Pulmonary REsistance modification under treatment with Sacubitil/valsartaN in paTients with HeartFailure with reduced ejection fraction

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Uniwersytecki Szpital Kliniczny W Poznaniu

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

12 Dec 2022 → 18 Jul 2025

Decision date (initial)

2024-12-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Medical Research Agency

External identifiers

EU CT number

2024-517975-19-00

EudraCT number

2020-006072-32

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

Assessment of the effect of sacubitril/valsartan (S/V) therapy in comparsion to the group treated with ACE inhibitor - enalapril, on the parameters of right heart catheterization in terms of reduction of pulmonary artery pressure and changes in pulmonary circulation resistance in patients with developed pulmonary hypertension (PH) due to heart failure with reduced ejection fraction (HFrEF)

Secondary objectives 1

1. Assessment of treatment efficacy in terms of the major adverse cardiac and cerebrovascular events (MACCE) composite endpoint and its components separately,: quality of life, safety assessment and treatment tolerance (assessment of Adverse Events (AE) and Serious Adverse Events and their assessment in terms of severity and relationship to the tested substance). Additionally, as part of the exploratory part of the study, the influence of therapy on the selected biomarkers will be analyzed.

Conditions and MedDRA coding

Heart Failure with reduced ejection fraction.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age ≥18 years of age who are able to complete and sign the informed consent form.
2. HF patients in NYHA II-IV in whom right heart catheterization (RHC) reveals post-capillary pulmonary hypertension (defined on the basis of the 2022 ESC guidelines as PAPm >20 mmHg and PAWP > 15 mmHg); both isolated post-capillary PH (IpcPH) (defined on the basis of the 2022 ESC guidelines as PVR <= 2 WU) as well as combined post- and pre-capillary PH (CpcPH) (defined on the basis of the 2022 ESC guidelines as PVR > 2WU).
3. Stable patients haemodynamics, which is defined as no change in diuretic use for at least 4 weeks prior to study entry
4. Heart failure during optimal treatment with ACE-I / ARB, beta blocker, MRA, SGLT2i except in cases where the above-mentioned treatment was contraindicated or not tolerated
5. Understanding and acceptance of the research assumptions and methods and signing the informed consent by the patient

Exclusion criteria 30

1. Current treatment with Sacubitryl/valsartan
2. Severe heart Failure HF NYHA IV functional class and/or cardiogenic shock
3. Current treatment with sildenafil
4. Patients ineligible or contraindicated for treatment with sacubitril/valsartan
5. Patients with a history of angioedema associated with ACE I or ARB treatment
6. Patients who have had a heart transplant or have had a circulatory support device
7. Patient on the urgent list for heart transplant
8. Isolated right heart failure secondary to lung disease
9. Documented untreated significant ventricular arrhythmia with syncope within the previous 3 months
10. Symptomatic bradycardia or second or third degree atrioventricular block not protected by a pacemaker
11. Factors that prevent RHC testing (e.g. very serious condition of the patient that makes it impossible to lie down, cardiogenic shock, allergy to contrast agents, etc.)
12. Pregnant or lactating women
13. Women of childbearing age, defined as the physiological possibility of becoming pregnant, unless using two methods of contraception
14. Acute coronary syndrome, including myocardial infarction (STEMI, NSTEMI), a condition with carotid revascularization or major cardiovascular surgery in the last 30 days
15. Stroke or transient cerebral ischemia (TIA) within the last 3 months
16. Previous CRT implantation in the last 3 months or planning for CRT implantation
17. Life expectancy <6 months
18. Severe renal failure, eGFR <30 ml / min / 1.73 m2 (calculated according to the MDRD formula)
19. Serum potassium> 5.2 mEqL
20. Liver failure or elevated liver transaminases (total bilirubin> 3 mg / dL and / or ALT and / or AST ≥3x ULN)
21. A major surgery planned within 6 months of randomization
22. Planned coronary angioplasty or pacemaker / ICD / CRT implantation within the next 6 months
23. Severe primary valve disease (NOT secondary mitral regurgitation) or obstructive hypertrophic cardiomyopathy
24. The presence of a malignant neoplasm of any organ system, ie clinical signs or no stable remission for at least 3 years after the end of the last treatment, with the exception of non-invasive basal cell carcinoma, squamous cell carcinoma of the skin or cervical epithelial dysplasia.
25. Diseases that significantly reduce physical performance:- Severe COPD putting off oxygen therapy; - Severe asthma, - Morbid obesity (BMI> 40 kg / m2), - Significant lower limb atherosclerosis with intense intermittent claudication
26. Significant lower limb atherosclerosis with intense intermittent claudication
27. Uncontrolled hypertension (SBP> 170 mmHg and / or DBP> 100 mmHg)
28. Symptomatic hypotension (SPB <90 mmHg)
29. Any situation that may make it impossible to perform the research in accordance with the protocol or express written consent in the opinion of the researcher, including abuse of alcohol, drugs or other psychoactive substances.
30. Participation in a study with a device or medicinal product within 3 months prior to randomization or 5 half-lives, whichever is longer, prior to the screening visit

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Change from baseline in mean pulmonary artery pressure (mPAP).
2. Change from baseline in pulmonary vascular resistance (PVR).

Secondary endpoints 10

1. Change from baseline in pulmonary wedge pressure (PWP).
2. Change from baseline in the diastolic pressure gradient (DPG; where DPG = diastolic mPAP – mean PWP ).
3. Change in the 6-minute walk test (6MWT) - analysis of changes from the baseline.
4. Evaluation of the parameters of the spiroergometric test (CPET, Cardio-Pulmonary Exercise Test) analysis of changes in relation to the baseline.
5. Assessment of echocardiographic parameters - analysis of changes in relation to the baseline
6. The incidence of the composite endpoint of MACCEs such as death from all causes, cardiac death, hospitalization due to worsening / decompensation of HF, stroke / transient ischemic attack (TIA), acute coronary syndrome (ACS) , the need for a heart transplant (HT), the need for a left ventricular assist device (LVAD) or biventricular , an unplanned hospitalization or an outpatient visit due to the need to administer intravenous diuretics or requiring an increase in the dose of diuretics >50% base
7. Hospitalization or an unplanned visit to the Emergency Department or an unplanned outpatient visit related to HF
8. The need for unplanned intravenous administration of diuretics.
9. Assessment of quality of life will be conducted between 0-52 weeks (QoL indicators - Kansas City Cardiomyopathy Questionnaire (KCCQ-12), WHO (WHOQOL-BREF), SF-36 questionnaire, EQ-5D-3L questionnaire) - change from the baseline
10. Assessment of the New York Heart Association (NYHA) and the World Health Organization (WHO) functional classes - change from the baseline

Investigational products

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

Test 1

Comparator 1

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Uniwersytecki Szpital Kliniczny W Poznaniu

Sponsor organisation

Uniwersytecki Szpital Kliniczny W Poznaniu

Address

Ul. Dluga 1/2

City

Poznan

Postcode

61-848

Country

Poland

Scientific contact point

Organisation

Uniwersytecki Szpital Kliniczny W Poznaniu

Contact name

Lead Principal Investigator

Public contact point

Organisation

Uniwersytecki Szpital Kliniczny W Poznaniu

Contact name

Koordynator

Third parties 1

Locations

1 EU/EEA country · 7 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 7 files

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

Application history

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