MR Antagonist for High Blood Pressure

Overseen By Andrea Haas, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: Brigham and Women's Hospital

Must be taking: Anti-hypertensives

Must not be taking: Others

Disqualifiers: Cardiac disease, Diabetes, Smoking, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treat high blood pressure, specifically in Black individuals with a certain genetic marker (LSD1 risk allele). The study compares two treatments: eplerenone (also known as Inspra), which targets a hormone receptor linked to blood pressure, and amlodipine, a common blood pressure medication. The goal is to determine if eplerenone more effectively lowers blood pressure and protects kidney function in people with this genetic marker. Individuals who have high blood pressure, are Black, and know they carry this specific genetic marker might be suitable for the trial. As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment benefits more patients.

Will I have to stop taking my current medications?

The trial allows participants to continue taking up to two anti-hypertensive medications and stable thyroid medication. Other medications may need to be stopped, but the protocol does not specify.

What is the safety track record for these treatments?

Research has shown that eplerenone, a medicine for high blood pressure, is generally safe. In studies, patients taking eplerenone effectively lowered their blood pressure without serious side effects. However, some patients experienced higher potassium levels, which require monitoring.

The FDA has approved eplerenone for treating high blood pressure and heart failure, indicating its safety is well understood. Consulting a doctor is important, especially for concerns about potassium levels or kidney health. Overall, evidence supports its safety when used as directed, making it a viable option for managing high blood pressure. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about eplerenone for treating high blood pressure because it targets the mineralocorticoid receptor, which is believed to be more active in people with the LSD1 risk allele. This precision medicine approach aims to offer a more tailored treatment compared to standard options like amlodipine, which doesn't specifically target this mechanism. By focusing on the genetic makeup of individuals, eplerenone could potentially provide more effective blood pressure control for those who are genetically predisposed to benefit from mineralocorticoid receptor blockade.

What is the effectiveness track record for Eplerenone in treating high blood pressure?

Research shows that eplerenone, one of the treatments in this trial, effectively lowers blood pressure. Studies indicate that taking 50 to 200 mg of eplerenone daily can reduce systolic blood pressure by 6 to 24 points. It works particularly well for individuals with primary hypertension, another term for high blood pressure. In addition to controlling blood pressure, eplerenone reduces the risk of heart-related deaths, making it a promising option for managing high blood pressure. Participants in this trial may receive either eplerenone or amlodipine, as the study aims to compare these treatments in individuals with the LSD1 risk allele. ^{4 6 7 8 9}

Who Is on the Research Team?

Andrea Haas, MD

Principal Investigator

Brigham and Women's

Are You a Good Fit for This Trial?

This trial is for Black individuals over 17 years old with high blood pressure, who may be on up to two blood pressure medications and have normal kidney function and lab tests. They must carry the rs587168 risk allele for LSD1. People with heart disease other than hypertension, diabetes, or a history of smoking are not eligible.

Inclusion Criteria

I have high blood pressure, treated or untreated.

My kidney function and blood tests are normal.

You identify yourself as being Black.

Exclusion Criteria

I have diabetes.

You are a smoker.

I have high blood pressure due to another health condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either eplerenone or amlodipine with dose escalations every 4 weeks if blood pressure is > 140/90

12 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Eplerenone

Trial Overview The study is testing whether using Eplerenone (an MR antagonist) can better control blood pressure and prevent kidney damage in Blacks carrying the rs587168 allele compared to Amlodipine, based on their genetic makeup.

How Is the Trial Designed?

Group I: Eplerenone Arm Experimental Treatment 1 Intervention

We posit that individuals who carry the LSD1 risk allele have increased mineralocorticoid receptor activity, which results in hypertension. Thus, our mechanistic clinical study will assess whether hypertensive LSD1 risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine). To test this hypothesis, we will perform a randomized, double-blind, active controlled study in hypertensive carriers of the LSD1 risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic blood pressure. Therefore, this mechanistic trial will provide support for using a genetic marker that identifies individuals who are uniquely responsive to mineralocorticoid receptor blockade--personalized, precision medicine.

