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

NCT ID: NCT05741060

Last Updated: 2025-09-29

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 369 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-29
• Study Completion Date: 2027-01-30

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.

Detailed Description

The ACE trial is an early-stage multi-center randomized controlled trial (RCT) designed to test the effect of a 24-month intervention of 10 mg/day equol supplementation on arterial stiffness, white matter lesions (WMLs) in the brain and cognitive decline among 400 individuals aged 65 and 85 without dementia. Recent studies in Japan reported that a diet high in soy and soy isoflavones is inversely associated with incident cognitive impairment and dementia. The Women's Isoflavone Soy Health (WISH) in the US, an RCT of soy isoflavones, however, showed no significant effect on cognition. We posit that the discrepant result is due to the difference in equol-producing capability. Equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most bioactive among all soy isoflavones and their metabolites. 50-70% of Japanese convert daidzein to equol in contrast to 20-30% of Americans. Arterial stiffness, a significant predictor of cognitive decline, is significantly improved in a short-duration RCT of 10 mg/day equol supplementation in middle-aged subjects. WMLs are a risk factor for age-related cognitive decline and dementia. We reported a longitudinal association of equol-producing status with WML% (WML volume normalized to total brain volume) in cognitively normal elderly in Japan. The subgroup analysis of WISH showed that equol producers had better cognition than the control group, suggesting that equol may slow cognitive decline. No previous study has tested the effect of equol supplementation on arterial stiffness, WMLs or cognitive decline in older adults.

Conditions

Arterial Stiffness; White Matter Lesions; Cognitive Decline

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Equol Arm

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

Group Type: EXPERIMENTAL

S-equol

Intervention Type: DRUG

Experimental drug

Placebo Arm

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

S-equol

Experimental drug

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

Equelle

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

• 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
• Women on estrogen replacement therapy
• Individuals unable to lay supine for 30-60 minutes
• Individuals with weight ≥300 lbs
• Individuals who are planning to move out of the area in the next 2 years
• Individuals who participated in another clinical trial in the past 3 months

• Individuals with Quick Dementia Rating System (QDRS) score ≥ 6.0
• 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.
• Blood pressure (BP) - systolic BP ≥ 180 mmHg or diastolic BP ≥ 110 mmHg
• Heart rate ≥110 or ≤40
• Hemoglobin <10 g/dL
• HbA1c ≥ 7.5%
• Blood creatinine > 2.0 mg/dL
• Liver function tests > 2 X upper limit of normal
• Abnormal thyroid function (Thyroid Stimulating Hormone)
• Vitamin B12 levels ≤ 210 pg/mL
• Hematocrit <30%
• White blood cell count <3,000 or >15,000
• Platelet count <100,000 or >600,000
• Urinary protein ≥ + by dipstick
• Any condition or therapy which, in the opinion of the investigator, might pose a risk to the participant or make participation in the study not in the participant's best interest

In addition, individuals with the following condition will be excluded because these conditions do not allow subjects to undergo examinations the investigators proposed in the project:

• Those who are contraindicated for 3 Tesla (3T) structural brain magnetic resonance imaging (MRI) such as pacemakers.
• Atrial fibrillation because pulse wave velocity is not accurately measured.
• Hearing impairment which interferes with cognitive testing
• Vision impairment which interferes with cognitive testing

*1 Few studies have investigated the association of equol, a metabolite of soy isoflavone daidzein, with breast cancer. These studies reported no significant association of serum or urine equol with the risk of breast cancer. Dietary intake of soy and soy isoflavones is generally considered to have benefits for menopausal symptoms, cardiovascular health, bone health, and cancers of the breast and prostate. Observational studies show that soy consumption is associated with a reduced risk of many cancers including breast cancer. Moreover, a prospective cohort study of 6,000+ North American women with breast cancer showed that dietary intake of soy and isoflavones was associated with reduced all-cause mortality. However, there is little evidence to support that the use of supplements containing soy isoflavones or soy protein powder to reduce cancer risk. A recent large prospective cohort study in France reported that supplementation of soy isoflavones increased the risk of estrogen receptor-negative breast cancer, especially among women who had a history of breast cancer in first-degree relatives.

The investigators recruit subjects without dementia. Thus, at the initial screening by phone, the investigators exclude individuals whose score for the Telephone Interview for Cognitive Status is 22 and below. Then, at the screening visit, investigators will exclude individuals with a Quick Dementia Rating System score ≥ 6.0.

• Minimum Eligible Age: 65 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Akira Sekikawa

OTHER

Sponsor Role: lead

Responsible Party

Akira Sekikawa

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Akira Sekikawa, MD, PhD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

Emory University

Atlanta, Georgia, United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 36233223 (View on PubMed)

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.

Reference Type: RESULT

PMID: 40838083 (View on PubMed)

Provided Documents

Document Type: Informed Consent Form

View Document

Other Identifiers

R01AG074971

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY22010165

Identifier Type: -

Identifier Source: org_study_id