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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Spironolactone; Other: Standard care

• Study Type: Interventional
• Enrollment (Estimated): 2000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anna Gustavsson (SWE); Phone Number: +46186110181; Email: anna.gustavsson@ucr.uu.se
• Study Contact Backup: Name: Will Simmons (US); Phone Number: 919-668-0541; Email: will.simmons@duke.edu

Study Locations

• Sweden
  • Angered, Sweden
    • Terminated
    • Angereds närsjukhus
  • Falun, Sweden
    • Recruiting
    • Falu Lasarett
    • Contact: Fahed Sulaiman
  • Finspång, Sweden
    • Terminated
    • Närsjukvården i Finspång
  • Flen, Sweden
    • Recruiting
    • Vårdcentralen Centrum i Flen
    • Contact: Kaj Possler
  • Göteborg, Sweden
    • Recruiting
    • Sahlgrenska Universitetssjukhuset
    • Contact: Charlotta Ljungman
  • Göteborg, Sweden
    • Recruiting
    • Sahgrenska University Hospital Östra
    • Contact: Mikael Fu
    • Principal Investigator: Mikael Fu
  • Hemse, Sweden
    • Recruiting
    • Hemse Vårdcentral
    • Contact: Ann Hovland-Tånneryd
  • Huddinge, Sweden
    • Recruiting
    • Karolinska University Hospital
    • Contact: Lars H Lund
    • Principal Investigator: Lars H Lund
  • Jönköping, Sweden, 55185
    • Recruiting
    • Länssjukhuset Ryhov
    • Contact: Patric Karlström
  • Karlskrona, Sweden, 37185
    • Active, not recruiting
    • Blekingesjukhuset
  • Karlstad, Sweden, 65230
    • Recruiting
    • Hjärtmottagningen, Centralsjukhuset
    • Contact: Edit Floderer
  • Kristianstad, Sweden
    • Terminated
    • Centralsjukhuset Kristianstad
  • Köping, Sweden
    • Recruiting
    • Västmanlands sjukhus Köping
    • Contact: Jalal Amin
    • Principal Investigator: Jalal Amin
  • Landskrona, Sweden
    • Recruiting
    • Lasarettet i Landskrona
    • Contact: Fredrik Kymle
  • Lidköping, Sweden
    • Recruiting
    • Skaraborgs sjukhus i Lidköping
    • Contact: Magnus Peterson
  • Linköping, Sweden, 58185
    • Recruiting
    • Linköpings Universitetssjukhus
    • Contact: Henriette van der Wal
  • Lund, Sweden, 22185
    • Terminated
    • VO Akut- och internmedicin, Skånes Universitetssjukhus
  • Lund, Sweden
    • Recruiting
    • Capio Citykliniken
    • Contact: Carl-Johan Lindholm
  • Lund, Sweden
    • Recruiting
    • FO Kranskärl/Svikt, Skånes Universitetssjukhus
    • Contact: Grunde Gjesdal
  • Malmö, Sweden, 20502
    • Terminated
    • Hjärtavdelningen, Skånes Universitetssjukhus
  • Malmö, Sweden
    • Recruiting
    • Kliniska forskningsenheten Skånes Universitetssjukhus
    • Principal Investigator: Patrik Svenson
  • Mariefred, Sweden
    • Recruiting
    • Mariefreds Vårdcentral
    • Contact: Tobias Reitberger
    • Principal Investigator: Tobias Reitberger
  • Mölndal, Sweden
    • Recruiting
    • Sahlgrenska University Hospital Mölndal
    • Contact: Pär Parén
    • Principal Investigator: Pär Parén
  • Norrköping, Sweden, 60182
    • Recruiting
    • Kardiologikliniken, Vrinnevisjukhuset
    • Contact: Dimitros Ftakas
  • Oskarshamn, Sweden
    • Active, not recruiting
    • Oskarshamns sjukhus
  • Skellefteå, Sweden
    • Recruiting
    • Skellefteå lasarett
    • Contact: Lars Gustafsson
  • Solna, Sweden
    • Recruiting
    • Karolinska University Hospital
    • Contact: Lars H Lund
    • Principal Investigator: Lars H Lund
  • Stockholm, Sweden, 11883
    • Recruiting
    • VO Kardiologi, Södersjukhuset AB
    • Contact: Carin Corovic Cabrera
  • Stockholm, Sweden
    • Recruiting
    • Capio S:t Görans sjukhus AB
    • Contact: Ulrika Löfström
    • Principal Investigator: Ulrika Löfström
  • Stockholm, Sweden
    • Recruiting
    • Danderyds sjukhus AB
    • Contact: Hans Persson
  • Sundsvall, Sweden
    • Recruiting
    • Länssjukhuset Sundsvall-Härnösand
    • Contact: Mohammad Kavianipour
  • Sundsvall, Sweden
    • Terminated
    • Sundsvalls Vårdcentral
  • Södertälje, Sweden
    • Terminated
    • Södertälje sjukhus
  • Uppsala, Sweden
    • Recruiting
    • Uppsala University Hospital, Cardiology dept
    • Contact: Christina Christersson, MD, Phd
    • Principal Investigator: Christina Christersson, MD, PhD
  • Uppsala, Sweden
    • Recruiting
    • Uppsala University Hospital, Internal Medicine dept
    • Contact: Michael Dimberg
  • Varberg, Sweden, 43281
    • Recruiting
    • Medicinkliniken, Hallands sjukhus
    • Contact: Petru Tutuainu
  • Västervik, Sweden
    • Active, not recruiting
    • Västerviks sjukhus
  • Västerås, Sweden
    • Recruiting
    • Västmanlands sjukhus Västerås
    • Contact: Ingmar Lönnberg
    • Principal Investigator: Ingmar Lönnberg
  • Ängelholm, Sweden
    • Terminated
    • Hälsostaden Ängelholms sjukhus
  • Örebro, Sweden
    • Recruiting
    • Orebro University Hospital
