Conditions: Septic Shock
Keywords: Human albumin Sepsis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 440
Healthy volunteers: no

Brief summary:
Albumin is a key regulator of fluid distribution within the extracellular space and possesses several properties beyond its oncotic activity, including binding and transport of several endogenous molecules, anti-inflammatory and anti-oxidant actions, nitric oxide modulation, and buffer function. The accumulating evidence suggests that supplementation of albumin may provide survival advantages only when the insult is severe as in patients with septic shock. Prospective randomized trials on the possible impact of albumin replacement in these patients with septic shock are lacking. The aim of the study is to investigate whether the replacement with albumin and the maintenance of its serum levels at least at 30 g/l for 28 days improve survival in patients with septic shock compared to resuscitation and volume maintenance without albumin. In this prospective, multicenter, randomised trial, adult patients (≥18 years) with septic shock will be randomly assigned within a maximum of 24 hours after the onset of septic shock after obtaining informed consents to treatment or control groups. Patients assigned to the treatment group will receive a 60 g loading dose of human albumin 20% over 2-3 hours. Serum albumin levels will be maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40-80 g human albumin 20% infusion. The control group will be treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock. The primary end point is 90 days mortality and secondary end points include 28-day, 60-day, ICU, and in-hospital mortality, organ dysfunction/failure, and length of ICU and hospital stay. In total 1412 patients need to be analyzed, 706 per group. Assuming a dropout rate of 15%, a total of 1662 patients need to be allocated.

Detailed description:
This is a prospective, multicentre, randomised, controlled, parallel-grouped, open-label, interventional clinical trial in which 1662 patients are planned to be allocated. Subjects will be randomized in a 1:1 ratio to receive either Albumin or routine treatment with crystalloids. Treatment will be continued at maximum for 28 days or until the patient leaves the ICU. Primary endpoint measurement will be carried out 90 days after randomisation

Arms:
arm 1: Patients assigned to the Albumin group will receive a 60 g loading dose of human albumin 20% over 2-3 hours. Serum albumin levels will be maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40-80 g human albumin 20% infusion. arm 2: The control group will be treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock.

Interventions: intervention 1: Albutein® 200 g/L or Plasbumin® 20
Intervention descriptions: intervention 1: The initial dose of the trial drug must be started within 6 to 24 hours after the beginning of the septic shock. Starting dose: 60 g human albumin 20% (Albutein® 200 g/L, infusion solution) over 2-3 h Daily administration of the trial drug will be based on the serum albumin concentration measured each day. Dose adjustment will follow a predetermined schedule with the aim of maintaining a serum albumin concentration of at least 30 g/l. Administration of the trial drug will continue for a maximum of 28 study days after randomisation and only as long as the participant is being treated in the ICU.

Protocol document:
Prot_002.pdf: 
ARISS 
 
EudraCT-Nr.: 2018-001874-89  
 
Study protocol, Version 3.0 
ZKSJ0112_ARISS 
 
 
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Clinical trial Protocol according to the German 
Medicinal Products Act (AMG) 
 
 
Title of the trial 
Randomised controlled multicentre study of 
albumin replacement therapy in septic shock  
Trial Acronym 
ARISS-Study 
Trial code, ZKS Jena 
ZKSJ0112 
Sponsor’s protocol code number 
ZKSJ0112_ARISS 
EudraCT number 
2018-001874-89 
Version/Version number 
Final 3.0 
Date 
18.07.2019 
Sponsor according to AMG 
Friedrich Schiller University Jena   
Sponsor’s legal representative (SpB) 
and principal investigator (LKP) 
 
Prof. Dr. Dr. Yasser Sakr 
Universitätsklinikum Jena  
Klinik für Anästhesiologie und Intensivmedizin  
Am Klinikum 1 
07747 Jena 
Phone: +49 (0) 3641 9323248  
Fax: +49 (0) 3641 9323102 
E-Mail: Yasser.Sakr@med.uni-jena.de 
Study statistician 
Dr. Ulrike Schumacher 
Universitätsklinikum Jena 
Zentrum für Klinische Studien 
Postfach, 07740 Jena 
Tel.: +49 (0) 3641 9396656  
Fax: +49 (0) 3641 9399969 
E-Mail: ulrike.schumacher@med.uni-jena.de 
Confidentiality 
The information in this study protocol is to be kept strictly confidential. It serves only to inform 
the investigators, their deputies, all medical and possibly further members of the trial group, 
other persons involved in the study, as well as the ethics committee and the authorities 
involved. The content of this protocol may not be disseminated orally or in writing to 
bystanders without the consent of the sponsor. 
 


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Table of Contents 
 
1. 
General information .................................................................................................................. 5 
1.1 
Overview of the clinical trial ......................................................................................................... 5 
1.2 
Organisational structure – involved persons and institutions ...................................................... 9 
1.3 
Signatures .................................................................................................................................12 
1.4 
List of abbreviations ..................................................................................................................13 
1.5 
Overview (flowchart) of the clinical trial process .......................................................................14 
1.6 
Schedule of the trial visits .........................................................................................................15 
2. 
Background to the clinical trial..............................................................................................17 
2.1 
Background and research questions ........................................................................................17 
2.2 
Benefit-risk assessment and justification of the project ............................................................18 
2.3 
Assessment of the generalisability of the expected study results .............................................19 
3. 
Objectives and endpoints of the clinical trial .......................................................................20 
3.1 
Primary objective and primary endpoint ....................................................................................20 
3.2 
Secondary objectives and secondary endpoints .......................................................................20 
4. 
Trial design ..............................................................................................................................21 
4.1 
Description of the clinical trial ....................................................................................................21 
4.2 
Feasibility of recruitment ...........................................................................................................21 
4.3 
Trial duration .............................................................................................................................21 
5. 
Participation in the clinical trial .............................................................................................22 
5.1 
Selection of participants ............................................................................................................22 
5.1.1 
Explanation of sex distribution of the study population ....................................................22 
5.1.2 
Inclusion criteria ................................................................................................................22 
5.1.3 
Exclusion criteria ...............................................................................................................22 
5.1.4 
Measures to prevent participation in further studies .........................................................23 
5.2 
Informed consent ......................................................................................................................23 
5.2.1 
Patients able to consent ...................................................................................................23 
5.2.2 
Patients who are unable to consent .................................................................................24 
5.2.3 
Patients who regain their ability to consent ......................................................................25 
5.2.4 
Information in the case of changes in course of the trial ..................................................26 
5.3 
End of participation in the clinical trial .......................................................................................26 
5.4 
Prerequisites for participation in the trial ...................................................................................26 
6. 
Trial drug ..................................................................................................................................27 
6.1 
Labelling of the trial drug ...........................................................................................................27 
6.2 
Drug Accountability ...................................................................................................................27 
6.2.1 
Transport by the manufacturer .........................................................................................27 
6.2.2 
Storage and delivery to the trial centres or their pharmacies ...........................................27 
6.2.3 
Storage and provision by the pharmacy of the trial centres .............................................27 
6.2.4 
Storage, use and tracing by the trial centre ......................................................................27 
6.3 
Administration of the trial drug (only in the albumin group) ......................................................28 
6.3.1 
Start dose ..........................................................................................................................28 
6.3.2 
Subsequent administration of the trial drug ......................................................................28 
6.3.3 
Scheduled discontinuation of the trial drug .......................................................................28 
6.4 
Premature discontinuation of the trial drug ...............................................................................29 
6.5 
Discontinuation of the trial interventions- discontinuation due to a medical reason .................29 
6.5.1 
Compliance .......................................................................................................................30 
6.6 
Instructions for the control group without albumin ....................................................................30 
6.7 
Permitted concomitant medication, concomitant therapies ......................................................30 
6.8 
Further treatment of participants after the end of participation .................................................30 
7. 
Start, course and end of the clinical trial/study visits .........................................................32 
7.1 
Screening and 24-h period before randomisation .....................................................................32 
7.2 
Time of randomisation ...............................................................................................................33 


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7.3 
Time period until 2 h after randomisation ..................................................................................33 
7.4 
Trial visit at 6 h after randomisation ..........................................................................................34 
7.5 
Trial visits on trial days 1 to 28 after randomisation ..................................................................34 
7.5.1 
Data collection at hospital discharge or at the end of the study .......................................34 
7.5.2 
Data collection at trial days 28, 60, and 90 after randomisation .......................................35 
7.6 
Premature end of the participation of a patient in the clinical trial ............................................35 
7.7 
End of the clinical trial ...............................................................................................................36 
7.7.1 
Scheduled end ..................................................................................................................36 
7.7.2 
Premature termination of the trial in a trial centre.............................................................36 
7.7.3 
Premature termination of the entire clinical trial ...............................................................37 
8. 
Safety and adverse events .....................................................................................................38 
8.1 
Assessment of the safety of the trial drug .................................................................................38 
8.2 
Adverse events..........................................................................................................................38 
8.3 
Duration of recording adverse events .......................................................................................39 
8.4 
Documentation of adverse events ............................................................................................39 
8.4.1 
Intensity of an adverse event ............................................................................................40 
8.4.2 
Causality – relationship between the adverse event and the trial drug ............................40 
8.4.3 
Procedures in case of adverse events .............................................................................41 
8.4.4 
Outcome of an adverse event ...........................................................................................41 
8.5 
Serious adverse event ..............................................................................................................41 
8.6 
Reporting serious adverse events ............................................................................................41 
8.6.1 
Obligations of the investigator/deputy ..............................................................................42 
8.6.2 
Obligations of the SpB ......................................................................................................42 
8.7 
Preexisting diseases .................................................................................................................42 
8.8 
Pregnancy .................................................................................................................................42 
8.9 
Data and safety monitoring board - SMC ..................................................................................43 
9. 
Documentation and data management .................................................................................44 
9.1 
List of responsibilities ................................................................................................................44 
9.2 
Documentation of screening .....................................................................................................44 
9.3 
Patient identification list .............................................................................................................44 
9.4 
Investigator site file (ISF) ..........................................................................................................44 
9.5 
Case report form (CRF) ............................................................................................................44 
9.6 
Data handling and data management .......................................................................................45 
9.7 
Data retention, archiving of documents ....................................................................................45 
9.7.1 
Data retention obligation of the SpB .................................................................................45 
9.7.2 
Data retention obligation of the trial centre .......................................................................45 
9.8 
Privacy and privacy statement ..................................................................................................46 
9.8.1 
Privacy statement .............................................................................................................46 
10. 
Quality assurance ...................................................................................................................47 
10.1 Standardisation and validation ..................................................................................................47 
10.2 Monitoring ..................................................................................................................................47 
10.3 Audits and inspections ..............................................................................................................47 
11. 
Statistical methods and determination of sample size .......................................................48 
11.1 Sample size ...............................................................................................................................48 
11.2 Randomisation ..........................................................................................................................48 
11.3 Statistical methods ....................................................................................................................49 
11.3.1 
Definition of the analysis populations ...............................................................................49 
11.3.2 
Data analysis ....................................................................................................................49 
11.3.3 
Subgroup analyses ...........................................................................................................50 
11.3.4 
Interim analysis .................................................................................................................50 
11.4 Presentation of results ..............................................................................................................51 
12. 
Regulatory and administrative aspects ................................................................................52 
12.1 Regulations ...............................................................................................................................52 
12.2 Ethic committees .......................................................................................................................52 
12.3 Competent authorities ...............................................................................................................52 


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12.3.1 
Federal authority ...............................................................................................................52 
12.3.2 
State authorities ................................................................................................................52 
12.4 Subsequent changes in the trial protocol - amendments ..........................................................52 
12.5 Registration ...............................................................................................................................53 
12.6 Insurance ...................................................................................................................................53 
12.7 Funding .....................................................................................................................................53 
12.8 Reports of the study results ......................................................................................................53 
12.9 Publications ...............................................................................................................................53 
13. 
Literature ..................................................................................................................................55 
14. 
Appendix ..................................................................................................................................57 
14.1 SOFA Score ..............................................................................................................................57 
14.2 Apache II Score .........................................................................................................................59 
14.3 New Simplified Acute Physiology Score (SAPS II) ...................................................................60 
14.4 Conversion tables .....................................................................................................................61 


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1. General information 
1.1 Overview of the clinical trial  
 
Title of the trial 
Randomised controlled multicentre study of albumin 
replacement therapy in septic shock 
Trial Acronym 
ARISS-Study 
Sponsor according to AMG 
Friedrich Schiller University Jena   
Sponsor’s legal 
representative (SpB) and 
principal investigator (LKP) 
 
Prof. Dr. Yasser Sakr 
Universitätsklinikum Jena  
Klinik für Anästhesiologie und Intensivmedizin  
Am Klinikum1 
07747 Jena 
Phone: +49 (0) 3641 9323248 
Fax: +49 (0) 3641 9323102 
E-Mail: Yasser.Sakr@med.uni-jena.de 
EudraCT Number 
2018-001874-89 
Study population 
Female and male patients ≥ 18 years treated in the 
intensive care unit (ICU) within 24 hours of septic shock 
diagnosis  
Study phase 
III b 
Trial design 
Prospective, multicentre, randomised, controlled, parallel-
grouped, open-label, interventional clinical trial according 
to the German Medicinal Products Act 
Aim of the trial 
Primary target:  
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 
Secondary targets:  
- 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 
Primary outcome (primary 
end-point) 
Secondary outcome 
(secondary end-point) 
 
 
 
Primary outcome: 90-day all-cause mortality 
 
Secondary outcomes: 
- 28- and 60-day mortality, mortality rates in the ICU and 
during hospitalization, organ dysfunction/failure as 
assessed by the SOFA score, ICU and hospital length of 
stay, ventilator and vasopressor free days. 


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- Cost-benefit parameters of volume replacement therapy 
(albumin, other colloids and crystalloids) 
- Total amount of fluid of fluid administration and total fluid 
balance in the ICU.  
- Safety related endpoints: Onset of AEs and SAEs, in 
particular anaphylactic shock, hypervolaemia, pulmonary 
oedema and sepsis-related clinical events 
Sample size 
Assuming a 90-day mortality of 50% in the control group 
without albumin and 42% in the albumin group, 1412 
patients need to be evaluated (power: 80%, Chi²Test alpha 
= 0.05). Taking into account a dropout rate of 15%, 1662 
patients should be randomised in the trial (831 in each 
arm). 
Inclusion criteria 
- The presence of septic shock meeting all of the following 
criteria (1): 
      o Clinically possible or probable or microbiologically 
confirmed infection according to the definitions of the 
International-Sepsis-Forums (ISF) (2) 
      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 level > 2 mmol/l (18 mg/dl) despite 
adequate volume therapy  
- Start of septic shock less than 24 hours prior to inclusion, 
so that the start dose of the trial drug in the albumin group 
will be possible within 6-24 hours after the start of the 
septic shock 
- Age: ≥ 18 years 
- Written informed consent of the patient or his/her legal 
representative 
or 
confirmation 
of 
the 
urgency 
of 
participation in the clinical trial and 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.  
- Patients of childbearing age: negative pregnancy test 
Exclusion criteria 
- Moribund conditions with life expectancy less than 28 
days because of comorbid conditions or advanced 
malignant disease and palliative situations with life 
expectancy less than 6 months 
- Presence of an "end of life" decision prior to obtaining 
informed consent: "Do Not Resuscitate (DNR)" and 
"Withhold/Withdraw Life-Sustaining measures" 
- Previous participation in this study 
- Participation in another interventional clinical trial within 
the past 3 months 
- Shock states that can be explained by other reasons, 
e.g. cardiogenic, anaphylactic, and neurogenic shock 
 


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- History of hypersensitivity to albumin or any other 
component of the trial drug, e.g., B., sodium caprylate, 
sodium N-acetyltryptophanate 
- Diseases in which albumin administration may be 
deleterious, e.g., decompensated heart failure or 
traumatic brain injury 
- Clinical conditions where albumin administration is 
indicated, e.g., hepatorenal syndrome, nephrosis, burns, 
intestinal malabsorption syndrome 
- Lactation 
Trial drug administered in 
the intervention group 
(albumin group) 
 
- Active substance: human albumin 200g/l 
- Product: Albutein® 200 g/l solution for infusion 
or  
Plasbumin® 20, solution for infusion 
Both drugs are manifactured according to the same 
procedure and considered to be interchangeable. 
- Manufacturer: Instituto Grifols, S.A., Barcelona, Spain 
- License holder: Grifols Deutschland GmbH, 
                            Frankfurt, 
- Approval number: 10577a / 97 
- Route of application: intravenous administration 
- Dosage: 
Starting dose: 60 g human albumin 20% (200 g/l, infusion 
solution) over 2-3 h 
Dose adjustment from study day 1 after randomisation 
  depending on serum albumin concentration: 
                  ≥ 30 g/l: no administration 
                  ≥ 25 g/l and <30 g/l: 40 g over 1-2 h 
                  ≥ 20 g/l and <25 g/l: 60 g over 2-3 h 
                  <20 g/l: 80 g over 3-4 h 
- Duration of use: maximum 28 days after randomisation 
Study-specific procedures 
- Woman of childbearing age: pregnancy test 
- If necessary, blood collection until 2 h after 
randomisation (determination of serum albumin 
concentration) 
- Albumin group only: administration of the starting dose 
and dose adjustment depending on the serum albumin 
concentration 
- Daily determination of serum albumin concentration 
between 4:00 - 9:00 in the morning, if this cannot be 
determined from blood taken during routine blood 
sampling at the respective trial centre.  
- Accompanying scientific project: Blood sampling during 
routine withdrawals at 4 different time points. 
Trial duration 
Patient-related duration of the trial 
- maximum duration of treatment (administration of the trial 
drug) in the albumin group: 28 days 
- Data collection: ends on study day 90 after randomisation 


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Trial-related duration of the trial 
- Planned recruitment period: approx. 36 months 
- End of clinical trial: Date on which all data in the eCRF 
have been recorded and monitored 
Number of contributing 
centres 
n = 40 - 50 centres 
Statistical methods 
- Descriptive analysis of all collected data 
- Primary end-point, 90-day mortality: generalised mixed 
model with random effects "centre" and "patient in 
centre" and fixed effects "SAPS II", "SOFA", "baseline 
serum albumin concentration" and "treatment group" 
- Secondary outcomes: descriptive analysis 
- Subgroup analyses according to baseline lactate, 
baseline quartiles of SOFA, SAPS II and APACHE II 
- AEs, SAEs and sepsis-related clinical events: frequency 
 
Financial support 
- Deutsche Forschungsgemeinschaft (DFG), 
Förderkennzeichen:  DFG SA 2167/3-1, Projektnummer: 
328809707 
- Instituto GRIFOLS S.A., Barcelona, Spanien 
- Klinik für Anästhesiologie und Intensivtherapie, 
Universitätsklinikum Jena  


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1.2 Organisational structure – involved persons and institutions 
 
Function/Qualification 
Name/contact person, 
facility 
Contact details 
Sponsor according to 
AMG 
Friedrich Schiller University Jena   
Sponsor’s legal 
representative (SpB) and 
principal investigator 
(LKP) 
Prof. Dr. Yasser Sakr 
Universitätsklinikum 
Jena,  
Klinik für Anästhesiologie 
und Intensivmedizin 
Am Klinikum 1, 07747 Jena 
Phone: +49 (0) 3641 9323248  
Fax: +49 (0) 3641 9323102 
E-Mail: Yasser.Sakr@med.uni-
jena.de 
Repesentative of the LKP 
Prof. Dr. Michael Bauer 
Universitätsklinikum 
Jena,  
Klinik für Anästhesiologie 
und Intensivmedizin 
Am Klinikum 1, 07747 Jena 
Phone: +49 (0) 3641 9323101  
Fax: +49 (0) 3641 9323102 
E-Mail: Michael.Bauer@med.uni-
jena.de 
Study statistician 
Dr. Ulrike Schumacher 
Universitätsklinikum 
Jena, 
Zentrum für Klinische 
Studien 
Postfach, 07740 Jena 
Phone: +49 (0) 3641 9396656  
Fax: +49 (0) 3641 9399969 
E-Mail: 
ulrike.schumacher@med.uni-
jena.de 
Protocol committee 
Prof. Dr. Yasser Sakr 
Prof. Dr. Michael Bauer 
Universitätsklinikum Jena  
Dr. Ulrike Schumacher 
Dr. Maria Breternitz 
Dr. Sabine Barta 
Universitätsklinikum Jena 
Zentrum für Klinische Studien 
Prof. Dr. Michael 
Hartmann 
PD Dr. Michael Kiehntopf 
Universitätsklinikum Jena  
Prof. Dr. Luciano 
Gattinoni 
Prof. Dr. Michael Quintel 
Universitätsklinikum Göttingen 
 
Contact person for the 
trial drug 
 
Cynthia Henning 
Investigator Sponsored 
Research Program 
Grifols Shared Services 
NA, Inc. 
Global Bioscience 
Scientific & Medical 
Affairs  
Avinguda de la Generalitat 152 -
Edificio 2, Plta 1 
08174- Sant Cugat del Vallès - 
Barcelona - SPAIN 
Phone: +323 227-7602 
E-Mail:  
cynthia.henning@grifols.com 
Instituto Grifols S.A. 
Francisco M. Mota 
Villaplana, Pharm D, 
MSc 
Senior Manager Medical 
Affairs - EU/ROW 
Intensive Care 
Avinguda de la Generalitat 152 -
Edificio 2, Plta 1 
08174- Sant Cugat del Vallès - 
Barcelona - SPAIN 
Phone: 93-571-07-19  
Mobile: 670-92-44-20 
E-Mail: francisco.mota@grifols.com 
Project management 
Universitätsklinikum 
Jena, 
Zentrum für Klinische 
Postfach, 07740 Jena 
Fax: +49 (0) 3641 9399969 
E-Mail: ZKS-


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Function/Qualification 
Name/contact person, 
facility 
Contact details 
Studien 
Projektmanagement@med.uni-
jena.de 
Data management  
Universitätsklinikum 
Jena, 
Zentrum für Klinische 
Studien 
Postfach, 07740 Jena 
Fax: +49 (0) 3641 9399984 
E-Mail: zks-support@med.uni-
jena.de 
Monitoring 
Universitätsklinikum 
Jena, 
Zentrum für Klinische 
Studien 
Postfach, 07740 Jena 
Fax: +49 (0) 3641 9399969 
Pharmacovigilance 
 (safety management) 
Universitätsklinikum 
Jena, 
Zentrum für Klinische 
Studien 
Postfach, 07740 Jena 
Fax: +49 (0) 3641 9399946  
E-Mail: 
ZKS_SAE_Management@med.uni-
jena.de 
Data and safety 
monitoring board -SMC 
See corresponding manual 
Laboratory (s) for the 
determination of serum 
albumin and arterial blood 
lactate concentrations 
local laboratories of the 
respective trial centres 
 
see respective trial centre 
documents 
 
Central pharmacy for 
storage and dispatch of 
the trial drug to trial centre 
pharmacies 
Prof. Dr. Michael 
Hartmann, Apotheke, 
Universitätsklinikum Jena 
Am Klinikum 1, 07747 Jena 
Phone: +49 (0) 9325401  
Fax: +49 (0) 9325402 
E-Mail: Michael.Hartmann@ 
med.uni-jena.de 
Pharmacies for the 
provision of the trial drug 
to the trial centres 
local pharmacy of the 
respective trial centre 
see respective trial centre 
documents 
Pharmacoeconomic 
analysis 
Prof. Dr. Michael 
Hartmann, Apotheke, 
Universitätsklinikum Jena 
Am Klinikum 1, 07747 Jena 
Phone: +49 (0) 3641 9325401  
Fax: +49 (0) 3641 9325402 
E-Mail: Michael.Hartmann@ 
med.uni-jena.de 
Responsible higher 
federal authority (BOB) 
 
Paul-Ehrlich-Institut 
(PEI),  
Bundesinstitut für 
Impfstoffe und 
biomedizinische 
Arzneimittel 
Paul-Ehrlich-Str. 51-59  
63225 Langen  
Phone: +49 (0)6103 77 0 
Leading ethics 
committee 
 
Ethik-Kommission der 
Friedrich-Schiller-
Universität Jena 
Universitätsklinikum Jena 
Postfach, 07740 Jena 
Phone: +49 (0) 3641 933770 
Fax: +49 (0) 3641 933771 
E-Mail: ethikkommission@med.uni-
jena.de 
Funding of the study, 
material and other 
support 
 
 
Deutsche 
Forschungsgemeinschaft 
e.V. 
Kennedyallee 40  
53175 Bonn 
Phone: +49 (0) 228 8851  
Fax: +49 (0) 228 8852777  
E-Mail: postmaster@dfg.de 


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Function/Qualification 
Name/contact person, 
facility 
Contact details 
Francisco M. Mota 
Villaplana, Pharm D, 
MSc 
Senior Manager Medical 
Affairs – EU/ROW 
Intensive Care 
Instituto Grifols, S.A. 
Avinguda de la Generalitat 152 –
Edificio 2, Plta 1 
08174- Sant Cugat del Vallès – 
Barcelona – SPAIN 
Phone: 93-571-07-19   
Mobile: 670-92-44-20 
E-Mail: francisco.mota@grifols.com 
Klinik für Anästhesiologie 
und Intensivmedizin, 
Universitätsklinikum Jena 
Am Klinikum 1, 07747 Jena 
Phone: +49 (0) 3641 9323101  
Fax: +49 (0) 3641 9323102 
E-Mail: Michael.Bauer@med.uni-
jena.de 


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1.3 Signatures 
 
The following persons confirm the accuracy of the contents of this trial protocol and confirm 
this with their signature. 
 
 
 
Prof. Dr. Yasser Sakr, Sponsor's legal representative and principal investigator            Date 
 
 
 
 
Dr. Ulrike Schumacher, Statistician 
 
 
 
 
 
 
    Date 
 
 
 
 


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1.4 List of abbreviations 
Abbreviation 
Explanation 
AC 
Arterial catheter  
AE 
Adverse event 
AMG 
Arzneimittelgesetz (medicinal products act) 
APACHE 
Acute Physiology and Chronic Health Evaluation 
ARDS 
Acute respiratory distress syndrome 
BOB 
Bundesoberbehörde (Federal authority) 
CO 
Cardiac output 
CRF 
Case report form 
CVC 
Central venous catheter 
CVP 
Central venous pressure 
Da 
Dalton 
DAP 
Diastolic blood pressure 
DFG 
Deutsche Forschungsgemeinschaft 
DIC 
Disseminated intravascular coagulopathy  
dl 
Deciilitre 
DRKS 
Deutsches Register klinischer Studien (German Registry of clinical trials) 
ECMO 
Extracorporeal membrane oxygenation 
EK 
Ethics Committee 
FiO2 
Fraction of inspired oxygen 
g 
Gram 
GCLP 
Good Clinical Laboratory Practice 
GCP 
Good Clinical Practice 
GCP-V 
GCP-Regulation 
h 
Hour 
IBBJ 
Integrated Biobank Jena  
ICU 
Intensive care unit 
ISF 
Investigator Site File 
ITN 
Intubation 
l 
Litre 
LKP 
Principal investigator 
MAP 
Mean arterial blood pressure 
mg 
Milligram 
mm Hg 
Millimetre mercury 
mmol 
Millimole 
NYHA IV 
New York Heart Association Class IV 
paCO2 
Partial pressure of carbon dioxide 
paO2 
Partial pressure of oxygen  
PEI 
Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel 
pH 
Negative logarithm of the hydrogen ion concentration 
RRT 
Renal replacement therapy 
SAP 
Systolic arterial blood pressure 
SAPS 
Simplified Acute Physiology Score 
SAE 
Serious adverse event 
ScO2 
Central venous oxygen saturation 
SMC 
Safety Monitoring Committee 
SO2 
Arterial oxygen saturation 
SOFA 
Sequential Organ Failure Assessment  
SpB 
Sponsor’s legal representative 
SUSAR 
Suspected unexpected serious adverse reaction 
SvO2 
Central venous oxygen saturation 
TMF 
Trial Master File 
ZKS 
Zentrum für klinische Studien (Centre for clinical studies) 


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1.5 Overview (flowchart) of the clinical trial process 
 
Patients >18 years, 
admitted to the Intensive Care Unit (ICU)
Septic shock
(onset < 24 h)
yes
no
Daily 
screening
Septic shock
(onset < 24 h)
yes
no
Exclusion criteria (briefly demonstrated) present?                                                                 
1) Moribund conditions
2) End of life decisions
3) Previous participation to this trial or any other interventional clinical trial
4) Known hypersensitivity to albumin or any component of the trial drug
5) Clinical conditions, where albumin adminstrationmay be unfavourable
6) Breast feeding
no
yes
Exclusion
Possible inclusion, informed consent
yes
Randomisation
Albumin group
Control group without albumin
Prior to intervention: demographic data, clinical and laboratory parameters, SAPSII  and SOFA-
scores, volume replacement therapy
Intervention: 
- Start 6-24 h after onsetof septic
shock and within 2 h after                
randomisation with an initial dose of 60 g 
human albumin 20% over 2-3 h
- max. 28 days after randomisation in the
ICU: Daily adminstration of human albumin
20% according to schedule, to maintain
albumin serum concentration of at least 30 
g/l 
Volume replacement therapy without
human albumin
ICU/ In-hospital:
Primary end point: 90-days all-cause mortality
Secondary end points: 28 and 60-days mortality, mortality rates in the ICU and in-hospital, 
organ dysfunction/failure as assessed by the SOFA score, ICU and hospital length of stay, cost-
benefit parameters of albumin replacement therapy among others.
Screening
Inclusion and
randomisation
Intervention/ 
data collection
Outcome
After hospital discharge:
Primary end point: 90-daysall-cause mortality
Secondary end points: 28 and 60 days mortality
no


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1.6 Schedule of the trial visits 
 
Screening/ 
Baseline 
maximal treatment duration with human albumin 20%  
(200 g/l, Infusionslösung) in the ICU 
Data collection at
discharge from 
the hospital or at 
the end of the tria
Data collection  
(if necessary by 
phone) 
Procedure, Event 
 
 24 h period before 
Randomisation 
Randomisation (max. 
2h after informed 
consent) 
until 2 h after 
Randomisation and  
6-24h after the onset 
of septic shock 
6 h after 
Randomisation 
Study day 1 until max. 28 days after randomisation 
 
Day 28, 60 and 90 
Checking  inclusion and exclusion criteria 
X 
 
 
 
 
 
 
Written informed consent 
X 
 
 
 
 
 
 
Pregnancy test (female patients in childbearing age)1 
X 
 
 
 
 
 
 
Collection of basic data2 
X 
 
 
 
 
 
 
Documentation of primary and secondary admission 
diagnoses 
X 
 
 
 
 
 
 
Documentation of comorbid conditions 
X 
 
 
 
 
 
 
Documentation of data on infection, microbiology and anti-
infective therapy (continuous collection of data) 
 
 
 
 
 
 
 
Collection of data on SAPS II-/APACHE II-Scores 
X 
 
 
 
 
 
 
Collection of data for calculation of SOFA-Scores 
X 
 
 
 
X 
 
 
Determination of serum albumin levels  
 
 
   X 3 
 
X 
 
 
Administration of the trial drug in the albumin group 
 
 
X 
 
X, Dose adjustment according to serum albumin levels 
 
 
Documentation of albumin adminstration (continuous) 
 
 
 
 
 
 
 
Detection of clinical parameters 4 
X 
X 
 
X 
X 
 
 
Documentation of concomitant medications  
X 5 
X 5 
 
X6 
X 
 
 
Collection of the results of routine laboratory parameters 7 
 
X8 
 
X 
X 
 
 
Documentation of procedures in the ICU 9  
X 
X 
 
X 
X 
 
 
Collection of AEs, SAE, sepsis-related clinical events 10 
 
 
 
 
 
(X) 
(X) 
Collection of data on the vital status 11 
 
 
 
X 
X 
X 
X 
Collection of data on ICU length of stay 
 
 
 
 
 
X 
 
Collection of data on hospital length of stay 
 
 
 
 
 
X 
 
1  After obtaining informed consent 


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2  Basic data: sex, age, weight, height, time of hospital admission, time of ICU admission, type of admission, referring facility prior to ICU admission, etc. from the 
24-hour period before randomisation, (data from ICU or normal ward) 
3  Albumin group: Determination of serum albumin concentration before administration of the starting dose of the trial drug 
4 Body temperature, respiratory rate and haemodynamic parameters (SAP, MAP, DAP, CVP, CO)   
5  Catecholamines, inotropic agents, diuretics, volume replacement therapy, including blood transfusion, adjunctive sepsis therapy  
6  Recording of concomitant medication with catecholamines and inotropes at the corresponding time point (+/- 1 hour); recording of concomitant medication with 
diuretics, volume therapeutics including transfusion therapy, adjunctive sepsis therapy) of the previous 6 h 
7  Haemoglobin, creatinine, bilirubin, C-reactive protein, procalcitonin, leucocytes, platelets, lactate, arterial blood gas analysis (PaCO2, PaO2, FiO2, SO2, pH, 
ScO2) 
8  24-h time period prior to randomisation     
9  ITN, CVC, AC, RRT, mechanical ventilation, ECMO, haemodynamic monitoring  
10 If AEs or SAEs are still "ongoing" after the end of treatment with the trial drug, observation will continue until the end of data collection (day 90). 
11 Data on the vital status (alive/dead), if applicable date of death and cause of death, residence after discharge, if applicable, recording of "End of Life"  
decisions 
 
 
 


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2. Background to the clinical trial  
2.1 Background and research questions 
Sepsis is the 10th leading cause of death in the developed world and is the leading cause of 
death in the intensive care unit (ICU) (3). It represents a significant burden on the healthcare 
system. The cost of treating critically ill patients with sepsis in German ICUs is approximately 
€ 4.97 billion a year (4). An analysis of administrative data from German hospitals showed a 
continuous increase in the prevalence of sepsis of 5.7% per year between 2007 and 2013 
(5). Although the mortality rate in this analysis of 33815 patients with septic shock showed a 
slight decrease in the last 3 years of the observation period, the hospital mortality rate in 
2013 was still 58.8% (5). 
 
Sepsis-related morbidity has also been demonstrated in several epidemiological studies, in 
particular multi-organ failure and prolonged length of stay in the ICU with a corresponding 
increase in healthcare expenditure (6-8). Several sepsis-specific therapeutic approaches 
have been evaluated for efficacy and effectiveness in recent decades, but failed to produce 
the expected results (9-12). 
 
Albumin is a natural protein with a molecular weight of about 65,000 Da, whose production 
requires 50% of the total energy expenditure of the liver (13). It is responsible for about 80% 
of the oncotic pressure in the plasma and thus has a key role in the distribution of 
extracellular fluid. In addition to its oncotic functions, albumin has a variety of other 
properties, including binding and transport of various endogenous molecules (13), anti-
inflammatory (14) and anti-oxidative effects (15), and modulation of nitric oxide metabolism 
(16). In addition, albumin has a buffer function (17). These properties are particularly relevant 
in critically ill patients, especially in patients with sepsis. An analysis of the oxidation state of 
the albumin molecule in patients with septic shock showed that up to 30% of circulating 
serum albumin loses its antioxidant capacity due to irreversible oxidation (unpublished data). 
Thus, albumin administration in both the early and maintenance phases of severe sepsis 
(septic shock) could offer a survival benefit in these patients, primarily by increasing the 
amount of functional albumin available to exert its anti-inflammatory, anti-oxidative and NO-
modulating properties. 
 
