Eplerenone for High Blood Pressure

Overseen By Gail K Adler, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Brigham and Women's Hospital

Must not be taking: MR antagonists, Amiloride

Disqualifiers: Uncontrolled diabetes, Renal disease, Hepatic disease, 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: 1

Duration: 9 months

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the medication eplerenone works compared to another treatment for people with high blood pressure and left ventricular hypertrophy (LVH), a thickening of the heart's wall. The goal is to determine if eplerenone can improve heart function and overall heart health. Participants will receive either eplerenone or a combination of chlorthalidone (a diuretic) and potassium to control their blood pressure. The study seeks individuals with a history of high blood pressure and an LVH diagnosis confirmed by an echocardiogram (a heart ultrasound). As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment benefits more patients.

Do I have to stop taking my current medications for this trial?

The trial does not specify if you need to stop taking your current medications, but you cannot have used MR antagonists or amiloride in the past year. You can participate if you have treated hypothyroidism or controlled diabetes with diet, exercise, or metformin.

What is the safety track record for these treatments?

Earlier studies have shown that eplerenone effectively lowers blood pressure in individuals with hypertension. It can reduce the systolic blood pressure by up to 24 points, a significant decrease. Research indicates it is generally well-tolerated, with no major safety concerns at recommended doses.

Similarly, chlorthalidone, another treatment for high blood pressure, maintains a good safety record. It effectively controls blood pressure throughout the day. Studies comparing chlorthalidone to similar medications have found it safe and effective for long-term use.

Both treatments have a strong safety record supported by research, allowing trial participants to feel confident about their safety while contributing to important medical research. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Eplerenone is unique because it targets high blood pressure through a mechanism different from many standard treatments like ACE inhibitors, diuretics, and calcium channel blockers. It works as a mineralocorticoid receptor antagonist, which helps reduce blood pressure by blocking the effects of aldosterone, a hormone that can increase blood pressure. Researchers are excited about eplerenone because it may offer a more targeted approach with potentially fewer side effects, especially for those who don’t respond well to traditional treatments. Additionally, by specifically addressing aldosterone's role, eplerenone could provide improved blood pressure control and cardiovascular benefits.

What evidence suggests that this trial's treatments could be effective for high blood pressure?

In this trial, participants will receive either eplerenone or chlorthalidone as part of their treatment regimen. Research has shown that eplerenone effectively lowers blood pressure, with studies finding that doses of 50 to 200 mg daily can reduce systolic pressure by about 9 to 24 points and diastolic pressure by about 4 points. Additionally, eplerenone may reduce the risk of death from any cause, particularly from heart-related issues. Chlorthalidone, known for its long-lasting effect, provides steady blood pressure control throughout the day. It has been found to lower blood pressure more effectively than some other similar medications. Both treatments have strong evidence supporting their effectiveness in managing high blood pressure. ^{1 2 6 7 8}

Who Is on the Research Team?

Gail K Adler, MD, PhD

Principal Investigator

Brigham and Women's Hospital

Are You a Good Fit for This Trial?

This trial is for men and women with high blood pressure and left ventricular hypertrophy (LVH), which means their heart's pumping chamber has thickened walls. Participants should have a history of hypertension but not severe illnesses like uncontrolled diabetes, serious heart failure, or recent major cardiovascular events. They must be between 18 to 70 years old and cannot be on certain medications like MR antagonists recently.

Inclusion Criteria

I have a history of high blood pressure.

My heart's muscle mass is above the normal range.

My heart's left ventricle mass index is over 110 g/m2.

Exclusion Criteria

I have had high blood pressure caused by another condition.

Your blood tests show abnormal levels of electrolytes, liver enzymes, or thyroid hormone.

