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Purpose

Heart failure with preserved ejection fraction (HFPEF) is common and deadly but without therapy. Inconclusive studies such as TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) suggest spironolactone may be effective in HFPEF, but it is generic and will not be studied by industry. SPIRRIT is a unique Registry-Randomized Clinical Trial (RRCT) that will test the hypothesis that spironolactone plus standard of care compared to standard of care alone reduces the composite of CV mortality and HF hospitalization as follows: Population: HFPEF patients in the Swedish Heart Failure Registry and HFPEF patients in US. HFPEF defined as symptoms/signs of HF, elevated NTproBNP (B-type Natriuretic Peptide; N-terminal pro b-type Natriuretic Peptide) and EF>=40%. Intervention and control: Randomized 1:1 to intervention: spironolactone + usual care vs. control: usual care alone. Outcome: Primary outcome cardiovascular death or time to HF hospitalization. Secondary outcomes include hospitalization for various causes, adverse events and treatment adherence. In Sweden outcomes are obtained automatically by linking with the Population, Patient and Drug Dispensed Registries. In the US, outcomes will be reported by sites and supplemented by data from a call center. The trial is event-driven with enrollment 7 years and study duration 9 years. For the primary outcome (CV Death or first HF hospitalization) with an event target of 721 events the sample size requires 1985 patients conservatively rounded to approximately 2000 patients.

Condition

Eligibility

Eligible Ages
Between 50 Years and 99 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Written informed consent - Age ≥50 years - Stable heart failure defined by symptoms and signs of heart failure as judged by local Investigator - Left ventricular ejection fraction (LVEF) ≥40% recorded in last 12 months (stratified to max 2/3rd in either 40-49% or ≥50% group) - Elevated natriuretic peptide levels, as defined by any of the following: 1. most recent NT-proBNP >300 ng/L (or BNP>100 pg/mL) in sinus rhythm at time of blood sampling; adjustments may be made for BMI according to table 3. 2. most recent NT-proBNP >750 ng/L (or BNP >250 pg/mL) in atrial fibrillation at time of blood sampling; adjustments may be made for BMI according to table 3. 3. NT-proBNP >1200 ng/L (or BNP >400 pg/mL) within the last 12 months even if most recent value is lower. - Regular use of loop diuretics, defined as daily or most days of the week - NYHA Class II-IV

Exclusion Criteria

Previously enrolled in this study - Known Ejection Fraction < 40% ever - Current absolute indication or contraindication for MRA (mineral receptor antagonist) in judgement of Investigator - Known chronic liver disease - Probable alternative explanations for symptoms: - Known primary cardiomyopathy (hypertrophic, constrictive, restrictive, infiltrative, congenital) - Primary hemodynamically significant valve disease - Right-sided HF not due to left-sided HF - Significant chronic pulmonary disease defined by Investigator or by requirement for home O2 - Symptomatic anemia, defined as Hemoglobin < 10 g/dL (100 g/L ) - Heart transplant or LVAD (left ventricular assist device) recipient - Presence of cardiac resynchronization therapy (CRT) device - Systolic blood pressure <90 or >160 mmHg - K (potassium) >5.0 mmol/L - eGFR (estimated glomerular filtration rate) by MDRD (Modification of Diet in Renal Disease) < 30 ml/min/1.73m2 or creatinine > 2.5 mg/dL (221 µmol/L ) - Current lithium use - Current dialysis - Actual or potential for pregnancy - Participation in another interventional clinical trial where a mineralocorticoid receptor antagonist is studied - Any condition that in the opinion of the Investigator may interfere with adherence to trial protocol

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Spironolactone treatment 		Spironolactone will be prescribed by the Investigator and filled by patient at conventional pharmacies as 25 mg tablets. The treatment will be on top of standard care. Initial dose is 25 mg/day, which will be increased to target dose 50 mg/day if tolerated. Eplerenone can be prescribed if spironolactone is not tolerated.
  • Drug: Spironolactone
    Treatment with Spironolactone tablets on top of standard care
Placebo Comparator
Standard care alone 		Patients in the control arm will get the standard care alone
  • Other: Standard care
    Standard care does not involve Spironolactone

More Details

Status
Recruiting
Sponsor
Uppsala University

Study Contact

Anna Gustavsson (SWE)
+46186110181
anna.gustavsson@ucr.uu.se

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.