Heart Failure
Conditions
Keywords
Spironolactone, Aldosterone
Brief summary
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
DRUGPlacebo
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.
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.
DRUGAldosterone
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.
Sponsors
Yale University
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| change in urine sodium to potassium ratio | 59 days | Change in sodium to potassium ratio between aldosterone vs vehicle infusion during the spironolactone vs. placebo arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urine Sodium output following saline load | 59 days | Effect of MRA and aldosterone infusion on natriuresis following a saline load |
| Natriuretic effect of adjuvant to loop diuretic therapy | 59 days | Effect of MRA and aldosterone infusion on natriuresis following IV bumetanide challenge |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJeffrey Testani, MD
Yale University
Outcome results
None listed