Clinical trial NCT02901184: Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction
Official title: Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction, SPIRRIT-HFPEF
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Heart Failure With Preserved Ejection Fraction
Lead sponsor: Uppsala University
Sponsor class: OTHER
Collaborators: name: Karolinska University
name: Duke Clinical Research Institute
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2016-09-15
Enrollment: 2000
Sex: ALL
Minimum age (years): 50
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Incidence rate for total heart failure (HF) hospitalizations or cardiovascular (CV) death
timeFrame: Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start)
Secondary outcomes:
measure: Time to CV Death or first HF hospitalization
timeFrame: Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start)
measure: Time to CV Death
timeFrame: Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start)
measure: Incidence rate for total HF hospitalizations
timeFrame: Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start)
measure: Time to HF hospitalizations
timeFrame: Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start)
measure: Time to all-cause mortality
timeFrame: Collected at data base lock, five (5) years after study start
measure: Incidence rate for all-cause hospitalizations
timeFrame: Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start)
measure: Time to all-cause hospitalizations
timeFrame: Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start)
measure: Incidence rate for all-cause hospitalizations or all-cause mortality
timeFrame: Collected at data base lock, five (5) years after study start (US: continuously until 5 years after study start)
Other outcomes:
Locations:
city: Alexander City
country: United States
facility: Advanced Cardiovascular LLC
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tucson
country: United States
facility: Banner - University Medical Group
state: Arizona
city: Washington
country: United States
facility: MedStar Cardiovascular Research Network
state: District of Columbia
city: Washington
country: United States
facility: Howard University Hospital
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Atlanta
country: United States
facility: Piedmont Atlanta Hospital
state: Georgia
city: Marietta
country: United States
facility: Wellstar Health System, Inc.
state: Georgia
city: Honolulu
country: United States
facility: Queens Medical Center
state: Hawaii
city: Aurora
country: United States
facility: Fox Valley Clinical Research Center, LLC
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Elk Grove Village
country: United States
facility: Alexian Brothers Medical Center
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Center of Illinois
state: Illinois
city: Indianapolis
country: United States
facility: St. Vincent Medical Group
state: Indiana
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Rockville
country: United States
facility: Shady Grove Adventist Hospital
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Haverhill
country: United States
facility: Pentucket Medical Associates
state: Massachusetts
city: Natick
country: United States
facility: Charles River Medical Associates
state: Massachusetts
city: Newton
country: United States
facility: Newton-Wellesley Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Grand Blanc
country: United States
facility: Ascension Genesys Hospital
state: Michigan
city: Haddon Heights
country: United States
facility: The Heart House Haddon Heights
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers University - Robert Wood Johnson Medical School
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Health Science Center
state: New Mexico
city: Buffalo
country: United States
facility: University at Buffalo
state: New York
city: Manhasset
country: United States
facility: Northwell Health - Manhasset
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Cente
state: New York
city: Charlotte
country: United States
facility: Mid Carolina Cardiology Research
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Germantown
country: United States
facility: Stern Cardiovascular Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Miami
country: United States
facility: University of Miami Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Angered
country: Sweden
facility: Angereds närsjukhus
city: Falun
country: Sweden
facility: Falu lasarett
city: Finspång
country: Sweden
facility: Närsjukvården i Finspång
city: Flen
country: Sweden
facility: Vårdcentralen Centrum i Flen
city: Göteborg
country: Sweden
facility: Sahgrenska University Hospital Östra
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Hemse
country: Sweden
facility: Hemse Vårdcentral
city: Huddinge
country: Sweden
facility: Karolinska University Hospital
city: Jönköping
country: Sweden
facility: Länssjukhuset Ryhov
city: Karlskrona
country: Sweden
facility: Blekingesjukhuset
city: Karlstad
country: Sweden
facility: Hjärtmottagningen, Centralsjukhuset
city: Kristianstad
country: Sweden
facility: Centralsjukhuset Kristianstad
city: Köping
country: Sweden
facility: Västmanlands sjukhus Köping
city: Landskrona
country: Sweden
facility: Lasarettet i Landskrona
city: Lidköping
country: Sweden
facility: Skaraborgs sjukhus i Lidköping
city: Linköping
country: Sweden
facility: Linköpings Universitetssjukhus
city: Lund
country: Sweden
facility: VO Akut- och internmedicin, Skånes Universitetssjukhus
city: Lund
country: Sweden
facility: Capio Citykliniken
city: Lund
country: Sweden
facility: FO Kranskärl/Svikt, Skånes Universitetssjukhus
city: Malmö
country: Sweden
facility: Hjärtavdelningen, Skånes Universitetssjukhus
city: Malmö
country: Sweden
facility: Kliniska forskningsenheten Skånes Universitetssjukhus
city: Mariefred
country: Sweden
facility: Mariefreds Vårdcentral
city: Mölndal
country: Sweden
facility: Sahlgrenska University Hospital Mölndal
city: Norrköping
country: Sweden
facility: Kardiologikliniken, Vrinnevisjukhuset
city: Oskarshamn
country: Sweden
facility: Oskarshamns sjukhus
city: Skellefteå
country: Sweden
facility: Skellefteå lasarett
city: Solna
country: Sweden
facility: Karolinska University Hospital
city: Stockholm
country: Sweden
facility: VO Kardiologi, Södersjukhuset AB
city: Stockholm
country: Sweden
facility: Capio S:t Görans sjukhus AB
city: Stockholm
country: Sweden
facility: Danderyds sjukhus AB
city: Sundsvall
country: Sweden
facility: Länssjukhuset Sundsvall-Härnösand
city: Sundsvall
country: Sweden
facility: Sundsvalls Vårdcentral
city: Södertälje
country: Sweden
facility: Södertälje sjukhus
city: Uppsala
country: Sweden
facility: Uppsala University Hospital, Cardiology dept
city: Uppsala
country: Sweden
facility: Uppsala University Hospital, Internal Medicine dept
city: Varberg
country: Sweden
facility: Medicinkliniken, Hallands sjukhus
city: Västervik
country: Sweden
facility: Västerviks sjukhus
city: Västerås
country: Sweden
facility: Västmanlands sjukhus Västerås
city: Ängelholm
country: Sweden
facility: Hälsostaden Ängelholms sjukhus
city: Örebro
country: Sweden
facility: Örebro University Hospital
Study officials:
affiliation: Karolinska Institutet
name: Lars H Lund, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Bertram Pitt
role: PRINCIPAL_INVESTIGATOR
References: