Effect of Equol Supplementation on Arterial Stiffness and Cognition in Healthy Volunteers

NCT05741060 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: STUDY22010165R01AG074971
• Study Type: interventional
• Target: 369
• Locations: 1 country
• Sites: 3

Brief Summary

The ACE Trial, funded by the National Institute on Ageing/National Institutes of Health (NIH), is a multicenter clinical trial. The ACE Trial will determine if taking the dietary supplement Equol could slow the progression of stiffening of the arteries, small blood vessel disease in the brain and memory decline. Equol is a soy-based supplement that has plant estrogen-like compounds in it. Equol is a metabolite of soy isoflavone. Our studies in Japan and other studies suggest that Equol may slow mechanisms related to memory decline. No previous studies in the United States have tested the effect of Equol on these mechanisms or memory decline. Supplementation of Equol in the ACE Trial is approved by the Food and Drug Administration (FDA). Researchers at the University of Pittsburgh, Pittsburgh, Pennsylvania, Wake Forest University, Winston-Salem, North Carolina, and Emory University, Atlanta, Georgia, are recruiting participants. The ACE Trial will ask participants to complete 7 clinic visits over a two-year period. The participants are asked to take Equol tablets daily for 24 months. Clinic procedures include Pulse Wave Velocity (to measure arterial stiffness), Magnetic Resonance Imaging (MRI) of the brain and tests of awareness and thinking.

Conditions

Arterial Stiffness; White Matter Lesions; Cognitive Decline

Keywords

s-equol; white matter lesion volume; vascular contributions to cognitive impairment and dementia; arterial stiffness; Alzheimer's disease and related dementias; estrogen receptor-beta agonist

Outcome Measures

Primary Outcomes (2)

• Change in arterial stiffness

  Arterial stiffness describes the rigidity of the arterial wall and is a significant predictor of cognitive decline. Arterial stiffness will be measured by pulse wave velocity (m/s) with a SphygmoCor device (Sydney, Australia). The range of pulse wave velocity is from 5 to 20 m/s.

  Change from baseline in arterial stiffness at 12 months

• Change in arterial stiffness

  Arterial stiffness describes the rigidity of the arterial wall and is a significant predictor of cognitive decline. Arterial stiffness will be measured by pulse wave velocity (m/s) with a SphygmoCor device (Sydney, Australia). The range of pulse wave velocity is from 5 to 20 m/s.

  Change from baseline in arterial stiffness at 24 months

Secondary Outcomes (3)

• Change in white matter lesion (WML) volume percent

  Change from baseline in WML volume percent at 24 months

• Change in cognitive score measured by the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) score

  Change from baseline in cognitive score measured by the PACC-5 at 12 months

• Change in cognitive score measured by the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) score.

  Change from baseline in cognitive score measured by the PACC-5 at 24 months

Other Outcomes (5)

• Change in NIH Toolbox (NIH-TB) cognition battery score

  Change from baseline in NIH-TB cognition battery score at 12 months

• Change in NIH Toolbox (NIH-TB) cognition battery score

  Change from baseline in NIH-TB cognition battery score at 24 months

• Changes in select brain markers other than white matter lesion (WML) volume percent

  Change from baseline in brain markers other than WML volume percent at 24 months

Study Arms (2)

Equol Arm

EXPERIMENTAL

S-equol - 10 mg per day tablet for 24 months.

Drug: S-equol

Placebo Arm

PLACEBO COMPARATOR

10 mg per day for 24 months of tablets that will be of the same size/shape/color as the experimental tablet.

Drug: Placebo

Interventions

S-equol DRUG

Experimental drug

Also known as: Equelle

Equol Arm

Placebo DRUG

Placebo - 10 mg per day for 24 months of tablets that will be the same size/shape/color as the s-equol tablets.

