Clinical Trials Register

Summary
EudraCT Number:	2020-003881-38
Sponsor's Protocol Code Number:	ESONIA
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:	2021-01-15
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

2020-003881-38

A.3

Full title of the trial

ESONIA - The evaluation of Efficacy and Safety Of Nebivolol in the treatment of arterial hypertension In Adolescents

ESONIA - Ocena skuteczności i bezpieczeństwa nebiwololu w leczeniu nadciśnienia tętniczego u nastolatków.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

ESONIA - The evaluation of Efficacy and Safety Of Nebivolol in the treatment of arterial hypertension In Adolescents

ESONIA - Ocena skuteczności i bezpieczeństwa nebiwololu w leczeniu nadciśnienia tętniczego u nastolatków.

A.3.2

Name or abbreviated title of the trial where available

ESONIA

A.4.1

Sponsor's protocol code number

ESONIA

A.5.4

Other Identifiers

Name:

Protocol identifier

Number:

ESONIA/01/2020

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	Warszawski Uniwersytet Medyczny
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	Agencja Badań Medycznych
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	Dr hab. n. med. Małgorzata Pańczyk-Tomaszewska
B.5.2	Functional name of contact point	Punkt Informacyjny Badania Kliniczn
B.5.3	Address:
B.5.3.1	Street Address	63a, Żwirki i Wigury
B.5.3.2	Town/ city	Warszawa
B.5.3.3	Post code	02-091
B.5.3.4	Country	Poland
B.5.4	Telephone number	4822317 96 53
B.5.5	Fax number	4822317 99 54
B.5.6	E-mail	mpanczyk1@wum.edu.pl

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	Nebilenin
D.2.1.1.2	Name of the Marketing Authorisation holder	ADAMED Sp. z o.o.
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.3.1	Product name	Nebivolol 5 mg
D.3.4	Pharmaceutical form	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	NEBIVOLOL HYDROCHLORIDE
D.3.9.1	CAS number	152520-56-4
D.3.9.4	EV Substance Code	SUB14632MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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	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

Arterial hypertension in adolescents

Nadciśnienie tętnicze u nastolatków

E.1.1.1

Medical condition in easily understood language

Arterial hypertension in adolescents

Nadciśnienie tętnicze u nastolatków

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10081425
E.1.2	Term	Arterial hypertension
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. Evaluation of the effect of nebivolol on peripheral arterial blood pressure assessed in oscillometric measurements at the in-patient visits in adolescents with hypertension.
2. Safety evaluation of nebivolol in adolescents with hypertension.

ocena wpływu leku nebiwolol na ciśnienia tętnicze obwodowe oceniane w oscylometrycznym pomiarze gabinetowym u nastolatków z nadciśnieniem tętniczym,
ocena bezpieczeństwa leku nebiwolol u nastolatków z nadciśnieniem tętniczym.

E.2.2

Secondary objectives of the trial

Assessment of the effect of nebivolol on blood pressure in the ABPM measurements (ambulatory blood pressure monitoring).

ocena wpływu leku nebiwolol na ciśnienie w badaniu ABPM (ang. ambulatory blood pressure monitoring)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age 12-17 years old, body weight ≥ 40 kg
2. Arterial hypertension diagnosed according to the Pediatric Division of the Polish Society of Hypertension (PTNT) from a year 2018.
3. Indication for the pharmacological treatment in children with hypertension according to the PTNT criteria: primary arterial hypertension that persists despite a 6-12 month of non-pharmacological regime; symptomatic, with organ changes in no more then one organ (evaluated within last three months); secondary, with chronic kidney disease in the stadium 1G-2G
4. No contraindication to postpone or withold a hypertension treatment for 6 weeks based on investigator’s judgement
5. Informed consent signed by the participant of the study and their legal guardian.

• wiek 12-17 lat, masa ciała ≥ 40 kg
• nadciśnienie tętnicze zdiagnozowane wg zaleceń Sekcji Pediatrycznej Polskiego Towarzystwa
• Nadciśnienia Tętniczego (PTNT) z roku 2018
• Wskazanie do farmakologicznego leczenia hipotensyjnego u dziecka z nadciśnieniem tętniczym wg kryteriów PTNT
• Możliwość odroczenia lub odstawienia leczenia hipotensyjnego na 6 tygodni w opinii badacza

E.4

Principal exclusion criteria

1. Hypersensitivity to the active ingredient or any excipients.
2. Acquired or congenital heart defects including coarctation of the aorta (also after succesfull medical treatment), congestive heart failure, cardiomyopathy, II-IIIrd degree atrioventricular block or other clinically relevant heart rhythm disorders (sick sinus syndrom including sinoatrial block, bradycardia with less then 60 beats per minute), bronchial asthma or repetetive episodes of obstruction in the medical record.
3. Chronic kidney disease in the stadium ≥3G defined accroding to KDIGO criteria, kidney transplantation, kidney disease during exacerbation (in ex. nephrotic syndrome) or acute kidney disease ( in ex. post-infectious glomerulonephritis) or with hypoalbuminemia (< 2,5 g/dl)
4. Diabetes
5. Symptomatic arterial hypertension requiring immediate antihypertensive treatment or hypertensive crisis, hypertension treated with ≥2 antihypertensive drugs
6. Organ changes in more then one target organ (left ventricular hypertrophy, microalbuminuria, fundus changes) or severe left ventricular hypertrophy (defined as left ventricular mass index > 51 g/m2,7) or severe fundus changes (III-IVth degree according to Keitha-Wegenera-Bakera)
7. Hepatic disfunction/hepatic disease defined as alanine or asparagine transferase activity or total bilirubine level > 2 x upper normal range
8. Other sever disease that can have an impact on the results or interpretaion of the study
9. Treatment with antipsychotic or antidepressant drugs
10. Treatment with sympathomimetic drugs (in systemic use)
11. Participation in other clinical trial in the last 30 days (excluding non-interventional and observational studies)
12. Pregnancy and lactation period with breast feeding (blood pregnancy test for beta HCG is performer at the study beginning)
13. Active infection with fever at the randomization visit (criterium for a temporary exclusion)

• nadwrażliwość na substancję czynną lub jakąkolwiek substancję pomocniczą
• nabyte lub wrodzone wady serca w tym koarktacja aorty (także po skutecznym leczeniu zabiegowym), zastoinowa niewydolność krążenia, kardiomiopatia, blok przedsionkowo-komorowy II-III st. lub inne klinicznie istotne zaburzenia rytmu (zespół chorego węzła zatokowego w tym blok zatokowo-przedsionkowy, bradykardia < 60 uderzeń/minutę), astma oskrzelowa lub nawracające epizody obturacji w wywiadzie
• przewlekła choroba nerek w stadium ≥3G definiowana wg kryteriów KDIGO , stan po przeszczepieniu nerki, choroba nerek w okresie zaostrzenia (np. zespół nerczycowy w rzucie) lub ostra choroba nerek (np. ostre poinfekcyjne kłębuszkowe zapalenie nerek) lub z hipoalbuminemią (< 2,5 g/dl)
• cukrzyca
• objawowe NT nakazujące natychmiastowe leczenie hipotensyjne lub przełom nadciśnieniowy, NT leczone ≥2 lekami hipotensyjnymi
• występowanie zmian narządowych w >1 narządzie docelowym (przerost lewej komory serca, mikroalbuminuria, zmiany na dnie oczu) lub występowanie ciężkiego przerostu lewej komory (definiowanego jako indeks masy lewej komory > 51 g/m) lub ciężkich zmian na dnie oczu (III-IV stopień wg Keitha-Wegenera-Bakera)
• dysfunkcja wątroby/choroba wątroby definiowana jako aktywność transaminazy alaninowej lub asparaginowej lub całkowita bilirubina > 2 x górny zakres normy
• inna ciężka choroba mogąca mieć wpływ na wyniki lub interpretację wyników badania
• przyjmowanie leków przeciwpsychotycznych lub przeciwdepresyjnych
• przyjmowanie leków sympatykomimetycznych (podawanych systemowo)
• udział w okresie ostatnich 30 dni w innym badaniu klinicznym (nie dotyczy chorych uczestniczących w badaniach obserwacyjnych i nieinterwencyjnych)
• ciąża lub karmienie (test ciążowy z krwi – stężenie beta HCG przed rozpoczęciem badania
• aktywna infekcja z gorączką w momencie randomizacji (kryterium wykluczające przejściowe)

E.5 End points

E.5.1

Primary end point(s)

1. Number of patients with normalization of blood pressure assessed at the in-patient visits at the end of the II period of the study (6 weeks) in each subgroup (A-B)
2. Number of patients with normalization of blood pressure assessed at the in-patient visits during the III period of the study (at week 38)
3. Number of patients with adverse events and serious adverse events in each subgroup (A-B) in the II period of the study
4. Number of patients with adverse events and serious adverse events in the III period of the study.

1. liczba pacjentów, u których doszło do normalizacji ciśnienia tętniczego ocenianego w pomiarze gabinetowym na koniec II okresu badania (6 tydzień) w każdej z grup (A-B)
2. liczba pacjentów, u których doszło do normalizacji ciśnienia tętniczego ocenianego w pomiarze gabinetowym w III okresie badania (38 tydzień)
3. liczba pacjentów, u których stwierdzono zdarzenia niepożądane i ciężkie zdarzenia niepożądane na zakończenie II okresu badania w każdej z grup (A-B).
4. liczba pacjentów, u których stwierdzono zdarzenia niepożądane i ciężkie zdarzenia niepożądane w III okresie badania.

E.5.1.1

Timepoint(s) of evaluation of this end point

week 6th (endpoint 1 and 3) and week 38th (endpoint 2 and 4)

tydzień 6 (endpoint 1 i 3) i tydzień 38 (endpoint 2 i 4)

E.5.2

Secondary end point(s)

1. Number of patients with normalization of blood pressure evaluated through ABPM (ambulatory blood pressure monitoring) measurements in each study subgroup (A-B) at the end of II study period (week 6) and at the end of III study period among all participants.
2. Change in mean and percentile values (Z-score) of systolic, diastolic and mean pressure assessed at the in-patient visit measurements and through ABPM tests in the second period of the study (week 6) in each subgroup (A-B) and in the third period of the study (week 38) among all participants.

1. liczba pacjentów, u których doszło do znormalizowania ciśnienia tętniczego ocenianego w badaniu ABPM na koniec II okresu badania (6 tydzień) w każdej z grup (A-B) oraz w III okresie badania u wszystkich pacjentów (38 tydzień)
2. zmiana w wartości średniej i centylowej (Z-score) ciśnienia skurczowego, rozkurczowego i średniego ocenianego w pomiarze gabinetowym i w badaniu ABPM w II okresie badania (6 tydzień) w każdej z grup (A-B) oraz w III okresie badania (38 tydzień) w badanej grupie

E.5.2.1

Timepoint(s) of evaluation of this end point

week 6th and week 38th

tydzień 6 i tydzień 38

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

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

Yes

E.8.1.7.1

Other trial design description

Trzy etapy: 1. Wash-out, 2. Podwójnie ślepa próba, 3. Nebiwolol na zasadzie otwartej próby

Three periods: 1 wash-out, 2. doble blind trial, 3: open-label trial nebiwolol only

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

150

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

150

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-01-15.

Yes

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

150

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)

None - standard treatment

Brak - leczenie zgodnie ze standardem

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

2022-02-21

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

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

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