PhytoSERM to Prevent Menopause Associated Decline in Brain Metabolism and Cognition

PhytoSERM Efficacy to Prevent Menopause Associated Decline in Brain Metabolism and Cognition: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Clinical Trial

This is a proof-of-concept phase 2 clinical trial to investigate the safety and effect of the phytoestrogenic supplement PhytoSERM on regional brain metabolism by fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) in peri- and postmenopausal women. The investigators hypothesize that there will be a significant difference between the PhytoSERM group and placebo group in glucose brain metabolism.

Study Overview

• Status: Active, not recruiting
• Conditions: Cognitive Change; Menopause; Brain Disorder, Metabolic
• Intervention / Treatment: Dietary supplement: PhytoSERM; Drug: Placebo

Detailed Description

This is a double-blinded, randomized, placebo-controlled, parallel designed, proof-of-concept phase 2 clinical trial to determine effect of PhytoSERM in regional brain metabolism, cognition and vasomotor symptoms in menopausal women. PhytoSERM or placebo pills will be administered orally once a week over 24 weeks. Safety and tolerability will also be assessed over the duration of the study.

To determine eligibility, all participants will undergo cognitive assessment, physical and neurological examination, imaging scans, electrocardiogram (ECG), clinical/safety laboratory assessment, and interviews. After a 2-4-week screening period, participants will be randomized to study intervention (PhytoSERM 50mg administered orally, once per day) or matching placebo, in a 1:1 allocation. Brain imaging to evaluate the primary endpoint (standardized uptake value ratio (SUVR) by FDG-PET) will be conducted at screening and 24 weeks (6 months). Study participants will be asked to complete a total of 7 study visits. All participants will be enrolled at a single site, at the Alzheimer's Prevention Program (APP) at Weill Cornell Medical Centre (WCMC, New York).

This study protocol will include an embedded single-dose, 24-hour pharmacokinetic (PK) study in a subset of 12 participants which will begin after the first dose of the study intervention.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85721
      • University of Arizona / Clinical & Translational Sciences Research Center (CATS
  • New York
    • New York, New York, United States, 10021
      • The Alzheimer's Prevention Program / Weill Cornell Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 41 years to 56 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Peri- or postmenopausal women with the latter defined as last menstrual period (LMP) completed ≥ 60 days and ≤ 4 years, per the Stages of Reproductive Aging Workshop (STRAW) criteria.
2. Age 45-60 years.
3. Presence of hot flashes ≥ 7 per day.
4. In good general health as evidenced by medical history.
5. Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the investigator.
6. No medical contraindications to study participation.
7. Stable medications for 4 weeks prior to the baseline visits.
8. Provision of signed and dated informed consent form.
9. Stated willingness to comply with all study procedures and availability for the duration of the study.
10. Ability to take oral medication and be willing to adhere to the PhytoSERM regimen.
11. For females of reproductive potential: Negative pregnancy test and use of highly effective contraception by male partner for at least 1 month prior to screening and agreement to use such a method during study participation.
12. Fluent in English or Spanish.

Exclusion Criteria:

1. Known allergies to isoflavones or soy-based products.
2. Evidence of cognitive impairment on the Mini-Mental State Examination (total score < 27).
3. Pregnancy
4. Use of estrogen or progestin compounds within 8 weeks of baseline.
5. Use of investigational agent within 12 weeks of baseline.
6. Concurrent neurologic, systemic, or psychiatric disease that would influence cognition or ability to provide informed consent and to participate.
7. Known or suspected estrogen-dependent neoplasia, active neoplastic disease, history of breast cancer, or at risk of developing breast cancer, endometrial hyperplasia.
8. History of epilepsy, focal brain lesion, head injury with loss of consciousness or Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse.
9. Thrombophlebitis, thrombosis, thromboembolic disorders, myocardial infarction, ischemic heart disease, cerebrovascular accident, stroke, transient ischemic attack (TIA).
10. Current use of tobacco or a history of alcohol abuse.
11. Use of drugs, herbs, or dietary supplements to treat menopausal or cognitive symptoms less than 8 weeks prior to baseline.
12. Evidence of any significant clinical disorder or laboratory finding.
13. Known allergy to soy-derived products/ proteins or branded over the counter products; hypersensitivity to estrogens or progestins.
14. Visual and auditory acuity inadequate for neuropsychological testing
15. Inability to undergo MRI scans
16. Inability to undergo PET scans

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PhytoSERM group; PhytoSERM 50mg tablet composed of the phytoestrogens daidzein, genistein and S-equol, administered orally every day for 24 weeks.	Dietary supplement: PhytoSERM; PhytoSERM is a dietary supplement containing equal amounts of genistein (16.7 mg ± 10%), daidzein (16.7 mg ± 10%) and S-equol (16.7 mg ± 10%).
Placebo Comparator: Placebo group; Placebo product with identical shape, size and color with absence of daidzein, genistein, and S-equol. Administered orally every day for 24 weeks.	Drug: Placebo; Placebo product with identical shape, size and color will be produced with absence of S-equol, daidzein and genistein. Ingredients include calcium carbonate, comprecel M102, croscarmellose sodium, stearic acid, Zeofree 5162, magnesium stearate, carnauba wax, coating cellulose clear (PEG), coating white (PEG), water.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardized uptake value ratio (SUVR) by 18F-FDG PET	Regional brain glucose metabolism SUVR	Baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trail Making Test (TMT)	The TMT is scored by how long it takes to complete the test. For TMT-B, an average score is 75 seconds, and a deficient score is greater than 273 seconds. Less is better.	Baseline to 24 weeks
List Sorting Working Memory Test	Test scores consisted of combined total items correct on the one- and two-list versions of the task (maximum 28). The raw sum score is then transformed to a standardized t-metric. More is better.	Baseline to 24 weeks
Picture Sequence Memory Test	Maximum raw score of 48 for ages 20-60 years. More is better.	Baseline to 24 weeks
Auditory Verbal Learning Test	The Rey is scored by taking the sum of the number of words recalled across all trials (possible range is 0-45 words).	Baseline to 24 weeks
Oral Symbol Digit Test	The Oral Symbol Digit Test is scored as the number of items answered correctly in 120 seconds (possible range is 0-144).	Baseline to 24 weeks
Hot flash Frequency Composite	Hot flash frequency and severity scores. Less is better.	Baseline to 24 weeks
Menopause Rating Scale (MRS) Score	The total score of the MRS ranges between 0 (asymptomatic) and 44 (highest degree of complaints).	Baseline to 24 weeks
Pittsburgh Sleep Quality Index	A global sum of "5" or greater indicates a "poor" sleeper.	Baseline to 24 weeks
Positive and Negative Affect Scale	Positive and negative affect items are summed separately and range from 0 to 50 with higher scores indicating higher positive affect and higher negative affect respectively.	Baseline to 24 weeks
Beck Depression Inventory - II	Maximum score is 63. Higher scores represent greater depressive symptoms.	Baseline to 24 weeks
Pharmacokinetics: Peak Plasma Concentration (Cmax)	The highest concentration of each phytoestrogen in the blood after a dose is given.	Baseline
Pharmacokinetics: Time of peak concentration (tmax)	Time required to achieve peak plasma levels.	Baseline
Pharmacokinetics: Half-life (t1/2)	The time required for plasma concentration of phytoSERMs to decrease by 50%	Baseline
Pharmacokinetics: Area under the plasma concentration versus time curve (AUC)	The concentration of phytoSERMs in blood plasma as a function of time. Gives insight into the extent of exposure to phytoSERM and its clearance rate from the body.	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional brain volume	T1-weighted volumetric MRI (mm3).	Baseline to 24 weeks
Fractional Anisotropy	Multi-band multi-shell Diffusion Tensor Imaging (DTI) to measure changes in white matter tract integrity.	Baseline to 24 weeks
Quantitative anisotropy	DTI to measure changes in white matter tract integrity. The amount of anisotropic spins that diffuse along the fiber orientation.	Baseline to 24 weeks
Functional connectivity	Resting state functional MRI (rs-fMRI) to measure changes in intrinsic connectivity, which also correlates to neuronal function.	Baseline to 24 weeks
Cerebral blood perfusion	Arterial spin labeling (ASL) to measure changes in cerebral blood flow, which correlates to neuronal function.	Baseline to 24 weeks
Inflammatory Biomarker: Cytokines	Change in laboratory value in inflammatory cytokines (Interleukin-6)	Baseline to 24 weeks
Lipid biomarker: Total Cholesterol	Laboratory value of total cholesterol in blood	Baseline to 24 weeks
Plasma Glucose	Laboratory value of glucose in plasma	Baseline to 24 weeks
Diabetic biomarker: Hemoglobin A1C (HbA1c)	Laboratory value	Baseline to 24 weeks
Menopause biomarker: Estradiol	Laboratory values	Baseline to 24 weeks
Menopause biomarker: Follicle-Stimulating Hormone (FSH)	Laboratory values	Baseline to 24 weeks

Collaborators and Investigators

• Sponsor: Roberta Brinton
• Collaborators: National Institute on Aging (NIA); Cornell University; ADM Diagnostics
• Investigators: Principal Investigator: Roberta D Brinton, PhD, University of Arizona; Principal Investigator: Gerson D Hernandez, MD, MPH, University of Arizona

Publications and helpful links

General Publications

• Hernandez G, Zhao L, Franke AA, Chen YL, Mack WJ, Brinton RD, Schneider LS. Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor beta-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women. Menopause. 2018 Feb;25(2):191-196. doi: 10.1097/GME.0000000000000984.
• Schneider LS, Hernandez G, Zhao L, Franke AA, Chen YL, Pawluczyk S, Mack WJ, Brinton RD. Safety and feasibility of estrogen receptor-beta targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial. Menopause. 2019 Aug;26(8):874-884. doi: 10.1097/GME.0000000000001325.

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2024
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): January 31, 2027

Study Registration Dates

• First Submitted: September 8, 2022
• First Submitted That Met QC Criteria: December 22, 2022
• First Posted (Actual): December 23, 2022

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Brain Diseases, Metabolic
• Other Study ID Numbers: Phyto-2022-01; R01AG075122 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No