Placebo Arm

Eligibility Criteria

• Age: 65 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

• Men and women age between 65 and 85 at entry of European Americans or African Americans
• Individuals who are able to provide informed consent
• Individuals who are willing to be randomized to the intervention or placebo group

You may not qualify if:

• Individuals who are regularly taking isoflavone supplements or eat soy product ≥ 2 times a week (by specific questionnaire)
• Individuals who do not agree to maintain isoflavone supplements or soy product intake described above during the study period.
• Individuals who have allergy or intolerance to soy isoflavones.
• Individuals whose score for the Telephone Interview for Cognitive Status is 22 and below.
• Individuals with stroke, neurological disorders, bipolar disease whether or not under medical treatment, cancer treatment in the past 6 months, head trauma or other condition which is not appropriate for the study (e.g., contraindication to magnetic resonance imaging (MRI)).
• Individuals with untreated depression
• Individuals with atrial fibrillation
• Individuals with heart failure
• Individuals with heart attack or coronary intervention in the past 6 months
• Individuals with carotid endarterectomy or peripheral artery disease
• Individuals currently undergoing treatment for pulmonary embolism or deep vein thrombosis
• Individuals with aortic (abdominal, thoracic) aneurysm
• Individuals with inflammatory bowel diseases
• Individuals currently undergoing hemodialysis
• Women with a past or family history of breast cancer.\*1

Sponsors & Collaborators

• Akira Sekikawa: lead
• National Institute on Aging (NIA): collaborator

Study Sites (3)

Emory University

Atlanta, Georgia, 30322, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (2)

• Sekikawa A, Wharton W, Butts B, Veliky CV, Garfein J, Li J, Goon S, Fort A, Li M, Hughes TM. Potential Protective Mechanisms of S-equol, a Metabolite of Soy Isoflavone by the Gut Microbiome, on Cognitive Decline and Dementia. Int J Mol Sci. 2022 Oct 7;23(19):11921. doi: 10.3390/ijms231911921.

  PMID: 36233223 BACKGROUND

• Sekikawa A, Wharton W, Murray-Krezan C, Wu M, Chang Y, Snitz BE, Coccari M, Yang S, Love ML, Cusick D, Wang R, Li M, Park C, Li J, DeConne TM, Smith C, Verble DD, Lancet MQ, Foroud T, Kim T, Nadkarni NK, Mettenburg JM, Zamora E, Lopez OL, Hughes TM. ACE trial design: Equol targeting estrogen receptor-beta in vascular and cognitive aging. Alzheimers Dement (N Y). 2025 Aug 18;11(3):e70144. doi: 10.1002/trc2.70144. eCollection 2025 Jul-Sep.

  PMID: 40838083 RESULT

MeSH Terms

Conditions

Cognitive Dysfunction; Dementia; Alzheimer Disease

Interventions

Equol

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Isoflavones; Flavonoids; Chromones; Benzopyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Akira Sekikawa, MD, PhD, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: The ACE Trial is an early stage multi-center randomized, parallel, double-blind placebo-controlled trial of 10 mg/day of equol for 24 months.

Study Record Dates

• First Submitted: February 13, 2023
• First Posted: February 23, 2023
• Study Start: June 29, 2023
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): January 30, 2027
• Last Updated: September 29, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: The final dataset(s) will be completely de-identified. These data will be released to an NIH Central Data Repository no later than 1 year after the end of the clinical activity (final patient follow-up, etc.) or immediately after the main paper of the trial has been published, whichever comes first.
• Access Criteria: Data Requestors must agree to the terms of the ACE Data Use Agreement (DUA) and will be asked to complete an online application for access to anonymized datasets. The agreement will be reviewed by the ACE Trial Steering Committee (SC). The ACE SC approval of the Data Requestor's Data Sharing Agreement request will trigger a process that allows access to the files described above and provides the requestor with an email notification of the review decision. All data and supporting documents selected by the project leadership for sharing will be made available for approved applicants to download. The review committee may require requestors to provide an annual update on their use of project data, to submit manuscripts for SC review and/or may revoke access for investigators who do not respond to annual update requests.

Locations

US (3)