Clinical Trials Register

Summary
EudraCT Number:	2019-002607-18
Sponsor's Protocol Code Number:	AmiloridNS-01
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-11-14
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

Germany - BfArM

A.2

EudraCT number

2019-002607-18

A.3

Full title of the trial

Randomized, controlled interventional trial to investigate the efficacy of amiloride for the treatment of edema in human nephrotic syndrome

Randomisierte, kontrollierte Interventionsstudie zur Untersuchung der Effektivität von Amilorid zur Behandlung der Ödeme beim nephrotischen Syndrom des Menschen

A.3.1

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

Clinical study on the efficacy of amiloride for the treatment of edema in nephrotic syndrome

Klinische Studie über die Wirksamkeit von Amilorid zur Behandlung der Ödeme beim nephrotischen Syndrom

A.3.2

Name or abbreviated title of the trial where available

Amiloride in nephrotic syndrome

A.4.1

Sponsor's protocol code number

AmiloridNS-01

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 Tuebingen
B.1.3.4	Country	Germany
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	Faculty of Medicine University of Tübingen
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Univerity Hospital Tuebingen
B.5.2	Functional name of contact point	Secretary's office Dep. Int.Med. IV
B.5.3	Address:
B.5.3.1	Street Address	Otfried-Mueller-Strasse 10
B.5.3.2	Town/ city	Tuebingen
B.5.3.3	Post code	72076
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49707129 83172
B.5.5	Fax number	+49707129 3174

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	Modamide 5 mg tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratoires GERDA, 24 rue Erlanger, 75016 Paris / France
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	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	AMILORIDE
D.3.9.1	CAS number	2609-46-3
D.3.9.4	EV Substance Code	SUB05433MIG
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.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	Furosemid-ratiopharm® 40 mg Tabletten
D.2.1.1.2	Name of the Marketing Authorisation holder	ratiopharm GmbH, Graf-Arco-Straße 3, 89079 Ulm, Germany
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	Furosemid-ratiopharm® 40 mgTabletten
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	FUROSEMIDE
D.3.9.2	Current sponsor code	Furosemide
D.3.9.4	EV Substance Code	SUB07849MIG
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	40
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

Nephrotic syndrome

Nephrotisches Syndrom

E.1.1.1

Medical condition in easily understood language

Nephrotic syndrome

Nephrotisches Syndrom

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Objective of the study is to prove the efficacy and superiority of amiloride for reduction of edema and overhydration in human nephrotic syndrome in comparison to standard medication with furosemide.

Ziel der Studie ist es, die Wirksamkeit und Überlegenheit von Amilorid zur Reduktion von Ödemen und Überwässerung beim humanen nephrotischen Syndrom im Vergleich zu der Standardmedikation mit Furosemid nachzuweisen.

E.2.2

Secondary objectives of the trial

Not applicable.

Nicht zutreffend.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Acute nephrotic syndrome with proteinuria > 3 g/day and formation of edema.
2. Age ≥ 18 years at the time of signing the informed consent.
3. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
4. Ability to adhere to the study visit schedule and other protocol requirements.
5. Subject (male or female) is willing to use highly effective methods of contraception.
6. Female Patients of childbearing potential (WOCBP) must agree to pregnancy testing within 7 days from first dosing of IMP.
7. Female Patients must agree to abstain from breastfeeding during study participation and 28 days after study drug discontinuation.
8. All subjects must agree not to share medication.

1. Akutes nephrotisches Syndrom mit Proteinurie > 3 g/Tag und Auftreten von Ödemen.
2. Alter ≥ 18 Jahre zum Zeitpunkt des Unterzeichnens der Einverständniserklärung.
3. Verstehen und freiwilliges Unterschrieben der Einverständniserklärung vor jeglicher studienassoziierten Untersuchung/Prozedur.
4. Fähigkeit, den Studienbesuchsplan und andere Protokollanforderungen einzuhalten.
5. Der Proband (männlich oder weiblich) ist bereit, hochwirksame Verhütungsmethoden anzuwenden.
6. Weibliche Patientinnen im gebärfähigen Alter (WOCBP) müssen sich mit einem Schwangerschaftstest innerhalb von 7 Tagen nach der ersten Gabe des IMP einverstanden erklären.
7. Patientinnen müssen sich einverstanden erklären, während der Teilnahme an der Studie und 28 Tage nach Beendigung der Studie auf das Stillen zu verzichten.
8. Alle Probanden müssen damit einverstanden sein, die Medikamente nicht weiterzugeben.

E.4

Principal exclusion criteria

1. Plasma Creatinine > 1,5 mg/dl or acute kidney injury KDIGO stage 2 or 3
2. Hypotension, systolic blood pressure < 90 mmHg
3. Hyperkalemia, plasma potassium concentration > 4.8 mmol/l
4. Hypokalemia, plasma potassium concentration < 3.3 mmol/l
5. Hyponatremia, plasma sodium concentration < 128 mmol/l
6. Hypercalcemia, ionized calcium > 2.0 mmol/l or total albumin corrected calcium > 3.0 mmol/
7. Signs of cardiac decompensation (orthopnoe, dyspnoe NYHA IV)
8. Hepatic coma or precoma
9. Symptoms of gout
10. Current therapy with potassium-sparing diuretics (e.g. spironolactone) or potassium supplements
11. Diuretic therapy in the last 48 hours before enrollment
12. Women during pregnancy and lactation
13. History of hypersensitivity to the investigational medicinal product, comparator or co-medication or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product, comparator or co-medication.
14. Any other clinical condition that would jeopardize the patient’s safety while participating in this clinical trial
15. Active participation in other clinical trials or observation period of competing trials.

