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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05989503
Other study ID # INITIATE-HFrEF
Secondary ID 2022-502409-14-0
Status Recruiting
Phase Phase 4
First received
Last updated
Start date August 4, 2023
Est. completion date February 2025

Study information

Verified date June 2023
Source Universidade do Porto
Contact João P. Ferreira, PhD
Phone (+351) 220426820
Email jpferreira@med.up.pt
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Heart failure (HF) is a condition in which the heart does not contract ("pump") or relax well, leading to insufficient perfusion of vital organs. Ankle swelling, fatigue, and breathlessness are some of the features of this syndrome. There are different causes for HF (e.g., infarct and hypertension) and two distinct types: HFpEF - HF with preserved ejection fraction - the heart "pumps" but does not relax well and HFrEF/HFmrEF - HF with reduced or mildly reduced ejection fraction - where the heart does not "pump" properly. Patients with HFrEF experience substantially shorter life expectancies compared with people in the general population of similar age. Compared to the different available therapeutics for HFrEF patients, angiotensin receptor-neprilysin inhibitor (ARNi), sacubitril/valsartan, has shown superiority for improving clinical outcomes. Furthermore, the new recently drug sodium-glucose cotransporter 2 inhibitor (SGLT2i) was proven to reduce mortality and morbidity on top of well-adapted background therapy. This work aims to test the safety of ARNi and SGLT2i initiation by comparing a strategy of simultaneous initiation of ARNi and SGLT2i versus sequential initiation of a SGLT2i first followed by an ARNi.


Description:

Sacubitril/valsartan and SGLT2i reduced HF hospitalizations and mortality in patients with heart failure and a reduced ejection fraction with a rapid onset of action, but the timing of initiation of each drug is uncertain. Clinicians may be reluctant to initiate both therapies simultaneously due to fear of adverse events (e.g., hypotension and worsening renal function) which may delay the initiation of (at least one) of these life-saving therapies. This study aims to fill this gap in knowledge by studying the initiation of sacubitril/valsartan and a SGLT2i simultaneously or in sequence. This study will better inform clinicians on their daily decisions.


Recruitment information / eligibility

Status Recruiting
Enrollment 172
Est. completion date February 2025
Est. primary completion date November 2024
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: 1. Age = 18 years 2. Heart failure symptoms (NYHA II, III or IV) 3. Left ventricle ejection fraction = 49% (assessed by transthoracic echocardiogram) 4. Glomerular filtration rate = 25 ml/min/1.73m2 (CKD-EPI formula) 5. Serum potassium (K+) = 5.4 mmol/L 6. Systolic blood pressure = 100 mmHg 7. Not treated with ARNi nor with SGLT2i within the previous month (30 days before inclusion, except if initiated 5 days before randomization) 8. If female, she must not be a woman of childbearing potential. That is, she must be: 1. Surgically sterilized (e.g., underwent hysterectomy, bilateral salpingectomy or bilateral oophorectomy) 2. Clinically diagnosed infertile 3. In a post-menopausal state, defined as no menses for 12 months without an alternative medical cause 9. If female patient of childbearing potential, she must have a negative serum pregnancy test at Visit 1 (Day 0) and must agree to consistently and correctly use (from 28 days prior to first study treatment administration until at least 7 days after last study treatment administration) one of the following highly effective methods of contraception: 1. Abstinence of heterosexual intercourse (when this is in line with preferred and usual lifestyle of the subject) 2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) 3. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) 4. Intrauterine device 5. Intrauterine hormone-releasing system 6. Bilateral tubal occlusion 7. Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner Exclusion Criteria: 1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site) 2. Participation in another clinical study with an investigational product during the last month 3. Unwilling to sign inform consent 4. Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the excipients of the products 5. Hospitalization due to non-cardiovascular causes, surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior month 6. Cancer (life limiting with an estimated life expectancy of less than 2 years based on investigator's judgement) 7. Previously confirmed cardiac amyloidosis 8. History of angioedema 9. Implantable cardioverter-defibrillators or cardiac resynchronization therapy within 3 months prior to screening or if there is an intent to implant either device in the 3 months following screening 10. Female patients currently pregnant (confirmed by a positive pregnancy test) or intent to become pregnant or breast feeding 11. Severe valvulopathy according to the echocardiogram report 12. Previous history of ketoacidosis due to SGLT2i

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Sacubitril-valsartan
Sacubitril-valsartan titration at the discretion of the treating physician
SGLT2 inhibitor
Either empagliflozin or dapagliflozin 10 mg/day

Locations

Country Name City State
Portugal Centro Hospitalar Universitário de Santo António Porto
Portugal Centro Hospitalar Universitário São João Porto
Portugal Centro Hospitalar Vila Nova de Gaia/Espinho Porto
Portugal Faculty of Medicine (FMUP) Porto
Portugal Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano Porto

Sponsors (4)

Lead Sponsor Collaborator
Universidade do Porto Faculty of Medicine (FMUP), Rede de Investigação em Saúde (RISE), Laboratório Associado, Unidade de Investigação e Desenvolvimento Cardiovascular (UnIC)

Country where clinical trial is conducted

Portugal, 

Outcome

Type Measure Description Time frame Safety issue
Primary Composite outcome (time-to-first event' occurrence during the 6 months of follow-up): Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion);
Hyperkalaemia (serum potassium >6.0 mmol/L);
Hypokalemia (serum potassium <3.0 mmol/L);
eGFR drop =50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis;
Increase in diuretic dose due to worsening heart failure;
Use of intravenous diuretics for worsening heart failure;
Heart failure hospitalization;
Death from cardiovascular causes.
visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion) Time to event' occurrence during the 6 months of follow-up visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Hyperkalaemia (serum potassium >6.0 mmol/L) Time to event' occurrence during the 6 months of follow-up visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Hypokalemia (serum potassium <3.0 mmol/L) Time to event' occurrence during the 6 months of follow-up visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary eGFR drop =50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis Time to event' occurrence during the 6 months of follow-up visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Increase in diuretic dose due to worsening heart failure Time to event' occurrence during the 6 months of follow-up visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Use of intravenous diuretics for worsening heart failure Time to event' occurrence during the 6 months of follow-up visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Heart failure hospitalization Time to event' occurrence during the 6 months of follow-up visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Death from cardiovascular causes Time to event' occurrence during the 6 months of follow-up visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary NT-pro BNP or BNP (log) Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary High sensitivity C-reactive protein Concentration measured in blood samples visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Atrial fibrillation/flutter Electrocardiogram (yes/no) visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Systolic and diastolic blood pressure Measure in the clinical appointments visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary High sensitivity Troponin Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Left atrial volume Transthoracic echocardiogram visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Left ventricular systolic volume Transthoracic echocardiogram visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Left ventricular diastolic volume Transthoracic echocardiogram visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary LV mass Transthoracic echocardiogram visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary LV ejection fraction Transthoracic echocardiogram visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Pulmonary artery systolic pressure Transthoracic echocardiogram visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Serum sodium Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Serum potassium Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Serum creatinine Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Glomerular filtration rate (eGFR) Calculated from the serum creatinine using the 2021 CKD-EPI creatinine-based formula visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Urinary sodium Spot urine sample visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Urinary potassium Spot urine sample visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Microalbuminuria Spot urine sample visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Total Cholesterol Concentration measured in blood samples visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary LDL Cholesterol Concentration measured in blood samples visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary HDL Cholesterol Concentration measured in blood samples visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Triglycerides Concentration measured in blood samples visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Glucose Measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Glycated hemoglobin (HbA1C) Concentration measured in blood samples visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Uric acid Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary TSH Concentration measured in blood samples visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary Free thyroxin Concentration measured in blood samples visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Secondary ALAT Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary ASAT Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Gamma-GT Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Alkaline Phosphatase Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Total bilirubin Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Serum iron Concentration measured in blood samples visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Ferritin Concentration measured in blood samples visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Transferrin saturation Concentration measured in blood samples visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Functional class (NYHA, New York Heart Association) Assessed by the medical doctors in the clinical appointments (I / II / III / IV) visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Quality of life (KCCQ, Kansas City Cardiomyopathy Questionnaire) HR-QoL assessed by the Kansas City Cardiomyopathy Questionnaire a 12-item instrument. All items are measured on a Likert scale with 5-7 response options. KCCQ scores are scaled from 0 to 100 and summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary Dosage titration of sacubitril/valsartan up to the dose 97/103 mg (b.i.d.) at 3 months Assessed by the medical doctors in the clinical appointments visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days)
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