Group II: Amlodipine Arm Experimental Treatment 1 Intervention

We posit that individuals who carry the LSD1 risk allele have increased mineralocorticoid receptor activity, which results in hypertension. Thus, our mechanistic clinical study will assess whether hypertensive LSD1 risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine). To test this hypothesis, we will perform a randomized, double-blind, active controlled study in hypertensive carriers of the LSD1 risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic blood pressure. Therefore, this mechanistic trial will provide support for using a genetic marker that identifies individuals who are uniquely responsive to mineralocorticoid receptor blockade--personalized, precision medicine.

Eplerenone is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Inspra for:

• Hypertension
• Heart failure

Approved in European Union as Eplerenone for:

• Hypertension
• Heart failure

Approved in Canada as Eplerenone for:

• Hypertension
• Heart failure

Approved in Japan as Eplerenone for:

• Hypertension
• Heart failure

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Published Research Related to This Trial

Eplerenone significantly reduces the risk of cardiovascular death and hospitalization for heart failure in patients with chronic systolic heart failure and mild symptoms, as demonstrated in the EMPHASIS-HF study.

The drug is generally well tolerated, with hyperkalemia being the most common side effect, while serious sexual adverse events are rare, indicating its selectivity for mineralocorticoid receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eplerenone: a review of its use in patients with chronic systolic heart failure and mild symptoms. Dhillon, S.[2021]

Eplerenone is a selective aldosterone receptor antagonist that shows promise in managing cardiovascular and renal diseases by providing protective effects on nonclassical tissues, which may reduce injury from excess aldosterone exposure.

Early clinical trials indicate that eplerenone can offer additional benefits in treating hypertension, heart failure, and nephropathy, but more long-term studies are needed to fully understand its impact on morbidity and mortality in patients with varying disease severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eplerenone: selective aldosterone antagonism in management of cardiovascular and renal disease. Brennan, BJ., Martin, NE.[2019]

Eplerenone is an effective antihypertensive agent, showing a dose-dependent reduction in blood pressure in over 3500 hypertensive patients across 11 randomized clinical trials, and is better tolerated than spironolactone.

Eplerenone not only effectively lowers blood pressure compared to placebo but also demonstrates comparable efficacy to amlodipine while being better tolerated, suggesting it should be more widely used for treating mild to moderate hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of mineralocorticoid receptors in mild to moderate arterial hypertension. Pelliccia, F., Rosano, G., Patti, G., et al.[2018]

Eplerenone, a selective mineralocorticoid receptor antagonist, effectively reduces the harmful effects of aldosterone in conditions like hypertension and heart failure, supported by both preclinical and clinical evidence.

Compared to spironolactone, a nonselective aldosterone blocker, eplerenone has a better side-effect profile due to its selective binding to the mineralocorticoid receptor, which minimizes unwanted transcriptional activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone. Hu, X., Li, S., McMahon, EG., et al.[2019]

Aldosterone contributes to cardiovascular disease by promoting inflammation, especially with moderate salt intake, highlighting the importance of managing its effects in hypertensive patients.

Mineralocorticoid receptor antagonists like spironolactone and eplerenone are effective treatments for hypertension, with eplerenone offering fewer side effects, and their use can reduce organ damage and improve survival in patients with cardiovascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mineralocorticoid receptor antagonists and hypertension: is there a rationale? Gumieniak, O., Williams, GH.[2019]

In a phase 3 study involving 1001 Japanese adults with essential hypertension, esaxerenone at doses of 2.5 mg and 5 mg per day effectively reduced blood pressure, showing at least equivalent efficacy to eplerenone (50 mg/day).

Esaxerenone was well-tolerated, with similar rates of mild to moderate adverse events compared to eplerenone, indicating it is a safe option for treating hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-Blind Randomized Phase 3 Study Comparing Esaxerenone (CS-3150) and Eplerenone in Patients With Essential Hypertension (ESAX-HTN Study). Ito, S., Itoh, H., Rakugi, H., et al.[2020]

Aldosterone contributes to hypertension and organ damage through the mineralocorticoid receptor (MR), and MR antagonists like eplerenone and spironolactone are used to manage hypertension, although they are not the first-line treatment.

Recent studies suggest that the use of MR antagonists is expanding, highlighting the need to differentiate between spironolactone and eplerenone based on their specific features and contraindications in Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mineralocorticoid receptor antagonists: their use and differentiation in Japan. Sato, A.[2018]

Eplerenone, at doses of 50 mg and 100 mg daily, significantly reduced both systolic and diastolic blood pressure in patients with mild-to-moderate hypertension compared to placebo and other antihypertensive agents, based on a pooled analysis of 2,698 patients from 11 Phase III studies.

The treatment was well tolerated, with headache being the most common side effect, and severe hyperkalemia occurred at very low rates (up to 0.4%), indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antihypertensive effect of the mineralocorticoid receptor antagonist eplerenone: a pooled analysis of patient-level data from comparative trials using regulatory-approved doses. Fernet, M., Beckerman, B., Abreu, P., et al.[2022]

In a study of 341 patients with uncontrolled hypertension on ACE-I or ARB therapy, adding eplerenone significantly reduced blood pressure by an average of -5.9 mmHg systolic and -2.4 mmHg diastolic, demonstrating its efficacy as an add-on treatment.

The study found that while eplerenone is safe and effective for lowering blood pressure, baseline levels of active plasma renin or serum aldosterone did not predict how well patients would respond to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy? Prisant, LM., Krum, H., Roniker, B., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1200656/

Eplerenone (Inspra), a new aldosterone antagonist for the ... After 12 weeks, significant reductions in diastolic BP were observed in the 50 mg, 100 mg, and 200 mg eplerenone groups. Significant reductions in systolic BP ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6464701/

Eplerenone for hypertension - PMC - PubMed Central - NIH Eplerenone 50 to 200 mg/day lowers blood pressure in people with primary hypertension by 9.21 mmHg systolic and 4.18 mmHg diastolic compared to placebo, with no ...

3. aafp.org aafp.org/pubs/afp/issues/2004/0215/p915.html

Eplerenone (Inspra) for Hypertension Effectiveness: In patients with hypertension, eplerenone (50 to 200 mg daily) will lower blood pressure an average of 6 to 24 mm Hg systolic and ...

4. bmccardiovascdisord.biomedcentral.com bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-024-04103-7

Comparative effectiveness and safety of eplerenone and ... Eplerenone showed a lower risk of all-cause mortality (HR = 0.78, 95%CI [0.64 to 0.94], P = 0.009) and cardiovascular mortality (HR = 0.54, 95% ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0167527314018117

Efficacy and safety of eplerenone in the management ... A total of 11 trials and 3566 patients were overall included. Compared to placebo, eplerenone significantly reduced either SBP [WMD − 8.07, 95% ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2016/021437s013lbl.pdf

INSPRA® (eplerenone) tablets, for oral use - accessdata.fda.gov 2.2 Hypertension​​ Higher dosages of INSPRA are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an ...

7. mayoclinic.org mayoclinic.org/drugs-supplements/eplerenone-oral-route/description/drg-20063677

Eplerenone (oral route) - Side effects & dosage If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease. You ...

8. webmd.com webmd.com/drugs/2/drug-64218/eplerenone-oral/details

Eplerenone (Inspra) - Uses, Side Effects, and More Eplerenone should not be taken if you have high potassium levels in your blood ... high blood pressure, heart failure, and certain kidney problems ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23810881/

Safety and efficacy of eplerenone in patients at high risk for ... Results: In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mmol/l but not of potassium >6.0 mmol/l, and of ...