Genistein for Amyloid Cardiomyopathy

(GASPAR Trial)

Overseen By Mark JK Chandy, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Lawson Health Research Institute

Must not be taking: Isoflavonoid, Genistein, Resveratrol, HRT

Disqualifiers: Pregnancy, Cancer, Liver dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 12 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests genistein, a treatment for Transthyretin (TTR) Amyloidosis, which affects heart function. Researchers aim to determine if genistein can safely improve heart health and exercise ability in individuals with this condition. Participants will take genistein pills for several weeks, while researchers monitor heart function and inflammation levels. Individuals with heart failure with reduced ejection fraction, or ATTR cardiomyopathy, who have not changed their heart medications in the past month may be suitable candidates. This study seeks to determine if genistein could be a beneficial treatment for heart failure. As a Phase 1, Phase 2 trial, this research focuses on understanding genistein's effects in people and measuring its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking heart treatment research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must have stable heart failure therapies for at least 3 months and cannot be on certain supplements like isoflavonoid, genistein, or resveratrol. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that genistein is likely to be safe for humans?

Research has shown that genistein, a substance found in soy, is generally safe for people. It has a good safety record, with studies reporting no major side effects. Most people can use genistein without problems. However, while researchers have studied genistein for other health issues, its safety for Transthyretin (TTR) Amyloidosis remains under investigation. This trial aims to gather more information on the safety and tolerability of genistein for individuals with this condition. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for amyloid cardiomyopathy?

Unlike the standard treatments for amyloid cardiomyopathy, which often focus on stabilizing the amyloid deposits or managing heart failure symptoms, genistein offers a unique approach. Genistein is derived from soy and is thought to have the potential to interfere with the formation of amyloid fibrils, which are the proteins that cause damage in this condition. Researchers are excited about genistein because it targets the root cause of amyloid buildup, potentially offering a more direct way to tackle the disease. Additionally, genistein's natural origin might present fewer side effects compared to some existing medications.

What evidence suggests that genistein might be an effective treatment for TTR Amyloidosis?

This trial will investigate the effects of genistein on heart health in participants with heart failure, including those with transthyretin amyloid (ATTR) cardiomyopathy. Studies have shown that genistein can enhance heart function and reduce damage in heart conditions. It has positive effects on heart problems, potentially helping individuals with these issues feel better. Genistein operates at a cellular level, possibly reducing inflammation and improving blood flow. This is crucial because, in conditions like Transthyretin (TTR) Amyloidosis, the heart struggles to function properly. While more research is needed, these findings suggest that genistein might be a promising option for improving heart health in people with TTR Amyloidosis. ^{2 4 6 7 8}

Who Is on the Research Team?

Mark JK Chandy, MD PhD

Principal Investigator

Lawson

Are You a Good Fit for This Trial?

This trial is for patients with Transthyretin (TTR) Amyloidosis, specifically affecting the heart. Participants should be able to provide consent and follow the study's procedures, including blood tests, echocardiography, and a walking test. Detailed inclusion and exclusion criteria are not provided.

Inclusion Criteria

I am between 40 and 80 years old.

My heart's pumping ability is weak, with an ejection fraction below 40%.

My heart failure medications have been stable for 3 months.

Exclusion Criteria

I do not have any current infections or sudden worsening of a long-term infection.

Pregnancy

I have been hospitalized recently, but not for heart failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive escalating doses of genistein: 250 mg twice a day for 4 weeks, 500 mg twice a day for 4 weeks, and 750 mg twice a day for 4 weeks

12 weeks

Weekly visits for dose escalation monitoring

Washout

Participants undergo a 6-week placebo washout period

6 weeks

1 visit (in-person) at the end of washout

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 weeks

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Genistein

Trial Overview

The trial is testing genistein's safety and effectiveness in TTR Amyloidosis patients. It involves taking increasing doses of genistein orally over 12 weeks followed by a six-week washout period. The study will measure changes in inflammation markers, cardiac function, and exercise capacity.

