Unmitigated Aldosterone Signaling During Standard Clinical MRA Dosing

Overview

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

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.

Interventions

• 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.
• 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.

Primary outcome measures

• change in urine sodium to potassium ratio [Time frame: 59 days]

Secondary outcome measures (2)

• Urine Sodium output following saline load [Time frame: 59 days]
• Natriuretic effect of adjuvant to loop diuretic therapy [Time frame: 59 days]

Eligibility criteria

Inclusion criteria

• Chronic stable heart failure at optimal volume status. Inclusion will require participants to be NYHA class I or II.
• eGFR > 30 ml/min/1.73m2
• Serum potassium ≤5.0 meq/L and ≥3.5 meq/L
• Stable heart failure medications without need or expectation for changes during the 8-week study period
• Free from heart failure decompensation for the preceding 60 day
• 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

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Basic science

Study locations

United States · 1 center

• Yale University — New Haven

Identifiers

NCT: NCT07281014 · 2000040063

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