In 1998, a Cochrane meta-analysis reported increased mortality associated with albumin 
administration in critically ill patients (18). However, when further clinical studies were 
included in another meta-analysis by Wilkes et al., the safety of albumin therapy was 
confirmed, but with no corresponding survival benefit (19). Interestingly, a later meta-analysis 
by Vincent et al. showed that the use of human albumin in critically ill patients could reduce 
morbidity (20). Significant improvement in organ function of critically ill patients was 
confirmed in a pilot study in which albumin therapy was administered with the aim of 
maintaining serum albumin concentrations greater than 30 g/l (21). Based on the 
contradictory literature cited earlier, a large randomised, prospective, double-blind study was 
performed in 7,000 critically ill patients (SAFE study) (22). In this study, the possible effect of 
volume replacement therapy with human albumin 4% on the outcome of these patients was 
compared to volume replacement therapy with only crystalloids. Although the survival rates 
in the two groups were similar, a post-hoc analysis of 1218 patients with severe sepsis 
showed decreased mortality in the albumin group compared to patients treated with 0.9% 
saline solution alone (23). Consequently, the AIFA, the Italian Medicines Agency, funded the 
randomised controlled ALBIOS study (ALBumin Italian Outcome Sepsis Study), which 
investigated the possible impact on outcome of albumin administration and maintenance of 
serum albumin concentrations to at least 30 g/l in 1810 patients with severe sepsis and 
septic shock (24). To investigate the possible influence of the timing of albumin 
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of the albumin therapy (within 6 h or 6-24 h after the onset of severe sepsis). The study 
showed no outcome difference between the study groups. Nevertheless, the results of the 
study gave two interesting signals: firstly, there was a tendency for a potential survival benefit 
of albumin therapy in patients who started therapy 6-24 h after onset of sepsis compared to 
those who started it earlier (relative risk of 90-day mortality = 0.9; 95% confidence interval: 
0.81-1.05, p = 0.2). Secondly, in the 1121 patients with septic shock, 90-day mortality was 
lower in the albumin group (564 patients) than in the non-albumin group (43.6 vs. 49%, p = 
0.03). Additional post-hoc analyses in various study subgroups confirmed a potential survival 
benefit in patients with increased disease severity (according to arterial blood pressure, 
lactate levels or SvO2 on randomization) (unpublished data). Taken together, the current 
evidence suggests that albumin administration in patients with severe and advanced sepsis 
who have potential impairment of the protective effects of serum albumin may provide a 
survival benefit. However, no prospective, randomised trial has adequately studied this 
hypothesis in patients with septic shock. 
 
The aim of the ARISS study is to investigate the effect of albumin administration and 
maintenance of a serum albumin concentration of at least 30 g/l for 28 days after onset of 
septic shock compared to volume replacement therapy without albumin on patient survival. 
The hypothesis is that albumin administration started within 6-24 hours after the onset of 
septic shock aimed at maintaining a serum albumin concentration of at least 30 g/l for 28 
days after the onset of septic shock will reduce 90-day all-cause mortality in these patients 
compared to volume replacement therapy without albumin. 
 
2.2  Benefit-risk assessment and justification of the project 
 
Therapeutic approaches in patients with septic shock are controversial. The arguments cited 
in 2.1 suggest that albumin administration may improve the outcome of such patients. 
However, there are no prospective randomised studies that have adequately investigated the 
possible impact of albumin therapy on the outcome of patients with septic shock. Although 
the current international guidelines for the treatment of sepsis and septic shock support 
albumin administration in the acute as well as the maintenance phase of sepsis and septic 
shock, the evidence for such treatment is grade "2C" (25), which may not justify the higher 
cost of routine albumin administration in these patients. Moreover, there are currently no 
specific recommendations regarding the maintenance of higher serum albumin levels in 
patients with septic shock. Therefore, based on the current evidence, both restrictive and 
liberal albumin administration may be justified. The treatment of patients in the two groups of 
the ARISS study does not therefore represent a deviation from standard practice. Inclusion in 
the clinical trial, therefore, poses no additional risks in this respect compared to standard 
practice. In addition, various methodological aspects have been taken into account to further 
shift the risk-benefit profile in favour of benefit. 
          
General treatment of patients with septic shock participating in the ARISS study will follow 
usual practice for patients with sepsis and septic shock and will be compliant with current 
guidelines for the treatment of such patients. Patients with a history of hypersensitivity to 
albumin or any other component of the trial product are excluded from participating in the 
study. Exclusion criteria also include disease situations in which albumin administration may 
be deleterious, as well as medical conditions in which the use of human albumin is indicated. 
This minimises the risk profile in the two groups. 
 
Patients will be randomised into two groups. The trial product will be administered only in the 
albumin group for a maximum of 28 days and only while in the ICU. Patients in the albumin 
group will receive the starting dose of the trial product for the first time within 6-24 h after the 
onset of septic shock, based on a subgroup analysis of the ALBIOS study (24), which 
demonstrated a survival advantage in the intervention group compared to the control group. 


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Patients will receive a starting dose of 60 g of 20% human albumin over 2-3 hours within 6-
24 h after the onset of septic shock. Crystalloids will be administered according to usual 
practice in this condition. The prescribed dose of albumin has been used in previous clinical 
trials and is considered to be safe (21-24). In addition, these studies showed a potential 
advantage of albumin administration in terms of morbidity (21) and mortality (24). 
 
The control group without albumin will be treated according to common practice with 
crystalloids as the volume replacement therapy of first choice. Therapy with human albumin  
in this group may be clinically indicated (dosing as low as possible) if, for example, the serum 
albumin concentration decreases below 15 g/l or after assessment of the clinical need for 
albumin administration by the treating physicians (member of the trial group). This minimises 
the risk of hypoalbuminaemia. The treatment concept in this group does not deviate from 
standard practice and therefore does not represent an additional risk factor. 
 
Serum albumin concentration will be determined once daily. No additional blood sampling is 
required for this determination, as the value can normally be determined from blood taken 
between 4:00 and 9:00 as part of routine blood sampling at the respective trial centre. These 
blood samples will be taken, if possible, from existing vascular catheters. Thus, the likelihood 
of study-related blood vessel puncture and associated risks is minimal. 
 
Dose adjustment will follow a predetermined schedule with the aim of maintaining serum 
albumin concentration at least at 30 g/l. The serum albumin concentration represents a valid 
treatment target for the trial drug. It is routinely determined in critically ill patients receiving 
albumin. The target value of at least 30 g/l corresponds to the target value from previous 
studies that showed a potential advantage of albumin administration in terms of morbidity 
(21) and mortality (24) without any safety concerns. Taken together, the study intervention is 
justified, low-risk and clinically relevant. 
 
The results of the clinical trial may influence the treatment of patients with septic shock. The 
expected improvement in patient survival may result in a reduction in the resources currently 
used in the treatment of these patients and in the socioeconomic burden of this disease. If 
the hypothesis cannot be confirmed, restrictive albumin administration will be justified and 
the costs of therapy can be significantly reduced. In both cases, the results of the clinical trial 
could reduce the socio-economic burden of the disease and will be of high clinical relevance. 
 
2.3 
Assessment of the generalisability of the expected study results 
 
It is expected that the exclusion criteria will not exclude more than 10-20% of patients with 
septic shock from participating in the clinical trial. Therefore, high generalisability of the 
results is expected. The results of the clinical trial are expected to impact on everyday clinical 
practice and will have a direct impact on guidelines for the treatment of patients with septic 
shock. If the established hypothesis can be confirmed, then albumin administration will 
improve the outcome of patients with septic shock and justify the higher costs of such 
therapy. 
  
 


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3. Objectives and endpoints of the clinical trial 
3.1 Primary objective and primary endpoint 
The primary objective of the clinical trial is 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 90-day all-cause mortality, compared to volume 
replacement therapy without albumin. 
 
The primary endpoint is 90-day all-cause mortality (EMA Guideline CHMP / EWP / 4713/03). 
Based on the subgroup analysis of the ALBIOS study (24), the potential benefit of albumin 
administration is most likely to be apparent 90 days after randomization. Based on 
experience with the previous SepNet study (26, 27), the risk of patients being discharged 
from hospital 90 days after randomisation, and thus unavailable for follow-up, will not 
significantly affect data collection at this time point. 
 
3.2 Secondary objectives and secondary endpoints 
The purpose of the clinical trial is to secondarily investigate whether albumin administration 
and the maintenance of serum albumin concentrations of at least 30 g/l for 28 days after the 
onset of septic shock will influence 28- and 60-day mortality, ICU and hospital mortality rates, 
organ dysfunction/failure as assessed by the SOFA score, ICU and hospital lengths of stay, 
as well as ventilator- and vasopressor-free days. A cost-benefit analysis of the volume 
replacement therapy for the ICU stay up to a maximum of day 28 is another objective of this 
clinical trial. 
 
Secondary end-points therefore are 
 28- and 60-day mortality,  
 ICU and hospital mortality, 
 organ dysfunction/failure as assessed by the SOFA-Score: recorded daily up to 28 days in 
the ICU after randomisation in the study, 
 ICU and hospital lengths of stay, 
 ventilator- and vasopressor-free days, 
 cost-benefit of volume replacement therapy: collection of data on the use of human 
albumin and other colloids and crystalloids,  
 Total amount of fluid administration and total fluid balance, and  
 safety-related parameters: occurrence of AEs and SAEs, especially anaphylactic shock, 
hypervolaemia, and pulmonary oedema. 
 
 
 


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4. Trial design 
4.1 Description of the clinical trial 
The ARISS study is a prospective, multicentre, randomised, controlled, parallel-grouped, 
open-label, interventional clinical trial (Phase IIIb) according to the German Medicines Act 
(AMG). Participants are male and female persons ≥ 18 years with septic shock. 
4.2 Feasibility of recruitment  
The SepNet Study Group is a network of physicians and scientists from around 50 clinics 
and universities throughout Germany. This interdisciplinary network brings together experts 
from various disciplines working in the field of clinical and experimental sepsis research. 
They have considerable experience and interest in clinical trials in sepsis patients. These 
clinical studies can be performed at the well-established SepNet regional centres and 
numerous associated centres with interdisciplinary, medical and surgical ICUs. Successful 
studies carried out by the SepNet study group in the past have proved the ability of this 
network to perform the ARISS study. Based on estimates of expected recruitment numbers 
provided by the requested trial sites, it is anticipated that the clinical trial will achieve the 
required number of cases within the planned recruitment period. 
Evaluation of data from the Jena Sepsis Registry (BMBF-ID: 01 E0 1002 and DRKS number: 
DRKS00008342) was carried out. In this registry, prospective data were collected from all 
patients with severe sepsis who were admitted to the 4 ICUs of the Jena University Hospital 
(2 surgical, 1 medical, 1 neurological) between January 2011 and December 2015. A total of 
1988 patients with severe sepsis (within 24 hours of the onset of sepsis) were identified, 
1478 of whom had septic shock. Only 176 patients had at least one of the exclusion criteria 
for the ARISS study. Sixty-two patients died or relocated to another facility within 24 hours of 
the onset of the septic shock. A total of 1,236 patients, i.e., approximately 247 patients per 
year, would have been suitable for the ARISS clinical trial. 
It is estimated that the clinical trial will require 40-50 trial sites to randomise 1,662 patients 
over 3 years; that is, about 13-14 patients per year per site. The ICUs that have confirmed 
participation in the ARISS study within the framework of the DFG application stated the 
possibility of including an average of 141 patients with septic shock. A recruitment rate of up 
to 21 patients per year per trial centre is, thus, expected. These figures show that the 
required recruitment figures can be achieved with an adequate safety margin. A drop-out rate 
of 15% of randomised patients is assumed, resulting in 11-12 patients per year per site and a 
total of 1412 patients from all sites to be be included in the final evaluation. 
  
4.3 Trial duration 
Approximately 36 months are planned for the recruitment of patients. 
Depending on the patients, study durations will vary in length. The trial product will be 
administered for a maximum of 28 study days after randomisation in the ICU. 
On day 90 after randomisation, data collection and thus participation in the study will end for 
the respective patient. 
  


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5. Participation in the clinical trial 
5.1 Selection of participants 
The target population for the clinical trial are male and female patients ≥ 18 years of age with 
septic shock treated in an ICU. 
Screening will be performed daily in the respective trial centres to see whether eligible 
patients are being treated in the ICUs. 
Patients ≥ 18 years of age with septic shock will be approached to obtain informed consent 
to participate in the study. No patient will be excluded from participation because of sex, 
race, ethnicity, or sexual preference. 
 
5.1.1 Explanation of sex distribution of the study population 
The clinical trial does not involve any sex-specific issues. Patients will be consecutively 
screened during routine clinical practice for eligibility to participate in the clinical trial and 
included accordingly. The trial intervention is not sex-dependent and sex-related differences 
will not be addressed in the trial. 
 
5.1.2 Inclusion criteria 
Patients who meet all the following inclusion criteria may be included in this clinical trial:  
• Presence of septic shock that meets all the following criteria (1): 
o Clinically possible, probable or microbiologically confirmed infection according to 
the definitions of the International-Sepsis-Forums (ISF) (2) 
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 
 
• 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 
• Age: ≥ 18 years 
• 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 (for more details see chapter 5.2) 
• Patient of childbearing age: negative pregnancy test 
 
5.1.3 Exclusion criteria 
Patients who meet any of the following exclusion criteria cannot be included in the trial: 
 
• 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 
• "End of life" decisions made before obtaining informed consent: "Do Not Resuscitate 
(DNR)" and "Withhold/Withdraw Life-Sustaining measures" 
• Previous participation in the study 
• Participation in another interventional clinical trial within the past 3 months 


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• Shock states that can be explained by other reasons, e.g. cardiogenic, anaphylactic, and 
neurogenic shock 
• History of hypersensitivity to albumin or any other component of the trial product, e.g., 
sodium caprylate, sodium N-acetyltryptophanate 
• Disease in which the use of albumin may be deleterious, e.g., decompensated heart failure 
or traumatic brain injury 
• Disease situations in which albumin administration may be advantageous, e.g., hepatorenal 
syndrome, nephrosis, burns, and intestinal malabsorption syndrome 
• Lactation  
 
5.1.4  Measures to prevent participation in further studies 
The trial centres shall ensure that patients are not included in any other interventional clinical 
trial during the course of the clinical trial, up to (and including) the 90th day after 
randomization. The trial centres will ensure that ARISS participants do not participate in 
ARISS again during the clinical trial recruitment period.  
5.2 Informed consent 
Informed consent will be obtained verbally and in writing using specific forms. The 
declaration of consent to participate in the clinical trial must be personally dated and signed 
by the consenting person. 
The declaration of consent must be signed in duplicate. One copy (original) will remain in the 
trial centre and must be kept in the investigator site file (ISF). The second copy (copy or 2nd 
original) will be handed to the consenting party together with the information document 
(explanatory document) and the general conditions of insurance. Participation of a patient in 
the clinical trial and delivery of the documentation and further information on the clinical trial 
should be noted in his/her medical record. 
 
5.2.1  Patients able to consent 
Eligible patients must be informed of the study by the investigator or a physician (member of 
the trial group) prior to initiating the study-related intervention. Informed consent must be 
obtained verbally and in writing including the nature of the study, objectives, duration, course, 
benefits, all risks and adverse effects, as well as other aspects of the clinical trial or use of 
the trial product. The informing physician must be sure that the information about the trial is 
understood by the patient. After informing the patient about the trial, each patient should be 
given enough time and opportunity to ask questions and decide on their participation. 
The patient must sign and date his/her consent to participation in the clinical trial on the 
consent form. The patient's consent must also expressly refer to the collection and 
processing of information about his/her health condition. Therefore, the patient should be 
explicitly informed about the purpose and scope of the trial and the use of personal data, in 
particular health-related data.  
 
If a patient is unable to sign the informed consent personally, but can give verbal consent, at 
least one independent witness must be present during this process. The witness may not be 
a person employed by the trial centre or a member of the trial group. The verbally given 
consent must be documented in writing by the witness who must sign with date and time the 
consent form to confirm the patient's oral consent. 
 
 


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5.2.2 Patients who are unable to consent 
Because of the expected high severity of illness in the trial population, most of the eligible 
patients will be unable to consent. In this case, it will not be possible to obtain written consent 
from the patient prior to initiating the study-related measures. 
In patients with septic shock, early therapy is a crucial determinant of prognosis of these 
patients. A therapeutic benefit from the intervention -albumin administration in the albumin 
group- can likely only be demonstrated if the clinical trial is started within the first few hours 
of the diagnosis of septic shock. 
Since, according to international guidelines, early initiation of therapy is one of the essential 
standard therapies for severe sepsis and septic shock, it may be justified to begin the clinical 
trial in the existing emergency situation (septic shock) without informed consent of a legal 
representative or a guardian. According to AMG, participation is legally possible even without 
informed consent if this cannot be obtained due to an emergency situation. These patients 
can be included in the study according to § 41 Abs. 1 AMG (29) which states that: if informed 
consent cannot be obtained because of an emergency situation, treatment indicated to be 
given without delay to rescue the life of the concerned persons, to restore their health or to 
minimize their suffering, can be promptly initiated. Consent for further participation must be 
obtained as soon as possible and reasonable. 
 
In this case, the trial centers should adopt the locally established procedure for including 
patients who are unable to consent and follow the recommendations of the local ethics 
committee. The presumed will of the patient should be considered. If she/he would refuse to 
participate, the patient should not be included in the clinical trial. 
 
Patients unable to consent – with a guardian or legal representative 
consent to participate in the clinical trial may be given in writing by the guardian or legal 
representative. A copy of the act of attorney or the identity card must be kept in the trial 
centre (ISF or separately). 
If the guardian or the legal representative considers that the patient would not have wanted 
to participate in the trial, or if the guardian or the legal representative refuses participation, 
the patient will not be included in the clinical trial.  
 
In the case of patients who are unable to consent and who have appointed a guardian or 
have a legal representative (supervisor) with a corresponding task designation, consent to 
participate in the clinical trial should be in accordance with § 41 (3) no. 2 AMG (29). The 
informed consent to participate in the clinical trial by the designated guardian or supervisor 
must be given in writing as soon as possible. A copy of the act of attorney or supervisor 
identification card must be kept at the trial center. If the guardian or supervisor refuses 
participation in the study, the patient will not be included in the clinical trial. 
If the guardian or the supervisor cannot be reached in a timely manner (max 72 h) despite 
repeated attempts or if she/he cannot attend in person to the trial center, the trial center must 
decide how to proceed in this specific patient (for example, to consider the independent 
consultant procedure). 
.   
Patients unable to consent – without a guardian or legal representative 
For patients who are unable to consent and have no guardian or legal representative, 
inclusion in the trial should be in accordance with the recommendations of the local ethics 
committee. The trial centres should adopt the locally established procedure for including 
these patients. 
If a legal representative is required, this must be done at the latest within 72 hours. The 
investigator should arrange for identification of a suitable person and apply to the respective 
court. 
It is crucial, if necessary by telephone, to inquire from the patient’s relatives about whether 
the patient would likely have wanted to participate in clinical trials and to confirm this in 


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writing. If the conversation with relatives reveals that it is likely the patient would not have 
wanted to participate, the patient will not be included in the clinical trial. If the patient is 
known to want to participate in clinical trials or if the patient’s relative agrees to participation 
in the study (provisionally), this information will be forwarded immediately to the competent 
court, which will promptly appoint a legal representative. In this case, the patient will be 
included in the clinical trial. Subsequently, with this provisionally granted consent, the written 
consent of the appointed legal representative must be obtained as soon as possible. If the 
patient dies before the legal representative has been appointed or consented, the patient 
should not be excluded from the analysis. If SAEs have occurred, they must be pursued 
further in accordance with the relevant requirements. 
 
In this case, the trial centers should adopt the locally established procedure for including 
patients unable to consent and follow the recommendations of the local ethics committee. 
The appropriate procedure must be documented. 
 
If, for example, the appointment of a legal representative (supervisor, health care task 
designation) is required, this must be done as soon as possible (at the latest, however, within 
72 hours). 
Written consent to the clinical trial or its continuation by the legal representative must be 
obtained. If this does not occur within a maximum of 72 hours of setting up the legal 
representation, or if the legal representative refuses (further) participation in the study, the 
patient will not be included in the clinical trial or his / her participation in the clinical trial will 
be terminated. 
If SAEs have occurred before the decision of the legal representative, theses will be 
prosecuted in accordance with the applicable requirements. 
If the patient dies before the legal representative has been appointed or has decided to 
participate, this must be documented accordingly in the eCRF. 
 
The “independent medical consultant procedure”  
In this procedure, confirmation of the urgency of participation in the clinical trial and possible 
benefit to the patient may be obtained by an independent consultant and the patient 
subsequently becomes a participant in the clinical trial. 
The consultant must be a specialist and have at least 6 months experience in intensive care 
medicine. The consultant should not be involved in the clinical trial or belong to the study 
department and should not be part of the patient's care team. The consultant must justify 
his/her decision in writing. Thereafter, inclusion of the patient is possible. The investigator 
must initiate appointment of a legal representative no later than 72 hours after inclusion in 
the clinical trial. Written consent for continuation of the clinical trial must be obtained from this 
legal representative. If this does not occur within a maximum of 72 hours of the 
establishment of a legal representative or she/he refuses participation in the study, 
participation in the clinical trial will be terminated for this patient. If SAEs have occurred, they 
must be pursued further in accordance with the relevant requirements. 
If the patient dies before a legal representative has been appointed or decided to participate 
in the study or not, this should be documented in the eCRF accordingly. 
. 
 
5.2.3 Patients who regain their ability to consent 
All patients who regain their ability to consent for participation in the trial should provide their 
informed consent to continue in the trial, as long as their health condition during 
hospitalization permits. If a formerly incapacitated patient decides at this time or later not to 
participate in the clinical trial, he/she may withdraw his/her from participation at any time and 
without stating a reason, without incurring any disadvantages for his/her further medical 
treatment. Patients in the albumin group may decide at this time or later not to continue 
administration of the trial product (discontinuation of treatment). The data collected until 
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5.2.4 Information in the case of changes in course of the trial 
Participants, guardians or legal representatives will be promptly notified if significant new 
findings or information about the trial product emerge during the clinical trial that may 
influence their willingness to continue to participate in the clinical trial. Disclosure of this 
information will be documented. The patient, guardian or legal representative will receive a 
copy of any changes or amendments to the patient information and a copy of the consent 
form, which may need to be re-signed and dated. 
5.3 End of participation in the clinical trial 
On study day 90 after randomisation, data collection and thus participation in the trial will end 
for the respective patient. 
5.4 Prerequisites for participation in the trial 
The ability to determine serum albumin concentrations and provide the results on the same 
day is a prerequisite for participation of a trial centre in the clinical trial. Albumin 
concentration can be measured using analytic methods available in the respective trial 
centre, its local or commissioned laboratory. The trial centre is responsible for quality control 
measures relating to the laboratory method used as part of Good Laboratory Practice. 
The qualifications of the trial centre, investigators, deputy and members of the trial group will 
be recorded before the start of the clinical trial. The investigator and his/her deputy must be 
qualified in accordance with the requirements for clinical trials according to the AMG and 
local ethics committees. The investigator must be an intensive care physician,  expert in the 
treatment of septic shock who treats patients with this condition regularly. He/she must 
appoint at least one deputy with comparable qualifications. 
The investigator must know and follow the legal and judiciary obligations as well as the 
principles of the ICH-GCP (30). According to § 40 AMG (1a) (29), the investigator should 
determine suitably qualified members of the trial group. He/she will guide and supervise them 
and provide them with the information necessary for their work in the conduct of the clinical 
trial, in particular the protocol and investigator information. 
The pharmacy of the respective trial centre or ICU must be able to store the trial product 
correctly in accordance with the trial centre qualification and the storage precautions required 
by the relevant technical information. 
All eligible centres will be screened for their suitability as a trial centre by means of a 
selection visit. The recruiting potential of the trial centres has already been requested in the 
context of the application for the DFG grant. 
Patient data will be recorded electronically (electronic CRF, eCRF). To do this, the test 
centres need a computer with an Internet connection. 
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6. Trial drug  
The trial drug is the approved commercial product “Albutein® 200 g/l or Plasbumin® 20, 
solution for infusion”. Both drugs are manifactured according to the same procedure and 
considered to be interchangeable. These product will be provided free of charge by Instituto 
Grifols SA (Barcelona, Spain), exclusively for the treatment of patients in the albumin group. 
The control group will be treated according to usual practice for patients with septic shock.  
6.1 Labelling of the trial drug 
Special labelling of the trial drug will be waived in accordance with § 5 (9) of the GCP 
Regulation (31). The trial drug is an approved product intended for use in the clinical trial 
without additional manufacturing measures. The design of the clinical trial makes it possible 
to dispense the trial drug without special labelling on the containers and the outer wrapping 
according to § 5 paragraphs 2 to 7.  
 
According to the Transfusion Act, the product name and the charge number must be 
documented for each treatment of a patient with Albutein® 200 g/l or Plasbumin® 20 to 
ensure the patient can be traced the patient and the charge used. This will be done, for 
example, by labelling the albumin vials (using the study acronym, EudraCT number, and 
Patient ID), via the consignment note in the patient record, and via the drug accountability log 
in the ISF.  
 
6.2 Drug Accountability 
6.2.1 Transport by the manufacturer 
The trial drug will be supplied by the manufacturer to the pharmacy of the Jena University 
Hospital.  
 
6.2.2 Storage and delivery to the trial centres or their pharmacies 
The pharmacy of Jena University Hospital will be responsible for the storage as well as the 
transport of the trial drug to the trial centres or their local pharmacies. 
 
The trial drug should be stored below 25°C and may not be frozen. 
 
The first delivery of the trial drug to a trial centre or its pharmacy by the pharmacy of Jena 
University Hospital Jena will be commissioned by the SpB. Each subsequent delivery of the 
trial drug will take place without approval of the SpB. Subsequent deliveries will be requested 
independently by Jena University Hospital pharmacy. All deliveries will be documented in the 
trial master file (TMF) and the ISF. Confirmation of the receipt of each delivery should be 
done in writing. 
 
6.2.3 Storage and provision by the pharmacy of the trial centres 
The pharmacy of the respective trial centre confirms the receipt of the delivered trial drug in 
writing. It is responsible for the correct storage of the trial drug in a room, secured against 
non-authorized access. It is also responsible for and short-term provision of the trial drug. 
The use of the trial drug outside the clinical trial should be prohibited. 
 
6.2.4  Storage, use and tracing by the trial centre 
Each trial centre should confirm the receipt of delivered trial drug in writing. 


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The respective ICU of the trial centre should be able to correctly store the trial drug. The 
respective investigator is responsible for the storage of the trial drug in the trial centre, which 
should be secured against unauthorised access.  
Administration of the trial drug per participant may only be carried out by the persons 
specified in the list of responsibilities and must be documented in writing in the ISF. The trial 
drug may only be used in the context of this clinical trial. It is usable until the given expiry 
date. 
Empty and opened bottles of the trial drug per participant will be collected and destroyed in 
the trial centre according to the specifications in the study manual. These processes will be 
documented accordingly.  
6.3 Administration of the trial drug (only in the albumin group) 
6.3.1 Start dose  
Administration of the initial dose of the trial drug must be started within 6 to 24 hours after the 
beginning of the septic shock. A maximum of 2 hours may elapse between randomisation 
and the start of administration of the initial dose. 
Before the initial dose is given, a blood sample must be drawn to determine the serum 
albumin concentration. 
 
Starting dose: 60 g human albumin 20% (200 g/l, infusion solution) over 2-3 h 
Application: The investigational product will be administered intravenously using an infusion 
device. The human albumin should not be mixed with other medications, whole blood or 
packed red blood cells. 
 
The study drug is ready to use and can be administered intravenously directly or after dilution 
with an isotonic solution (e.g., 5% glucose or 0.9% sodium chloride). Albumin solutions 
should not be diluted with water for injections as this may cause haemolysis in the treated 
patients. 
The solution should be clear or slightly opalescent. Infusion solutions that are cloudy or have 
sediment should not be used. This may suggest that the product is unstable or the solution is 
contaminated. After opening the packaging of each vial, the solution should be used 
immediately.  
 
6.3.2 Subsequent administration of the trial drug 
Subsequent doses of the trial drug, starting from study day 1 will depend on the routine 
treatment day at each trial centre. A day begins when a new daily file is created at the trial 
centre. Study day 1 is thus defined as the 1st full day of treatment (24 h) after the day of 
randomisation. 
 
Administration of the trial drug will be based on the serum albumin concentration measured 
each day. Dose adjustment will follow a predetermined schedule with the aim of maintaining 
a serum albumin concentration of at least 30 g/l. 
 
Dose adjustment according to serum albumin concentration: ≥ 30 g/l: no administration 
 
 
 
 
 
 
 
≥ 25 g/l and <30 g/l: 40 g over 1-2 h 
 
 
 
 
 
 
 
≥ 20 g/l and <25 g/l: 60 g over 2-3 h 
 
 
 
 
 
 
 
<20 g/l: 80 g over 3-4 h 
 
6.3.3 Scheduled discontinuation of the trial drug  
Administration of the trial drug will continue for a maximum of 28 study days after 
randomisation and only as long as the participant is being treated in the ICU. 


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6.4 Premature discontinuation of the trial drug  
 
Administration of the trial drug may end prematurely in the following conditions: 
• Discharge of the participant from the ICU before day 28 after randomisation 
• Death of the participant 
• Failure to obtain consent to continuation of the clinical trial from the guardian or the legal 
representative according within the respective time window in patients who participated after 
confirmation of the urgency of participation in the clinical trial by an independent consultant 
or other procedure established in the trial centre to include patients who are unable to 
provide informed consent 
• Withdrawal of consent to participate in the clinical trial 
• Termination of treatment at own request, withdrawal of consent for participation  
• Occurrence of a medical reason, as described under 6.5 
 
Termination of treatment at own request 
Each participant (or, in the case of a non-consenting patient, his/her guardian or legal 
representative) has the right to opt-out at any time (no further administration of the trial drug) 
and without stating reasons, without incurring any disadvantage for the further medical 
treatment of the patient. 
The patient (or guardian or legal representative) will be asked to give the reasons for this 
decision, but without any obligation to do so. 
Observation and documentation for this patient will be continued. 
The SpB must be informed about the cancellation of the treatment at own request.  
6.5 Discontinuation of the trial interventions- discontinuation due to a medical 
reason 
The decision to discontinue or to continue treatment with the trial drug from a medical point 
of view will be at the discretion of the treating physicians (members of the trial group). 
Premature discontinuation of treatment with the trial drug does not lead to termination of the 
study. Further observation and documentation will be continued. 
 
Human albumin is a normal component of human plasma and does not differ in its effects 
from physiological albumin. According to the current drug information brochure, toxicity tests 
for single-use human albumin in animals are of little relevance and do not enable 
determination of the toxic or lethal dose or a dose-response relation. The target serum 
albumin concentration in the clinical trial is within the normal range of human plasma albumin 
(mindestens 30 g/l), so that overdose is unlikely.  
 
According to the current drug information brochure, the following adverse effects may occur 
with Albutein® 200 g/l or Plasbumin® 20: 
• Mild reactions, such as flush, urticaria, fever, and nausea, are rare. 
• In very rare cases, anaphylactic shock can occur. 
• The possibility of transmitting an infection cannot be completely ruled out despite standard 
measures of preventing infections caused by drugs made from human blood or plasma. This 
also applies to all unknown or newly emerging viruses or other pathogens. 
 
MIld reactions, such as flush, urticaria, fever and nausea, usually disappear quickly when the 
infusion rate is reduced or the infusion is stopped. 
If such reactions occur, appropriate therapy should be initiated if clinically indicated. This 
includes therapy with antihistamines and symptomatic therapy. 
In these cases, the trial drug should be subsequently administered over a longer period of 
time (up to twice the prescribed duration), with close monitoring of the relevant clinical 


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parameters. A new clinical evaluation and, if necessary, treatment with the trial drug should 
continue on the following day. If the reaction reoccurs, the trial preparation will be 
permanently stopped.  
 
If anaphylactic shock occurs, infusion of the trial drug should be discontinued and adequate 
treatment should be initiated according to current recommendations for treating shock. 
Administration of the trial drug will be permanently stopped. 
 
If hypervolaemia is suspected, the trial drug should be administered over a longer period of 
time (up to 2x the prescribed duration) under close observation of the appropriate 
haemodynamic parameters. If the association between the trial drug and hypervolaemia is 
confirmed, an increase in the severity of hypervolaemia is observed, or life-threatening 
consequences such as pulmonary oedema occur, administration of the trial drug for that day 
should be stopped. A new clinical evaluation and, if necessary, continuation of the trial drug 
should take place on the following day. 
The SpB must be informed about the permanent termination of the trial drug (discontinuation 
of treatment). The patient, guardian or legal representative will be informed about 
discontinuation of treatment for medical reasons as well as the follow-up procedure. 
 
6.5.1 Compliance 
Compliance of administration of the trial drug by the patient need not be monitored, because 
the drug will always be administered by the attending physician (member of the trial group) or 
caregiver on the ICU or checked by these persons and documented in the medical record.  
6.6 Instructions for the control group without albumin 
Patients in the control group are treated according to standard practice with any crystalloid 
solution as volume replacement therapy of first choice. In patients of the control group, 
albumin administration should not be considered. If, however, according to the judgment of 
the treating physician (member of the trial group), it is necessary to consider albumin 
replacement therapy for clinical reasons, this can of course be done. This may be the case if, 
for example, the serum albumin level decreases below 15 g/l. The following factors should be 
considered: 
 
• Active substance of the administered product: Albumin, but do not use the product provided 
for use in the trial! 
• Application: intravenous, following the instructions in the respective drug information 
brochure 
• Dosage: as low as possible 
• Documentation of the drug 
 
The administration of albumin to a participant in the control group leads to exclusion of this 
patient from the per-protocol analysis. 
6.7 Permitted concomitant medication, concomitant therapies 
There are no restrictions to concomitant medication and therapies during the trial. 
Concomitant medication and therapies must be documented. 
6.8 Further treatment of participants after the end of participation 
Specific aftercare or follow-up is not needed after a maximum of 28 study days of 
administration of the trial drug to patients in the albumin group, or after discharge from the 
ICU or withdrawal of consent in both groups. Treatment with the trial drug is an intensive 
care measure that is of no consequence to subsequent medical care. The administration of 


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human albumin 200 g/l solution for infusion as a trial drug while participating in a clinical trial 
will be communicated to the treating physician in the discharge report. 


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7. Start, course and end of the clinical trial/study visits 
 
General remarks: 
 Patients in the participating ICUs will be screened during the ICU stay to see whether they 
fullfil the inclusion criteria and do not meet exclusion criteria. Informed consent for 
participation in the trial will be sought from all patients ≥18 years of age with septic shock. 
 General treatment of patients participating in the clinical trial will follow usual practice for 
this condition and will be consistent with current guidelines for the treatment of such 
patients (25). 
 Crystalloids will be administered in both groups according to usual practice. 
 Antimicrobial therapy should be performed according to PK/PD principles. Increasing the 
dosage of antimicrobial agents with high protein binding capacity should be weighed in 
patients with hypoalbuminemia.  
 Collection of microbiological samples as part of the primary diagnosis of sepsis or of 
developing infections is at the discretion of the treating physician and is not trial-related. 
Nonetheless, microbiologic diagnostics should be sought, especially in the form of blood 
cultures, before starting antimicrobial therapy. 
 Trial-related measures may only take place after consent! 
 A patient may be included in the trial only if all the inclusion criteria (including negative 
pregnancy test) are met and all exclusion criteria are absent. 
 In the case of a woman of childbearing potential, a pregnancy test should be carried out 
after obtaining informed consent. Before the result is available, the patient must not be 
randomised. If the pregnancy test is positive, participation in the clinical trial for the patient 
will end promptly. 
 A study day is defined by the treatment day according to the routine practice of the 
respective trial centre. A study day changes when a new daily data record sheet is 
created in the trial centre. The 1st day after randomisation (1st study day) is the 1st full 
treatment day (24 h) after the day of randomisation. 
 
7.1 Screening and 24-h period before randomisation 
 Obtaining written informed consent or confirming the urgency of participating in the clinical 
trial with possible patient benefit by an independent consultant or other procedures 
established in the trial centre to include patients who are unable to provide informed 
consent 
 Checking the inclusion and exclusion criteria (including pregnancy test (blood or urine) for 
women of childbearing age) 
 Recording the time of onset of septic shock 
 Collection of basic data (sex, age, weight, height, time of hospital admission, time of ICU 
admission, type of admission, referring facility prior to transfer to the ICU, etc.) 
 Documentation of primary or secondary admission diagnoses 
 Documentation of concomitant diseases present on admission to the ICU 
 Collection of data on infection, microbiology and anti-infective therapy 
 Collection of raw data for the calculation of APACHE II, SAPS II, and SOFA scores from 
the routine laboratory requests (not for study purposes) from the 24-h period before 
randomisation (data from ICU or normal ward) (see Appendix) 
 Assessment of concomitant medication (catecholamines, inotropes, diuretics, fluid therapy 
including transfusion, adjunctive sepsis therapy) from the 24-h period prior to 
randomization 
 Recording of intensive care interventions (intubation (ITN), central venous catheter (CVC), 
arterial catheter (AC), renal replacement therapy (RRT), ventilation, extracorporeal 


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membrane oxygenation (ECMO), haemodynamic monitoring during the 24-h period before 
randomisation 
 Recording 
of 
clinical 
parameters 
(body 
temperature, 
respiratory 
frequency, 
haemodynamic parameters (SAP, MAP, DAP, CVP, CO) from the 24-h period before 
randomisation 
7.2 Time of randomisation 
Randomisation leads to the assignment of a participant to the albumin group or to the control 
group without albumin. 
 
The randomisation day is defined as the treatment day on which the randomisation takes 
place. It ends when a new daily treatment sheet is created. 
 
Randomisation must be performed within two hours of the written informed consent or 
confirmation of urgency of participation in the clinical trial with possible benefit to the patient 
by an independent consultant or other procedures established in the trial centre to include 
patients who are unable to provide informed consent 
The randomisation is carried out by an automated internet-based service, which is provided 
by the Centre for Clinical Studies Jena (ZKS). The group assignment is retrieved via a 
validated electronic tool (PaRANDies) by the respective trial centre. The group assignment of 
the patient must be documented (patient record, e-CRF). Each participant will receive a 
randomisation number.  
 
 Collection of data on infection, microbiology and anti-infective therapy 
 Recording 
of 
clinical 
parameters 
(body 
temperature, 
respiratory 
frequency, 
haemodynamic parameters) at the time of randomisation (+/- 1 hour) 
 Recording of concomitant medication (catecholamines, inotropes, diuretics, fluid therapy 
including transfusion, adjunctive sepsis therapy) at the time of randomisation (+/- 1 hour) 
 Collection of routine data from the laboratory (not trial-related), performed in the 24-h 
period before randomisation: haemoglobin, creatinine, bilirubin, C-reactive protein, 
procalcitonin, leucocytes, platelets, lactate, arterial blood gas analysis (PaCO2, PaO2, 
FiO2, SO2, pH , ScO2) 
 Recording of intensive care interventions (ITN, CVC, AC, RRT, ventilation,  ECMO, 
haemodynamic monitoring) at the time of randomisation (+/- 1 hour) 
 Start capturing AEs, SAEs, sepsis-related clinical events 
7.3 Time period until 2 h after randomisation  
 Collection of data on infection, microbiology and anti-infective therapy 
 Capture of AEs, SAEs, sepsis-related clinical events 
 Procedure according to group allocation: 
 
Albumin group:  
1. Blood sampling to determine serum 
albumin concentration within 2 
hours after randomisation  
2. Starting dose of the trial product 
within 6-24 h after the onset of 
septic shock: 60 g Human albumin 
20% (200 g/l solution for infusions) 
over 2-3 h 
3. Data 
collection 
on 
trial 
drug 
administration 
(continuous 
collection).  
Control group without albumin:  
1. Blood sampling to determine serum 
albumin concentration within 2 hours 
after randomisation 
2. Treatment according to usual practice 
with crystalloids as the first-choice 
fluid treatment. 
 
 
 


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7.4 Trial visit at 6 h after randomisation 
 Collection of data on infection, microbiology and anti-infective therapy 
 Recording of co-medication with catecholamines and inotropes at this specific time-point 
(+/- 1 hour) 
 Recording of concomitant medication with diuretics, fluid therapy including transfusion, 
adjunctive sepsis therapy) during the past 6 h 
 Recording of clinical parameters (respiratory frequency, haemodynamic parameters) at 
this specific time point (+/- 1 hour) 
 Collection of routine laboratory data (not trial-related) at this specific time point (+/- 1 
hour): haemoglobin, lactate, arterial blood gas analysis (PaCO2, PaO2, FiO2, SO2, pH, 
ScO2) 
 Recording of intensive care interventions (ITN, RRT, ECMO, mechanical ventilation, 
haemodynamic monitoring) from the previous 6 hours 
 Capturing of AEs/SAEs and sepsis-related clinical events (continuous) 
 Recording vital status (alive/dead) 
 Data collection about administration of the trial drug (continuous), including information on 
the administered dose, interruption or discontinuation of the dose if necessary 
7.5 Trial visits on trial days 1 to 28 after randomisation 
These visits should only be performed if the patient is still being treated in the ICU. 
 
• Blood sampling to determine the serum albumin concentration, including recording the time 
of blood sampling 
• Blood samples for serum albumin concentration determination may be performed as part of 
the routine blood sampling procedure at the respective trial centre, provided that they are 
taken between 4:00 and 9:00 in the morning. 
• Collection of data on infection, microbiology and anti-infective therapy 
• Recording of the raw data for calculation of the SOFA score on the respective study day 
from the routine laboratory results (not for trial purposes); the "worst" daily value should be 
recorded 
• Recording of concomitant medication with catecholamines and inotropes, diuretics, fluid 
therapy (including transfusion therapy, adjunctive sepsis therapy) on the respective trial day 
• Recording of intensive care interventions (ITN, CIC, AC, RRT, mechanical ventilation, 
ECMO, haemodynamic monitoring) on the respective trial day 
 Recording the amount of enteral and parentral fluid adminstration on the trial day 
• Collection of routine laboratory data (not trial-related), taken between 4:00 - 9:00 in the 
morning: haemoglobin, creatinine, bilirubin, C-reactive protein, procalcitonin, leucocytes, 
platelets, lactate, arterial blood gas analysis (PaCO2, PaO2, FiO2, SO2, pH, ScO2) 
• Recording of clinical parameters (body temperature, respiratory frequency and 
haemodynamic parameters), 24 h urinary output, other fluid loss on the trial day  
• Capturing of AEs/SAEs and sepsis-related clinical events (continuous) 
• Recording of vital status (live / dead) 
• Albumin group: administration of the trial drug according to serum albumin concentration, 
dose adjustment according to the given scheme 
• Data collection regarding administration of the trial drug (continuous), including information 
on the administered dose, interruption or discontinuation of the dose if necessary 
Note: After administration of the trial drug on day 28, no further doses are given. 
 
 
7.5.1 Data collection at hospital discharge or at the end of the study 
Data will be collected from participants at one of the following time points, whichever comes 
first: 
 


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• Discharge from the hospital before or on trial day 28 
• Discharge from the hospital up to and including trial day 90 
• Trial day 90 reached in the hospital (regular end of study) 
• Early termination of the clinical trial as described in 7.6 
 
 
Data collection: 
 
• Recorde data on ongoing SAEs and serious sepsis-related clinical events 
• Vital status (alive/dead): if applicable date of death and cause of death; if applicable, 
recording of "end of life" decisions, stay after discharge 
• ICU length of stay (of the first ICU stay after study participation) 
• Hospital length of stay (first hospital stay after study participation) 
 
If the patient is discharged from the ICU or the hospital during the 90-day observation period, 
this time will be defined as the endpoint for determining the ICU length of stay and/or hospital 
stay. If the patient returns to the ICU or hospital within the 90 days, this is no longer relevant 
for the collection of trial endpoints. 
. 
 
7.5.2 Data collection at trial days 28, 60, and 90 after randomisation 
At these time points, data will be collected on the primary and secondary "mortality" 
outcomes. If the patient has already left the hospital before these time points, contact with 
the patient, his guardian or legal representative will take place to collect the required data. 
 
• Vital status (alive/dead): if applicable date of death and cause of death; if applicable, 
recording of "end of life" decisions, stay after discharge 
• Verification of the documentation of SAEs already detected and serious sepsis-related 
clinical events, possibly AEs, which are "ongoing" at the respective time point 
7.6 Premature end of the participation of a patient in the clinical trial 
Participation of a patient in the clinical trial may be prematurely terminated for the following 
circumstances: 
• Death of the participant 
• Failure to obtain consent to the continuation of the clinical trial by a guardian or a legal 
representative according to the respective time windows in patients who participated after 
confirmation of the urgency of participation in the clinical trial by an independent consultant 
or other procedures, established in the trial centre to include patients who are unable to 
provide informed consent 
• Refusal to continue the clinical trial by formerly incapacitated patients who have regained 
their ability to consent 
• Abort at own request, withdrawal of consent to participate in the clinical trial 
• Occurrence of any of the circumstances described in 7.7.2 and 7.7.3 
 
Termination of participation in the trial, drop-out at own request 
Participation in the clinical trial is voluntary. Each participant has the right, at any time and 
without stating reasons, to withdraw his/her consent prematurely from the clinical trial without 
incurring disadvantages for his/her further medical treatment. Withdrawal of consent leads to 
termination of the clinical trial in the patient. 


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• The patient, his/her guardian or legal representative will be asked to give the reason for his 
decision, but without any obligation to do so. 
• The patient, his/her guardian or legal representative will be informed that no further study-
related measures will be carried out, but that the stored data may continue to be used, as far 
as is necessary to determine the effects of the intervention and to ensure that patient’s 
interests will not be affected. 
• The patient, his/her guardian or legal representative should be asked to provide the data 
requested at the end of the study. 
• The patient's observations and documentation related to the clinical trial will be terminated. 
• The SpB must be informed of the termination of participation at own request. 
7.7 End of the clinical trial 
7.7.1 Scheduled end 
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. According to GCP-V § 13 (30), the sponsor will 
inform the competent authority, the competent higher federal authority and the responsible 
ethics committee within 90 days of the termination of the clinical trial. Within one year of 
completion of the clinical trial, the sponsor will submit a summary report of the clinical trial 
covering all results of the clinical trial to the competent higher federal authority and the 
relevant ethics committee. 
 
7.7.2 Premature termination of the trial in a trial centre 
The SpB will decide on the interruption or termination of the clinical trial in a trial centre, 
possibly in coordination with the Safety Committee and the biometrician. 
The clinical trial may be discontinued or terminated at a trial centre if 
• the trial centre does not meet the technical requirements specified in the study protocol, 
• the procedures related to the clinical trial do not comply with the protocol, 
• there are serious, unexplained problems with the quality of the collected data (insufficient 
quality of data), 
• the recruitment rate in the trial centre is inadequate, 
• unpredictable circumstances have occurred in the respective trial centre that do not allow 
continuation of the clinical trial (e.g., lack of personnel and equipment capacity, the required 
logistics can no longer be applied) 
If there are ethical concerns about the continuation of the clinical trial by an investigator, 
deputy, or a medical member of the trial group, this must be reported immediately to the 
SpB. If termination of the clinical trial in a trial centre is initiated by the trial centre itself, the 
latter must give written reasons for this decision. 
Investigators, deputies, or members of the trial group at a trial centre who are no longer 
participating in the clinical trial must inform SpB immediately about their decision. The 
decision must be justified. 
It is the responsibility of the investigators and the SpB to comply with the disclosure, 
documentation and notification requirements of GCP-V (30). 
In the event that a trial centre has to be closed prematurely, a final visit will be made by the 
trial monitor. Details are described in the Monitoring Manual. 
 


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7.7.3  Premature termination of the entire clinical trial 
The SpB is entitled to interrupt or prematurely terminate the clinical trial for relevant medical 
and administrative causes. Any interruption or premature termination of the entire clinical trial 
should be discussed in advance with the SMC. The reasons for interrupting or terminating 
the trial should be documented in detail. 
The SpB is entitled to suspend or terminate the entire clinical trial if: 
• the recruitment rate is inadequate, 
• there are serious, unexplained problems with the quality of the collected data, 
• unacceptable risks have arisen (decision after new benefit-risk assessment), 
• new scientific evidence does not allow continuation of the clinical trial during the clinical trial 
period, or 
• a risk to patient safety emerges. 
Since the clinical trial is carried out in accordance with the provisions of the German 
Medicinal Products Act, the responsible BOB can also revoke the license or cancel it. 
The trial procedures for all patients whose participation in the clinical trial has not yet ended 
must be determined. 
The participant must be informed immediately of any interruption or early termination of the 
trial. Appropriate further treatment or follow-up must be guaranteed. The date and reason for 
the interruption or premature termination must be documented. 
The data available until early termination must be evaluated and a final clinical trial report 
must be prepared. If clinical examination is discontinued or interrupted by the SpB, the trial 
centres should be informed. In accordance with GCP-V § 13 (8) (30), the SpB should inform 
the competent state authority, the competent BOB and the responsible ethics committee 
within 15 days, stating the reasons for the termination or interruption of the trial. It is the 
responsibility of the investigators and the SpB to comply with the duties of disclosure, 
documentation and notification under GCP-V. 
Details of the final visit of the trial monitor in the trial centres are described in the Monitoring 
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8. Safety and adverse events 
8.1 Assessment of the safety of the trial drug 
The trial drug contains human albumin as an active substance. Human albumin is a normal 
component of human blood plasma and does not differ in its effects from physiological 
albumin. According to the valid information brochure, there are only a few rare or very rare 
adverse effects. Data on safety and compatibility are described in the valid information 
brochure. For the clinical trial, safe application can be assumed. Safety management will 
ensure patient safety for the clinical trial. In addition, adverse events observed during the 
clinical trial will be recorded, evaluated, and regularly reviewed by an independent safety 
committee.   
8.2 Adverse events  
According to GCP-V § 3 (30), an Adverse Event (AE) is any unfavourable event that occurs 
to a patient participating in a clinical trial who has received an investigational medicinal 
product and that is not necessarily causally related to the treatment. According to ICH-GCP 
(29), these may be symptoms (including, for example, abnormal laboratory values), diseases 
or signs that are associated with the use of an investigational medicinal product. This is 
independent of whether the event is causally related to the investigational product or not. For 
the ARISS study, assessment of adverse events will also be done in patients of the control 
group without albumin. 
 
Septic shock, which is the basic inclusion criterion of this clinical trial in all study patients, is 
one of the most life-threatening clinical pictures. The ICU mortality from severe sepsis and 
septic shock is 47% according to the prevalence study of the sepsis competence network (7). 
Many of the patients need mechanical ventilation and about half the patients have acute 
kidney failure. Hepatic and metabolic parameters are almost always altered depending on 
the severity of sepsis. Previous studies investigating severe sepsis or septic shock, such as 
MAXSEP (EudraCT 2006-006984-21) and SISPCT (EudraCT 2007-004333-42), have 
therefore performed selective AE evaluation that has been shown to be reliable and which 
should also be used in the ARISS study. 
Because most septic patients have altered laboratory values and symptoms because of  the 
underlying disease and are constantly evolving as the disease progresses, the definition of 
AE is restricted as follows in this clinical trial: 
An adverse event in the ARISS is any adverse event that occurs to a study subject that is 
not necessarily causally related to the trial drug. If an adverse event can be explained by the 
underlying sepsis, the following applies:   
 
Events plausibly explainable by sepsis are recorded in both groups as sepsis-related clinical 
events in the daily eCRF visits, but not as AEs. This rule concerns the following clinical 
events: 
 
• Death caused by severe sepsis or septic shock 
• Cardiovascular event requiring the administration of vasoactive substances 
• Respiratory event: e.g., decrease in PaO2/FiO2 ratio, hypoxia, ARDS, acute pulmonary 
dysfunction, and mechanical ventilation 
• Hepatic event: e.g., Liver failure or liver dysfunction 
• Renal event: e.g., Kidney failure, renal insufficiency 
• Haematological event: e.g., coagulopathy, DIC, thrombocytopaenia, thrombocytosis 
• Neurological event: e.g., delirium, confusion 
 
Each sepsis-related clinical event must be documented in the eCRF during the respective 
visit with specific parameters. The investigator assesses the sepsis-related clinical event in 


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terms of an association with the trial drug and classifies it as "possible" or "not possible". 
Documentation of the sepsis-related clinical event as an AE occurs only if the examiner 
suspects a connection with the administration of the trial drug, which is therefore only 
possible in the albumin group. 
However, the following effects of the trial drug may be substance-specific and must be 
documented as AE: 
 
• Flush 
• Urticaria 
• Fever 
• Nausea 
• Anaphylactic shock 
• Hypervolaemia 
• Pulmonary oedema 
• Transmission of infection (in addition to sepsis, see corresponding section of the valid 
information brochure). 
 
