Clinical Trial Page

Summary
EudraCT Number:2020-006072-32
Sponsor's Protocol Code Number:2019/ABM/01/00078
National Competent Authority:Poland - Office for Medicinal Products
Clinical Trial Type:EEA CTA
Trial Status:Ongoing
Date on which this record was first entered in the EudraCT database:2021-01-29
Trial results
A. Protocol Information
A.1Member State ConcernedPoland - Office for Medicinal Products
A.2EudraCT number2020-006072-32
A.3Full title of the trial
Pulmonary REsistance modification under treatment with Sacubitil/valsartaN in paTients with HeartFailure with reduced ejection fraction
Sakubitryl/walsartan w leczeniu nadciśnienia płucnego wtórnego do niewydolności serca z obniżoną frakcją wyrzutową.
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
Association between sacubitril/valsartan use and pulomonary resistance in patients with heart failure with reduced ejection fraction.
Związek między zastosowaniem sakubitrylu/walsartanu a leczeniem nadciśnienia płucnego wtórnego u pacjentów z niewydolnością serca z obniżoną frakcją wyrzutową.
A.3.2Name or abbreviated title of the trial where available
PRESENT-HF Study
A.4.1Sponsor's protocol code number2019/ABM/01/00078
A.7Trial is part of a Paediatric Investigation Plan No
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorHeliodor Święcicki Clinical Hospital of the Poznań University of Medical Sciences
B.1.3.4CountryPoland
B.3.1 and B.3.2Status of the sponsorNon-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportMedical Research Agency
B.4.2CountryPoland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationSCIENTIA RESEARCH INSTITUTE Sp. z o.o.
B.5.2Functional name of contact pointCRO representative
B.5.3 Address:
B.5.3.1Street AddressBydgoskich Przemyslowców 6
B.5.3.2Town/ cityBydgoszcz
B.5.3.3Post code85-862
B.5.3.4CountryPoland
B.5.4Telephone number+48602 146 500
B.5.6E-mail[email protected]
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.1.1Trade name ENTRESTO 24mg/26mg caoted tablets
D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
D.2.1.2Country which granted the Marketing AuthorisationPoland
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.4Pharmaceutical form Film-coated tablet
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNSacubitril
D.3.9.1CAS number 149709-62-6
D.3.9.4EV Substance CodeSUB170848
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number24.3
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNValsartan
D.3.9.1CAS number 137862-53-4
D.3.9.4EV Substance CodeSUB00017MIG
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number25.7
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 2
D.1.2 and D.1.3IMP RoleComparator
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.1.1Trade name ENALAPRIL 2.5mg tablets
D.2.1.1.2Name of the Marketing Authorisation holderRatiopharmGmbH
D.2.1.2Country which granted the Marketing AuthorisationPoland
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.4Pharmaceutical form Film-coated tablet
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNENALAPRIL
D.3.9.1CAS number 75847-73-3
D.3.9.4EV Substance CodeSUB06514MIG
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number2.5
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.8 Information on Placebo
D.8 Placebo: 1
D.8.1Is a Placebo used in this Trial?Yes
D.8.3Pharmaceutical form of the placeboFilm-coated tablet
D.8.4Route of administration of the placeboOral use
D.8 Placebo: 2
D.8.1Is a Placebo used in this Trial?Yes
D.8.3Pharmaceutical form of the placeboCoated tablet
D.8.4Route of administration of the placeboOral use
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical condition(s) being investigated
Heart Failure with reduced ejection fraction.
E.1.1.1Medical condition in easily understood language
Heart Failure with reduced ejection fraction.
E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 20.0
E.1.2Level LLT
E.1.2Classification code 10078289
E.1.2Term Heart failure with reduced ejection fraction
E.1.2System Organ Class 100000004849
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main objective of the trial
Assessment of the effect of 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 HFrEF.
E.2.2Secondary objectives of the trial
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).
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
1)Age ≥18 years of age who are able to complete and sign the informed consent form.
