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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Porto

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

4 Aug 2023 → 31 Jul 2025

Decision date (initial)

2023-04-12

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Novartis Farma - Produtos Farmacêuticos, S.A. – Portugal

External identifiers

EU CT number

2022-502409-14-00

ClinicalTrials.gov

NCT05989503

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To compare the safety of two different initiation strategies:
1) initiation of ARNi and SGLT2i simultaneously (same day or within ± 5 days)
2) sequential prescription: initial SGLT2i prescription and addition of ARNi between week 4 and 12 after randomization

The null hypothesis is that: the safety of a simultaneous initiation of ARNi and a SGLT2i is non-inferior to a sequential initiation of SGLT2i first followed by an ARNi in patients with HFrEF or HFmrEF.

Secondary objectives 1

1. To compare the safety of two distinct initiation treatment strategies: 1) initiation of ARNi and SGLT2i simultaneously (same day or within ± 5 days) 2) sequential prescription: initial SGLT2i prescription and addition of ARNi between week 4 and 12 after randomization on the components identified in the primary outcome; circulating levels of NT-proBNP; high-sensitivity C-reactive protein; high-sensitivity troponin I; occurrence of arrhythmias such as fibrillation or atrial flutter; systolic and diastolic blood pressure; cardiac structural and functional parameters (left atrium volume, left ventricular volume, left ventricular mass, left ventricular ejection fraction, pulmonary artery systolic pressure); serum sodium, potassium, creatinine, glomerular filtration rate, urinary sodium and potassium levels, albuminuria, cholesterol levels, triglycerides, glucose, uric acid, thyroid function, liver function and iron metabolism, HF functional classification (NYHA), quality of life and proportion of patients who reach the maximum titration of ARNi at 3 months of follow-up.

Conditions and MedDRA coding

Heart failure with reduced ejection fraction

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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; patients treated with an ACEi or ARB can be included and maintain their therapy until the switch to an ARNi is performed))
8. If female, female patient of non-childbearing potential (detailed in full protocol)
9. If female patient of childbearing potential, she must have a negative serum pregnancy test at Visit 1 (Day 0) and must agree to use one highly effective method of contraception (detailed in full protocol) consistently and correctly

Exclusion criteria 12

1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
2. Female patients currently pregnant (confirmed by a positive pregnancy test) or intent to become pregnant or breast feeding
3. Severe valvulopathy according to the echocardiogram report
4. Previous history of ketoacidosis due to SGLT2i
5. Participation in another clinical study with an investigational product during the last month
6. Unwilling to sign inform consent
7. Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the excipients of the products
8. Hospitalization due to non-cardiovascular causes, surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior month
9. Cancer (life limiting with an estimated life expectancy of less than 2 years based on investigator’s judgement)
10. Previously confirmed cardiac amyloidosis
11. History of angioedema
12. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Composite outcome (time-to-first event’ occurrence during the 6 months of follow-up): Symptomatic hypotension; Hyperkalaemia; Hypokalemia; eGFR drop ≥50% from baseline; or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis; Increase in diuretic dose due to worsening HF; Use of intravenous diuretics for worsening HF; HF hospitalization; Death from CV causes

Secondary endpoints 31

1. Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion)
2. Hyperkalaemia (serum potassium >6.0 mmol/L)
3. Hypokalemia (serum potassium <3.0 mmol/L)
4. eGFR drop ≥50% from baseline; or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis
5. Increase in diuretic dose due to worsening heart failure
6. Use of intravenous diuretics for worsening heart failure
7. Heart failure hospitalization
8. Death from cardiovascular causes
9. NT-pro BNP or BNP (log)
10. High sensitivity C-reactive protein
11. Atrial fibrillation/flutter
12. Systolic and diastolic blood pressure
13. High sensitivity Troponin
14. Left atrial volume
15. Left ventricular (LV) systolic and diastolic volume
16. LV mass
17. LV ejection fraction
18. Pulmonary artery systolic pressure
19. Serum sodium
20. Serum potassium
21. Creatinine and glomerular filtration rate
22. Urinary sodium and potassium and albuminuria
23. Total Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides
24. Glucose and HbA1C
25. Uric acid
26. TSH and free T4
27. ALT, AST, Gamma-GT, Alkaline Phosphatase, Bilirubin
28. Iron, Ferritin and Sat. transferrin
29. Functional class (NYHA, New York Heart Association)
30. Quality of life (KCCQ, Kansas City Cardiomyopathy Questionnaire)
31. Dosage titration of sacubitril/valsartan up to the dose 97/103 mg (b.i.d.) at 3 months

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Porto

Sponsor organisation

University Of Porto

Address

Alameda Professor Hernani Monteiro

City

Porto

Postcode

4200-319

Country

Portugal

Scientific contact point

Organisation

University Of Porto

Contact name

João Pedro Ferreira

Public contact point

Organisation

University Of Porto

Contact name

João Pedro Ferreira

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications