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

Sponsor

Akira Sekikawa (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05741060

Collaborator

National Institute on Aging (NIA) (NIH)

400

Enrollment

Locations

Arms

37.1

Anticipated Duration (Months)

133.3

Patients Per Site

3.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Arterial Stiffness White Matter Lesions Cognitive Decline	Drug: S-equol Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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.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.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Arterial Stiffness, Cognition and Equol

Anticipated Study Start Date :

Feb 28, 2023

Anticipated Primary Completion Date :

Apr 1, 2026

Anticipated Study Completion Date :

Apr 1, 2026

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Change in arterial stiffness [Change from baseline in arterial stiffness at 12 months]
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 in arterial stiffness [Change from baseline in arterial stiffness at 24 months]
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.

Secondary Outcome Measures

Change in white matter lesion (WML) volume percent [Change from baseline in WML volume percent at 24 months]
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 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]
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 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]
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.

Other Outcome Measures

Change in NIH Toolbox (NIH-TB) cognition battery score [Change from baseline in NIH-TB cognition battery score at 12 months]
NIH-TB Cognition battery, comprised of computerized tests of fluid and crystallized cognitive abilities, via proctored iPad administration.
Change in NIH Toolbox (NIH-TB) cognition battery score [Change from baseline in NIH-TB cognition battery score at 24 months]
NIH-TB Cognition battery, comprised of computerized tests of fluid and crystallized cognitive abilities, via proctored iPad administration.
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]
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 in ultrasound measurements of carotid artery [Change from baseline in ultrasound measurements of carotid artery at 24 months]
Ultrasound measurements of carotid artery include carotid plaque and intima-media thickness. We will use a high-resolution ultrasound system equipped with a variable frequency transducer (NextGen LOGIQ*e R7).
Change in select plasma biomarkers [Change from baseline in select plasma biomarkers at 24 months]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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, major depression/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 endartectomy or peripheral artery disease
Individuals currently undergoing treatment for pulmonary embolism or deep vein thrombosis
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 BMI ≥40
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 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 we proposed in the project:

Those who are contraindicated for 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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30322
2	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
3	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213