Genistein in trAnSthyretin recePtor Amyloid caRdiomyopathy

NCT06634108 | Recruiting Phase 1 DMC

• 1 other identifier: 13179
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Amyloid Cardiomyopathy

Outcome Measures

Primary Outcomes (3)

• 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.

  These parameters will be assessed at baseline (week 0) and with each dose escalation (week 4, week 8, and week 12) and after washout (week 18).

• 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.

  These parameters will be assessed at baseline (week 0) and with each dose escalation (week 4, week 8, and week 12) and after washout (week 18).

• 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.

  These parameters will be assessed at baseline (week 0) and with each dose escalation (week 4, week 8, and week 12) and after washout (week 18).

Secondary Outcomes (6)

• The impact of genistein on exercise capacity

  This parameters will be assessed at baseline (week 0) and after washout (week 18).

• The impact of genistein on cardiac volume

  This parameters will be assessed at baseline (week 0) and after washout (week 18).

• The impact of genistein on cardiac mass

  This parameters will be assessed at baseline (week 0) and after washout (week 18).

• The impact of genistein on cardiac systolic function

  This parameters will be assessed at baseline (week 0) and after washout (week 18).

• The impact of genistein on cardiac diastolic function

  This parameters will be assessed at baseline (week 0) and after washout (week 18).

Other Outcomes (4)

• Exploratory Blood Biomarkers

  These parameters will be assessed at baseline (week 0) and with each dose escalation (week 4, week 8, and week 12) and after washout (week 18).

• Microbiome DNA sequencing

  These parameters will be assessed at baseline (week 0) and with each dose escalation (week 4, week 8, and week 12) and after washout (week 18).

• Microbiome RNA sequencing

  These parameters will be assessed at baseline (week 0) and with each dose escalation (week 4, week 8, and week 12) and after washout (week 18).

Study Arms (1)

Genistein Treatment and Washout

EXPERIMENTAL

The Investigators plan to recruit 40 heart failure participants, including 20 participants with heart failure with reduced ejection fraction (LVEF\<40%) and 20 participants with transthyretin amyloid (ATTR) cardiomyopathy. After an initial telephone call to screen participants, the Investigators will invite qualified people for informed consent and a baseline fasting blood draw. Participants will receive escalating doses of genistein after their baseline fasting blood and stool sample collections. At baseline and again at 3 months, the Investigators will also perform transthoracic echocardiography and a 6-minute walk test.

Drug: Genistein

Interventions

Genistein DRUG

The 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.

Genistein Treatment and Washout

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age: 40-80 years
• Heart failure with Reduced Ejection Fraction
• ischemic or nonischemic etiology
• LVEF \<40% by echocardiography, MUGA, or MRI
• ATTR cardiomyopathy
• any LVEF by echocardiography, MUGA, or MRI
• Stable optimally tolerated dosages of HF therapies for 3 months with no change in medical management regimen for at least 1 month
• NT-proBNP
• for participants \< 75 years old with NT-proBNP \> 125 pg/mL
• for participants \> 75 years old with NT-proBNP \> 450 pg/mL

You may not qualify if:

• Coronary intervention in the past 3 months
• Pregnancy
• Endometriosis
• Uterine fibroids
• Cancer:
• including breast cancer
• predisposition to cancer such as abnormal mammogram
• family history
• BRCA1 or BRCA2 positive
• Patients on a vegan diet
• Patients taking supplements such as isoflavonoid, genistein, or resveratrol
• Ethanol abuse
• Men: \>4 drinks on any day or more than 14 drinks per week
• Women: \>3 drinks on any day or more than 7 drinks per week
• Liver dysfunction:

Sponsors & Collaborators

• London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's: lead
• Greenstone Biosciences: collaborator
• Stanford University: collaborator

Study Sites (1)

London Regional Health Science Centre

London, Ontario, N6A 5A5, Canada

RECRUITING

MeSH Terms

Conditions

Amyloid Neuropathies, Familial

Interventions

Genistein

Condition Hierarchy (Ancestors)

Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Amyloid Neuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amyloidosis, Familial; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Amyloidosis; Proteostasis Deficiencies

Intervention Hierarchy (Ancestors)

Isoflavones; Flavonoids; Chromones; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Mark JK Chandy, MD PhD

  Lawson

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mark JK Chandy, MD PhD

CONTACT

5196612111; mark.chandy@lhsc.on.ca

Kerry-Ann Nakrieko, PhD

CONTACT

5196112111; knakrie@uwo.ca

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: Phase 1b/2a study to evaluate 1. the safety of escalating doses of genistein 2. the effects on cardiac function and exercise capacity

Study Record Dates

• First Submitted: May 29, 2024
• First Posted: October 9, 2024
• Study Start: September 27, 2024
• Primary Completion: September 1, 2025
• Study Completion: December 1, 2025
• Last Updated: June 15, 2025

Record last verified: 2025-06

Locations

CA (1)