How Is the Trial Designed?

Group I: Genistein Treatment and Washout Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Lawson Health Research Institute

Lead Sponsor

Trials

684

Recruited

432,000+

London Health Sciences Centre Research Institute and Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

686

Recruited

427,000+

London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

678

Recruited

421,000+

London Health Sciences Centre OR Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

668

Recruited

424,000+

Greenstone Biosciences

Collaborator

Trials

3

Recruited

70+

Stanford University

Collaborator

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

In a double-blind placebo-controlled trial involving 104 postmenopausal women, genistein (54 mg/day) significantly reduced plasma levels of D-dimer, a marker associated with blood clotting, compared to placebo, suggesting a potential cardioprotective effect.

While genistein did not affect other markers of the haemostatic system (PAI-1 and F1+2), the decrease in D-dimer indicates that it may help improve cardiovascular health in postmenopausal women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haemostatic effects of phytoestrogen genistein in postmenopausal women. Trifiletti, A., Gaudio, A., Lasco, A., et al.[2013]

In a rat model of myocardial ischaemia-reperfusion injury, genistein significantly reduced myocardial necrosis, improved heart contractility, and decreased the occurrence of ventricular arrhythmias, indicating its protective effects on the heart.

Genistein also lowered levels of inflammatory markers such as TNF-alpha and ICAM-1, suggesting it limits the inflammatory response associated with heart injury, making it a potential therapeutic agent for cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury. Deodato, B., Altavilla, D., Squadrito, G., et al.[2018]

Genistein (Gen) effectively protects PC12 cells from neurotoxicity induced by aggregated amyloid beta (Aβ25-35) by inhibiting the activation of the p-JNK pathway, which is crucial for neuronal apoptosis.

The study reveals that Gen reduces the activation of pro-apoptotic factors and caspase-3 activity, suggesting that it mitigates Aβ25-35 induced cell death through a mitochondrial pathway, providing new insights into potential therapeutic mechanisms for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genistein protects against A&#946;25-35 induced apoptosis of PC12 cells through JNK signaling and modulation of Bcl-2 family messengers. You, F., Li, Q., Jin, G., et al.[2019]

Genistein, a natural compound from soy, shows potential as a cardio-protective agent by reducing apoptosis in heart cells treated with isoproterenol, a norepinephrine analog, indicating its efficacy in protecting heart cells from stress-induced damage.

The protective effects of genistein are linked to its ability to modulate key survival pathways, including the expression of proteins like p-Akt and p-Erk1/2, suggesting it could be a safe alternative to traditional hormone therapies for heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genistein suppresses the isoproterenol-treated H9c2 cardiomyoblast cell apoptosis associated with P-38, Erk1/2, JNK, and NFκB signaling protein activation. Hu, WS., Lin, YM., Ho, TJ., et al.[2023]

Genistein, an isoflavone from soybeans, effectively prevented hypertension and cardiac remodeling in rats induced by L-NAME, demonstrating its potential as a cardioprotective agent.

The protective effects of genistein are likely due to its ability to reduce oxidative stress and modulate the Ang II/AT1R/NADPH oxidase/TGF-β1 signaling pathway, as evidenced by decreased levels of angiotensin II and improved antioxidant enzyme activities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genistein Prevents Nitric Oxide Deficiency-Induced Cardiac Dysfunction and Remodeling in Rats. Poasakate, A., Maneesai, P., Rattanakanokchai, S., et al.[2021]

Genistein and equol significantly inhibit cytochrome P450 enzymes, specifically CYP2E1 and CYP1A1, with IC50 values indicating varying potency, suggesting potential interactions with drug metabolism.

