Clinical Trials Register

Summary
EudraCT Number:	2018-004159-19
Sponsor's Protocol Code Number:	2018-00938
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-06-03
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

Germany - BfArM

A.2

EudraCT number

2018-004159-19

A.3

Full title of the trial

Use of Copeptin Measurement after Arginine Infusion for the Diagnosis of Diabetes Insipidus - the CARGOx Study

Copeptin Messung nach Arginininfusion zur Diagnose des Diabetes insipidus (die CARGOx Studie)

A.3.1

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

Use of Copeptin Measurement after Arginine Infusion for the Diagnosis of Diabetes Insipidus - the CARGOx Study

Copeptin Messung nach Arginininfusion zur Diagnose des Diabetes insipidus (die CARGOx Studie)

A.3.2

Name or abbreviated title of the trial where available

CARGOx

A.4.1

Sponsor's protocol code number

2018-00938

A.5.4

Other Identifiers

Name:

clinicaltrials.gov

Number:

NCT03572166

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 Basel
B.1.3.4	Country	Switzerland
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	Swiss National Science Foundation
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Basel
B.5.2	Functional name of contact point	Andrea Widmer
B.5.3	Address:
B.5.3.1	Street Address	Petersgraben 4
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4031
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4161268 68 14

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	L-Arginin-Hydrochlorid 21 % Braun
D.2.1.1.2	Name of the Marketing Authorisation holder	B. Braun Melsungen AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	L-Arginin-Hydrochlorid 21 % Braun
D.3.2	Product code	3899.99.99
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Parenteral use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Argininhydrochlorid
D.3.9.1	CAS number	1119-34-2
D.3.9.3	Other descriptive name	ARGININE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB00579MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	210.7
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.2.1.1.1	Trade name	Natriumchlorid Braun 20%
D.2.1.1.2	Name of the Marketing Authorisation holder	B. Braun Melsungen AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Natriumchlorid Braun 20 %
D.3.2	Product code	6697716.01.00
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Parenteral use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Natriumchlorid
D.3.9.3	Other descriptive name	SODIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12581MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Polyuria-polydipsia syndrome (PPS) is divided into the three main entities central (complete or partial) diabetes insipidus (DI), nephrogenic DI and primary polydipsia (PP).

Polyurie-Polydipsie-Syndrom (zentraler Diabetes insipidus oder primäre Polydipsie).

E.1.1.1

Medical condition in easily understood language

The polyuria-polydipsia-syndrome includes central diabetes insipidus, a dysfunction of the pituitary gland and primary polydipsia, which is usually the result of a learned drinking behavior.

Das Polyurie-Polydipsie-Syndrom beinhaltet den zentralen Diabetes insipidus, eine Störung der Hirnanhangsdrüse und die primäre Polydipsie, welche das Resultat eines erlernten Trinkverhaltens ist.

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The aim of the study is to find a new, safe and easy-to-use diagnostic test for the diagnostic distinction between central diabetes insipidus and primary polydipsia. For that reason we compare the diagnostic accuracy of copeptin measurement after stimulation with arginine infusion to the current best diagnostic test copeptin measurement after hypertonic saline infusion.

Das Ziel der Studie ist einen neuen, sicheren und einfach zu verwendenden diagnostischen Test für die diagnostische Unterscheidung zwischen einem zentralen Diabetes insipidus und eine primären Polydipsie zu finden. Aus diesem Grund vergleichen wir die diagnostische Genauigkeit der Copeptin-Messung nach Stimulation mit Arginin-Infusion mit dem derzeit besten diagnostischen Test mit Messung des Copeptin nach hypertoner Kochsalzinfusion.

E.2.2

Secondary objectives of the trial

1. Abschätzung der Sensitivität, Spezifität und des positiven und negativen prädiktiven Wertes beider Diagnoseverfahren für jede Diagnose (primäre Polydipsie, partieller oder kompletter zentraler Diabetes insipidus) gemäß den empfohlenen diagnostischen Testkriterien und dem zuvor festgelegten Grenzwert.
2. Festlegung von diagnostischen Copeptin-Cut-Off-Werten für die Unterscheidung zwischen primärer Polydipsie, partiellem oder komplettem zentralem Diabetes insipidus
3. Vergleich der Symptome zwischen den beiden Tests
4. Vergleich der subjektiven Belastung zwischen den beiden Tests
5. Subjektive Testpräferenz
6. Vergleich der Kosteneffizienz zwischen den beiden Tests

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years  
2. Hypotonic polyuria / polydipsia syndrome defined as:
- polyuria >50ml/kg body weight/24h and polydipsia >3l /24h or known diabetes insipidus under treatment with DDAVP
- Urine-Osmolality <800mOsm/L

1. Alter ≥ 18 Jahre
2. Hypotones Polyurie / Polydipsie-Syndrom, definiert als:
- Polyurie> 50 ml / kg KG / 24h und Polydipsie> 3l / 24h oder bekannter Diabetes insipidus unter Behandlung mit DDAVP
- Urin-Osmolalität <800mOsm / L