2)Heart failure patients in NYHA functional class II-IV with a reduced left ventricular ejection fraction (LVEF) ≤ 40% - (HFrEF) (confirmed by an examination such as echocardiography or cardiac magnetic resonance within the last 6 months) who underwent the right heart catheterization (RHC), features of extrapillary pulmonary hypertension (defined on the basis of the 2015 ESC guidelines: PAPm ≥25 mmHg and PCWP> 15 mmHg) were found, both of the isolated extracapillary PH (Ipc-PH) (defined on the basis of the 2015 ESC guidelines: DPG < 7 mm Hg and / or PVR ≤ 3 WU) as well as complex extra- and pre-capillary PH (Cpc-PH) (defined on the basis of the 2015 ESC guidelines: DPG ≥ 7 mm Hg and / or PVR> 3 WU)
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

E.4Principal exclusion criteria
1)Current treatment with sacubitril / 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:
26)Severe COPD putting off oxygen therapy
27)Severe asthma
28)Morbid obesity (BMI> 40 kg / m2)
29)Significant lower limb atherosclerosis with intense intermittent claudication
30)Uncontrolled hypertension (SBP> 170 mmHg and / or DBP> 100 mmHg)
31)Symptomatic hypotension (SPB <90 mmHg)
32)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.
33)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
E.5 End points
E.5.1Primary end point(s)
1. Change from baseline in mean pulmonary artery pressure (mPAP).
2. Change from baseline in pulmonary vascular resistance (PVR).
E.5.1.1Timepoint(s) of evaluation of this end point
Primary endpoint will be evaluate during visit 2-13.
E.5.2Secondary end point(s)
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% from baseline.
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 in one-, three-, six-month follow-up (QoL indicators - Kansas City Cardiomyopathy Questionnaire (KCCQ), WHO (WHOQOL), 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.
E.5.2.1Timepoint(s) of evaluation of this end point
Primary endpoint will be evaluate during visit 2-13.
E.6 and E.7 Scope of the trial
E.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy Yes
E.6.4Safety Yes
E.6.5Efficacy Yes
E.6.6Pharmacokinetic No
E.6.7Pharmacodynamic No
E.6.8Bioequivalence No
E.6.9Dose response No
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others No
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) No
E.7.1.1First administration to humans No
E.7.1.2Bioequivalence study No
E.7.1.3Other No
E.7.1.3.1Other trial type description
E.7.2Therapeutic exploratory (Phase II) No
E.7.3Therapeutic confirmatory (Phase III) No
E.7.4Therapeutic use (Phase IV) Yes
E.8 Design of the trial
E.8.1Controlled Yes
E.8.1.1Randomised Yes
E.8.1.2Open No
E.8.1.3Single blind No
E.8.1.4Double blind Yes
E.8.1.5Parallel group Yes
E.8.1.6Cross over No
E.8.1.7Other No
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) Yes
E.8.2.2Placebo No
E.8.2.3Other No
E.8.2.4Number of treatment arms in the trial2
E.8.3 The trial involves single site in the Member State concerned No
E.8.4 The trial involves multiple sites in the Member State concerned Yes
E.8.4.1Number of sites anticipated in Member State concerned3
E.8.5The trial involves multiple Member States No
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA No
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.7Trial has a data monitoring committee No
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
LVLS
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years2
E.8.9.1In the Member State concerned months3
E.8.9.1In the Member State concerned days
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 No
F.1.1.1In Utero No
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3Newborns (0-27 days) No
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.5Children (2-11years) No
F.1.1.6Adolescents (12-17 years) No
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 117
F.1.3Elderly (>=65 years) Yes
F.1.3.1Number of subjects for this age range: 143
F.2 Gender
F.2.1Female Yes
F.2.2Male Yes
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations Yes
F.3.3.1Women of childbearing potential not using contraception No
F.3.3.2Women of child-bearing potential using contraception Yes
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state260
F.4.2 For a multinational trial
F.4.2.2In the whole clinical trial 260
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
After end of study patients will be treated according standard of care.
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2022-10-05
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2021-02-04
P. End of Trial
P.End of Trial StatusOngoing