PhytoSERM to Prevent Menopause Associated Decline in Brain Metabolism and Cognition

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Menopause, Cognitive Change, Brain Disorder, Metabolic

Intervention / Treatment
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* Dietary Supplement: PhytoSERM
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Age 45-60 years. Presence of hot flashes ≥ 7 per day. In good general health as evidenced by medical history. Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the investigator. No medical contraindications to study participation. Stable medications for 4 weeks prior to the baseline visits. Provision of signed and dated informed consent form. Stated willingness to comply with all study procedures and availability for the duration of the study. Ability to take oral medication and be willing to adhere to the PhytoSERM regimen. 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. Fluent in English or Spanish. Exclusion Criteria: Known allergies to isoflavones or soy-based products. Evidence of cognitive impairment on the Mini-Mental State Examination (total score < 27). Pregnancy Use of estrogen or progestin compounds within 8 weeks of baseline. Use of investigational agent within 12 weeks of baseline. Concurrent neurologic, systemic, or psychiatric disease that would influence cognition or ability to provide informed consent and to participate. Known or suspected estrogen-dependent neoplasia, active neoplastic disease, history of breast cancer, or at risk of developing breast cancer, endometrial hyperplasia. 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. Thrombophlebitis, thrombosis, thromboembolic disorders, myocardial infarction, ischemic heart disease, cerebrovascular accident, stroke, transient ischemic attack (TIA). Current use of tobacco or a history of alcohol abuse. Use of drugs, herbs, or dietary supplements to treat menopausal or cognitive symptoms less than 8 weeks prior to baseline. Evidence of any significant clinical disorder or laboratory finding. Known allergy to soy-derived products/ proteins or branded over the counter products; hypersensitivity to estrogens or progestins. Visual and auditory acuity inadequate for neuropsychological testing Inability to undergo MRI scans Inability to undergo PET scans

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PhytoSERM group<br>PhytoSERM 50mg tablet composed of the phytoestrogens daidzein, genistein and S-equol, administered orally every day for 24 weeks. | Dietary Supplement: PhytoSERM<br>* 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%).<br>|
| Placebo Comparator: Placebo group<br>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<br>* 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.<br>|

What is the study measuring?
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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 |