Unmitigated Aldosterone Signaling During Standard Clinical MRA Dosing

The purpose of this research study is to understand the biology related to the potential shortcomings of existing anti-aldosterone therapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Placebo; Drug: Spironolactone 25mg; Drug: Aldosterone

Detailed Description

This is a randomized, double blind, double dummy, placebo-controlled, crossover study where aldosterone will be infused intravenously (IV) with and without guideline recommended low dose oral mineralocorticoid receptor antagonists therapy. Participants will receive, in a randomized order, 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone. Each crossover period will be separated by 2 weeks to allow for steady state blood level of spironolactone and metabolites to be reached (or complete washout from prior spironolactone). The broad study design will be designed around evaluation of change in urine sodium to potassium ratio, sodium output following a sodium chloride challenge, and collecting the necessary biospecimens to test our hypotheses.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Chronic stable heart failure at optimal volume status. Inclusion will require participants to be NYHA class I or II.
2. eGFR > 30 ml/min/1.73m2
3. Serum potassium ≤5.0 meq/L and ≥3.5 meq/L
4. Stable heart failure medications without need or expectation for changes during the 8-week study period
5. Free from heart failure decompensation for the preceding 60 day
6. Systolic blood pressure >90 mmHg if not taking an MRA at screening. If patients are already taking an MRA at the time of screening a systolic blood pressure needs to be >80 mmHg.

Exclusion Criteria:

1. Uncontrolled hypertension (SBP > 160 mmHg)
2. Severe bladder dysfunction
3. Current MRA dose > 50mg spironolactone or equivalent or non MRA potassium sparing diuretic such as amiloride
4. Contraindication to initiation or withdrawal of spironolactone per study procedures
5. History of severe hyperkalemia (K>6.0 meq/l)
6. Brittle volume sensitive heart failure, recurrent flash pulmonary edema, restrictive cardiomyopathy or other pathology that would make aldosterone infusion high risk
7. Pregnant or breastfeeding

8. Women of childbearing potential that are not receiving a highly effective form of contraception. Females of childbearing potential must agree to use a highly effective method of birth control until 14 days after the last dose of study drug. The following are highly effective methods for this study:

   • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
   • Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable
   • Intrauterine device (IUD)
   • Intrauterine hormone-releasing system (IUS)
   • Bilateral tubal occlusion
   • Vasectomized partner
   • Sexual abstinence

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo/placebo; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.	Drug: Placebo; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.
Active Comparator: Placebo/Sprironolactone; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.	Drug: Placebo; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.; Drug: Spironolactone 25mg; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.
Active Comparator: placebo/aldosterone; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.	Drug: Placebo; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.; Drug: Aldosterone; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.
Active Comparator: aldosterone/spironolactone; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.	Drug: Spironolactone 25mg; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.; Drug: Aldosterone; This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations 1) IV Vehicle infusion plus oral placebo pill 2) IV Vehicle infusion plus oral 25mg spironolactone 3) IV Aldosterone infusion plus oral placebo pill 4) IV Aldosterone infusion plus oral 25 mg spironolactone on Day 14, 29, 44, 59.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in urine sodium to potassium ratio	Change in sodium to potassium ratio between aldosterone vs vehicle infusion during the spironolactone vs. placebo arms.	59 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine Sodium output following saline load	Effect of MRA and aldosterone infusion on natriuresis following a saline load	59 days
Natriuretic effect of adjuvant to loop diuretic therapy	Effect of MRA and aldosterone infusion on natriuresis following IV bumetanide challenge	59 days

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Jeffrey Testani, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: December 3, 2025
• First Submitted That Met QC Criteria: December 3, 2025
• First Posted (Actual): December 15, 2025

Study Record Updates

• Last Update Posted (Actual): August 26, 2026
• Last Update Submitted That Met QC Criteria: August 24, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Spironolactone; Aldosterone
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Organic Chemicals; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Lactones; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Spironolactone; Aldosterone
• Other Study ID Numbers: 2000040063

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No