Despite showing inhibition of CYP1A1, the high IC50 values for genistein and equol imply that their chemopreventative effects observed in animal studies may not be relevant at dietary levels in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of mouse and human CYP 1A- and 2E1-dependent substrate metabolism by the isoflavonoids genistein and equol. Helsby, NA., Chipman, JK., Gescher, A., et al.[2019]

Recent studies confirm that genistein, a phytoestrogen, can have both beneficial and harmful effects on reproduction and estrogen-dependent diseases, depending on exposure levels and the estrogenic status of individuals.

The increased exposure to phytoestrogens due to industrial soybean processing raises concerns about their role as modern endocrine disruptors, necessitating further research into their effects on human and animal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks and benefits of phytoestrogens: where are we now? Bennetau-Pelissero, C.[2023]

In male mice with hypertrophic cardiomyopathy (HCM), a soy-based diet containing phytoestrogens like genistein and daidzein worsened heart conditions, while female mice were not negatively affected by the same diet, indicating a sex-specific response to these compounds.

Estrogen treatment did not provide protection against HCM in either male or female mice and was found to be lethal in male mice on a phytoestrogen diet, highlighting the potential risks of phytoestrogens and the lack of protective effects of estrogen in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease. Haines, CD., Harvey, PA., Luczak, ED., et al.[2022]

Phytoestrogens (PEs) have been shown to significantly reduce heart damage in animal models of myocardial ischemia-reperfusion injury (MIRI), as evidenced by decreased myocardial infarct size and improved heart function metrics such as left ventricular ejection fraction and fractional shortening.

The analysis of 20 studies involving 355 animals demonstrated that PEs also lowered harmful biomarkers like creatine kinase and cTnI, indicating their potential as a multi-targeted cardioprotective treatment, although further research in larger animal models and clinical trials is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review and Meta-Analysis of Phytoestrogen Protects Against Myocardial Ischemia/Reperfusion Injury: Pre-Clinical Evidence From Small Animal Studies. Wang, Y., Shou, X., Fan, Z., et al.[2022]

Genistein, a natural flavonoid found in Leguminoseae plants, shows promise as a potential anti-hypertensive agent, with evidence suggesting it can help lower blood pressure through various mechanisms.

Despite its beneficial effects observed in experimental models, there is a lack of clinical trials to support its use in treating hypertension, indicating that more research is needed before it can be recommended for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypotensive effects of genistein: From chemistry to medicine. Sureda, A., Sanches Silva, A., Sánchez-Machado, DI., et al.[2017]

Both genistein (aglycone) and genistin (glycoside) effectively suppressed the production of pro-inflammatory cytokines in rats, indicating their potential anti-inflammatory effects in vivo.

Unlike genistein, genistin did not cause thymic atrophy, suggesting that the glycoside form may be safer for consumption, especially in long-term dietary studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral administration of soy-derived genistin suppresses lipopolysaccharide-induced acute liver inflammation but does not induce thymic atrophy in the rat. Zhao, JH., Arao, Y., Sun, SJ., et al.[2023]

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Objective The main objective of this review is to summarize the pharmacological effects of genistein, elucidating its potential mechanisms of action.

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pmc.ncbi.nlm.nih.gov/articles/PMC8301030/

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Genistein, an isoflavone, has cancer-suppressing effects on estrogen receptor-positive (ER+) cancers, including breast cancer. It suppresses the function of ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC1253540/

Genistein, a natural product from soy, is a potent inhibitor of ...

Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and ...

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withpower.com

withpower.com/trial/phase-2-cardiomyopathies-8-2024-02ac8

Genistein for Amyloid Cardiomyopathy (GASPAR Trial)

Is genistein safe for human use? Genistein, found in soy, has shown both beneficial and adverse effects in studies. · How is the drug Genistein unique in ...

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ccs.ca

ccs.ca/news/emerging-research-project-aims-to-assess-the-safety-and-efficacy-of-genistein-in-patients-with-ttr-amyloidosis/

Emerging Research Project Aims to Assess the Safety and ...

First, it will provide data on the safety and tolerability of genistein in humans with TTR Amyloidosis, which has been largely unexplored.