1. Plasma Kreatinin > 1,5 mg/dl oder Akute Nierenschädigung KDIGO Stadium 2 oder 3
2. Hypotonie, systolischer Blutdruck < 90 mmHg
3. Hyperkaliämie, Plasma Kalium Konzentration > 4.8 mmol/l
4. Hypokaliämie, Plasma Kalium Konzentration < 3.3 mmol/l
5. Hyponatriämie, Plasma Natrium Konzentration < 128 mmol/l
6. Hypercalcämie, ionisiertes Calcium > 2.0 mmol/l oder gesamtes Albumin-korrigiertes Calcium > 3.0 mmol/
7. Zeichen der kardialen Dekompensation (Orthopnoe, Dyspnoe NYHA IV)
8. Hepatisches Koma oder Präkoma
9. Gichtsymptomatik
10. Gegenwärtige Therapie mit Kalium sparenden Diuretika (z.B. Spironolacton) oder Kaliumsubstitution
11. Frauen während der Schwangerschaft und Stillzeit
12. Bekannte Unverträglichkeit für das Prüfpräparat, Vergleichspräparat oder die Co-Medikation oder für jedes Arzneimittel mit ähnlicher chemischer Struktur oder für jeden Hilfsstoff, der in der pharmazeutischen Form des Prüfpräparats, Vergleichspräparats oder der Co-Medikation enthalten ist
13. Jeder andere klinische Zustand, der die Sicherheit des Patienten während der Teilnahme an dieser klinischen Studie gefährden würde
14. Aktive Teilnahme an anderen klinischen Studien oder Beobachtungszeitraum von konkurrierenden Studien.

E.5 End points

E.5.1

Primary end point(s)

Decrease of overhydration (OH) after 8 days, compared to baseline. OH is measured using bioimpedance spectroscopy with the device Body Composition Monitor (Fresenius Medical Care AG & Co; BCM), and expressed as percent of extracellular water (% ECW).

Abnahme der Überwässerung (OH) nach 8 Tagen, verglichen zum Ausgangswert. OH wird gemessen mittels Bioimpedanzspektroskopie mit dem Gerät Body Composition Monitor (Fresenius Medical Care AG & Co; BCM), und wird als Prozent des extrazellulärem Wassers angegeben (% ECW).

E.5.1.1

Timepoint(s) of evaluation of this end point

After 8 days of study medication.

Nach 8 Tagen mit Studienmedikation.

E.5.2

Secondary end point(s)

1. Decrease of OH after 16 days
2. Decrease of body weight after 8 and 16 days
3. Decrease of edema circumference after 8 and 16 days
4. Decrease of systolic and diastolic blood pressure after 8 and 16 days
5. Increase of urine volume and natriuresis after 8 and 16 days
6. Course of plasma renin activity and serum aldosterone concentration after 8 and 16 days
7. Number of required changes of dose of study medication
8. Need for co-medication with HCT after 8 days
9. Occurrence of adverse events

1. Abnahme der OH nach 16 Tagen
2. Abnahme des Körpergewichts nach 8 und 16 Tagen
3. Abnahme des Ödemumfangs nach 8 und 16 Tagen
4. Abnahme des systolischen und diastolischen Blutdrucks nach 8 und 16 Tagen
5. Zunahme des Urinvolumens und der Narium-Ausschieidung nach 8 und 16 Tagen
6. Verlauf der Plasma Renin Aktivität und der Serum Aldosteron Konzentration nach 8 und 16 Tagen
7. Anzahl an notwendigen Dosisanpassungen der Studienmedikation
8. Bedarf an Ko-Medikation mit HCT nach 8 Tagen
9. Auftreten von unerwünschten Ereignissen

E.5.2.1

Timepoint(s) of evaluation of this end point

After 8 and 16 days of study medication.

Nach 8 und 16 Tagen mit Studienmedikation.

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)

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

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

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

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)

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.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)

At the end of study tretmant, further medication for nephrotic syndrome will be determined by the nephrologist of the patient’s medical practice or the attending physician in the nephrologic outpatient clinic of the University Hospital Tübingen. There are no special requirements regarding the termination of study medication.

Am Ende der Studienmedikaiton wird die weitere Behandlung für das nephrotische Syndrom durch den niedergelassenen Nephrologen des Patienten oder den behandelnden Arzt in der nephrologischen Ambulanz des Universitätsklinikums Tübingen festgelegt. Es gibt keine besonderen Anforderungen bezüglich der Beendigung der Studienmedikation.

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

2020-02-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-04-30

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