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

300 Participants Needed

Trial Summary

What is the purpose of this trial?

Lysine specific demethylase-1 (LSD1) is an epigenetic regulator of gene transcription involved in the pathophysiology of elevated blood pressure and likely renal damage in Blacks. This project investigates whether a genetically driven anti-hypertensive approach proves superior in controlling blood pressure and mitigating renal injury in Blacks who carry the risk allele for LSD1 (rs587168). The findings of these investigations may lead to a new approach in treating a subset (\~30%) of the essential hypertension population (Black LSD1 risk allele hypertensives).

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 data supports the effectiveness of the drug Eplerenone (Inspra) for high blood pressure?

Research shows that Eplerenone is effective in lowering blood pressure, especially when other medications like ACE inhibitors or ARBs are not enough. It works well alone or with other drugs, and is better tolerated than some alternatives, making it a good option for treating high blood pressure. ^{1 2 3 4 5}

Is eplerenone safe for treating high blood pressure?

Eplerenone, also known as Inspra, is generally well tolerated in humans, with the most common side effect being hyperkalemia (high potassium levels in the blood). It has a lower incidence of certain side effects compared to similar drugs, making it a safer option for some patients. ^{1 3 5 6 7}

How is the drug Eplerenone unique in treating high blood pressure?

Eplerenone is unique because it selectively blocks the mineralocorticoid receptor, reducing the effects of aldosterone, a hormone that can increase blood pressure. Unlike other similar drugs, it has fewer side effects related to hormones, making it a safer option for some patients. ^{1 2 3 8 9}

Research Team

Andrea Haas, MD

Principal Investigator

Brigham and Women's

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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, 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 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]

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, 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 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]

References

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

Mineralocorticoid receptor antagonists and hypertension: is there a rationale? [2019]

2. England pubmed.ncbi.nlm.nih.gov

Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy? [2018]

3. New Zealand pubmed.ncbi.nlm.nih.gov

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

4. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of mineralocorticoid receptors in mild to moderate arterial hypertension. [2018]

5. New Zealand 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. [2022]

6. United States 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). [2020]

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

Eplerenone: selective aldosterone antagonism in management of cardiovascular and renal disease. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone. [2019]

9. England pubmed.ncbi.nlm.nih.gov

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