Clinical Trials Register

Summary
EudraCT Number:	2012-001131-31
Sponsor's Protocol Code Number:	FHC-1-2012
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-06-14
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

Denmark - DHMA

A.2

EudraCT number

2012-001131-31

A.3

Full title of the trial

Effekts of nebivolol on the nitric oxide system in patients with essentiel hypertension

Effekten af nebivolol på NO-systemet hos patienter med essentiel hypertension

A.3.1

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

Effekts of nebivolol on the nitric oxide system in patients with high blood pressure

Effekten af nebivolol på NO-systemet hos patienter med forhøjet blodtryk

A.3.2

Name or abbreviated title of the trial where available

NEBI

A.4.1

Sponsor's protocol code number

FHC-1-2012

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	Department of Medical Research
B.1.3.4	Country	Denmark
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	Private and public funding
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Holstebro Hospital
B.5.2	Functional name of contact point	Department of Medical Research
B.5.3	Address:
B.5.3.1	Street Address	Laegaardvej 12
B.5.3.2	Town/ city	Holstebro
B.5.3.3	Post code	7500
B.5.3.4	Country	Denmark
B.5.4	Telephone number	4578436589
B.5.5	Fax number	4578436582
B.5.6	E-mail	frchri@rm.dk

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	Hypoloc
D.2.1.1.2	Name of the Marketing Authorisation holder	Menarini International Operations Luxembourg, S.A. 1, Avenue de la Gare L-1611 Luxembourg
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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
D.3.2	Product code	21458
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
D.3.9.1	CAS number	99200-09-6
D.3.9.3	Other descriptive name	Nebivolol
D.3.9.4	EV Substance Code	SUB09175MIG
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

Essential Hypertension

Essentiel hypertension

E.1.1.1

Medical condition in easily understood language

High blood pressure

Forhøjet blodtryk

E.1.1.2

Therapeutic area

Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10015488
E.1.2	Term	Essential hypertension
E.1.2	System Organ Class	10047065 - Vascular 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

The purpose is to investigate if nebivolol is involded in regulation of systemic and renal nitric oxide system

Formålet er at klarlægge om nebivolol er involveret produktion / regulation af kroppens NO-system.

E.2.2

Secondary objectives of the trial

The objective is to measure the effect of nebivolol on L-NMMA induced changes in the renal tubular transport of sodium and water (FENa, u-ENaCβ, u-ENaCγ, CH2O, u-AQP2), hemodynamics (SBP, DBP, hjertefrekvens, central BP, AI) and plasma concentrations of vasoactive homones (renin, aldosterone, atrial natriuretic peptide, brain natriuretic peptide, vasopressin, endothelin) in patients withessential hypertension.

Formålet er at måle effekten af nebivolol på L-NMMA inducerede ændringer i den renale tubulære transport af natrium og vand (FENa, u-ENaCβ, u-ENaCγ, CH2O, u-AQP2), central hæmodynamik (SBP, DBP, hjertefrekvens, central BP, AI) og vasoaktive hormoner (PRC, p-ang-II, p-Aldo, p-ANP, p-BNP, p-AVP, p-Endot) hos patienter med essentiel hypertension.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Men and women
• Age 40-70 years
• Ambulatory blood pressure > 135 mmHg systolic and/or 85 mmHg diastolic in daytime during amlodipine treatment with either 5 or 10 mg
• Informed consent
• Fertiel women must take contraception

• Mænd og kvinder
• Alder 40-70 år
• Forhøjet blodtryk under amlodipin 5 eller 10 mg daglig ved døgnblodtrykssmåling, dvs > over 135 mmHg systolisk og/eller 85 mmHg diastolisk i dagtiden.
• Underskrevet samtykke
• Fertile kvinder skal anvende sikker antikonception i hele forsøgsperioden, og i en periode efterfølgende, der svarer til 5 gange plasma halveringstiden (sikker antikonception defineres som: p-piller, spiral, depotinjektion af gestagen, subdermal implantation, hormonal vaginalring samt transdermal depotplaster)

E.4

Principal exclusion criteria

• Diabetes mellitus
• eGFR < 30
• Albuminuria > 1,5 g/L
• Renografi indicating sekundary hypertension
• clinical signs of pheoocromocyta eller abnormal p-metanefrin.
• Clinical important signs of lung, heart, liver or thyroid disease l
• Clinical important abnormalities in screening blood samples and ECG
• Clinical important hypokalimia
• Clinical important abnormalities in plasma calcium
• Neplastic diseases
• Alcoholabuse
• Drug or medical abuse
• Pregnancy or nursing
• Intolerans towards nebivolol
• Bloddonationwithin a month
• Uacceptable side effects to amlodipine
• Ambulatory BP above 170/105 mmHg on hightest dose amlodipine 10mg)

• Diabetes mellitus
• eGFR < 30
• Albuminuri > 1,5 g/L
• Renografi med mistanke om renovaskulær hypertension eller afløbshindring
• Klinisk mistanke om phæocromocytom eller abnorm p-metanefrin.
• Klinisk betydende lunge-, hjerte-, lever- og stofskiftesygdomme
• Klinisk betydende afvigelser i screeningsblodprøver samt EKG
• Klinisk betydende hypokaliæmi
• Klinisk betydende afvigelser i plasma calcium
• Aktuelle neoplastiske lidelser
• Alkoholmisbrug, dvs. >14 genstande/uge for kvinder og > 21 genstande/uge for mænd
• Stofmisbrug
• Medicinmisbrug
• Graviditet eller amning
• Intolerans overfor nebivolol
• Bloddonation indenfor den seneste måned inden undersøgelsesdagen i første forsøgssekvens.
• Uacceptable bivirkninger af amlodipin
• Ambulant blodtryk ved gentagne ambulante målinger er over 170/105 mmHg på højeste dosis amlodipin (10mg)

E.5 End points

E.5.1

Primary end point(s)

Fractional excretion of sodium (FENa)

Fraktionelle salt udskillelse

E.5.1.1

Timepoint(s) of evaluation of this end point

End of trial

Afslutning

E.5.2

Secondary end point(s)

Systolic BP, Diastolic BP, central BP, Augmentation Index (AI), Arteriel stiffness (Pulse wave velocity).
Plasma concentrations of renin, aldosterone, atrial natriuretic peptide, brain natriuretic peptide, vasopressin, endothelin
Urinary flow, free water clearance (CH2O), glomerular filtration rate (GFR)
Protein excretion from epithelial sodium channels (u- EnaCβ, u- EnaCγ) and aquaporins (U-AQP2)

SBP, DBP, central BP, Augmentation Index (AI), Arteriel stivhed (Pulsbølgehastighed)
PRC, p-Ang-II, p-Aldo, p-ANP, p-BNP, p-AVP, p-Endothelin
Urinflow, CH2O, GFR
U-AQP2, u- EnaCβ, u- EnaCγ

E.5.2.1

Timepoint(s) of evaluation of this end point

End of trial

Afslutning

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

E.6.5

Efficacy

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.6

Cross over

Yes

E.8.1.7

Other

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

Yes

E.8.4

The trial involves multiple sites in the 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

Yes

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

The end of the last visit of the last subject

Sidste forsøgspersons sidste besøg

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

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.4.2.1

In the EEA

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)

Normal treatment of the condition

Normal behandling for sygdommen

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

2012-06-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-04-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-09-12

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