Mar 14.

    PubMed 36918389

  • Al-Khazraji BK, Buch S, Kadem M, Matushewski BJ, Norozi K, Menon RS, Shoemaker JK. Protocol-dependence of middle cerebral artery dilation to modest hypercapnia. Appl Physiol Nutr Metab. 2021 Sep;46(9):1038-1046. doi: 10.1139/apnm-2021-0220. Epub 2021 Jun 17.

    PubMed 34139129

  • Alzheimer's Society of Canada. Rising Tide: The Impact of Dementia on Canadian Society. 2010; ISBN 978-0-9733522-2-1

  • Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M, Croteau E, Bocti C, Fulop T, Castellano CA. Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer's Disease. Front Mol Neurosci. 2016 Jul 8;9:53. doi: 10.3389/fnmol.2016.00053. eCollection 2016.

    PubMed 27458340

  • Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S, Eckert A, Harvey J, Jeggo R, Jhamandas JH, Kann O, la Cour CM, Martin WF, Mithieux G, Moreira PI, Murphy MP, Nave KA, Nuriel T, Oliet SHR, Saudou F, Mattson MP, Swerdlow RH, Millan MJ. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov. 2020 Sep;19(9):609-633. doi: 10.1038/s41573-020-0072-x. Epub 2020 Jul 24.

    PubMed 32709961

  • Frei M, Berres M, Kivisaari SL, Henzen NA, Monsch AU, Reinhardt J, Blatow M, Kressig RW, Krumm S. Can you find it? Novel oddity detection task for the early detection of Alzheimer's disease. Neuropsychology. 2023 Oct;37(7):717-740. doi: 10.1037/neu0000859. Epub 2022 Oct 6.

    PubMed 36201797

  • GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022 Feb;7(2):e105-e125. doi: 10.1016/S2468-2667(21)00249-8. Epub 2022 Jan 6.

    PubMed 34998485

  • Han YM, Bedarida T, Ding Y, Somba BK, Lu Q, Wang Q, Song P, Zou MH. beta-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4. Mol Cell. 2018 Sep 20;71(6):1064-1078.e5. doi: 10.1016/j.molcel.2018.07.036. Epub 2018 Sep 6.

    PubMed 30197300

  • Harris JA, Benedict FG. A Biometric Study of Human Basal Metabolism. Proc Natl Acad Sci U S A. 1918 Dec;4(12):370-3. doi: 10.1073/pnas.4.12.370. No abstract available.

    PubMed 16576330

  • Iadecola C. The pathobiology of vascular dementia. Neuron. 2013 Nov 20;80(4):844-66. doi: 10.1016/j.neuron.2013.10.008.

    PubMed 24267647

  • Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. doi: 10.1016/S1474-4422(09)70299-6.

    PubMed 20083042

  • Jensen NJ, Nilsson M, Ingerslev JS, Olsen DA, Fenger M, Svart M, Moller N, Zander M, Miskowiak KW, Rungby J. Effects of beta-hydroxybutyrate on cognition in patients with type 2 diabetes. Eur J Endocrinol. 2020 Feb;182(2):233-242. doi: 10.1530/EJE-19-0710.

    PubMed 31821157

  • Jessen F, Wiese B, Bachmann C, Eifflaender-Gorfer S, Haller F, Kolsch H, Luck T, Mosch E, van den Bussche H, Wagner M, Wollny A, Zimmermann T, Pentzek M, Riedel-Heller SG, Romberg HP, Weyerer S, Kaduszkiewicz H, Maier W, Bickel H; German Study on Aging, Cognition and Dementia in Primary Care Patients Study Group. Prediction of dementia by subjective memory impairment: effects of severity and temporal association with cognitive impairment. Arch Gen Psychiatry. 2010 Apr;67(4):414-22. doi: 10.1001/archgenpsychiatry.2010.30.

    PubMed 20368517

  • Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chetelat G, Dubois B, Dufouil C, Ellis KA, van der Flier WM, Glodzik L, van Harten AC, de Leon MJ, McHugh P, Mielke MM, Molinuevo JL, Mosconi L, Osorio RS, Perrotin A, Petersen RC, Rabin LA, Rami L, Reisberg B, Rentz DM, Sachdev PS, de la Sayette V, Saykin AJ, Scheltens P, Shulman MB, Slavin MJ, Sperling RA, Stewart R, Uspenskaya O, Vellas B, Visser PJ, Wagner M; Subjective Cognitive Decline Initiative (SCD-I) Working Group. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement. 2014 Nov;10(6):844-52. doi: 10.1016/j.jalz.2014.01.001. Epub 2014 May 3.

    PubMed 24798886

  • Jessen F, Amariglio RE, Buckley RF, van der Flier WM, Han Y, Molinuevo JL, Rabin L, Rentz DM, Rodriguez-Gomez O, Saykin AJ, Sikkes SAM, Smart CM, Wolfsgruber S, Wagner M. The characterisation of subjective cognitive decline. Lancet Neurol. 2020 Mar;19(3):271-278. doi: 10.1016/S1474-4422(19)30368-0. Epub 2020 Jan 17.

    PubMed 31958406

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ketone monoester (KME) supplement in people with Subjective Cognitive Decline, run by McMaster University at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 26 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Walsh ((905) 525-9140, walshj18@mcmaster.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Global cerebral blood flow (gCBF) (time frame: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06588946, which also lists 33 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2025.

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