Cardiovascular Genistein Therapy for Heart Failure Inflammation
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Inflammatory markers
研究概览
简要总结
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.
详细描述
BACKGROUND.
Heart Failure (HF) is a complex clinical syndrome when the heart cannot meet the metabolic demands of the body. HF is a growing health and economic burden in the United States. Between 2013 to 2017, there were over 1.2 million hospitalizations per year and costs of over $30 billion per year. The prognosis of HF is quite poor, with the number of deaths per year increasing from 275,000 in 2009 to 310,000 in 2014.
HF is caused by ischemic cardiomyopathy, valvular disease, and non-ischemic cardiomyopathy, which includes infiltrative cardiac disease such as amyloidosis. The link between inflammation and HF is well characterized and plays a significant role in heart failure. The immune system is activated in response to myocardial injury, decreased peripheral perfusion, or neurohormonal activation. Cytokines are released from inflammatory cells and destabilize cardiovascular function. When a cardiomyocyte is damaged by infarction or stretch from volume or pressure overload, the surrounding myocytes secrete inflammatory cytokines that further exacerbate HF.
Inflammatory cytokines serve as reliable indicators of HF severity, providing prognostic value and a means to assess the effectiveness of therapeutic interventions. A host of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-a (TNF-alpha), and interferon g (IFN-gamma), have been identified as key players in the pathogenesis of HF. Chronic HF management includes correcting the underlying cause, treating symptoms, and long-term pharmacological and device therapy. In the chronic setting, pharmacological interventions such as β-blockers, ACE inhibitors, aldosterone antagonists, and sodium-glucose cotransporter-2 inhibitors (SGLT2i) combined with implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) can markedly improve symptoms and survival.
GENISTEIN
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •Coronary intervention in the past 3 months
- •Pregnancy
- •Endometriosis
- •Uterine fibroids
- •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:
- •aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3X ULN
- •total bilirubin greater than 1.5 times ULN
- •hormone replacement therapy (HRT)
- •thyroid supplement
- •Renal dysfunction (eGFR less than 25 mL/min/1.73 m2)
- •Uncontrolled diabetes (HgbA1c >10%)
- •Coagulopathies
- •Cytopenia:
- •leukocytopenia
- •hemoglobin < 9 mg/dl
- •platelets <100x103/mm3
- •Any patients who had been hospitalized in the past 3 months for reasons other than heart failure
- •NYHA Functional Class I or Functional Class IV symptoms.
- •Acute bacterial or viral infectious disease, or acute exacerbation of a chronic infectious disease
- •allergy to genistein or inulin
- •allergy to perflutren dye used in contrast echocardiography
研究组 & 干预措施
Genistein Treatment and Washout
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.
干预措施: Genistein (Drug)
结局指标
主要结局
Inflammatory markers
时间窗: 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).
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
时间窗: 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).
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
时间窗: 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).
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.
次要结局
- 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).)
- The impact of genistein on cardiac function using strain imaging(This parameters will be assessed at baseline (week 0) and after washout (week 18).)
研究者
Mark Chandy
Assistant Professor
London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's