I experience significant drops in blood pressure when standing up.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Treatment Assessment

Participants are transitioned to enalapril and weaned off other anti-hypertensives

2 weeks

1 visit (in-person)

Treatment

Participants receive randomized treatment with eplerenone or chlorthalidone + potassium, with dose adjustments and potential addition of amlodipine

9 months

Regular visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Chlorthalidone
• Eplerenone

Trial Overview The study tests if Eplerenone (a drug blocking certain hormone receptors) is better than Chlorthalidone (a diuretic) at improving heart vessel function and efficiency in people with LVH due to high blood pressure. It's a randomized controlled trial where participants are assigned by chance to one of the treatments.

How Is the Trial Designed?

Group I: Eplerenone Active Control 1 Intervention

Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 50 mg eplerenone . At 2 weeks, eplerenone will be increased to 100 mg. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of \<135/85 mmHg.

Group II: Chlorthalidone + potassium Active Control 2 Interventions

Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of \<135/85 mmHg.

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, 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]

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 aldosterone blocker, significantly improves mortality and morbidity in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction, as demonstrated in the EPHESUS trial with a well-defined patient population.

While eplerenone is generally well tolerated, it does have a higher incidence of hyperkalaemia compared to placebo, but it also results in significantly lower rates of hypokalaemia, making it a valuable addition to standard therapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eplerenone : a review of its use in left ventricular systolic dysfunction and heart failure after acute myocardial infarction. Keating, GM., Plosker, GL.[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]

In a study involving 3,166 patients with essential hypertension, eplerenone (Selara) demonstrated a significant reduction in blood pressure over 12 weeks, with systolic pressure decreasing from 152.1 mmHg to 134.8 mmHg and diastolic pressure from 85.8 mmHg to 77.7 mmHg.

The safety profile of eplerenone was favorable, with a low incidence of adverse drug reactions at 2.4%, primarily including hyperkalemia (0.6%) and dizziness, indicating it is a safe option for hypertension treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Antihypertensive Effect of Selara® (Eplerenone): Results from a Postmarketing Surveillance in Japan. Takahashi, S., Hiramatsu, M., Hotta, S., 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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2212270

Chlorthalidone vs. Hydrochlorothiazide for Hypertension– ... Evidence suggests that chlorthalidone has a longer duration of action, with improved 24-hour blood-pressure control18,19 and other pleotropic ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11831197/

Comparison of Cardiovascular Outcomes Between ... For secondary outcomes, cardiovascular mortality was 0.2% in both groups (p = 0.92). Myocardial infarction occurred in 0.3% of CLTD users and ...

3. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2818672

Chlorthalidone vs Hydrochlorothiazide for Hypertension ... Chlorthalidone has a longer half-life and has been shown to be more effective in reducing 24-hour BP compared with HCTZ. Chlorthalidone also has ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10220471/

Comparison of the Effectiveness and Safety of Chlorthalidone ... Our analysis showed that chlorthalidone was superior to hydrochlorothiazide in controlling both SBP and DBP, with no significant heterogeneity reported.

5. jacc.org jacc.org/doi/10.1016/j.jacc.2015.10.083

Efficacy of Low-Dose Chlorthalidone and ... This study compared chlorthalidone, 6.25 mg daily, with HCTZ, 12.5 mg daily, by 24-h ambulatory blood pressure (ABP) monitoring and evaluated efficacy.

6. jamanetwork.com jamanetwork.com/journals/jamainternalmedicine/fullarticle/2760777

Comparison of Cardiovascular and Safety Outcomes ... Ernst et al found better chlorthalidone nighttime blood pressure control at a 1:2 dose ratio, which could explain some increased safety signals.

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK553174/

Chlorthalidone - StatPearls - NCBI Bookshelf - NIH Chlorthalidone is a thiazide-like diuretic used to treat hypertension. This activity discusses chlorthalidone's indications and contraindications.

8. mayoclinic.org mayoclinic.org/drugs-supplements/chlorthalidone-oral-route/description/drg-20071817

Chlorthalidone (oral route) - Side effects & dosage High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled.