PhytoSERM to Prevent Menopause Associated Decline in Brain Metabolism and Cognition

Menopause Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05664477
• Other study ID #: Phyto-2022-01
• Secondary ID: R01AG075122
• Status: Recruiting
• Phase: Phase 2
• Start date: January 10, 2024
• Est. completion date: February 28, 2028

Study information

• Verified date: February 2024
• Source: University of Arizona
• Contact: Claudia M Lopez, BS
• Phone: 5206266276
• Email: claudiml[@]arizona.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: February 28, 2028
• Est. primary completion date: August 28, 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 45 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Diseases
• Cognitive Change
• Menopause

Intervention

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%).

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.

Locations

Country	Name	City	State
United States	The Alzheimer's Prevention Program / Weill Cornell Medicine	New York	New York

Sponsors (4)

Lead Sponsor	Collaborator
Roberta Brinton	ADM Diagnostics, Cornell University, National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Regional brain volume	T1-weighted volumetric MRI (mm3).	Baseline to 24 weeks
Other	Fractional Anisotropy	Multi-band multi-shell Diffusion Tensor Imaging (DTI) to measure changes in white matter tract integrity.	Baseline to 24 weeks
Other	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
Other	Functional connectivity	Resting state functional MRI (rs-fMRI) to measure changes in intrinsic connectivity, which also correlates to neuronal function.	Baseline to 24 weeks
Other	Cerebral blood perfusion	Arterial spin labeling (ASL) to measure changes in cerebral blood flow, which correlates to neuronal function.	Baseline to 24 weeks
Other	Inflammatory Biomarker: Cytokines	Change in laboratory value in inflammatory cytokines (Interleukin-6)	Baseline to 24 weeks
Other	Lipid biomarker: Total Cholesterol	Laboratory value of total cholesterol in blood	Baseline to 24 weeks
Other	Plasma Glucose	Laboratory value of glucose in plasma	Baseline to 24 weeks
Other	Diabetic biomarker: Hemoglobin A1C (HbA1c)	Laboratory value	Baseline to 24 weeks
Other	Menopause biomarker: Estradiol	Laboratory values	Baseline to 24 weeks
Other	Menopause biomarker: Follicle-Stimulating Hormone (FSH)	Laboratory values	Baseline to 24 weeks
Primary	Standardized uptake value ratio (SUVR) by 18F-FDG PET	Regional brain glucose metabolism SUVR	Baseline to 24 weeks
Secondary	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
Secondary	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
Secondary	Picture Sequence Memory Test	Maximum raw score of 48 for ages 20-60 years. More is better.	Baseline to 24 weeks
Secondary	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
Secondary	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
Secondary	Hot flash Frequency Composite	Hot flash frequency and severity scores. Less is better.	Baseline to 24 weeks
Secondary	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
Secondary	Pittsburgh Sleep Quality Index	A global sum of "5" or greater indicates a "poor" sleeper.	Baseline to 24 weeks
Secondary	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
Secondary	Beck Depression Inventory - II	Maximum score is 63. Higher scores represent greater depressive symptoms.	Baseline to 24 weeks
Secondary	Pharmacokinetics: Peak Plasma Concentration (Cmax)	The highest concentration of each phytoestrogen in the blood after a dose is given.	Baseline
Secondary	Pharmacokinetics: Time of peak concentration (tmax)	Time required to achieve peak plasma levels.	Baseline
Secondary	Pharmacokinetics: Half-life (t1/2)	The time required for plasma concentration of phytoSERMs to decrease by 50%	Baseline
Secondary	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