Clinical Trials Register

Summary
EudraCT Number:	2018-001874-89
Sponsor's Protocol Code Number:	ZKSJ0112_ARISS
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-11-19
Trial results	View 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 - PEI

A.2

EudraCT number

2018-001874-89

A.3

Full title of the trial

Randomised controlled multicentre study of albumin replacement therapy in septic shock

Randomisierte kontrollierte multizentrische Studie zur
Albuminersatztherapie im septischen Schock

A.3.1

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

A Clinical Study of Replacement with Human Albumin in Patients with
Septic shock

Klinische Studie zur Behandlung mit Humanalbumin bei Patienten mit
Septischem Schock

A.3.2

Name or abbreviated title of the trial where available

ARISS

A.4.1

Sponsor's protocol code number

ZKSJ0112_ARISS

A.5.4

Other Identifiers

Name:

ZKSJ0112_ARISS

Number:

ZKSJ0112

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	Friedrich-Schiller-Universität Jena
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	Deutsche Forschungsgemeinschaft (DFG)
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Grifols S.A.
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Department of Anesthesiology and Intensive Care, Uniklinikum Jena
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	Universitätsklinikum Jena, Zentrum für Klinische Studien
B.5.2	Functional name of contact point	Center for Clinical Studies
B.5.3	Address:
B.5.3.1	Street Address	S.-Allende-Platz 27
B.5.3.2	Town/ city	Jena
B.5.3.3	Post code	07747
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049036419396652
B.5.5	Fax number	0049036419399969
B.5.6	E-mail	ZKS-Projektmanagement@med.uni-jena.de

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	Albutein 200 g/l, Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	Grifols Deutschland GmbH
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	Albutein 200g/l
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Albumin (human)
D.3.9.3	Other descriptive name	ALBUMIN
D.3.9.4	EV Substance Code	SUB20532
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	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	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	Plasbumin 20, Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	Grifols Deutschland GmbH
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	Plasbumin 20
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Albumin (human)
D.3.9.3	Other descriptive name	ALBUMIN
D.3.9.4	EV Substance Code	SUB20532
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	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Septic Shock

Septischer Schock

E.1.1.1

Medical condition in easily understood language

Infection associated failure of the performance of the heart and blood vessels

Infektionsassoziertes Herz-Kreislaufversagen

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10001559
E.1.2	Term	Albumin abnormal
E.1.2	System Organ Class	100000004848

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10035167
E.1.2	Term	Plasma albumin abnormal
E.1.2	System Organ Class	100000004848

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 whether albumin administration and maintenance of serum albumin concentrations of at least 30 g/L in the ICU for up to 28 days after the onset of septic shock, will reduce total 90-day mortality compared to volume replacement therapy without albumin

Untersuchung, ob nach Eintritt des septischen Schocks die Albumingabe und die Aufrechterhaltung eines Albumin-Serumwerts von mindestens 30 g/l auf Intensivstation für bis zu 28 Tagen im Vergleich zu Volumenersatztherapie ohne Albumin die 90-Tage-Gesamtmortalität verringern wird

E.2.2

Secondary objectives of the trial

- To investigate whether albumin administration and maintenance of serum albumin concentrations of at least 30 g/L in the ICU for up to 28 days after the onset of septic shock would influence ICU, hospital, 28- and 60-day mortality rates, rates of organ dysfunction/failure as assessed by the SOFA score, ICU/hospital lengths of stay, ventilator and vasopressor-free days.
- Cost-benefit analysis of volume replacement therapy from ICU admission until maximum day 28

- Untersuchung, ob nach Eintritt des septischen Schocks die Albumingabe und die Aufrechterhaltung eines Albumin-Serumwerts von mindestens 30 g/l auf der Intensivstation für bis zu 28 Tagen die 28- bzw. 60-Tage-Mortalität, die Mortalitätsraten auf der Intensivstation und während des Krankenhausaufenthaltes, Organdysfunktion/-versagen nach SOFA-Score und Intensivstation- bzw. Krankenhausverweildauer, die Anzahl der Tage ohne Beatmungspflicht und ohne Vasopressorgabe beeinflussen kann
- Kosten-Nutzen-Analyse der Volumenersatztherapie des ersten ITS-Aufenthaltes bis maximal Tag 28

