Clinical trial NCT04023227: Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC
Official title: A Multicenter, Prospective, Randomized, Open-label, Blinded-endpoint, Phase 4 Study to Evaluate the Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With Chronic Chagas' Cardiomyopathy. The Study is Also Know as Prevention And Reduction of Adverse Outcomes in Chagasic Heart failUre Trial Evaluation (PARACHUTE-HF).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chagas Disease
Heart Failure
Keywords: Chagas' disease
heart failure
angiotensin receptor-neprilysin inhibitor
ARNI
ARB
ACEI
sacubitril/valsartan
enalapril
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-07-17
Enrollment: 918
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a Phase 4, multinational, multicenter, parallel-group, prospective, randomized, open-label, blinded-endpoint adjudication, active-controlled study to demonstrate superiority of sacubitril/valsartan over enalapril in improving a composite of CV events (CV death or first HF hospitalization), or in causing greater reduction or lesser increase in NT-proBNP levels at Week 12 in participants with HFrEF caused by CCC.
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the effect of sacubitril/valsartan 200 mg BID compared with enalapril 10 mg BID, in addition to conventional heart failure (HF) treatment, in improving a hierarchical composite of cardiovascular (CV) events (i.e. CV death or the occurrence of first HF hospitalization) and causing a greater reduction in n terminal prohormone of brain natriuretic peptide (NT-proBNP, at Week 12 from Baseline) in participants with HF with reduced ejection fraction (HFrEF) caused by CCC.


Eligibility criteria: Key Inclusion Criteria:

* Male or female ≥ 18 years of age
* Diagnosis of NYHA Class II-IV HFrEF established by:

  1. LVEF ≤ 40% within 12 months prior to Visit 1 made by any local measurement using echocardiography, multiple gated acquisition scan (MUGA), computerized tomography (CT) scanning, magnetic resonance imaging (MRI), or ventricular angiography, provided no subsequent measurement above 40% AND
  2. NT-proBNP ≥ 600 pg/mL (or BNP ≥ 150 pg/mL) at Visit 1 OR
  3. NT-proBNP ≥ 400 pg/mL (or BNP ≥ 100 pg/mL) at Visit 1 and a hospitalization for HF within the last 12 months
* Chagas' disease diagnosis confirmed by at least two different serological tests for anti-Trypanosoma cruzi based on different principles or with different antigenic preparations, such as: enzyme-linked immunosorbent assay \[ELISA\], indirect immunofluorescence \[IFI\], indirect hemagglutination \[IHA\], western blot (WB), chemiluminescent immunoassay (CLIA). If documented history is not available, the tests may be performed during the screening

Key Exclusion Criteria:

* Patients with history of suspected or proven angioedema or unable to tolerate ACEIs, ARBs or ARNI (e.g., due to cough, hypotension, renal dysfunction, hyperkalemia)
* Use of sacubitril/valsartan in the past 3 months
* Patients requiring continuous intravenous inotropic therapy or with indication of advanced support intervention for HF:

  1. already on list for a heart transplantation
  2. with current indication of left ventricular assist device, or cardiac resynchronization therapy (CRT)
* Systemic systolic blood pressure lower than 95 mmHg or symptomatic hypotension
* Serum potassium \> 5.2 mmol/L
* Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 of body surface area
* Severe gastrointestinal form of chronic Chagas' disease (demonstrated megaesophagus and/or important megacolon, e.g.: with compromised oral intake or surgical indication).
* Clinical conditions or systemic diseases limiting proper patient participation
* Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception
* Presence of other cardiac conditions:

  1. Previous cardiac surgery
  2. Heart failure where, in the Investigator's judgement, there is a possible alternative primary etiology e.g., due to coronary artery disease, valve disease, congenital heart disease or other causes.
  3. Untreated arrhythmia or serious conduction disease e.g., bradyarrhythmias, atrial fibrillation with rapid ventricular response, second or third degree atrioventricular block, etc.
  4. Primary uncorrected valvar pathology like moderate to severe aortic stenosis, mitral stenosis and primary mitral regurgitation
  5. Planned organ transplantation (or in listing for transplantation), planned cardiac or other major surgery (including ventricular assist device implantation)
* History of malignancy of any organ system within the past 5 years.
* Current confirmed COVID19 infection
* Past COVID19 infection with persistent symptom burden suspected due to COVID19 (persistent symptoms may include, but are not limited to, continued cough, breathing difficulty, muscle/joint aches, and gastrointestinal symptoms from the time of COVID19 infection onward)

