Effect of Eplerenone on Novel Biomarkers of Mineralocorticoid Receptor Activation (ENOVA) (ENOVA)

This blinded cross-over clinical trial will enroll participants with mild stage 1 hypertension to evaluate whether urinary extracellular transcript abundance predicts response to an mineralocorticoid receptor (MR) antagonist, eplerenone.

Eligible participants will have a 2 week wash-in period followed by 4 weeks of treatment with placebo or eplerenone. There will be a 2 week wash out period from study medications and then participants will take the other drug (placebo or eplerenone) for 4 weeks. In addition, participants will also provide urine and blood samples during the trial, have physical assessments, and be monitored for safety.

Study Overview

• Status: Withdrawn
• Conditions: Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Eplerenone 50mg

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• History of mild stage 1 systemic hypertension as defined by:

  1. Systolic blood pressure (SBP) ≥ 140 millimeters of Mercury (mmHg) or diastolic blood pressure (DBP) ≥ 90 mmHg on 2 occasions and

  2. Treatment with 1-2 antihypertensive medications (stable dose for 6 weeks)

     Exclusion Criteria:

• Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
• Stage 2 hypertension (history of blood pressure ≥ 160/100 mmHg)
• History of hypertensive urgency, hypertensive crisis, or hospitalizations for hypertension
• Current mineralocorticoid antagonist use
• Type II Diabetes with microalbuminuria
• Primary adrenal insufficiency
• Current glucocorticoid use
• Electrolyte abnormality on baseline laboratory assessment
• Current potassium supplementation
• Positive test for leukocyte esterase on urinalysis
• Creatinine clearance < 50 mL/min on baseline laboratory assessment
• Hyperkalemia
• Potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene)
• Serum potassium >5.0 milliequivalents per liter (mEq/L) on baseline laboratory assessment
• Current use of strong CYP3A4 inhibitors (some include: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir).
• Serum creatinine > 1.5 mg/dL in males on baseline laboratory assessment
• Serum creatinine > 1.3 mg/dL in females
• Current beta blocker use
• Any other condition thought by the Principal Investigator to place the participant at increased risk of injury during the clinical trial or compromise the scientific integrity of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants will be randomized to receive 4 weeks of placebo and then 4 weeks of Eplerenone.	Drug: Placebo; Participants will go through a 2-week wash-in period. During the wash-in period, the participant will be asked not to take their usual antihypertensive medications for their mild hypertension. After the 2-week wash-in period, the participants will begin a 4-week treatment period and will take a placebo once a day for 4 weeks. After the 4 weeks, the participants will have a 2-week wash-out period where they will be off the study treatment. After the 2-week wash-out period, the participants will begin the Eplerenone treatment for another 4 weeks.
Experimental: Eplerenone; Participants will be randomized to receive 4 weeks of Eplerenone and then 4 weeks of Placebo.	Drug: Eplerenone 50mg; Participants will go through a 2-week wash-in period. During the wash-in period, the participant will be asked not to take their usual antihypertensive medications for their mild hypertension. After the 2-week wash-in period, the participants will begin a 4-week treatment period of Eplerenone for 4 weeks. After the 4 weeks, the participants will have a 2-week wash-out period where they will be off the study treatment. After the 2-week wash-out period, the participants will then begin the Placebo treatment for another 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) Cycle threshold (Ct) value of mineralocorticoid receptor-regulated gene messenger ribonucleic acid (mRNA)	Cycle threshold of urinary mRNA biomarker following treatment with placebo and following treatment with eplerenone will be measured using RT-qPCR.	Week 6 (after first study treatment)
RT-qPCR Ct value of mineralocorticoid receptor-regulated gene mRNA	Cycle threshold of urinary mRNA biomarker following treatment with placebo and following treatment with eplerenone will be measured using RT-qPCR.	Week 12 (after second study treatment)

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: J Brian Byrd, MD, MS, University of Michigan

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2023
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: January 12, 2021
• First Submitted That Met QC Criteria: February 5, 2021
• First Posted (Actual): February 9, 2021

Study Record Updates

• Last Update Posted (Estimate): February 20, 2023
• Last Update Submitted That Met QC Criteria: February 16, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: blood pressure; aldosterone; eplerenone; mineralocorticoid; mineralocorticoid receptor
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Eplerenone
• Other Study ID Numbers: HUM00170418; 1K23HL128909-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

We will de-identify participant information and will share it with a trusted repository, such as National Institutes of Health (NIH) Figshare or The Inter-university Consortium for Political and Social Research (ICPSR).

We will de-identify and share data obtained from analyzing urinary mRNA biomarkers and measuring the systolic and diastolic blood pressure following consumption of a high-sodium and low-sodium diet. Additionally, specific lab values that support the validity and quality of the study treatment will be shared in a trusted repository.

• IPD Sharing Time Frame: De-identified data will be deposited into a repository within 1 year of the conclusion of the study.
• IPD Sharing Access Criteria: No additional access restrictions will be placed on the de-identified data, beyond those required by the repository to access or download the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No