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients who meet all the following inclusion criteria may be included in this clinical trial:
1) Presence of septic shock that meets all the following criteria:
o Clinically possible, probable or microbiologically confirmed infection in accordance with the definitions of the "International Sepsis Forum (ISF)"
o Despite adequate volume therapy, vasopressors are required to maintain mean arterial pressure (MAP) ≥ 65 mm Hg for at least 1 hour
o Serum lactate concentration > 2 mmol/l (18 mg/dl) despite adequate volume therapy
2) Onset of septic shock less than 24 hours prior to study inclusion, so that administration of the initial dose of the trial product is possible within 6-24 hours after the onset of septic shock in the albumin group
3) Age: ≥ 18 years
4) Written informed consent of the patient or his/her legal representative (guardian) or confirmation of the urgency of participation in the clinical trial and the possible benefit to the patient by an independent consultant or the implementation of other established procedures according to the local regulations of the contributing centre to include patients who are unable to provide informed consent in whom subsequent consent may be obtained retrospectively
5) Patient of childbearing age: negative pregnancy test

Personen, die alle der folgenden Einschlusskriterien erfüllen, können Teilnehmer an dieser klinischen Prüfung sein:
1) Vorliegen eines septischen Schocks, bei dem alle der folgenden Kriterien erfüllt sind:
o klinisch mögliche bzw. wahrscheinliche oder mikrobiologisch gesicherte Infektion unter Beachtung der Definitionen des „International-Sepsis-Forums (ISF)“
o trotz adäquater Volumentherapie ist für mindestens 1 Stunde die Aufrechterhaltung eines arteriellen Mitteldruckes (MAP) ≥ 65 mm Hg nur unter Einsatz von Vasopressoren möglich
o Serum-Laktatspiegel > 2 mmol/l (18 mg/dl) trotz adäquater Volumentherapie
2) Beginn des septischen Schocks vor weniger als 24 h, so dass Beginn der Gabe der Startdosis des Prüfpräparates in der Albumingruppe innerhalb von 6-24 h nach Beginn des septischen Schocks möglich sein wird
3) Alter: ≥ 18 Jahre
4) schriftliche Einwilligung des Patienten oder seines Bevollmächtigten oder seines gesetzlichen Vertreters (Betreuers) bzw. Bestätigung der Dringlichkeit der Teilnahme an der klinischen Prüfung mit möglichem Nutzen für den Patienten durch unabhängigen Konsiliararzt oder Anwendung einer im Prüfzentrum etablierten Vorgehensweise zum Einschluß einwilligungsunfähiger Patienten mit nachträglicher Einholung einer Einwilligung
5) Patientin im gebärfähigen Alter: negativer Schwangerschaftstest

E.4

Principal exclusion criteria

Patients who meet any of the following exclusion criteria cannot be included in the trial:
1) Moribund conditions with life expectancy less than 28 days due to secondary diseases or advanced malignant disease and palliative situations with life expectancy less than 6 months
2) "End of life" decisions made before obtaining informed consent: "Do Not Resuscitate (DNR)" and "Withhold/Withdraw Life-Sustaining measures"
3) Previous participation in the study
4) Participation in another interventional clinical trial within the past 3 months
5) States of shock that are explainable by other causes, e.g. cardiogenic shock, anaphylactic shock, neurogenic shock
6) History of hypersensitivity to albumin or any other component of the trial product, e.g., sodium caprylate, sodium N-acetyltryptophanate
7) Disease in which the use of albumin may be deleterious, e.g., decompensated heart failure or traumatic brain injury
8) Disease situations in which albumin administration may be advantageous, e.g., hepatorenal syndrome, nephrosis, burns, and intestinal malabsorption syndrome
9) Lactation

Personen, auf die eines der folgenden Ausschlusskriterien zutrifft, können nicht in die klinische Prüfung eingeschlossen werden:
1) infauste Prognose mit Lebenserwartung unter 28 Tagen aufgrund von Nebenerkrankungen bzw. fortgeschrittene maligne Erkrankung und palliative Situation mit Lebenserwartung unter 6 Monaten
2) „End of life“- Entscheidungen vor Einwilligung bekannt: „Do Not Resuscitate (DNR)“ und „Withhold/Withdraw of Life-Sustaining measures“
3) vorherige Teilnahme an dieser Studie
4) Teilnahme an einer anderen interventionellen klinischen Prüfung innerhalb der zurückliegenden 3 Monate
5) Schockzustände, die durch andre Ursachen erklärbar sind, z.B. kardiogener Schock, anaphylaktischer Schock, neurogener Schock
6) anamnestisch bekannte Überempfindlichkeit gegenüber Albumin oder einem sonstigen Bestandteil des Prüfpräparates, z. B. Natriumcaprylat, Natrium-N-Acetyltryptophanat
7) Krankheitszustand, der gegen eine Anwendung von Albumin spricht, z. B. dekompensierte Herzinsuffizienz oder Schädel-Hirn-Trauma
8) Umstand, bei dem Albumingabe vorteilhaft ist, z. B. hepatorenales Syndrom, Nephrose, Verbrennungen, intestinales Malabsorptionssyndrom
9) Stillzeit

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is 90-day all-cause mortality

Als primärer Endpunkt wird die 90-Tage-Gesamtmortalität gewählt

E.5.1.1

Timepoint(s) of evaluation of this end point

90-day after randomisation

Tag 90 nach Randomisierung

E.5.2

Secondary end point(s)

1) 28- and 60-day mortality,
2) ICU and hospital mortality,
3) organ dysfunction/failure as assessed by the SOFA-Score: recorded daily up to 28 days in the ICU after randomisation in the study,
4) ICU and hospital lengths of stay,
5) ventilator- and vasopressor-free days,
6) cost-benefit of volume replacement therapy: collection of data on the use of human albumin and other colloids and crystalloids,
7) total fluid intake and total fluid balance, and
8) safety-related parameters: occurrence of AEs and SAEs, especially anaphylactic shock, hypervolaemia, and pulmonary oedema.

1) 28- bzw. 60-Tage-Mortalität,
2) Mortalitätsraten auf der Intensivstation und während des Krankenhausaufenthaltes,
3) Organdysfunktion/-versagen nach SOFA-Score: tägliche Erfassung bis maximal zu Tag 28 nach Randomisierung auf der Intensivstation,
4) Intensivstation- bzw. Krankenhausverweildauer,
5) Tage ohne Beatmungspflicht, Tage ohne Vasopressoren,
6) Kosten-Nutzen-Parameter der Volumenersatztherapie: Erfassung der gegebenen Mengen von Albumin, anderen Kolloiden und Kristalloiden,
7) Gesamtflüssigkeitsaufnahme und Gesamtflüssigkeitsbilanz,
8) bezogen auf Sicherheit: Auftreten von AEs und SAEs, insbesondere anaphylaktischer Schock, Hypervolämie, Lungenödem

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 28- and 60-day after randomisation
2) ICU and hospital discharge
3) Daily up to 28 days in the ICU after randomisation in the study

1) Tag 28 and 60 nach Randomisierung
2) Intensivstation- und Krankenhausentlassung
3) Täglich bis 28 Tage nach Randomisierung auf der Intensivstation

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

Yes

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

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Volumenersatztherapie ohne Albumin

Volume therapy without albumin

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

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 scheduled end of the clinical trial is defined as the date on which all follow-up data have been recorded and monitored in the eCRF.
At that time point data base hardlock will be performed. This cannot take place before data entry to the eCRF is finalized.

Das reguläre Ende der klinischen Prüfung ist definiert als das Datum, an dem alle Nachbeobachtungsdaten im eCRF erfasst und monitoriert sind. Zu diesem Zeitpunkt wird der Datenbank-Hardlock ausgeführt. Dies kann nicht stattfinden, bevor die Dateneingabe in den eCRF abgeschlossen ist.

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:

1000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

412

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 2018-11-19.

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

In this case, the trial centers should adopt the locally established procedure for including these patients according to the local ethics committee.

Die Prüfzentren sollen hierbei die lokal etablierte Vorgehensweise zum Einschluss nicht einwilligungsfähiger Patienten beibehalten bzw. gemäß den Empfehlungen der lokalen Ethikkommission vorgehen.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

1662

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

Keine

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Center for Sepsis Control and Care (CSCC)
G.4.3.4	Network Country	Germany
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Sepsis Stiftung - SepNet Studiengruppe
G.4.3.4	Network Country	Germany

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-02-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-07

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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