    • Contact: Barna Szabó
    • Principal Investigator: Barna Szabó
• United States
  • Alabama
    • Alexander City, Alabama, United States, 35010
      • Terminated
      • Advanced Cardiovascular LLC
    • Birmingham, Alabama, United States, 35294
      • Terminated
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Terminated
      • Banner - University Medical Group
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Terminated
      • MedStar Cardiovascular Research Network
    • Washington, District of Columbia, United States, 20060
      • Terminated
      • Howard University Hospital
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Terminated
      • Holy Cross Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Terminated
      • Piedmont Atlanta Hospital
    • Marietta, Georgia, United States, 30060
      • Terminated
      • Wellstar Health System, Inc.
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Terminated
      • Queens Medical Center
  • Illinois
    • Aurora, Illinois, United States, 60506-1400
      • Terminated
      • Fox Valley Clinical Research Center, LLC
    • Chicago, Illinois, United States, 60612
      • Terminated
      • University of Illinois at Chicago
    • Elk Grove Village, Illinois, United States, 60007
      • Terminated
      • Alexian Brothers Medical Center
    • Peoria, Illinois, United States, 61636
      • Terminated
      • Methodist Medical Center of Illinois
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Terminated
      • St. Vincent Medical Group
  • Louisiana
    • New Orleans, Louisiana, United States, 85724
      • Terminated
      • Ochsner Medical Center
  • Maryland
    • Rockville, Maryland, United States, 20850
      • Terminated
      • Shady Grove Adventist Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Terminated
      • Brigham and Women's Hospital
    • Haverhill, Massachusetts, United States, 01830
      • Terminated
      • Pentucket Medical Associates
    • Natick, Massachusetts, United States, 01760
      • Terminated
      • Charles River Medical Associates
    • Newton, Massachusetts, United States, 02462
      • Terminated
      • Newton-Wellesley Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Terminated
      • University of Michigan Medical Center
    • Grand Blanc, Michigan, United States, 48439
      • Terminated
      • Ascension Genesys Hospital
  • New Jersey
    • Haddon Heights, New Jersey, United States, 08035
      • Terminated
      • The Heart House Haddon Heights
    • New Brunswick, New Jersey, United States, 08901
      • Terminated
      • Rutgers University - Robert Wood Johnson Medical School
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • Terminated
      • University of New Mexico Health Science Center
  • New York
    • Buffalo, New York, United States, 14203
      • Terminated
      • University at Buffalo
    • Manhasset, New York, United States, 11030
      • Terminated
      • Northwell Health - Manhasset
    • New York, New York, United States, 10029
      • Terminated
      • Mount Sinai Medical Cente
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Terminated
      • Mid Carolina Cardiology Research
    • Durham, North Carolina, United States, 27710-4000
      • Terminated
      • Duke University
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0542
      • Terminated
      • University of Cincinnati Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Terminated
      • Penn State Milton S Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Terminated
      • Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • Terminated
      • University of Pittsburgh Medical Center
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Terminated
      • Stern Cardiovascular Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Terminated
      • Baylor University Medical Center
    • Miami, Texas, United States, 33136
      • Terminated
      • University of Miami Hospital
    • San Antonio, Texas, United States, 78229
      • Terminated
      • University of Texas Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years to 97 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Uppsala University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Duke Clinical Research Institute; Karolinska University
• Investigators: Principal Investigator: Lars H Lund, MD, PhD, Karolinska Institutet; Principal Investigator: Bertram Pitt, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2017
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 9, 2016
• First Submitted That Met QC Criteria: September 14, 2016
• First Posted (Estimated): September 15, 2016

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: U-2015-030; U01HL134679-01 (U.S. NIH Grant/Contract); U01HL134694-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No