Renin-Guided MRA Therapy for Primary Aldosteronism

(RETAME-PA Trial)

Recruiting at 1 trial location

Overseen By Remi Goupil, MD MSc

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal

Must be taking: Mineralocorticoid antagonists

Must not be taking: Potassium-sparing diuretics

Disqualifiers: Kidney problems, High potassium, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

58 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment method for Primary Aldosteronism (PA), a condition that causes high blood pressure due to excess aldosterone. The goal is to determine if adjusting medication based on renin levels is more effective than the usual method. Participants will be divided into two groups: one will have treatment adjusted using renin levels, while the other will not use renin measurements. The study seeks individuals recently diagnosed with PA who have not used certain blood pressure medications in the past three months. The trial aims to find the best way to use medication to control PA while minimizing side effects. As an unphased trial, it offers a unique opportunity to contribute to innovative research that could improve future treatment strategies for PA.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications, but you cannot have used mineralocorticoid receptor antagonists or potassium-sparing diuretics in the past 3 months. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that adjusting treatment based on renin levels, known as renin-guided therapy, could effectively manage Primary Aldosteronism (PA). This approach seeks to enhance treatment effectiveness while monitoring safety issues like potassium levels and kidney health.

One study found that patients with higher renin levels after treatment had a lower risk of heart problems, suggesting this method might be safe and effective. However, mineralocorticoid receptor antagonists (MRAs), the main treatment for PA, can cause side effects. These include high potassium levels, breast changes in men, changes in menstrual cycles in women, and reduced sex drive.

While research on renin-guided therapy continues, the standard use of MRAs for PA provides some confidence in their safety when properly monitored. This trial aims to make MRA treatment safer by determining the right dose for each person, potentially reducing side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about renin-guided MRA therapy for primary aldosteronism because it offers a personalized approach to treatment. Unlike standard treatments that adjust medication based solely on achieving normal potassium levels, this method uses renin measurements to fine-tune therapy, aiming for both renin unsuppression and normokalemia. By tailoring the therapy to individual renin levels, there's potential for more precise blood pressure control and reduced reliance on additional antihypertensive drugs. This approach could lead to more effective management of primary aldosteronism, improving outcomes for patients.

What evidence suggests that this trial's treatments could be effective for Primary Aldosteronism?

In this trial, participants in the renin-guided arm will receive therapy where researchers measure renin levels before each follow-up appointment and adjust MRA therapy to achieve renin unsuppression and normokalemia. Research has shown that renin-guided therapy can effectively treat Primary Aldosteronism (PA). In one study, 82% of patients reached normal renin levels, which is important because normal levels are linked to a lower risk of heart problems. This approach aims to block the hormone effectively while reducing side effects. Evidence suggests that this method could be a promising way to treat PA safely and effectively. Meanwhile, participants in the renin-blinded arm will not have renin levels measured during follow-up, and MRA therapy will be titrated to achieve normokalemia. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

Adults diagnosed with Primary Aldosteronism who need long-term treatment with mineralocorticoid receptor antagonists (MRA) can join. They must have low renin levels and not be pregnant, breastfeeding, or have used MRA recently. People with severe kidney issues, high potassium levels, or those unable to consent are excluded.

Inclusion Criteria

I have been diagnosed with pulmonary arterial hypertension.

Your blood test shows low levels of a hormone called renin before starting the treatment.

I am over 18 years old.

Exclusion Criteria

Your blood potassium level has been higher than 4.8 mmol/L in the past 3 months.

I have not used potassium-sparing diuretics or mineralocorticoid receptor antagonists in the last 3 months.

Stopping my current medications for a new treatment is considered unsafe for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MRA therapy, with adjustments based on renin levels for the renin-guided group, and without renin level checks for the renin-blinded group

12 months

Regular follow-up visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of renin levels, blood pressure, and side effects

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Renin measurements

Trial Overview

The trial is testing if adjusting the dose of MRA based on renin hormone levels is more effective than standard care in controlling aldosterone action. Participants will be randomly assigned to either a 'renin-guided' group or a 'standard care' group for comparison over 12 months.

How Is the Trial Designed?

Group I: Renin-guided arm Experimental Treatment 1 Intervention

Renin levels will be measured prior to each follow-up appointment and MRA therapy will be titrated to achieve renin unsuppression and normokalemia. Once this is achieved, any other class of antihypertensive drugs mais be used to achieve normal BP levels.

Group II: Renin-blinded arm Active Control 1 Intervention

No measurements of renin levels will be allowed during follow-up. MRA therapy will be titrated to achieve normokalemia. Once this is achieved, any other class of antihypertensive drugs mais be used to achieve normal BP levels.

Renin measurements is already approved in United States, European Union for the following indications:

Approved in United States as Aldactone for:

• High blood pressure
• Heart failure
• Liver disease
• Nephrotic syndrome
• Excessive aldosterone secretion
• Early puberty in boys
• Acne
• Excessive hair growth in women

Approved in European Union as Aldactone for:

• High blood pressure
• Heart failure
• Liver disease
• Nephrotic syndrome
• Excessive aldosterone secretion
• Early puberty in boys
• Acne
• Excessive hair growth in women

Who Is Running the Clinical Trial?

Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal

Lead Sponsor

Trials

17

Recruited

4,600+

Published Research Related to This Trial

This study will evaluate the effects of mineralocorticoid-receptor antagonists (MRA) and angiotensin receptor blockers (ARB) on the aldosterone/renin ratio (ARR) in 40 patients diagnosed with primary aldosteronism (PA), aiming to determine if these treatments can be safely continued during screening without compromising blood pressure control or causing hypokalemia.

By comparing plasma aldosterone and active renin concentrations before and after one month of treatment with MRA alone and then with the addition of ARB, the study seeks to clarify whether these medications can be used during ARR testing, potentially improving patient management in PA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of mineralocorticoid and AT-1 receptor antagonism on the aldosterone-renin ratio (ARR) in primary aldosteronism patients (EMIRA Study): rationale and design. Rossitto, G., Cesari, M., Ceolotto, G., et al.[2020]

AZD9977, a nonsteroidal selective mineralocorticoid receptor modulator, was found to be generally well-tolerated in a phase I study with 27 healthy male participants, showing a lower incidence of adverse events compared to placebo (22.2% vs. 66.7%).

The study indicated that AZD9977 does not significantly alter serum potassium levels or urinary electrolyte excretion, suggesting a reduced risk of hyperkalemia compared to conventional MR antagonists, which is crucial for its potential use in treating heart failure and chronic kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study. Whittaker, A., Kragh, ÅM., Hartleib-Geschwindner, J., et al.[2021]

In a study of 62 patients with suspected primary aldosteronism (PA) and 35 healthy volunteers, the aldosterone/direct renin concentration ratio (ADRR) showed a strong correlation with the aldosterone/plasma renin activity ratio (ARR), indicating that ADRR can be a reliable screening method for PA.

Both ARR and ADRR ratios of ≥ 100 demonstrated high specificity (99%) for diagnosing PA, while ratios of ≥ 30 also provided good sensitivity and specificity, suggesting that ADRR could be a practical alternative to ARR for evaluating patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The ratios of aldosterone / plasma renin activity (ARR) versus aldosterone / direct renin concentration (ADRR). Glinicki, P., Jeske, W., Bednarek-Papierska, L., et al.[2022]

In a study involving 110 patients with primary hyperparathyroidism, treatment with the mineralocorticoid receptor blocker eplerenone did not significantly change the aldosterone to renin ratio (ARR), suggesting that current guidelines recommending a 4-week withdrawal before measuring ARR may not be necessary for this condition.

However, in a small group of 4 patients with primary aldosteronism, eplerenone treatment significantly reduced the ARR, indicating that MR blocker treatment can affect ARR in patients with primary aldosteronism and highlighting the need for further research on its diagnostic utility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mineralocorticoid Receptor Blockers and Aldosterone to Renin Ratio: A Randomized Controlled Trial and Observational Data. Pilz, S., Trummer, C., Verheyen, N., et al.[2018]

In a study of 39 patients with low-renin hypertension or probable primary aldosteronism, empiric treatment with mineralocorticoid receptor antagonists (MRAs) targeting unsuppressed renin levels led to significant reductions in both systolic and diastolic blood pressure.

