Unmitigated Aldosterone Signaling During Standard Clinical MRA Dosing

Yale University

Status and phase: Not yet enrolling; Phase 4

Conditions: Heart Failure

Treatments: Drug: Spironolactone 25mg; Drug: Aldosterone; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT07281014

2000040063

Details and patient eligibility

About

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

Full 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.

Enrollment: 20 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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20 participants in 4 patient groups, including a placebo group

Placebo/placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Placebo/Sprironolactone

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo

Drug: Spironolactone 25mg

placebo/aldosterone

Active Comparator group

Description:

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.

Treatment:

Drug: Aldosterone

Drug: Placebo

aldosterone/spironolactone

Active Comparator group

Description:

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.

Treatment:

Drug: Aldosterone

Drug: Spironolactone 25mg