Clinical trial NCT05741060: Effect of Equol Supplementation on Arterial Stiffness and Cognition in Healthy Volunteers
Official title: Arterial Stiffness, Cognition and Equol
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
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
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2023-02-23
Enrollment: 372
Sex: ALL
Minimum age (years): 65
Maximum age (years): 85
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: PREVENTION

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.

Eligibility criteria: 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 \&lt;10 g/dL
* HbA1c ≥ 7.5%
* Blood creatinine \&gt; 2.0 mg/dL
* Liver function tests \&gt; 2 X upper limit of normal
* Abnormal thyroid function (Thyroid Stimulating Hormone)
* Vitamin B12 levels ≤ 210 pg/mL
* Hematocrit \&lt;30%
* White blood cell count \&lt;3,000 or \&gt;15,000
* Platelet count \&lt;100,000 or \&gt;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.

Primary outcomes:
measure: Change in arterial stiffness
timeFrame: Change from baseline in arterial stiffness at 12 months
measure: Change in arterial stiffness
timeFrame: Change from baseline in arterial stiffness at 24 months
Secondary outcomes:
measure: Change in white matter lesion (WML) volume percent
timeFrame: Change from baseline in WML volume percent at 24 months
measure: Change in cognitive score measured by the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) score
timeFrame: Change from baseline in cognitive score measured by the PACC-5 at 12 months
measure: Change in cognitive score measured by the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) score.
timeFrame: Change from baseline in cognitive score measured by the PACC-5 at 24 months
Other outcomes:
measure: Change in NIH Toolbox (NIH-TB) cognition battery score
timeFrame: Change from baseline in NIH-TB cognition battery score at 12 months
measure: Change in NIH Toolbox (NIH-TB) cognition battery score
timeFrame: Change from baseline in NIH-TB cognition battery score at 24 months
measure: Changes in select brain markers other than white matter lesion (WML) volume percent
timeFrame: Change from baseline in brain markers other than WML volume percent at 24 months
measure: Change in ultrasound measurements of carotid artery
timeFrame: Change from baseline in ultrasound measurements of carotid artery at 24 months
measure: Change in select plasma biomarkers
timeFrame: Change from baseline in select plasma biomarkers at 24 months
Locations:
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Akira Sekikawa, MD, PhD, PhD
role: PRINCIPAL_INVESTIGATOR
References: