Heart Failure With Reduced Ejection FractionPhase 4INITIATENCT05989503
Initiation of ARNi and SGLT2i in Patients With HFrEF
A Phase 4 study testing Sacubitril-valsartan and SGLT2 inhibitor in people with Heart Failure With Reduced Ejection Fraction, run by Universidade do Porto at 5 sites in Portugal.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure With Reduced Ejection Fraction
- What is being tested?
- Sacubitril-valsartan and SGLT2 inhibitor
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 62 participants
- Where
- 5 sitesPortugal
- Study dates
- 4 Aug 2023to 31 Jul 2025
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Heart failure symptoms (NYHA II, III or IV)
- Left ventricle ejection fraction ≤ 49% (assessed by transthoracic echocardiogram)
- Glomerular filtration rate ≥ 25 ml/min/1.73m2 (CKD-EPI formula)
- Serum potassium (K+) ≤ 5.4 mmol/L
- Systolic blood pressure ≥ 100 mmHg
Show all 19Show fewer
- Not treated with ARNi nor with SGLT2i within the previous month (30 days before inclusion, except if initiated 5 days before randomization; patients treated with an ACEi or ARB can be included and maintain their therapy until the switch to an ARNi is performed)
- If female, she must not be a woman of childbearing potential. That is, she must be:
- Surgically sterilized (e.g., underwent hysterectomy, bilateral salpingectomy or bilateral oophorectomy)
- Clinically diagnosed infertile
- In a post-menopausal state, defined as no menses for 12 months without an alternative medical cause
- 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:
- Abstinence of heterosexual intercourse (when this is in line with preferred and usual lifestyle of the subject)
- Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
- Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
- Intrauterine device
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner
Who cannot join
- Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
- Participation in another clinical study with an investigational product during the last month
- Unwilling to sign inform consent
- Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the excipients of the products
- Hospitalization due to non-cardiovascular causes, surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior month
- Cancer (life limiting with an estimated life expectancy of less than 2 years based on investigator's judgement)
Show all 12Show fewer
- Previously confirmed cardiac amyloidosis
- History of angioedema
- 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
- Female patients currently pregnant (confirmed by a positive pregnancy test) or intent to become pregnant or breast feeding
- Severe valvulopathy according to the echocardiogram report
- Previous history of ketoacidosis due to SGLT2i
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Portugal5 sites
Centro Hospitalar Universitário de Santo António
Porto, Porto District, 4099-001
Centro Hospitalar Universitário São João
Porto, 4200-319
Faculty of Medicine (FMUP)
Porto, 4200-319
Centro Hospitalar Vila Nova de Gaia/Espinho
Porto, 4434-502
Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano
Porto
About this study
Official title: Initiation of Angiotensin Receptor-neprilysin Inhibitor (ARNi) and Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF): the INITIATE-HFrEF Randomized Open-label Trial
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, here referred to as having HFrEF.
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.
Read the detailed 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.
- Being tested
- Sacubitril-valsartan, SGLT2 inhibitor
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sacubitril-valsartanDrug
Sacubitril-valsartan titration at the discretion of the treating physician
SGLT2 inhibitorDrug
Either empagliflozin or dapagliflozin 10 mg/day
| Study group | Role | What they receive |
|---|---|---|
| Simultaneous initiation | Active comparator | ARNi ((i.e. sacubitril/valsartan, irrespectively of brand name, at an initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and SGLT2i (either empagliflozin or dapagliflozin or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10mg/d) on the same day or within ± 5 days. Receives: Drug: Sacubitril-valsartan; Drug: SGLT2 inhibitor |
| Sequential initiation | Active comparator | Initial (at randomization day) SGLT2i prescription (either empagliflozin or dapagliflozin, or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10 mg/d) followed by an ARNi initiated between weeks 4 and 12 after randomization (sacubitril/valsartan at an initial dose of 24/26mg b.i.d. or 49/51mg b.i.d., and titrated to 97/103mg b.i.d. if tolerated, according to assistant physician decision) Receives: Drug: Sacubitril-valsartan; Drug: SGLT2 inhibitor |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary outcomes (46)
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
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Hyperkalaemia (serum potassium >6.0 mmol/L)
Time to event' occurrence during the 6 months of follow-up
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Hypokalemia (serum potassium <3.0 mmol/L)
Time to event' occurrence during the 6 months of follow-up
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
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
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Increase in diuretic dose due to worsening heart failure
Time to event' occurrence during the 6 months of follow-up
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Use of intravenous diuretics for worsening heart failure
Time to event' occurrence during the 6 months of follow-up
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Heart failure hospitalization
Time to event' occurrence during the 6 months of follow-up
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Death from cardiovascular causes
Time to event' occurrence during the 6 months of follow-up
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
NT-pro BNP or BNP (log)
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
High sensitivity C-reactive protein
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Atrial fibrillation/flutter
Electrocardiogram (yes/no)
Measured: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Systolic and diastolic blood pressure
Measure in the clinical appointments
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
High sensitivity Troponin
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Left atrial volume
Transthoracic echocardiogram
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Left ventricular systolic volume
Transthoracic echocardiogram
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Left ventricular diastolic volume
Transthoracic echocardiogram
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
LV mass
Transthoracic echocardiogram
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
LV ejection fraction
Transthoracic echocardiogram
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Pulmonary artery systolic pressure
Transthoracic echocardiogram
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Serum sodium
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Serum potassium
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Serum creatinine
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Glomerular filtration rate (eGFR)
Calculated from the serum creatinine using the 2021 CKD-EPI creatinine-based formula
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Urinary sodium
Spot urine sample
Measured: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Urinary potassium
Spot urine sample
Measured: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Microalbuminuria
Spot urine sample
Measured: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Total Cholesterol
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
LDL Cholesterol
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
HDL Cholesterol
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Triglycerides
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Glucose
Measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Glycated hemoglobin (HbA1C)
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Uric acid
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
TSH
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Free thyroxin
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
ALAT
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
ASAT
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Gamma-GT
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Alkaline Phosphatase
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Total bilirubin
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Serum iron
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Ferritin
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Transferrin saturation
Concentration measured in blood samples
Measured: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Functional class (NYHA, New York Heart Association)
Assessed by the medical doctors in the clinical appointments (I / II / III / IV)
Measured: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
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
Measured: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
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
Measured: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Aug 2023
- Study start4 Aug 2023
- Primary completion31 Jul 2025
- Study completion31 Jul 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Heart Failure With Reduced Ejection FractionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Pragmatic study to be conducted in real-life routine practice conditions with a two-arm open randomization, to evaluate the efficacy (on surrogate markers) and safety of ARNi and SGLT2i combination in patients with HFrEF/HFmrEF and the doses of ARNi. 1. initiation of ARNi and SGLT2i simultaneously (same day or within ± 5 days); 2. initial SGLT2i initiation followed by ARNi between week 4 and 12 after randomization. Assuming a primary outcome frequency of 30% in the sequential group, if there is a true difference between the intervention groups (simultaneous vs sequential) of 10%, then 62 patients are required to be 80% certain that the upper limit of a one-sided 95% confidence interval will exclude a difference in favour of the sequential group of more than 20%.
- Masking
- None (open label)
- Enrolment
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universidade do Porto
- Sponsor type
- University, hospital or other
- Collaborators
- Unidade de Investigação e Desenvolvimento Cardiovascular (UnIC), Rede de Investigação em Saúde
- Responsible party
- Sponsor
- Investigators
- João P. Ferreira, MD, PhD, Principal investigator, Universidade do Porto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05989503
- Sponsor's protocol ID
- INITIATE-HFrEF
- Other IDs
- 2022-502409-14-00
- Acronym
- INITIATE
- Status last verified
- Aug 2025
- First submitted
- 14 Jul 2023
- Last updated
- 19 Nov 2025
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Initiation of Angiotensin Receptor-neprilysin Inhibitor (ARNi) and Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF): the INITIATE-HFrEF Randomized Open-label Trial
- ClinicalTrials.gov ID
- NCT05989503
- Acronym / sponsor ID
- INITIATE / INITIATE-HFrEF
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- Universidade do PortoUniversity, hospital or other
- Collaborators
- Unidade de Investigação e Desenvolvimento Cardiovascular (UnIC), Rede de Investigação em Saúde
- Study start
- 4 Aug 2023 (actual)
- Primary completion
- 31 Jul 2025 (actual)
- Study completion
- 31 Jul 2025 (actual)
- First posted
- 14 Aug 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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, here referred to as having HFrEF.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Pragmatic study to be conducted in real-life routine practice conditions with a two-arm open randomization, to evaluate the efficacy (on surrogate markers) and safety of ARNi and SGLT2i combination in patients with HFrEF/HFmrEF and the doses of ARNi. 1. initiation of ARNi and SGLT2i simultaneously (same day or within ± 5 days); 2. initial SGLT2i initiation followed by ARNi between week 4 and 12 after randomization. Assuming a primary outcome frequency of 30% in the sequential group, if there is a true difference between the intervention groups (simultaneous vs sequential) of 10%, then 62 patients are required to be 80% certain that the upper limit of a one-sided 95% confidence interval will exclude a difference in favour of the sequential group of more than 20%.