E.4

Principal exclusion criteria

1. Polyuria / polydipsia secondary to diabetes mellitus, hypercalcemia or hypokalemia
2. Nephrogenic diabetes insipidus (defined as baseline copeptin level >21.4pmol/L)
3. Evidence of any acute illness
4. Epilepsy requiring treatment
5. Uncontrolled arterial hypertension (blood pressure >160/100mmHg at baseline)
6. Cardiac failure (NYHA III-IV)
7. Liver cirrhosis (Child B-C)
8. Uncorrected adrenal or thyroidal deficiency
9. Patients refusing or unable to give written informed consent
10. Pregnancy or breast feeding
11. End of life care

1. Polyurie / Polydipsie infolge von Diabetes mellitus, Hyperkalzämie oder Hypokaliämie
2. Nephrogener Diabetes insipidus (definiert als Basis-Copeptin-Spiegel> 21.4pmol / L)
3. Nachweis einer akuten Erkrankung
4. Behandlungsbedürftige Epilepsie
5. Unkontrollierte arterielle Hypertonie (Blutdruck> 160/100 mmHg bei Studienbeginn)
6. Herzversagen (NYHA III-IV)
7. Leberzirrhose (Child B-C)
8. Nicht behandelter Nebennierenhormon- oder Schilddrüsenhormonmangel
9. Patienten, die eine schriftliche Einwilligung nicht geben können oder wollen
10. Schwangerschaft oder Stillen
11. Palliative Behandlung

E.5 End points

E.5.1

Primary end point(s)

The primary outcome is the overall diagnostic accuracy – defined as the proportion of correct diagnoses – of each diagnostic procedure in differentiating patients with central diabetes insipidus from patients with primary polydipsia. Copeptin measurement after arginine-stimulation will be compared for non-inferiority to the current best diagnostic test copeptin measurement after hypertonic saline infusion.

Der primäre Endpunkt ist die allgemeine diagnostische Genauigkeit - definiert als der Anteil korrekter Diagnosen - für jedes diagnostische Verfahren bei der Differenzierung von Patienten mit zentralem Diabetes insipidus von Patienten mit primärer Polydipsie. Die Copeptin-Messung nach der Arginin-Stimulation wird verglichen mit der derzeit besten Testmethode, Copeptin-Messung nach hypertoner Kochsalzinfusion.

E.5.1.1

Timepoint(s) of evaluation of this end point

At follow up Evaluation after 3 months

Im Rahmen der Follow-up-Visite nach 3 Monaten.

E.5.2

Secondary end point(s)

1. Estimation of sensitivity, specificity, and positive- and negative predictive value of both diagnostic procedures for each diagnosis (Primary polydipsia, partial or complete central diabetes insipidus) according to recommended diagnostic test criteria and a priori defined cut-off value.
2. best fit diagnostic copeptin cut-off values for differentiation between each diagnosis (Primary polydipsia, partial or complete central diabetes insipidus) upon arginine stimulation and hypertonic saline infusion stimulation
3. Accuracy, sensitivity and specificity of the copeptin cut-offs for both tests.
4. Frequency and severity of thirst, headache, nausea, vertigo and general malaise, assessed by visual analogue scale (VAS) during the tests
5. subjective burden assessed by visual analogue scale (VAS) during the tests
6. frequency of test preference according to evaluation at follow up visit
7. Health care costs of both tests

1. Berechnung der Sensitivität, Spezifität und des positiven und negativen prädiktiven Wertes beider Diagnoseverfahren für jede Diagnose (Primäre Polydipsie, partieller oder vollständiger zentraler Diabetes insipidus) gemäß den empfohlenen diagnostischen Testkriterien und einem zuvor festgelegten Grenzwert.
2. Berechnung der am besten geeigneten diagnostischen Copeptin-Cut-off-Werte für die Differenzierung zwischen jeder Diagnose (primäre Polydipsie, partieller oder vollständiger zentraler Diabetes insipidus) bei Argininstimulation und Stimulation mit hypertoner Kochsalzlösung
3. Genauigkeit, Sensitivität und Spezifität der Copeptin-Cutoffs für beide Tests.
4. Häufigkeit des Auftretens und Schweregrad von Durst, Kopfschmerzen, Übelkeit, Schwindel und allgemeinem Unwohlsein, beurteilt durch visuelle Analogskala (VAS) während der Tests
5. subjektive Belastung anhand der visuellen Analogskala (VAS) während der Tests
6. Testpräferenz nach Auswertung bei der Follow-up-Visite
7. Gesundheitskosten für beide Tests

E.5.2.1

Timepoint(s) of evaluation of this end point

At 3 months follow-up-visit

Im Rahmen der Follow-up-Visite nach 3 Monaten.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Switzerland

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

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:

135

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

152

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)

Follow-up visit 3 months after diagnostics are completed.

Follow-up Visite 3 Monate nach Beendigung der Diagnostik.

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

2019-09-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Ongoing

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