Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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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.

Official Title
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Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction, SPIRRIT-HFPEF

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Spironolactone
* Other: Standard care


Participation Criteria
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Eligibility Criteria
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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: 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. 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. 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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Spironolactone treatment<br>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<br>* Treatment with Spironolactone tablets on top of standard care<br>|
| Placebo Comparator: Standard care alone<br>Patients in the control arm will get the standard care alone | Other: Standard care<br>* Standard care does not involve Spironolactone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate for total heart failure (HF) hospitalizations or cardiovascular (CV) death | Sweden: Information on Death from the Swedish Causes of death registry and information on hospitalization collected from Swedish Patient Registry US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to CV Death or first HF hospitalization | Sweden: Information on Death from the Swedish Causes of death registry US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start) | 
| Time to CV Death | Sweden: Information on Death from the Swedish Causes of death registry US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start) | 
| Incidence rate for total HF hospitalizations | Sweden: Information on Death from the Swedish Causes of death registry and information on hospitalization collected from Swedish Patient Registry. US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start) | 
| Time to HF hospitalizations | Sweden: Information on information on hospitalization collected from Swedish Patient Registry. US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start) | 
| Time to all-cause mortality | Sweden: Information on Death from the Swedish Causes of death registry. US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start | 
| Incidence rate for all-cause hospitalizations | Sweden: Information on information on hospitalization collected from Swedish Patient Registry. US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start) | 
| Time to all-cause hospitalizations | Sweden: Information on information on hospitalization collected from Swedish Patient Registry. US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start) | 
| Incidence rate for all-cause hospitalizations or all-cause mortality | Sweden: Information on Death from the Swedish Causes of death registry and information on hospitalization collected from Swedish Patient Registry. US: Collected in eCRF or via call center interview | Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start) |