The treatment was safe, with no patients needing to stop due to adverse reactions, and it also resulted in a notable decrease in proteinuria among those with detectable levels, indicating potential benefits for kidney health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Using Renin Activity to Guide Mineralocorticoid Receptor Antagonist Therapy in Patients with Low Renin and Hypertension. Mansur, A., Vaidya, A., Turchin, A.[2023]

In a study of 450 hypertensive patients, the aldosterone-to-direct renin concentration ratio (ADRR) was found to be a reliable screening method for primary aldosteronism (PA), with an optimal cutoff value of 2.93 (ng/dL)/(mU/L) showing 80.33% sensitivity and 92.11% specificity.

The study also established that the traditional aldosterone-to-plasma renin activity ratio (ARR) remains effective, with a cutoff of 25.28 (ng/dL)/(ng/mL/h), achieving 76.92% sensitivity and 93.38% specificity, indicating that both methods are clinically useful for diagnosing PA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of Screening Primary Aldosteronism by Aldosterone-to-Direct Renin Concentration Ratio Derived from Chemiluminescent Immunoassay Measurement: Diagnostic Accuracy and Cutoff Value. Li, T., Ma, Y., Zhang, Y., et al.[2022]

In a pilot study of 10 patients with primary aldosteronism treated with eplerenone for 3 months, vascular endothelial function improved significantly, as indicated by an increase in the reactive hyperemia index (RHI) from 1.71 to 2.21.

The study suggests that plasma renin activity (PRA) could be a useful marker for adjusting the dose of mineralocorticoid receptor antagonists (MRA) like eplerenone, as it correlates with changes in vascular function during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eplerenone Improves Vascular Endothelial Function in Patients with Primary Aldosteronism: A Pilot Study. Kurozumi, A., Okada, Y., Tanaka, Y.[2021]

Primary aldosteronism (PA) is a significant cause of hypertension, affecting 5-10% of patients, and is associated with a cardiovascular risk profile that is double that of essential hypertension, highlighting the importance of screening for PA in all hypertensive patients.

Treatment options for PA include laparoscopic adrenalectomy for unilateral cases and low-dose mineralocorticoid receptor antagonists (MRAs) for bilateral cases, with new MRAs in development to improve efficacy and reduce side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary Aldosteronism: Present and Future. Funder, JW.[2019]

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist (MRA) approved in the US, has been shown to slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes without significantly lowering blood pressure, based on data from over 13,000 patients in the FIDELIO-DKD and FIGARO-DKD trials.

Nonsteroidal MRAs like finerenone and esaxerenone offer distinct advantages over traditional steroidal MRAs, such as fewer adverse effects, expanding treatment options for diabetic kidney disease (DKD) and potentially improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of nonsteroidal mineralocorticoid receptor antagonists in patients with diabetic kidney disease. Lerma, E., White, WB., Bakris, G.[2023]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10345469/

Evidence and Uncertainties Surrounding Renin-Guided ...

Using a highly pragmatic approach to MR antagonist dose titration, 82% of patients did achieve an unsuppressed renin. In terms of efficacy, this corresponded to ...

2.

clinicaltrials.gov

clinicaltrials.gov/show/NCT06108427

REnin-guided TherApy With MinEralocorticoid Receptor ...

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

3.

thelancet.com

thelancet.com/journals/landia/article/PIIS2213-8587(25)00263-3/abstract

Post-treatment renin status and cardiovascular, renal, and ...

For the primary meta-analysis, individuals with unsuppressed post-treatment renin had a significantly lower risk of cardiovascular events ...

4.

ahajournals.org

ahajournals.org/doi/10.1161/HYPERTENSIONAHA.124.23385

Update on Low-Renin Hypertension

This review provides an overview of our evolving understanding of the causes of low-renin hypertension, the expanding spectrums of pathophysiology, key ...

5.

ccjm.org

ccjm.org/content/88/4/221

Our evolving understanding of primary aldosteronism

As noted, the most widely accepted threshold for a positive screening test is an aldosterone-renin ratio of 30 ng/dL per ng/mL/hour or higher ...

6.

ahajournals.org

ahajournals.org/doi/10.1161/HYPERTENSIONAHA.124.22642

Clinical Management of Primary Aldosteronism: An Update

The aldosterone:renin ratio (ARR) is the most commonly used screening test. Low cutoffs, such as 20.6 ng/mIU, are used to boost its sensitivity ...

7.

nature.com

nature.com/articles/s41371-024-00931-4

rationale and study design | Journal of Human Hypertension

This randomized, single-blinded, titration-to-effect aims to investigate whether targeted treatment in low-renin hypertension with MRA is better compared to ...