Clinical Trials Register

Summary
EudraCT Number:	2013-003800-38
Sponsor's Protocol Code Number:	SAFA-1-2014
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:	2013-12-09
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

2013-003800-38

A.3

Full title of the trial

The effects of tolvaptan on renal handling of water and sodium, vasoactive hormones and circulatory system, during basal conditions and during inhibition of the nitric oxide system in healthy subjects. A dose-response study.

Effekten af tolvaptan på nyrernes behandling af vand og natrium, vasoaktive hormoner samt kredsløbet, basalt og efter hæmning af nitrogenoxid-systemet hos raske forsøgspersoner. Et dosis-respons studie.

A.3.1

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

The effects of tolvaptan on renal handeling of water and salt, hormones in the blood and the circulation, during blocking of the nitric oxide (NO) system in healthy subjects. A dose-response study.

Effekten af tolvaptan på nyrernes behandling af vand og salt, hormoner i blodet samt kredsløbet ved samtidig blokering af nitrogenoxid( NO)-systemet hos raske forsøgspersoner. Et dosis-respons studie.

A.3.2

Name or abbreviated title of the trial where available

DOVA

A.4.1

Sponsor's protocol code number

SAFA-1-2014

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	Public and private 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	Lægårdvej 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	00457878436589
B.5.5	Fax number	004578436582
B.5.6	E-mail	safatherwani@hotmail.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	Samsca
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutival Europe Ltd Hunton House Highbridge Business Park Oxford Road Uxbridge Middlese
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	Tolvaptan
D.3.2	Product code	C03XA01
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	Tolvaptan
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	C03XA01
D.3.9.3	Other descriptive name	TOLVAPTAN
D.3.9.4	EV Substance Code	SUB22755
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	15 to 30
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

Hyponatremia
SIADH (Syndrome of Inappropriate Antidiuretic Hormone secretion)

Hyponatriæmi
SIADH (Syndrome of Inappropriate Antidiuretic Hormone secretion)

E.1.1.1

Medical condition in easily understood language

Decreased salt in blood
Overhydration

Lavt saltindhold i blodet
Overhydrering

E.1.1.2

Therapeutic area

Body processes [G] - Physiological processes [G07]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10021038
E.1.2	Term	Hyponatremia
E.1.2	System Organ Class	100000004861

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10040626
E.1.2	Term	SIADH
E.1.2	System Organ Class	100000004860

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the effects of tolvaptan on the nitric oxide system.

At undersøge effekten af tolvaptan på nitrogenoxid-systemet.

E.2.2

Secondary objectives of the trial

The purpose of the study is to measure the effects of tolvaptan on: (1) Renal handling of water and sodium (GFR, UV, CH2O, u-AQP2, u-ENaCγ, u-cAMP, CNa, FeNa, CK, FEK), (2) vasoactive hormones (PRC, p-AngII, p-Aldo , p-AVP, p-ANP, p-BNP and p-endothelial-I) and (3) Central hemodynamics (cBT, PWV and AI), basal and under basal conditions and during inhibition of the nitric oxide synthesis in healthy subjects in a dose-response study.

Formålet er at måle effekten af tolvaptan på nyrernes behandling af (1) vand og natrium (GFR, UV, CH20, u-AQP2, u-ENaCγ, u-cAMP, CNa, FENa, CK, FEK), (2) vasoaktive hormoner (PRC, p-AngII, p-Aldo, p-AVP, p-ANP, p-BNP og p-Endot-I), (3) den centrale hæmodynamik (cBT, PWV og AI), dels basalt, dels efter hæmning af nitrogenoxid syntesen hos raske forsøgspersoner i et dosis-respons studie.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Caucasian men and women
2) age 18-40 years
3)BMI between 18.5 and 30 kg/m2.

1) Kaukasiske mænd og kvinder
2) Alder 18-40 år
3) BMI mellem 18,5-30 kg/m2

E.4

Principal exclusion criteria

1) Arterial hypertension, defined as consultation blood pressure above 140 mmHg systolic and / or 90 mmHg diastolic. 2) Medically important or clinical signs of diseases of the heart, lungs, liver, endocrine organs and brain or neoplastic disease, 3) alcohol or drug abuse, 4) medical treatment except oral contraceptives, 5) smoking, 6) pregnancy or breastfeeding, 7) clinically important abnormalities in blood or urine sample at the inclusion 8) clinically important changes in the electrocardiogram, 9) blood donation for the past month prior to the examination days, and 10) allergy to tolvaptan.

1)Arteriel hypertension dvs. konsultationsblodtryk over 140 mmHg systolisk og/eller 90 mmHg diastolisk, 2) betydende kliniske tegn på hjertesygdom, sygdomme i lunger, lever, nyrer, endokrine organer eller hjernen samt neoplastiske lidelser, 3) alkoholmisbrug, dvs. >14 genstande/uge for kvinder og > 21 genstande/uge for mænd, 4) stofmisbrug, 5) medicinsk behandling fraset orale antikonceptiva, 6) rygning, 7) graviditet eller amning, 8) klinisk betydende abnorme fund ved blodprøver (b-Hb, b-leukocytter, b-trombocytter, p-Na, p-K, p-albumin, p-creatinin, b-glucose, p-bilirubin, p-alaninaminotransferase (ALAT), p-basisk fosfatase, p-kolesterol) eller urinprøven (nitrit, leukocytter, blod, glukose og protein Hos kvinder foretages desuden graviditetstest) ved inklusionsundersøgelsen, 9) klinisk betydende kliniske forandringer i elektrokardiogram, 10) bloddonation indenfor den seneste måned inden undersøgelsesdagen i første forsøgssekvens, 11) allergi overfor Tolvaptan, 12) 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.5 End points

E.5.1

Primary end point(s)

CH2O ( free water clearance)

CH2O ( frit vands clearance)

E.5.1.1

Timepoint(s) of evaluation of this end point

End of study.

Ved forsøgets afslutning.

E.5.2

Secondary end point(s)

(1) Renal function (GFR, UV, CH2O, u-AQP2, u-ENaCγ, u-cAMP, CNa, FeNa, CK, FEK), (2) vasoactive hormones (PRC, p-AngII, p-Aldo , p-AVP, p-ANP, p-BNP and p-endothelial-I), (3) central hemodynamics (cBT, PWV and AI) amd (4)p-nitrite, p-nitrate, u-nitrite, u-nitrate.

1)Nyrefunktion: GFR, UV, CH20, u-AQP-2, u-ENaCγ, CNa, FENa, CK, FEK, 2)Hæmodynamik: cBT, PWV, AI, 3) Vasoaktive hormoner: PRC, p-AngII, p-Aldo, p-AVP, p-ANP, p-BNP og p-Endot-I, 4) p-nitrit, p-nitrat, u-nitrit, u-nitrat.

E.5.2.1

Timepoint(s) of evaluation of this end point

End of study

Ved forsøgets 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

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)

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 last visit of the last subject.

Sidste besøg af sidste forsøgsperson.

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)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

None.

Ingen.

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

2013-12-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-10-17

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