Phytoserms for menopause symptoms and age associated memory decline
Description
Detailed Description
Background and rationale:Selective estrogen receptor (ER) targeting may be a novel therapeutic target for the development of therapies for a range of conditions including cognitive impairment and age-related ovarian failure (menopause). There are plausible mechanisms by which ER receptor stimulation could lead to improved cognition, feelings of well being, reduced risks for cognitive impairment and improved vasomotor symptoms.A formulation composed of rationally-selected ER-selective phytoestrogens (phytoSERMs) was developed that provides a greater effect than the various food supplements ("nutraceuticals") that are mixtures with both ER and ER selective components. This formulation is composed of content that includes synergistic rather than antagonistic effects on estrogen receptors and could likely generate salutary therapeutic effects. The formulation enhances ER responses by adding equol to genistein and daidzein in equal amounts moderating potencial influences of inter-individual differences in the production of equol. Advantages of the formulation are: (1) reduction of antagonistic interactions that occur in complex soy-derived isoflavone preparations; and (2) minimization of adverse effects associated with ER activation in reproductive tissues. Thus, it may serve as an alternative to current over-the-counter therapies.Primary objectives and pupose:To examine in a randomized, placebo-controlled trial of 12 weeks duration evidence for safety, improved cognitive performance and vasomotor symptoms for a specific phytoSERM formulation Secondary objectives:1. To assess single-dose pharmacokinetics of the three constituents of phytoSERM combination over 24 hours in a subset of 18 participants randomly assigned 100 mg, 50 mg, or placebo tablets.2. To assess safety, tolerability of a 100 mg and 50 mg daily dose compared to placebo over 4 weeks3. To assess potential efficacy indicators of phytoSERM combination on cognitive performance and vasomotor symptoms by means of a 4-week treatment, 2 period, placebo-controlled crossover design for a subset of participants4. To develop biomarkers for response (i.e., for peripheral lipid peroxidation and mitochondrial function)Study design:Two stage, dose-range, double-blinded, parallel-group, placebo-controlled adaptive design 12 week treatment duration trial; with an embedded 2-period, 4-week treatment, crossover design for a subset of participants; and an embedded single-dose, 24 hour, pharmacokinetic study for a subset of participants. Allocation ratio will initially be 1:1:1, 100 mg, 50 mg, and placebo dose for the first 36 participants, with a possible change in allocation based on the adaptation (see protocol)Study endpoints:Adverse events over the first 4 weeks, and over 12 weeks;Cognitive performance on a 6-test battery, vasomotor symptoms, and behavioral symptoms at 4, 8, and 12 weeks.Blood levels of the three constituents of phytoSERM combination over 24 hours in the subset in the pharmacokinetic study; and blood levels at 4, 8 and 12 weeks for all participantsBlood for biomarker development at baseline, 4, 8, and 12 weeksEligibility criteria:Generally healthy, peri to postmenopausal women, ages 45 to 60, intact uteri and ovaries, last natural menstrual cycle completed from 60 days to less than 4 years prior to screening, having at least 1 cognitive complaint and 1 vasomotor-related symptom per day (on the Memory Assessment Questionnaire and Greene Climacteric Scale). Intervention:Oral tablets consisting of equal parts genestein, daidzein, and S-equol) totaling 100 mg per tablet and 50 mg per tablet; and mathching placeboProcedures and data collection: At baseline, physical exam, neuropsychological tests, vasomotor symptoms and mood scales;In person visits for screening, baseline, weeks 4, 8, and 12 during which medication effects will be assessed, cognitive and behavioral tests performed, and blood for plasma levels and biomarkers obtained; Telephone contacts at weeks 1, 2, 6, and 10; An in-person visit or telephone contact at 16 weeks (4 weeks after discontinuation); Blood samples for drug levels and pharmacokinetics during the first 24 hours for the subset participating;Blood at baseline, weeks 4, 8, and 12 for drug levels and biomarker development for the whole sampleStatistical considerations:Two-stage adaptive design. Analysis of first stage at 4 weeks after 36 participants are randomized and followed: Primary analysis will use Generalized Estimating Equation (GEE) methods to assess group differences in the outcomes in a modified intent-to-treat sample (i.e., randomized, took at least one dose, and had at least one follow-up with outcomes measures. Observed cases (at least 80% compliant and completed all outcomes) will be assessed in secondary analyses
Phase
OtherInclusion and Exclusion Criteria
- post-menopausal women
- ages 48
- 58 (inclusive)
- must have a vasomotor symptom (e.g., hot flash) and a memory complaint
- history of clinically significant stroke
- current evidence or history in past 2 years of epilepsy, seizure, focal brain lesion, head injury with loss of consciousness or any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse
- Known allergy to soy derived products; hypersensitivity to estrogens or progestins
Sites
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California
- USC Keck School of Medicine, Los Angeles, California, 90033
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