Unmitigated Aldosterone Signaling During Standard Clinical MRA Dosing

Purpose

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

Condition

  • Heart Failure

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

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 Design

Phase
Phase 4
Study Type
Interventional
Allocation
Randomized
Intervention Model
Crossover Assignment
Primary Purpose
Basic Science
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
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.

Recruiting Locations

Yale University
New Haven 4839366, Connecticut 4831725 06510
Contact:
Veena Rao, PhD
203-785-7917
veena.s.rao@yale.edu

More Details

Status
Recruiting
Sponsor
Yale University

Study Contact

Veena Rao
2037857917
veena.s.rao@yale.edu

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.