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

Arterial Stiffness, Cognition and Equol

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.

Study Overview

• Status: Recruiting
• Conditions: Cognitive Decline; Arterial Stiffness; White Matter Lesions
• Intervention / Treatment: Drug: S-equol; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Akira Sekikawa, MD, PhD, PhD; Phone Number: 412-383-1063; Email: akira@pitt.edu
• Study Contact Backup: Name: Monica Love, MLIS; Phone Number: 412-383-1895; Email: lovem@edc.pitt.edu

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University
      • Contact: Whitney Wharton, PhD; Phone Number: 404-712-7359; Email: w.wharton@emory.edu
      • Contact: Danielle Verble, MA; Phone Number: 404-712-7085; Email: danelle.d.verble@emory.edu
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Wake Forest University Health Sciences
      • Contact: Timothy Hughes, PhD; Phone Number: 336-713-3851; Email: tmhughes@wakehealth.org
      • Contact: Carrie Smith; Phone Number: 336-713-3851; Email: suscsmit@wakehealth.edu
      • Principal Investigator: Timothy Hughes, PhD
      • Sub-Investigator: Ezequiel Zamora, MD
      • Sub-Investigator: Mia Yang, MD, MS
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh
      • Contact: Akira Sekikawa, MD, PhD, PhD; Phone Number: 412-383-1063; Email: akira@pitt.edu
      • Contact: Monica Love, MLIS; Phone Number: 412-383-1895; Email: lovem@edc.pitt.edu
      • Sub-Investigator: Emma Barinas-Mitchell, PhD
      • Sub-Investigator: Caterina Rosano, MD, MPH
      • Sub-Investigator: Beth Snitz, PhD
      • Sub-Investigator: Minjie Wu, PhD
      • Sub-Investigator: Yuefang Chang, PhD
      • Sub-Investigator: Cristina Murray-Krezan, PhD
      • Sub-Investigator: Neelesh Nadkarni, PhD
      • Sub-Investigator: Tae Kim, PhD
      • Sub-Investigator: Joseph Mettenburg, MD, PhD
      • Sub-Investigator: Oscar Lopez, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 85 years (Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Men and women age between 65 and 85 at entry of European Americans or African Americans

Inclusion criteria via screening visit:

• Individuals who are able to provide informed consent
• Individuals who are willing to be randomized to the intervention or placebo group

Exclusion Criteria:

Exclusion criteria via initial screening by phone

• 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

Exclusion criteria via screening visit

• 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

Exclusion criteria at structural brain MRI Any other conditions 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

*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.

Exclusion criteria at the baseline visit

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Equol Arm; S-equol - 10 mg per day tablet for 24 months.	Drug: S-equol; Experimental drug; Other Names: Equelle
Placebo Comparator: Placebo Arm; 10 mg per day for 24 months of tablets that will be of the same size/shape/color as the experimental tablet.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in white matter lesion (WML) volume percent	WMLs are a significant predictor of cognitive decline. WMLs will be measured using an automated brain magnetic resonance imaging method. WML volume percent will be calculated by dividing WML volume by total brain volume as a percentage. The range of WML volume percent is from 0 to 4.2%.	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	The PACC-5 is a composite neuropsychological measure optimized to detect subtle changes over time in cognitively unimpaired older adults. The range of PACC-5 score is from -3 to 3.	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.	The PACC-5 is a composite neuropsychological measure optimized to detect subtle changes over time in cognitively unimpaired older adults. The range of PACC-5 score is from -3 to 3 where 3 represents better cognition.	Change from baseline in cognitive score measured by the PACC-5 at 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NIH Toolbox (NIH-TB) cognition battery score	NIH-TB Cognition battery, comprised of computerized tests of fluid and crystallized cognitive abilities, via proctored iPad administration.	Change from baseline in NIH-TB cognition battery score at 12 months
Change in NIH Toolbox (NIH-TB) cognition battery score	NIH-TB Cognition battery, comprised of computerized tests of fluid and crystallized cognitive abilities, via proctored iPad administration.	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	Brain markers other than WML volume percent will be measured using MRI, including cerebral blood flow, venous oxygenation, white matter organization lacunar infarct and cortical thickness.	Change from baseline in brain markers other than WML volume percent at 24 months
Change in select plasma biomarkers	Plasma biomarkers of inflammation and endothelial function (C-reactive protein, intracellular adhesion molecule, vascular cell adhesion molecule, glial fibrillary acidic protein, neurofilament light) as well as amyloid-β40, amyloid-β42 and phosphorylated tau 181 will be measured.	Change from baseline in select plasma biomarkers at 24 months
Change in ultrasound measurements of carotid artery	Ultrasound measurements of carotid artery include carotid plaque and intima-media thickness. Investigators will use a high-resolution ultrasound system equipped with a variable frequency transducer (NextGen LOGIQ*e R7).	Change from baseline in ultrasound measurements of carotid artery at 24 months

Collaborators and Investigators

• Sponsor: Akira Sekikawa
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Akira Sekikawa, MD, PhD, PhD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2023
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: February 13, 2023
• First Submitted That Met QC Criteria: February 13, 2023
• First Posted (Actual): February 23, 2023

Study Record Updates

• Last Update Posted (Actual): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: arterial stiffness; Alzheimer's disease and related dementias; s-equol; white matter lesion volume; vascular contributions to cognitive impairment and dementia; estrogen receptor-beta agonist
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens, Non-Steroidal; Estrogens; Phytoestrogens; Equol
• Other Study ID Numbers: STUDY22010165; R01AG074971 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Center for Clinical Trial & Data Coordination (CCDC), University of Pittsburgh, has rich experience as the Data Core (DC) for other NIH-funded studies, in reporting to and providing final datasets for an NIH Central Data Repository. The final dataset(s) will include demographic and clinical data at baseline, study arm assignment, and all primary and secondary outcomes for the ACE trial. 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. The files available will include original copies of the case report forms, a detailed codebook of variable names, value labels, formats, missing data reports, and linkage files for samples. The analytic dataset may also include derived variables that were created during the analytic process.
• IPD Sharing 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.

IPD Sharing 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.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No