Primary outcomes:
measure: Hierarchical composite endpoint composed of time to CV death, time to first HF hospitalization, relative change in NT-proBNP from baseline to Week 12
timeFrame: Total follow up time up to approximately 36 months
Secondary outcomes:
measure: Time to the first occurrence of a composite of CV events
timeFrame: From the date of randomization to the first occurrence (total follow up time up to approximately 36 months)
measure: Time to all-cause mortality
timeFrame: From date of randomization until the date of death from any cause assessed up to the end of the study, which is estimated to be up to approximately 36 months
measure: Time to sudden death or resuscitated sudden cardiac arrest
timeFrame: From date of randomization until the date of the sudden death or resuscitated sudden cardiac arrest assessed up to the end of the study, which is estimated to be up to approximately 36 months
measure: Number of visits to an ER due to HF (where intravenous therapy is required)
timeFrame: From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.
measure: Number of days alive out of the hospital
timeFrame: From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.
measure: Number of ventricular fibrillation or sustained ventricular tachycardia
timeFrame: From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.
measure: Number of anti-tachycardia pacing or shock therapies
timeFrame: From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ramos Mejia
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: San Martin
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Temperley
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Villa Maria
country: Argentina
facility: Novartis Investigative Site
state: Cordoba
city: Ciudad de Salta
country: Argentina
facility: Novartis Investigative Site
state: Provincia De Salta
city: Tucuman
country: Argentina
facility: Novartis Investigative Site
state: San Miguel De Tucuman
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: San Miguel de Tucuman
country: Argentina
facility: Novartis Investigative Site
state: Tucuman
city: San Miguel de Tucuman
country: Argentina
facility: Novartis Investigative Site
state: Tucuman
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Corrientes
country: Argentina
facility: Novartis Investigative Site
city: Formosa
country: Argentina
facility: Novartis Investigative Site
city: Formosa
country: Argentina
facility: Novartis Investigative Site
city: Mendoza
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Santiago del Estero
country: Argentina
facility: Novartis Investigative Site
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Fortaleza
country: Brazil
facility: Novartis Investigative Site
state: CE
city: Brasila
country: Brazil
facility: Novartis Investigative Site
state: DF
city: Brasilia
country: Brazil
facility: Novartis Investigative Site
state: DF
city: Brasilia
country: Brazil
facility: Novartis Investigative Site
state: Distrito Federal
city: Goiania
country: Brazil
facility: Novartis Investigative Site
state: Goias
city: Goiania
country: Brazil
facility: Novartis Investigative Site
state: GO
city: Goiania
country: Brazil
facility: Novartis Investigative Site
state: GO
city: Sao Luis
country: Brazil
facility: Novartis Investigative Site
state: MA
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Uberaba
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Uberlandia
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: Minas Gerais
city: Montes Claros
country: Brazil
facility: Novartis Investigative Site
state: Minas Gerais
city: Passos
country: Brazil
facility: Novartis Investigative Site
state: Minas Gerais
city: Uberlandia
country: Brazil
facility: Novartis Investigative Site
state: Minas Gerais
city: Belem
country: Brazil
facility: Novartis Investigative Site
state: PA
city: Recife
country: Brazil
facility: Novartis Investigative Site
state: PE
city: Teresina
country: Brazil
facility: Novartis Investigative Site
state: Piaui
city: Londrina
country: Brazil
facility: Novartis Investigative Site
state: PR
city: Natal
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Norte
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Botucatu
country: Brazil
facility: Novartis Investigative Site
state: Sao Paulo
city: Braganca Paulista
country: Brazil
facility: Novartis Investigative Site
state: Sao Paulo
city: Ribeirao Preto
country: Brazil
facility: Novartis Investigative Site
state: Sao Paulo
city: Santo Andre
country: Brazil
facility: Novartis Investigative Site
state: Sao Paulo
city: Sao Jose do Rio Preto
country: Brazil
facility: Novartis Investigative Site
state: Sao Paulo
city: Sao Jose do Rio Preto
country: Brazil
facility: Novartis Investigative Site
state: Sao Paulo
city: Campinas
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Campinas
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Campinas
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Indaiatuba
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Marilia
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Ribeirao Preto
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Jose do Rio Preto
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Tatui
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Votuporanga
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Ijui
country: Brazil
facility: Novartis Investigative Site
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
city: Bogota
country: Colombia
facility: Novartis Investigative Site
state: Cundinamarca
city: Santa Marta
country: Colombia
facility: Novartis Investigative Site
state: Magdalena
city: San Gil
country: Colombia
facility: Novartis Investigative Site
state: Santander
city: Bogota DC
country: Colombia
facility: Novartis Investigative Site
city: Florida Blanca
country: Colombia
facility: Novartis Investigative Site
city: Floridablanca
country: Colombia
facility: Novartis Investigative Site
city: Merida
country: Mexico
facility: Novartis Investigative Site
state: Yucatan
city: Ciudad De
country: Mexico
facility: Novartis Investigative Site
city: Oaxaca
country: Mexico
facility: Novartis Investigative Site
city: Xalapa
country: Mexico
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: