This Phase 1b/2a study aims to investigate the safety and efficacy of genistein in patients with Transthyretin (TTR) Amyloidosis. The focus is on its impact on inflammatory and cardiometabolic biomarkers, along with the effects on cardiac function and exercise capacity.
Blood samples will be collected at baseline, following each dose of genistein, and after a six-week placebo washout period. These samples will undergo extensive analyses, including profiling for inflammatory cytokines and novel molecular markers, and routine tests like CBC, Chem 7, LFT, HbA1c, NT-proBNP, CRP, troponin T, and serum TTR. RNA-seq analyses on peripheral blood mononuclear cells (PBMCs) and isolation of plasma exosomes for inflammatory biomarkers are also part of the protocol.
Following ESC/AHA guidelines, echocardiography will assess cardiac structure and function, focusing on the left and right ventricles and valvular function. Additionally, exercise capacity will be evaluated through a standardized 6-minute walk test, and NT-proBNP levels will be measured as a cardiac stress biomarker.
The trial will include an 18-week follow-up period post-enrolment, with the primary endpoint being the change in inflammatory markers from baseline to three months. Secondary endpoints are cardiac function and exercise capacity changes over the same timeframe. This study aims to provide significant insights into genistein's therapeutic potential for TTR Amyloidosis and its broader implications in managing heart failure.
Following ethical committee approval and written informed consent, the Investigators aim is to enroll 40 participants. This is an open-label study. Each patient will receive genistein by mouth: 250 mg twice a day for 4 weeks (500 mg total/day), 500 mg twice a day for 4 weeks (1000 mg total/day), and 750 mg twice a day (1500 mg total/day) for an additional 4 weeks. This will be followed by a 6-week washout period to conclude the study. An 18-month study is anticipated based on the average enrollment rates. Results from this study are expected to offer critical insights for future larger studies.
Age: 40-80 years
Heart failure with Reduced Ejection Fraction
ischemic or nonischemic etiology
LVEF <40% by echocardiography, MUGA, or MRI
Coronary intervention in the past 3 months
Pregnancy
Endometriosis
Uterine fibroids
Single group
Genistein
DrugThe genistein capsules are manufactured and obtained from MCS Formulas, and each capsule contains 250 mg genistein and 50 mg inulin. The genistein is certified to be 98% pure genistein by HPLC and is certified by Good Laboratory Practice (GLP). They will consume 250 mg of genistein BID (500 mg total) by mouth for the first 4 weeks before blood and stool samples are collected. Then, participants will take 500 mg of genistein BID (1000 mg total) for the next 4 weeks before collecting fasting blood and stool samples. Afterward, participants will take 750 mg of genistein BID (1500 mg total) for 4 weeks before collecting fasting blood and stool samples. Afterward, participants will have a washout for 6 weeks before returning for fasting blood and stool sample collection.
Inflammatory markers
To assess the safety profile and effect of genistein on key inflammatory biomarkers in patients with heart failure, the following markers will be assessed using specified measurements: Interleukin-6 (IL-6): Measured using ELISA. Interleukin-8 (IL-8): Measured using ELISA. Tumor Necrosis Factor-alpha (TNF-α): Measured using ELISA. Interferon-gamma (IFN-γ): Measured using ELISA.
Cardiac markers
To assess the safety profile and effect of genistein on key cardiometabolic biomarkers in patients with heart failure, the following markers will be assessed using specified measurements: B-type Natriuretic Peptide (BNP): Measured using immunoassay. C-reactive Protein (CRP): Measured using immunoassay.
Complete metabolic profile
To assess the safety profile and effect of genistein on key cardiometabolic biomarkers in patients with heart failure, the following markers will be assessed using specified measurements: Hemoglobin A1C (HgA1C): Measured using standard laboratory methods. Complete Blood Count (CBC): Measured using automated hematology analyzer. Comprehensive Metabolic Panel (Chem 7): Measured using standard laboratory methods. Liver Function Tests (LFT): Measured using standard laboratory methods.
The impact of genistein on exercise capacity
Exercise capacity will be evaluated by 6-minute walk test, which will be performed by a blinded observer according to the standard protocol.
The impact of genistein on cardiac volume
Cardiac size will be evaluated by echocardiography. The scans will assess left ventricle end-systolic- and end-diastolic volumes (LVESV and LVEDV).
The impact of genistein on cardiac mass
Cardiac mass will be evaluated by echocardiography.
The impact of genistein on cardiac systolic function
Echocardiography will evaluate cardiac function. The scans will assess global left ventricular systolic function, left ventricular ejection fraction (LVEF), and RV systolic function.
Exploratory Blood Biomarkers
The Investigators will assess alterations in blood biomarkers through unbiased proteomics post-Genistein treatment and benchmark against baseline. The specific biomarkers and measurement tools are as follows: Proteomics Analysis: * Platform: OLink or RayBiotech proteomic profiling array. * Biomarkers: A comprehensive panel of proteins related to inflammation, oxidative stress, and cardiovascular health will be assessed. Examples of Biomarkers: * Cytokines: IL-6, IL-8, TNF-α, IFN-γ. * Acute Phase Proteins: CRP, Serum Amyloid A. * Growth Factors: VEGF, EGF. * Metabolic Proteins: Adiponectin, Leptin. Units of Measure: • The biomarkers will be measured in their respective units, typically in picograms per milliliter (pg/mL) or nanograms per milliliter (ng/mL).
Microbiome DNA sequencing
The effects of genistein on the microbiome will be studied by collecting stool samples at baseline, after each dose escalation, and after washout. Participant stool samples will have DNA sequencing to detect alternations in the microbial flora with genistein treatment. Units of Measure: The DNA sequencing analysis will identify genetic signatures of microbial flora.
Microbiome RNA sequencing
The effects of genistein on the microbiome will be studied by collecting stool samples at baseline, after each dose escalation, and after washout. Participant stool samples will have RNA sequencing to detect alternations in the microbial flora with genistein treatment. Units of Measure: The RNA sequencing dataset will be normalized to the baseline as a relative fold expression.
Microbiome:
The effects of genistein on the microbiome will be studied by collecting stool samples at baseline, after each dose escalation, and after washout. Participant stool samples will have metabolomics to detect alternations in the microbial flora with genistein treatment. Units of Measure: The metabolome will be assessed with mass spectrometry for changes in microbial metabolomics.
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London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Lead sponsor
Greenstone Biosciences
Collaborator
Stanford University
Collaborator