| Arm | Type | Receives |
|---|---|---|
| Simultaneous initiation | Active comparator | Drug: Sacubitril-valsartan, Drug: SGLT2 inhibitorARNi ((i.e. sacubitril/valsartan, irrespectively of brand name, at an initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and SGLT2i (either empagliflozin or dapagliflozin or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10mg/d) on the same day or within ± 5 days. |
| Sequential initiation | Active comparator | Drug: Sacubitril-valsartan, Drug: SGLT2 inhibitorInitial (at randomization day) SGLT2i prescription (either empagliflozin or dapagliflozin, or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10 mg/d) followed by an ARNi initiated between weeks 4 and 12 after randomization (sacubitril/valsartan at an initial dose of 24/26mg b.i.d. or 49/51mg b.i.d., and titrated to 97/103mg b.i.d. if tolerated, according to assistant physician decision) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Age ≥ 18 years
- Heart failure symptoms (NYHA II, III or IV)
- Left ventricle ejection fraction ≤ 49% (assessed by transthoracic echocardiogram)
- Glomerular filtration rate ≥ 25 ml/min/1.73m2 (CKD-EPI formula)
- Serum potassium (K+) ≤ 5.4 mmol/L
Key exclusion criteria (12 listed)
- Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
- Participation in another clinical study with an investigational product during the last month
- Unwilling to sign inform consent
- Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the excipients of the products
- Hospitalization due to non-cardiovascular causes, surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior month
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sacubitril-valsartanSacubitril-valsartan titration at the discretion of the treating physician | Drug | Sequential initiation, Simultaneous initiation |
| SGLT2 inhibitorEither empagliflozin or dapagliflozin 10 mg/day | Drug | Sequential initiation, Simultaneous initiation |
Primary outcome
Composite outcome (time-to-first event' occurrence during the 6 months of follow-up):
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
* 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.
46 secondary outcomes
Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion)
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Hyperkalaemia (serum potassium >6.0 mmol/L)
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Hypokalemia (serum potassium <3.0 mmol/L)
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
eGFR drop ≥50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Increase in diuretic dose due to worsening heart failure
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Use of intravenous diuretics for worsening heart failure
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Heart failure hospitalization
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Death from cardiovascular causes
Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
NT-pro BNP or BNP (log)
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
High sensitivity C-reactive protein
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Atrial fibrillation/flutter
Time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Systolic and diastolic blood pressure
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
High sensitivity Troponin
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Left atrial volume
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Left ventricular systolic volume
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Left ventricular diastolic volume
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
LV mass
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
LV ejection fraction
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Pulmonary artery systolic pressure
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Serum sodium
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Serum potassium
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Serum creatinine
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Glomerular filtration rate (eGFR)
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Urinary sodium
Time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Urinary potassium
Time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Microalbuminuria
Time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Total Cholesterol
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
LDL Cholesterol
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
HDL Cholesterol
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Triglycerides
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Glucose
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Glycated hemoglobin (HbA1C)
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Uric acid
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
TSH
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
Free thyroxin
Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
ALAT
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
ASAT
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Gamma-GT
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Alkaline Phosphatase
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Total bilirubin
Time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Nov 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
João P. Ferreira, MD, PhD principal investigator
Universidade do Porto
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Sacubitril-valsartan and SGLT2 inhibitor in people with Heart Failure With Reduced Ejection Fraction, run by Universidade do Porto at 5 sites in Portugal.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Portugal. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Composite outcome (time-to-first event' occurrence during the 6 months of follow-up): (time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2025.