PhytoSERM for Menopausal Hot Flashes and Sustained Brain Health

PhytoSERM for Menopausal Hot Flashes and Sustained Brain Health: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Clinical Trial

This is a proof-of-concept phase 2 clinical trial to investigate the effect of the phytoestrogenic supplement PhytoSERM on vasomotor symptoms and other symptoms associated with the menopausal transition, and on blood-based biomarkers in peri- and postmenopausal women.

After the screening period, participants will be randomized to PhytoSERM 50 mg pills (administered orally, once per day) or matching placebo, 1:1 allocation, for a period of 12 weeks. After 12 weeks, all participants in the placebo group will be crossed-over to receive PhytoSERM pills for the remainder of the study (open-label phase).

This is a double-blinded, randomized, placebo-controlled, parallel designed, proof-of-concept phase 2 clinical trial to determine effect of PhytoSERM on vasomotor symptoms and other symptoms associated with the menopausal transition. PhytoSERM or placebo pills will be administered orally once a day over 24 weeks. Safety and tolerability will also be assessed over the duration of the study.

A total of 132 peri- or postmenopausal women aged 45-60 years and who are experiencing hot flashes will be enrolled in this trial. To determine eligibility, all participants will undergo cognitive assessment, physical assessment, ECG, clinical/safety laboratory assessment, and interviews. After a 2-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. After 12 weeks, participants in the placebo group will be crossed-over to PhytoSERM 50 mg for the remaining 12 weeks (open-label extension period). Hot flashes will be measured both objectively and subjectively. Objective data will be skin conductance levels collected via a wearable device that enables real-time physiological data acquisition, including activity and sleep data. Study participants will be asked to complete a total of 8 study visits. Study visits will occur at 4-week intervals after the baseline, except for visits # 6 and 7 (open-label period) which will occur at 6-week intervals after visit # 5 (final outcomes assessments visit). Visits 1, 2, 5 and 7 will last approximately 2-4 hours; visits 3, 4, 6 and 8 will last approximately 45 minutes.

All participants will be enrolled at a single site, at the University of Arizona (UA) Clinical & Translational Sciences Research Center (CATS).

Inclusion Criteria:

• Peri- or postmenopausal women, defined by any of the following:

  1. Last menstrual period (LMP) completed ≥ 60 days and ≤ 8 years, per the Stages of Reproductive Aging Workshop (STRAW) criteria.
  2. Post-hysterectomy or endometrial ablation ≥ 3 months and supported by FSH levels.

• Age 45-60 years.

• Presence of hot flashes ≥ 7 per day.

• Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the investigator.

• Mammogram within normal limits in the past 2 years: Breast Imaging Reporting and Data System (BI-RADS) category 1-2 or 3 with findings stable for 3 years.

• No medical contraindications to study participation.

• Stable medications for 4 weeks prior to the baseline visits.

• 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.

Exclusion Criteria:

• Use of isoflavone containing supplements.
• Known allergies to isoflavones or soy-based products.
• Montreal Cognitive Assessment total score < 22.
• 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 (breast, ovarian and uterine cancers), active neoplastic disease, history of breast cancer, and endometrial hyperplasia.
• History within the last 5 years of any other primary or recurrent malignant disease, with the exception of resected cutaneous squamous cell carcinoma in situ, and basal cell carcinoma.
• History of epilepsy, focal brain lesion, head injury with loss of consciousness or 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, TIA.
• Current use of tobacco or a history of alcohol abuse.
• Use of anticoagulants.
• Chronic use of most benzodiazepines
• Use of drugs, herbs, or dietary supplements to treat menopausal or cognitive symptoms less than 8 weeks prior to baseline (e.g., SSRIs, rhubarb, red clover, licorice, kudzu, black cohosh, ginseng or other similar roots, etc.)
• Evidence of any significant clinical disorder or laboratory finding, including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal, or other systemic disease or laboratory abnormality.
• Known allergy to soy-derived products/ proteins or branded over the counter products; hypersensitivity to estrogens or progestins.