Genistein for Amyloid Cardiomyopathy

(GASPAR Trial)

Overseen By Mark JK Chandy, MD PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Lawson Health Research Institute

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

Disqualifiers: Pregnancy, Cancer, Liver dysfunction, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Genistein for treating amyloid cardiomyopathy?

Research shows that Genistein, a compound found in soybeans, has protective effects on the heart by reducing inflammation and preventing heart damage in various models of heart disease. It has been shown to lower heart tissue damage and improve heart function in animal studies, suggesting potential benefits for heart conditions. ^{1 2 3 4 5}

Is genistein safe for human use?

Genistein, found in soy, has shown both beneficial and adverse effects in studies. It can have estrogen-like effects and may cause issues in males with certain heart conditions, but it also has anti-inflammatory properties. More research is needed to fully understand its safety, especially with long-term use. ^{1 3 6 7 8}

How is the drug Genistein unique in treating amyloid cardiomyopathy?

Genistein is unique because it is a natural compound found in soybeans that acts as a phytoestrogen, potentially offering heart protection by reducing oxidative stress and inflammation, which are not typical targets of standard treatments for amyloid cardiomyopathy. ^{1 4 9 10 11}

Research Team

Mark JK Chandy, MD PhD

Principal Investigator

Lawson

Eligibility Criteria

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 have had a heart procedure within the last 3 months.

Pregnancy

I have been diagnosed with endometriosis.

Trial Timeline

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

Treatment Details

Interventions

• Genistein (Cancer Vaccine)

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Genistein Prevents Nitric Oxide Deficiency-Induced Cardiac Dysfunction and Remodeling in Rats. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Haemostatic effects of phytoestrogen genistein in postmenopausal women. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease. [2022]

4. Singapore 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. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Inhibition of mouse and human CYP 1A- and 2E1-dependent substrate metabolism by the isoflavonoids genistein and equol. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Risks and benefits of phytoestrogens: where are we now? [2023]

8. Netherlands 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. [2023]

9. England 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. [2019]

10. Switzerland 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. [2022]

11. Ireland pubmed.ncbi.nlm.nih.gov

Hypotensive effects of genistein: From chemistry to medicine. [2017]