Clinical Trials Register

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:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-01-29
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Poland - Office for Medicinal Products

A.2

EudraCT number

2020-006072-32

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

PRESENT-HF Study

A.4.1

Sponsor's protocol code number

2019/ABM/01/00078

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Hospital in Poznań
B.1.3.4	Country	Poland
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Medical Research Agency
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SCIENTIA CRO Sp. z o.o.
B.5.2	Functional name of contact point	CRO representative
B.5.3	Address:
B.5.3.1	Street Address	Ogińskiego 2
B.5.3.2	Town/ city	Bydgoszcz
B.5.3.3	Post code	85-092
B.5.3.4	Country	Poland
B.5.4	Telephone number	+48602 146 500
B.5.6	E-mail	beata.maciejewska@scientiacro.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Entresto
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Poland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sacubitril/valsartan
D.3.9.1	CAS number	936623-90-4
D.3.9.3	Other descriptive name	SACUBITRIL VALSARTAN
D.3.9.4	EV Substance Code	SUB171905
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	50 to 200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.2	Name of the Marketing Authorisation holder	RatiopharmGmbH
D.2.1.2	Country which granted the Marketing Authorisation	Poland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ENALAPRIL
D.3.9.1	CAS number	75847-73-3
D.3.9.4	EV Substance Code	SUB06514MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart Failure with reduced ejection fraction.

E.1.1.1

Medical condition in easily understood language

Heart Failure with reduced ejection fraction.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	27.0
E.1.2	Level	PT
E.1.2	Classification code	10078289
E.1.2	Term	Heart failure with reduced ejection fraction
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary 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.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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

E.4

Principal 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.5.1

Primary end point(s)

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoint will be evaluate during visit 2-13.

E.5.2

Secondary 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 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.

E.5.2.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-10-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-04

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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