Clinically relevant worsening of a pre-existing disease not related to sepsis should be 
considered and documented as an AE. 
. 
8.3 Duration of recording adverse events 
Recording of AEs and sepsis-related adverse events begins at randomisation. Because the 
study drug is human albumin, which is a normal constituent of human blood plasma, and 
does not differ in its effects from physiologic albumin, recording and follow-up of AEs and 
SAEs for a maximum of 24 hours after the last dose of the trial drug is considered to be 
sufficient. Therefore,  AEs and sepsis-related adverse events will be recorded 
• in the albumin group until 24 h after the last dose of the trial drug and 
• in the control group without albumin until day 28 after randomisation or until discharge from 
the ICU, if it occurs before day 28 after randomisation. 
 
In the event that AEs or SAEs are still "ongoing" after the above dates, they will be tracked 
until maximum the end of data collection (Day 90). If they are "ongoing" on day 90, they are 
documented as "not recovered," "recovered with sequelae," or "unknown." 
. 
8.4 Documentation of adverse events 
All AEs will be recorded promptly by the trial centres in the eCRF. Sepsis-related clinical 
events will be documented in the daily visits section, all others in the AE section of the eCRF. 
 
Events which should not be documented as an AE: 
• Medical or surgical interventions (diseases or symptoms that lead to a necessary 
intervention are documented as an AE) 
• Interventions to treat a pre-existing condition that were already planned before consenting 
to the clinical trial, 
• Daily fluctuations in the clinical picture, 
• Normal progression of the disease severity of sepsis, 
• Illnesses that existed before consenting to the clinical trial (this will be documented as 
concomitant disease and not AEs). 
 
Each AE is to be checked to see whether it meets the criteria for an SAE and, if necessary, 
proceed according to the SAE declaration procedure (see corresponding chapter 8.6). 
 


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At the trial centre, care should be taken to ensure that all persons involved in the treatment of 
participants are adequately informed about the responsibilities in the event of adverse 
events. 
 
8.4.1 Intensity of an adverse event 
The intensity of adverse events will be stratified according to the following 3-point scale. 
 
• Mild: a clinical symptom or sign that is well/easily tolerated and usually requires no 
intervention 
• Moderate: clinical symptom or sign sufficient to interfere with normal/daily activity, 
intervention may be required 
• Severe: a clinical symptom or sign that results in severe disability, inability to work or 
inability to perform everyday activities = daily activities/work not possible, treatment or 
intervention usually required. 
 
If the intensity of an event changes, only the higher intensity should be documented on the 
corresponding AE section. If an AE decreases in intensity, the previous rating must not be 
changed. 
 
Mild, moderate, and severe adverse event can be serious or not. The above terms describe 
the intensity (medical severity) of certain events (e.g., a mild, moderate or severe myocardial 
infarction). However, the event may also be of secondary medical relevance (e.g., severe 
headache) and it is not necessarily "serious." "Seriousness" serves in the sense of the law as 
a definition for further reporting obligations. 
 
8.4.2 Causality – relationship between the adverse event and the trial drug 
For each AE, whether an association with the trial drug can be excluded or not will be 
assessed. 
 
The type and pattern of response, timing of administration, clinical status of the patient, 
concomitant medication and other relevant clinical parameters should be considered. 
The following classification is used for the assessment of causality: 
 
yes - possible 
• There is a justified causal relationship between the trial drug and the event 
• The event reacts to the discontinuation of the trial drug 
• The event appears on resumption of the trial drug (if clinically feasible) 
• Information on discontinuation of the trial drug is missing or unclear 
• A connection between the trial drug and the event cannot be reasonably excluded 
 
no - unlikely 
• There is a temporal relationship to the administration of the trial drug, but no causal 
connection between the drug and the event 
• There is no temporal correlation with the administration of the trial drug (too early, too late) 
• There is a reasonable causal relationship between another medication, a concomitant 
disease or other circumstances and the event 
• there is a clear alternative explanation or implausibility (e.g., diagnosis of a cancer a few 
days after the first administration of the trial drug) 
 
The following factors should be considered in the assessment: 
• Temporal relationship (event occurs after administration of the trial drug) 
• Response to discontinuation and reproduction of the trial drug 
• Underlying concomitant diseases 


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• Concomitant medication or non-drug treatment 
• Pharmacodynamics/pharmacokinetics of the trial drug 
 
8.4.3  Procedures in case of adverse events 
Procedures for the patient: 
If the patient requires treatment as a result of the adverse event, it must be performed 
according to best available evidence to restore the patient's health. 
Treatment of an AE should be documented as follows: 
• No action taken 
• Medication 
• Surgical procedure 
• Additional intensive medical care 
• Other measures 
 
Procedures in relation to the trial drug 
The handling of the trial drug with regard to an AE must be documented as follows: 
• Administration of trial drug interrupted - temporarily 
• Trial drug discontinued - permanently 
• Dose reduction 
• No dose change 
• Not applicable, as administration of trial drug had already been terminated or was never 
given.  
 
8.4.4  Outcome of an adverse event 
The outcome of an adverse event will be classified as follows:  
 Resolved  
 Resolved with sequelae  
 Not resolved 
 Fatal  
 Unknown 
8.5 Serious adverse event 
According to GCP-V § 3 (30), a Serious Adverse Event (SAE) or a Serious Adverse Reaction 
(SAR) is any adverse event or adverse reaction that is fatal or life-threatening, requires 
hospitalisation or prolongation of the length of stay, results in permanent or serious disability 
or disability or invalidity, or results in a congenital anomaly or birth defect. An SAE may also 
be 
an 
AE 
which, 
according 
to 
the 
medical 
assessment 
of 
the 
assessing 
investigator/deputy/medical member of the trial group, fulfils a comparable criterion. 
A serious adverse event must be documented as an AE in the eCRF and reported with the 
SAE sheet. 
 
8.6 Reporting serious adverse events 
Obligations for documentation and appropriate reporting of SAEs should be followed 
according to GCP-V § 12 (4) – (6) und § 13 (1) – (6) (30).  
 


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8.6.1 Obligations of the investigator/deputy 
The trial centre should inform ZKS Jena, which is commissioned by the SpB, without delay 
(at the latest within 24 hours after recognition), using an SAE form, about the occurrence of a 
serious adverse event, with the exception of events that do not need to be reported 
immediately according to the study protocol. 
The "SAE registration form" should be sent by fax to: 
 
ZKS Jena 
Fax: +49 (0) 3641 9399946 
If further information on the SAE becomes available at a later date, it must also be reported 
to ZKS Jena without delay. The report from the trial centre will be checked for completeness 
and plausibility. If necessary, queries will be processed and tracked. 
For all notifications, personal data must be pseudoanonymised prior to transmission using 
the subject ID (patient identification number of the participant). The primary report and all 
follow-up reports must be aggregated using the Subject ID. 
.  
 
8.6.2  Obligations of the SpB  
For each SAE submitted by the trial centre, the SpB should arrange a secondary assessment 
by an experienced medical specialist with regard to the criteria "serious", "causal 
relationship" and "expectation". If a SUSAR (Suspected Unexpected Serious Adverse 
Reaction) is determined by the secondary assessment, the event should be reported to the 
PEI, ethics committee and investigators of ZKS Jena, including the report of the second 
assessor of the SpB. 
A SUSAR is a suspected adverse effect that is both severe and unexpected. An unexpected 
adverse effect according to GCP-V § 3 (30) is an adverse effect that does not match the type 
and severity of the known information about the trial drug, i.e., the product information 
brochure of Albutein® 200 g/l or Plasbumin® 20, solution for infusion. 
The SpB is responsible for continuously reviewing the benefit-risk assessment of the clinical 
trial. Occasions for the reassessment of benefit and risk as well as measures to protect 
against immediate danger should be reported in accordance with the law within the specified 
deadlines. 
All responsibilities, information channels and deadlines are defined in the SAE Manual. 
8.7 Preexisting diseases 
See 8.4 concomitant diseases 
8.8 Pregnancy  
According to the valid product information brochure, embryo-foetal toxicity, mutagenic or 
carcinogenic potential has not been reported in relation to the trial drug. Nevertheless, 
women of childbearing age can only participate if there is a negative pregnancy test. 
Breastfeeding women are also excluded from participating in the clinical trial. Onset of 
pregnancy during the clinical trial is not expected to occur because of the severity of the 
underlying disease and the time-limited administration of albumin. Therefore, explicit 


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information about contraceptive measures and pregnancy tests during the course of the 
clinical trial will be waived.  
8.9 Data and safety monitoring board - SMC 
The data and safety monitoring board is an independent committee composed of a group of 
individuals (four independent physicians/scientists, one of them a statistician) with relevant 
experience. The main task of the Committee will be to monitor the safety and efficacy of the 
use of the trial drug during the clinical trial. This committee makes recommendations for the 
continuation, modification or termination of the clinical trial. 
The SMC will receive all safety-related data and information every 6 months or year to 
conduct an independent review of the safety of the clinical trial. The results will be brought to 
the attention of the BOB and the leading ethics committee as part of the annual safety report, 
the DSUR, or as necessary. Responsibilities and details of the SMC are described in the 
corresponding manual for the members of the committee.  
 


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9. Documentation and data management 
9.1 List of responsibilities 
Every person responsible for documentation in the eCRF must be identifiable. A list of 
signatures and abbreviations for persons who are allowed to make entries in the eCRF 
(Signature and Responsibility Log) must be filed in the ISF and in the TMF. This list also 
identifies other individuals involved in the clinical trial with their names, signatures, and 
abbreviations, as well as their responsibilities and authority. 
9.2 Documentation of screening 
For all patients potentially eligible to participate in the clinical trial, inclusion and exclusion 
criteria will be reviewed. Documentation of these patients in the screening and enrolment log 
is required. For eligible patients, whether randomisation takes  place or not must be 
documented. Reasons for non-participation of an eligible patient must be indicated 
(screening failure). 
9.3 Patient identification list 
A Patient Identification List will be kept at the trial centre, listing any patient who has 
consented to participate in the clinical trial. 
In the patient identification list, the complete name, randomisation number and, if applicable, 
further identification data (e.g., date of birth, sex) will be recorded for each patient and 
assigned to a subject ID (patient identification number, pseudonym). The Subject ID is 
created using a special algorithm with the Subject ID Generator. 
This list must be treated with absolute confidentiality, must not leave the trial centre and must 
be filed in the ISF. It is necessary that patients can be identified for later requests by the data 
management team. 
The patient identification list remains in the trial centre and must be archived for at least 30 
years after the end of the clinical trial. 
 
A patient's participation in the clinical trial must be noted in the patient records along with 
other clinical trial-related information. 
  
9.4 Investigator site file (ISF) 
The ISF will keep the documents required for the clinical trial, and will provide an overview on 
the clinical trial at the respective trial centre. The ISF contains the essential documents, such 
as the trial protocol, patient information and consent form, approval of the competent BOB, 
approval of the responsible ethics committee (s), notification to the competent state 
authorities, investigators' CVs, list of responsibilities, trial-related correspondence, and other 
relevant documents. As part of the monitoring process, the ISF will be checked to ensure it is 
up-to-date and complete in accordance with the regulations. Each ISF must be archived for 
at least 30 years after the end of the clinical trial. 
9.5 Case report form (CRF)    
Source data according to the ICH-GCP E6 (29) in this clinical trial are all routine data and 
laboratory reports and any other documents required for the clinical trial. The vast majority of 
the data to be collected will be routinely collected from patients and entered directly into the 
regular patient records. The data relevant for the clinical trial are collected via RDE (Remote 
Data Entry). For this purpose, the data will be entered by the investigator or an authorised 
member of the trial group on an online workstation into special masks, which represent an 
electronic CRF. The data will be transferred directly to the trial database in ZKS Jena via the 
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The CRF consists of individual sections, including inclusion and randomisation, visits during 
the course of the trial, AE/SAE, end of intervention and discontinuation of the clinical trial. 
The entries to be recorded in the relevant sections are specified when the CRF is created. 
It is the responsibility of the investigators to ensure that all data collected during the clinical 
trial are entered correctly and completely in the database created specifically for this clinical 
trial. 
Corrections in the eCRF may only be made by authorised persons or by the responsible 
investigator/deputy/medical member of the test group and must be justified. Corrections are 
recorded so that the old entry can still be retrieved. All data and corrections will be 
automatically logged with date, time and the person entering. 
A paper-based CRF as a "copy" will be provided to the trial centres as part of the ISF. 
9.6 Data handling and data management 
Data collection serves a scientific purpose. The data will be generated in the participating 
trial centres and recorded via a web application on the servers of the ZKS of the Jena 
University Hospital using the study management software "OpenClinica®". The software 
complies with regulatory requirements (ICH-GCP, 21CFRPart11) (29, 30). The data will be 
recorded using an encrypted data connection (HTTPS) in input masks via a web browser. To 
ensure pseudonymised data analysis, each patient will be assigned a unique Subject ID 
(Patient Identification Number) as mentioned above. 
For data management, the study management software "OpenClinica®" will be used. 
Verification of the accuracy of the data will be done by range, validity and consistency 
checks. Implausible or missing data will be requested from the test centre. Any change to the 
data, e.g., due to the incorporation of answered questions, will be documented via an 
automatic change tracking (audit trail) in the database. By using a hierarchical, role-based 
access concept, unauthorised access to the data will be impossible. 
9.7 Data retention, archiving of documents 
As a documentation centre, ZKS Jena will also be responsible for data storage. The backup 
of electronic data will occur regularly. The data storage facilities are located in a locked, 
central room, accessible only to system administrators. 
 
9.7.1 Data retention obligation of the SpB 
According to GCP-V § 13 (32), the SpB must ensure that the main clinical trial documents, 
including the data entry forms, are kept for at least 30 years after termination of the clinical 
trial. Other regulations for the storage of medical records remain unaffected. 
All documents must be kept in a safe place and kept confidential. If necessary (e.g., because 
of legal regulations or after consultation with the SpB), the documents may be revoked 
beyond the abovementioned period. It is the responsibility of the SpB to inform the 
appropriate persons if the documents no longer need to be kept and how to dispose of them. 
 
9.7.2 Data retention obligation of the trial centre 
Records and documents related to the clinical trial or use of the trial drug, e.g., patient 
identification list, informed consent forms, lists of trial drug distribution, correspondence with 
the Ethics Committee, competent authorities, SpB, and other relevant documents must be 
kept in accordance with GCP-V § 13 (32) for at least 30 years (or longer, if required by law). 
The medical records and other original data must be kept for the longest possible period of 
time allowed by the hospital, institution or private practice (according to the archiving period 
valid for the trial centres and according to local methods and premises), but not less than 30 
years. The investigator must take precautions to prevent the accidental or premature 
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9.8 Privacy and privacy statement 
This clinical trial will serve a scientific goal of considerable clinical relevance. To achieve this 
goal, it is necessary to collect and process medical data from individual patients. Data 
collection will take place in the involved trial centres. All collected medical data will be 
entered in the trial centres with the aid of a computer-aided online data collection system and 
transmitted directly to the documentation centre based at the ZKS of the Jena University 
Hospital. Name-related identification of individual patients by the documentation centre is not 
required at any time during the clinical trial. During data collection and data processing, 
therefore, all necessary measures will be taken at the earliest possible date in order to 
establish de facto anonymisation. 
Transfer of patient-related medical data from the trial centres to the documentation centre will 
be carried out using a pseudonym. No features will be transferred that enable immediate 
identification of specific patients by the documentation centre. However, to conduct queries 
within the framework of the ongoing monitoring of the quality of documentation, it is 
necessary for the documentation centre to assign pseudonyms to specific trial centres. 
In the case of revocation of consent, no further data will be collected. Data already collected 
will not be deleted. 
The data entry, processing and evaluation carried out at ZKS Jena comply with the 
provisions of the Data Protection Act. Only employees of ZKS Jena will have access to all 
clinical trial data. These persons are sworn to secrecy. The data will be protected against 
unauthorised access. 
 
9.8.1 Privacy statement 
According to § 7 para. 2 no. 15 GCP-V (31), the concerned persons, in whom transmission of 
their pseudoanonymised data within the scope of the documentation and notification 
obligations under § 12 and § 13 GCP-V (31) is necessary, should be informed about the 
nature of the transmitted data. Persons who disagree with the disclosure of their 
pseudoanonymised data will not be included in the clinical trial. 
The relevant data protection provisions (Thuringian Data Protection Act, Federal Data 
Protection Act, EU General Data Protection Regulation) must be complied with. 
. 
 


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10. 
Quality assurance 
10.1 Standardisation and validation 
The responsible local laboratories of the trial centres must have a QM system and 
appropriate internal and external quality assurance measures. Successful participation in 
external quality assurance measures must be demonstrated by the submission of 
appropriate proficiency test certificates, accreditation certificates or similar documents. The 
laboratory tests required for the clinical trial must be GCLP-compliant and follow procedures 
established in the study manual. 
For the required determination of the serum albumin concentrations at the respective trial 
centres, comparable CE-IVD certified methods should be used. The method equivalency of 
the device must be substantiated prior to the start of the clinical trial by providing appropriate 
information on the performance of the methods used locally, reference ranges, intra- and 
inter-assay variation, accuracy, etc. 
10.2 Monitoring 
According to ICH-GCP E6 (R2) (29), continuous monitoring of a clinical trial or its 
implementation is an indispensable quality assurance tool. The purpose of such monitoring is 
to ensure that the clinical trial has been conducted in accordance with the approved protocol 
and that the legal regulations and standards have been followed. The SpB entrusts ZKS 
Jena with the monitoring of the trial. The monitoring includes selection visits, initiation visits 
for training and briefing of the trial group prior to the start of recruitment or a central initiation, 
regular on-site visits as well as concluding visits for the correct closure of the trial centres. 
The monitoring will be carried out according to the standard operating instructions of ZKS 
Jena. Detailed information on the scope, procedure and content of the monitoring, as well as 
procedures for securing data quality and necessary measures in the event of deviations from 
the trial protocol will be described in a monitoring plan to be released by the SpB. 
The investigators will provide the Monitor, for the purposes of monitoring the clinical trial, 
direct access to the original data and documents. The Monitor is required to treat all 
information confidentially and to protect the participants' fundamental right to integrity and 
privacy. The Monitor will report to the SpB in writing on the progress and results of his/her 
monitoring activities. 
10.3 Audits and inspections 
Within the scope of quality assurance, the SpB can have an independent audit conducted at 
any time in the participating institutions. In this case, the investigator or the participating 
institution will grant the auditor access to all documents necessary for the audit. 
 
Inspections as part of the monitoring of ongoing or already completed clinical trials are 
carried out by the competent authority in accordance with § 64 (1) of the AMG (28). The 
inspection conducted by the competent authority shall be carried out in accordance with a 
written procedure and a pre-determined plan. 
The SpB and all participating trial centres are committed to supporting inspections by 
competent authorities and, in this regard, to grant authorised persons access to the original 
data and documents. 
 
 


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11. 
Statistical methods and determination of sample 
size 
11.1 Sample size 
The 90-day mortality in the control arm is estimated to be about 50% (taking into account the 
possible use of albumin in the control group) (4, 7, own pilot study). 
For the sample size estimation, a 15% reduction in 90-day mortality is assumed, i.e., an 
absolute reduction of 7.5 percentage points to 42.5% (relative risk 1.18). This limit was 
chosen because the relatively costly albumin therapy can only be justified if there is a 
sufficiently clear treatment effect. This assumed effect size has the potential to affect current 
standard of care and international treatment guidelines and lies between the observed 
reduction in 90-day mortality in patients with septic shock (13%) and the assumed effect size 
in the ALBIOS study (23). Following the recommendation of the reviewers of the DFG 
application of the ARISS study, the sample size was estimated taking into account a centre 
variability (probably about 50 centres) in mortality of patients in the control arm of the study 
between 40% and 60% and a risk reduction between 12% and 18% (coincidentally uniform). 
A Mantel-Haenszel Chi² test at a two-tailed significance level of 0.05 with a power of 80% 
requires 1412 patients to be analysed, 706 per arm, to demonstrate such an effect. 
This case number estimate can be considered conservative for the planned analysis 
(nonlinear mixed model taking into account random centre effects). 
The case number estimation was performed using SAS 9.4 (SAS Institute Inc., Cary, NC, 
USA). 
 
Dropout Rate: 
Approximately 15%, through 
• "loss to follow up" until day 90 
• refusal to continue in the clinical trial by incapacitated patients who regain their capacity to 
consent, and 
• failure to consent to the continuation of the clinical trial by the guardian or the legal 
representative within the respective time windows in patients who became participants after 
confirmation of the urgency of participation in the clinical trial by an independent consultant  
or other procedures, established in the trial centres to include patients who are aunable to 
provide informed consent (VISEP 10.5%). MaxSep 8.2%) (25, 26). 
Assuming a dropout rate of 15%, 1662 patients need to be randomised. 
. 
11.2 Randomisation 
Randomisation will be stratified according to:  
 Serum lactate levels within 24 h before inclusion in the trial: ≤ 8 mmol/l vs. > 8 mmol/l 
and 
 centre 
in the treatment groups  
 albumin group  
and 
 control group without albumin 
 
Albumin administration will be adjusted after the starting dose according to serum albumin 
concentrations. Therefore, blinding will not be possible. 
 
Group assignment will be determined using a validated electronic tool (PaRANDies) after 
inclusion of the patient. Randomisation will be based on a randomisation list created in 
advance with nQuery Advisor 7.0. 


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11.3 Statistical methods 
11.3.1 Definition of the analysis populations 
Intention-to-Treat (ITT) 
The intention-to-treat (ITT) population will include all patients enrolled in the study and 
randomised with at least one observation made after randomisation. 
The primary efficacy analysis will be performed in the ITT population. 
All variables collected will be analysed in the ITT population. 
Per-Protocol (PP) 
The Per-Protocol population will include all ITT patients who do not have major study plan 
deviations. A protocol deviation will be classified as "major" if it significantly affects the main 
target parameter (90-day mortality). 
In particular, administration of albumin in the interest of patient safety outside the limits 
specified in the interventional group, albeit approved by the protocol, will always result in 
exclusion from the PP analysis. 
As a sensitivity analysis, the primary efficacy analysis will be repeated in the PP population. 
If there are differences between the randomised and the actual treatment, an additional 
sensitivity "as-treated" analysis will be performed. 
Details on trial protocol deviations will be described in the statistical analysis plan. 
Listing-Only-Set (LOS) 
Data from all patients not included in the ITT analysis can be listed as needed. The reasons 
for the exclusion will be recorded and analysed as far as possible. 
Safety Analysis 
The safety analysis will be carried out in the ITT group. 
 
11.3.2 Data analysis 
General methodology: 
All collected data will be analysed using descriptive methods in the two treatment groups. 
This includes at least: 
• the number of values collected and missing, mean, standard deviation, minimum, quartiles 
including median and maximum for continuous variables and 
• frequency analyses for ordinal and categorical data. 
• At baseline, the last available value will be used no later than the period up to 2 hours after 
randomisation, but before the start of albumin administration. 
 
Baseline and population characteristics, demographics: 
Demographic variables, SAPS II, APACHE II: descriptive analysis 
 
Primary analysis: 
The primary endpoint, "90-day mortality" (M90), will be calculated using a generalised mixed 
model with the random effects "centre" and "patient in centre" and the fixed effects SAPS II, 
SOFA and "baseline serum albumin value" as well as " treatment group "to the significance 
level Alpha = 0.05 analysed bilaterally. 
The null hypothesis, M90 (control group) = M90 (albumin infusion), will be tested against the 
alternative M90 (control group) ≠ M90 (albumin infusion). 
The primary analysis will be conducted in the ITT population. 
 
Additional sensitivity analyses: 
• Analysis in the PP population 
• If more than 10% of M90 data are missing: multiple imputation analysis based on observed 
mortality rates, SOFA scores, ICU stay, and hospital stay. 
 
Secondary endpoints: 


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• 28-day, 60-day, intensive care and hospital mortality: descriptive statistics, Kaplan-Meier 
estimates on mortality. 
• Organ failure defined as increase in the daily recorded SOFA (day 1 to 28) from a value <2 
to a value ≥ 2, individual number of organ failures in the period from day 1 to day 28: 
descriptive statistics, Kaplan-Meier estimates for the date of the individual first organ failure 
• SOFA score: descriptive statistics 
• Length of stay (after randomisation, until first discharge) in ICU, hospitalisation after 
randomisation (until first discharge to rehabilitation, transitional care, long-term care or 
home): descriptive statistics, Kaplan-Meier estimates, censored after drop-out and death. 
• Ventilation-free days, vasopressor-free days until (first) discharge of ICU or maximum 28 
days: descriptive statistics 
• Total amount of fluid administration in the ICU (individual average amount of fluids given 
enterally or parentrally, including volume therapy) and total fluid balance in the ICU 
(individual average difference between daily fluid administration – urinary output and other 
fluid loss): descriptive statistics, especially quartiles.  
 
All secondary endpoints, unless included in the primary analysis model, will be exploratively 
compared using appropriate parametric and nonparametric tests between treatment groups. 
 
Health economics: 
In the context of the ARISS study, a health economic cost-benefit analysis of volume 
replacement therapy of the ICU stay will be carried out up to a maximum of day 28. The 
direct costs of colloid, crystalloid and albumin administration will be recorded and the length 
of stay (first hospitalisation and stay since study participation) evaluated economically to 
assess whether albumin administration has an effect on hospital costs or not. At the patient 
level, DEALE (declining exponential approximation of life expectancy) (27) will be applied to 
calculate patient-specific life expectancy based on mortality rates in the general population 
and in the disease-specific population. The subsequent cost-effectiveness analysis will yield 
the cost per year of life for albumin administration. The robustness of the analysis will be 
checked with one-way and multi-way analyses as well as probabilistic sensitivity analysis. 
 
Analysis of safety parameters: 
 
Frequencies of AEs and SAEs will be analysed using frequency tables. In addition, 
frequencies of selected AEs (sepsis-related clinical events) will be analysed. 
 
11.3.3 Subgroup analyses 
The primary endpoint and selected secondary endpoints (SOFA, organ failure defined as 
SOFA organ failure score ≥ 2) will be described for the following subgroups: 
Baseline lactate ≤ 8 mmol/L versus> 8 mmol/L 
SOFA total and subscores, SAPS II, APACHE II: by baseline quartiles 
Details of the statistical analyses will be described in the Statistical Analysis Plan. 
 
11.3.4 Interim analysis 
Not planned. 


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11.4 Presentation of results 
The final statistical report will be based on the specifications and checklist of the CONSORT 
statement on the publication of randomised controlled trials in parallel group design (33) and 
on regulatory requirements. 


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12. 
Regulatory and administrative aspects  
12.1 Regulations 
The clinical trial will be conducted according to the current protocol, in agreement with the 
current versions of the German Law on Marketing Authorisation for Medicinal Products 
(AMG) (28), the ordinance on the Application of Good Clinical Practice in Conducting Clinical 
Trials with Medicinal Products (GCP-V) (31), the principles published in the ICH GCP 
Guideline (29), and the ethical principles set out in the Helsinki Declaration in 2008 for 
clinical trials as a recognised ethical basis (34). 
12.2 Ethic committees 
According to § 40 AMG (28), a clinical trial on a medicinal product in humans may only be 
started if the competent Ethics Commission (EC) has approved it in accordance with § 42 
(1). For multicentre clinical trials that are carried out within the scope of the AMG in more 
than one trial centre, each further EC (involved EC) will receive a copy of the application and 
the documents from the SpB at the same time, according to state law for the respective 
investigator. Each investigator will receive from the applicant a copy of the approval of the IC 
for the ISF. 
12.3 Competent authorities 
12.3.1 Federal authority 
For this clinical trial under the AMG, the Federal Institute for Vaccines and Biomedical Drugs 
(Paul-Ehrlich-Institut (PEI) in Langen) is the competent higher federal authority (BOB). 
According to § 40 AMG (28), the clinical testing of a medicinal product in humans may only 
be started if the competent higher federal authority has approved it in accordance with § 42 
(3). 
Each investigator will receive from the applicant a copy of the authorization for the ISF. 
 
12.3.2 State authorities 
Pursuant to § 67 AMG (28), each registered investigator/deputy has a general obligation to 
notify the competent authority. Pursuant to Section 12 GCP-V (31), the investigator may 
entrust the sponsor with the execution of the notification to the competent authority and must 
document this. 
In each case, the government authorities or the competent authorities in the countries in 
which a trial centre is located are responsible for the clinical trial. When the sponsorship is 
taken over by the Friedrich Schiller University Jena or the Jena trial Centre, notification will 
be made to the Thüringer Landesamt für Verbraucherschutz (TLV) in Bad Langensalza. The 
respective state report must be filed in the respective trial centre folder. 
.  
12.4 Subsequent changes in the trial protocol - amendments 
According to § 10 (1) GCP-V (31), changes in the trial protocol requiring approval are to be 
applied for by the SpB and only after approval by the responsible EC, insofar as they relate 
to the information and documents pursuant to § 7 (2), (3) or (3a) and if they have been 
approved by the responsible BOB, insofar as they relate to the information and documents 
pursuant to § 7 (2) or (4). This excludes amendments that are necessary in order to avert 
immediate danger to the concerned persons (§ 11 GCP-V, (31)), which must be implemented 
immediately. The SpB will immediately inform the responsible BOB and the responsible EC 
about these new circumstances. A favourable evaluation should be obtained from the 
responsible EC and approval should be requested from the responsible BOB. The 


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application must be reasoned. Even changes that are only subject to approval by the 
responsible EC are to be reported to the responsible BOB. To ensure largely comparable 
conditions in all trial centres and in the interest of a flawless data evaluation, there is no 
intention to perform any amendment or changes to the trial conditions agreed upon in the 
trial protocol (i.e., study design, course of study or evaluation procedure). 
 
12.5 Registration 
Registration of the clinical trial will be done before randomisation of the first patient in the 
WHO-recognised German Register of Clinical Trials (DRKS, www.drks.de). In addition, the 
clinical trial will be registered at clinicaltrials.gov. The registry entries will be maintained 
continuously. 
12.6 Insurance 
According to § 40 AMG (29), insurance must be taken out by the SpB for all patients 
participating in the trial. 
Subject insurance will be concluded for all patients included according to § 40 AMG in the 
context of the proband year contract of the hospital of Friedrich-Schiller-University Jena with 
the HDI Gerling Industrie Versicherung AG, 30659 Hannover. The seat, policy number, 
telephone number and fax number of the insurance company will be included in the patient 
information form. Travel accident insurance will not be taken out. Patients will be informed 
about their rights and obligations in connection with the insurance. Each participant in the 
clinical trial will receive the conditions of insurance in writing. 
12.7 Funding  
The German Research Foundation (DFG) will fund the clinical trial within the framework of 
the program "clinical studies", grant number DFG SA 2167 / 3-1, project number 328809707. 
The Department of Anaesthesiology and Intensive Therapy of the University Hospital, Jena 
will take over the financing of the remaining duration of the clinical trial after the DFG funding 
period has expired. 
The trial drug for treatment of the albumin group will be provided free of charge by GRIFOLS 
SA (Jesus y Maria 6, 08822 Barcelona). 
12.8 Reports of the study results 
All information concerning this clinical trial must be treated confidentially. According to AMG 
§ 42 b (29), the SPB is required to publish the results of clinical trials within certain deadlines 
and in compliance with certain requirements. 
The SpB is responsible for the preparation of the final report. 
12.9 Publications 
The aim will be to publish the results of this clinical trial in a prestigious international medical 
journal. 
Authorship will be governed by the guidelines of the New England Journal of Medicine 
(http://www.icmje.org/). It will be based on the following criteria: 
 
• Substantial contribution to the conception or design of the manuscript or to the collection, 
analysis and interpretation of data for the manuscript 
• Substantial intellectual contribution to manuscript preparation 
• Final assessment or approval of the manuscript version to be published 
• Declaration of responsibility for all aspects of the work to ensure that issues related to the 
accuracy or integrity of part of the work are adequately investigated and answered 
 
Authors should meet all four criteria. The Acknowledgment section of the publication should 
list the names of all the key personnel involved in the clinical trial in the trial sites. The trial 


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centres are entitled to scientifically use the data generated in this clinical trial. According to 
the contractual agreements or after consultation with the Executive Committee, the trial 
centres can use these data to process their own scientific questions and publish the results 
under their own names. 
Publication or presentation of the results requires prior comment and approval from the SpB. 
All publications will ensure privacy rules are met for all patients. 
 
 
 
 
 


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13. 
Literature  
 
1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus 
Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315 (8):801-
10. 
2. Calandra T and Cohen J.  The international sepsis forum consensus conference on definitions 
of infection in the intensive care unit. Crit Care Med 2005; Jul;33(7):1538-48 
3. Martin GS, Mannino DM, Eaton S et al. The epidemiology of sepsis in the United 
States from 1979 through 2000. N Engl J Med 2003, 348: 1546-1554. 
4. Brunkhorst FM, Hagel S, Ludewig K et al. Direct costs related to severe sepsis in 
Germany: an update. Infection 2011; A S144-145. 
5. Fleischmann C, Thomas-Rüddel DO, Hartmann M et al. Fallzahlen und 
Sterblichkeitsraten von Sepsis-Patienten im Krankenhaus. Deutsches Ärzteblatt 
2016, 113 10:159-166. 
6. Vincent JL, Sakr Y, Reinhart K, et al. Is albumin administration in the acutely ill 
associated with increased mortality? Results of the SOAP study. Crit Care. 2005; 
9(6): R745-54. 
7. Vincent JL, Marshall JC, Namendys-Silva SA, et al.  Assessment of the worldwide 
burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir 
Med. 2014; 2(5):380-6. 
8. SepNet Critical Care Trials Group. Incidence of severe sepsis and septic shock in 
German intensive care units: the prospective, multicentre INSEP study. Intensive 
Care Med. 2016; 42(12):1980-1989. 
9. Holst LB, Haase N, Wetterslev J, et al.; TRISS Trial Group.; Scandinavian Critical 
Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic 
shock. N Engl J Med. 2014 Oct 9; 371(15):1381-91.   
10. The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-Directed 
Resuscitation for Patients with Early Septic Shock. N Engl J Med 2014; 371:1496-
1506. 
11.  Mouncey PR, Osborn TM, Power GS, et al. for the ProMISe Trial Investigators. Trial 
of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med 2015; 
372:1301-1311. 
12.  The ProCESS Investigators. A Randomized Trial of Protocol-Based Care for Early 
Septic Shock. N Engl J Med 2014; 370:1683-1693. 
13. . Fanali G, di Masi A, Trezza V, et al. Human serum albumin: from bench to bedside. 
Mol Aspects Med. 2012; 33(3):209-90. 
14.  O'Brien AJ, Fullerton JN, Massey KA, et al. Immunosuppression in acutely 
decompensated cirrhosis is mediated by prostaglandin E2. Nat Med 2014; 20(5):518-
23.  
15.  Taverna M, Marie AL, Mira JP, et al. Specific antioxidant properties of human serum 
albumin. Ann Intensive Care 2013; 15; 3(1):4.  
16.  Walley KR, McDonald TE, Wang Y,et al. Albumin resuscitation increases 
cardiomyocyte contractility and decreases nitric oxide synthase II expression in rat 
endotoxemia. Crit Care Med. 2003 Jan; 31(1):187-94. 
17. Tokunaga C, Bateman RM, Boyd J, et al. Albumin resuscitation improves ventricular 
contractility and myocardial tissue oxygenation in rat endotoxemia. Crit Care Med 
2007 May; 35(5):1341-7. 
18. Cochrane Injuries Group Albumin Reviewers. BMJ. Human albumin administration in 
critically ill patients: systematic review of randomised controlled trials. 1998 Jul 25; 
317(7153):235-40.  
19. Wilkes and Navickis. Patient survival after human albumin administration. A meta-
analysis of randomized, controlled trials. Ann Intern Med 2001; 135:149-64.   


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20.  Vincent JL1, Navickis RJ, Wilkes MM. Morbidity in hospitalized patients receiving 
human albumin: a meta-analysis of randomized, controlled trials. Crit Care Med. 2004 
Oct; 32(10):2029-38.   
21.  Dubois MJ, Orellana-Jimenez C, Melot C et al. Albumin administration improves 
organ function in critically ill hypoalbuminemic patients: A prospective, randomized, 
controlled study. Crit Care Med. 2006; 34(10): 2536-40. 
22.  Finfer S1, Bellomo R, Boyce N,et al. A comparison of albumin and saline for fluid 
resuscitation in the intensive care unit. N Engl J Med. 2004 27; 350(22):2247-56.   
23.  SAFE Study Investigators. Impact of albumin compared to saline on organ function 
and mortality of patients with severe sepsis. Intensive Care Med. 2011 Jan; 37(1):86-
96. 
24.  Caironi P, Tognoni G, Masson S, et al. ALBIOS Study Investigators. Albumin 
replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014. 10; 
370(15):1412-21. 
25. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International 
Guidelines for Management of Sepsis and Septic Shock: Intensive Care Med. 2017 
Mar; 43(3):304-377.  
26.  Brunkhorst FM, Engel C, Reinhart K et al. for the German Competence Network 
Sepsis (SepNet): A Trial of Intensive Insulin Therapy and Pentastarch Resuscitation 
in Severe Sepsis. N Engl J Med 2008; 358(2):125-39.   
27.   Brunkhorst FM, Oppert M, Reinhart K, et al. Effect of empirical treatment with 
moxiﬂoxacin and meropenem vs. meropenem on sepsis-related organ dysfunction in 
patients with severe sepsis: a randomized trial. JAMA. 2012 13; 307(22):2390-9. 
28.  Barnett AG, Beyersmann J, Allignol A, et al. The time-dependent bias and its effect 
on extra length of stay due to nosocomial infection. Value in health: the journal of the 
International Society for Pharmacoeconomics and Outcomes Research. 2011; 
14(2):381-6. 
29.  Gesetz über den Verkehr mit Arzneimitteln (Arzneimittelgesetz - AMG): 
Arzneimittelgesetz in der Fassung der Bekanntmachung vom 12. Dezember 2005 
(BGBl. I S. 3394), das zuletzt durch Artikel 1 des Gesetzes vom 18. Juli 2017 (BGBl. I 
S. 2757) geändert worden ist.  
30. ICH Topic E 6 (R2) Guideline for Good Clinical Practice (CHMP/ICH/135/1995). 2016, 
European Medicines Agency, London.  
31. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1
1 
32.  Verordnung über die Anwendung der Guten klinischen Praxis bei der Durchführung 
von klinischen Prüfungen mit Arzneimitteln zur Anwendung am Menschen (GCP-
Verordnung, GCP-V) vom 9.8.2004 2004, BGBl. I 2004 S. 2081 zuletzt durch Artikel 8 
des Gesetzes vom 19. Oktober 2012 (BGBl. I S. 2192) geändert. 
33. Schulz, K.F., D.G. Altman, and D. Moher, CONSORT 2010 statement: updated 
guidelines for reporting parallel group randomised trials. BMJ 340: p. c332.  
34.  World Medical Association, Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects 2008, 59. WORLD MEDICAL ASSOCIATION 
General Assembly: Seoul, Südkorea. 


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14. 
Appendix 
14.1 SOFA Score 
Organ dysfunction is defined according to the SOFA score variables. The worst value of the 
parameter each day will be used to calculate the score. The parameters of the SOFA score 
are determined until day 28 exclusively in the intensive care unit and are calculated from the 
sum of the evaluation points of the individual organ systems listed below. The parameters for 
calculating the SOFA subscore are also part of the CRF. The score points of each organ 
system range from 0 to 4. The SOFA score is calculated in the data management center 
(ZKS Jena). The subscores of the SOFA score are determined as follows: 
 
 
Cardiovascular System 
Mean arterial pressure (MAP) and the need for catecholamine determine the assigned 
points. The lowest MAP value of the past 24 hours is part of the CRF. The highest 
catecholamine dosage> 1 h of the past 24 hours is part of the individual variables in the CRF. 
 
Score 
Cardiovascular status 
0 
MAP > 70 and no vasopressors 
1 
MAP < 70 and no vasopressors 
2 
Dopamine <5 µg/kg/min oder Dobutamine (and dose) 
3 
Dopamine >5 – <15 µg/kg/min or (nor)adrenalin <0.1 µg/kg/min  
4 
Dopamine>15 µg/kg/min or (nor)adrenalin >0.1 µg/kg/min 
 
Pulmonary system 
The PaO2/FiO2 ratio determines this sub-score. If the blood gas analysis is not available for 
the day or the patient is no longer intubated, but relies on oxygen therapy, conversion tables 
will be used. 
Score 
PaO2/FiO2 
0 
> 400 mmHg (> 53.2 kPa) 
1 
301–400 mmHg (39.9–53.1 kPa) 
2 
201–300 mmHg (26.6–39.8 kPa) 
3 
101–200 mmHg (13.3–26.5 kPa) 
4 
< 100 mmHg (< 13.3 kPa) 
 
Coagulation system: 
The platelet count determines this sub-score. The lowest platelet count of the past 24 hours 
is part of the CRF variables. 
 
Score 
Platelet count 
0 
>150  103/mm3 
1 
100-149 103/mm3 
2 
50–99 103/mm3 
3 
20–49 103/mm3 
4 
<20 103/mm3 
 
Renal system: 
Serum creatinine and urinary output determine this sub-score. The worst value is part of the 
CRF variables. 
 


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Score 
Serum creatinine and urinary output 
0 
<1.2 mg/dl (<110 µmol/l) 
1 
1.2–1.9 mg/dl (110 –170 µmol/l) 
2 
2.0–3.4 mg/dl (171– 299 µmol/l) 
3 
3.5–4.9 mg/dl (300–440 µmol/l) or urinary output <500 ml/24h 
4 
>5,0 mg/dl (> 441 µmol/l) or urinary output <200 ml/24h 
 
Hepatic system: 
Total bilirubin determines this value. The worst value is part of the CRF variables. 
Score 
Total bilirubin 
0 
<1.2 mg/dl (< 20 µmol/l) 
1 
1.2–1.9 mg/dl (20–32 µmol/l) 
2 
2.0–5.9 mg/dl (33–101 µmol/l) 
3 
6.0–11.9 mg/dl (102–204 µmol/l) 
4 
>12 mg/dl (>205 µmol/l) 
 
Central nervous system (CNS):  
The CNS is assessed by the Glasgow Coma Scale (GCS). If the patient is sedated, the 
assessment of conscious level is based on the observer’s assumption that the patient is not 
sedated. In addition to this esteemed GCS, the actual GCS should also be documented. The 
worst estimated and worst actual GCS is part of the CRF variables. 
 
Score 
Glasgow Coma Scale 
0 
15 
1 
13–14 
2 
10–12 
3 
6–9 
4 
< 5 
 
Glasgow Coma Scale 
The Glasgow Coma Scale is a neurological assessment scoring system composed of three 
individual assessments, which are summed up below. 
 
 
Score 
 
Score 
 
Score 
Eye openning 
Spontaneous 
On demand 
Painful stimulation 
None 
 
4 
3 
2 
1 
Best motoric response  
Obey commands 
Painful stimulation 
localisation 
flexion 
Abnormal flexion 
Extention (decerebrate) 
None 
 
6 
 
5 
4 
3 
2 
1 
 
Beste verbal 
Response 
Response to verbal 
contact 
oriented 
confused 
Words 
Sounds 
None 
 
 
 
 
5 
4 
3 
2 
1 
Refernce: Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure 
Assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996;22(7):707–710. 
 
 
 
 
 
 
 


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59 
 
14.2 Apache II Score 
 
Parameter/points 
4 
3 
2 
1 
0 
1 
2 
3 
4 
Core temperature 
41 
39–40.9 
 
38.5–38.9 
36–38.4 
34–35.9 
32–33.9 
30–31.9 
29.9 
Mean art. pressure (mmHg) 160 
130–159 
110–129 
 
70–109 
 
50–69 
 
49 
Heart rate (/min) 
180 
140–179 
110–139 
 
70–109 
 
55–69 
40–54 
39 
Respiratory rate (/min) 
Spontaneous or ventilated 
 
50 
 
35–49 
 
 
 
25–34 
 
12–24 
 
10–11 
 
6–9 
 
 
5 
Oxygenation (mmHg) 
a) 
FiO20,5: AaDO2 
b) 
FiO2<0,5: PaO2 
 
500 
 
350–499 
 
200–349 
 
 
<200 
>70 
 
 
61–70 
 
 
 
 
 
55–60 
 
 
<55 
Arterial pH 
7.7 
7.6–7.69 
 
7.5–7.59 
7.33–7.49 
 
7.25–7.32 7.15–7.24 
<7.15 
Natrium (mmol/l) 
180 
160–179 
155–159 
150–154 
130–149 
 
120–129 
110–119 
<110 
Kalium (mmol/l) 
7 
6–6.9 
 
5.5–5.9 
3.5–5.4 
3–3.4 
2.5–2.9 
 
<2.5 
Creatinine (mg/dl)1 
3,5 
2–3.4 
1.5–1.9 
 
0.6–1.4 
 
<0.6 
 
 
Hematocrite ( %) 
60 
 
50–59.9 
46–49.9 
30–45.9 
 
20–29.9 
 
<20 
Leucocytes (103/mm3) 
40 
 
20–39.9 
15–19.9 
3–14.9 
 
1–2.9 
 
<1 
Glasgow Coma Scale 2 
Score=15 minus GCS 
Venous HCO3 (mmol/l)3 
52 
41–51.9 
 
32–40.9 
22–31.9 
 
18–21.9 
15–17.9 
<15 
1 In case of acute renal failure 2 
2 see page 58 
3 only when arterial blood gases are missing 
 
- The following points are assigned according to age: <=42 years: 0; 45 – 54 years: 2; 55 – 
64 years: 3; 65 – 74 Jahre: 5; >=75 years: 6 
 
- The following data about chronic diseases are collected (yes/no):  
 
Liver:  
Cirrhosis (biopsy) and proven portal hypertension or gastrointestinal 
haemorrhage caused by portal hypertension or previous episodes of liver 
failure, encephalopathy, coma 
Cardiovascular: 
NYHA IV  
Respiratory: 
Chronic, restrictive, obstructive or vascular diseases that cause serious 
disability (for example, inability to climb stairs or do household chores); 
proven chronic hypoxia, hypercapnia, secondary polycythemia, severe 
pulmonary hypertension (> 40 mmHg), need for ventilation 
Renal: 
Need for chronic dialysis 
Immunsuppresive: Therapies that reduce resistance to infections (e.g., immune suppression, 
chemotherapy, radiation, long-term treatment (up to 30 days prior to 
hospitalization), or treatment with high-dose steroids (> 16mg / kg for 5 
days)); the presence of a disease that has progressed so far that the 
immune system is severely impaired (e.g. leukemia, lymphoma, AIDS) 
 
 
0 points, if the answer to all five questions is "no" 
 
2 points, if the answer to at least one question is "yes" and the patient is in an elective 
post-operative state  
 
5 points, if the answer to at least one question is "yes" and the patient is in a post-
operative emergency or has not undergone surgery 
 
Reference: Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med 1985;13(10):818–829. 
 
 


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60 
 
14.3 New Simplified Acute Physiology Score (SAPS II) 
Parameter 
Befund 
Punktwert 
Age (years) 
<40 
0 
40–59 
7 
60–69 
12 
70–74 
15 
75–79 
16 
80 
18 
Heart rate (/min) 
<40 
11 
40–69 
2 
70-119 
0 
120–159 
4 
160 
7 
Systolic blood pressure (mmHg) 
<70 
13 
70–99 
5 
100–199 
0 
200 
2 
Körpertemperatur (°C) 
<39 
0 
39 
3 
PaO2/FiO2 (bei mechanical 
ventilation or CPAP) (mmHg) 
<100 
11 
100–199 
9 
200 
6 
Urine output (l/24h) 
<0.5 
11 
0.5–0.999 
4 
1.0 
0 
Urea (mg/dl) [mmol/l] 
<28 [4,6] 
0 
84 [13,9] 
10 
Leucocytes (103/mm3) 
<1.0 
12 
1.0–19.9 
0 
20 
3 
Kalium (mmol/l) 
<3.0 
3 
3.0–4.9 
0 
5.0 
3 
Natrium (mmol/l) 
<125 
5 
125–144 
0 
145 
1 
Bicarbonate (mmol/l) 
<15 
6 
15–19 
3 
20 
0 
Bilirubin (mg/dl) [µmol/l] 
<4.0 (68.4) 
0 
4.0–5.9 (68.4–102.5) 
4 
6.0 (102.5) 
9 
Glasgow Coma Score (s page 58) 
<6 
26 
6–8 
13 
9–10 
7 
Chronic diseases 
Metastatic cancer 
9 
Hematologic 
malignancy 
10 
AIDS 
17 
Type of admission 
Planned OP 
0 
Medical admission 
6 
Emergency surgery 
8 
Reference: Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) 
based on a European/North American multicentre study. JAMA 1993;270(24):2957–2963. 
 
 
 


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61 
 
14.4 Conversion tables 
PaO2/FiO2 Ratio 
The following conversion table is used when blood gas analyzes are not available to 
determine PaO2 / FiO2: 
 
 
O2 Saturation conversion table 
SO2 (%) 
estimated PaO2 (mmHg) 
80 
44 
81 
45 
82 
46 
83 
47 
84 
49 
85 
50 
86 
52 
87 
53 
88 
55 
89 
57 
90 
60 
91 
62 
92 
65 
93 
69 
94 
73 
95 
79 
96 
86 
97 
96 
98 
112 
99 
145 
 
FiO2 on oxygen therapy 
Method 
O2 Flow (l/min) 
estimated FiO2 ( %) 
Nasal cannula 
1 
2 
3 
4 
5 
6 
24 
28 
32 
36 
40 
44 
Nasopharyngeal catheter 
4 
5 
6 
40 
50 
60 
Face mask 
5 
6–7 
7–8 
40 
50 
60 
Face mask with reservoir 
6 
7 
8 
9 
10 
60 
70 
80 
90 
95 
 
 

SAP_003.pdf: 
BI03-H-A2 V03 
Statistical Analysis Plan 
03.04.2017 
ZKSJ0112 ARISS 
- 1 von 8 - 
SAP 01 06.04.2023 
 
A Randomized Controlled Multicenter Trial on Albumin 
Replacement in Septic Shock 
ZKSJ0112 ARISS 
Statistical Analysis Plan 
 
Version 01 
 06.04.2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BI03-H-A2 V03 
Statistical Analysis Plan 
03.04.2017 
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Contents 
1 
Study Background 
3 
1.1 
Study Objective 
3 
1.2 
Study Design 
3 
1.3 
Protocol Version and Amendments 
3 
2 
Analysis Sets 
3 
2.1 
Full Analysis Set (FAS) 
3 
2.2 
Per-Protocol Set (PPS) 
3 
2.3 
Safety 
3 
2.4 
Listing Only Set (LOS) 
4 
2.5 
Predictable Major Protocol Deviations 
4 
3 
Study Centers 
4 
4 
Study Variables 
4 
4.1 
Population Characteristics and Baseline Data 
4 
4.2 
Primary Endpoint 
4 
4.3 
Secondary Endpoints 
4 
4.4 
Safety Variables 
4 
4.4.1 
Adverse Events 
4 
4.4.2 
Laboratory Parameters 
4 
4.4.3 
Other Safety Data 
5 
5 
Handling of Missing Values and Outliers 
5 
5.1 
Missing Values 
5 
5.2 
Outliers 
5 
5.3 
Other Data Rules 
5 
6 
Statistical Methodology 
6 
6.1 
Sample Size Considerations 
6 
6.2 
General Principles 
6 
6.3 
Population Characteristics and Baseline Data 
6 
6.4 
Previous and Concomitant Diseases and Therapies 
6 
6.5 
Exposition to Therapy / Compliance 
6 
6.6 
Primary Analysis 
6 
6.7 
Secondary Analyses 
6 
6.8 
Safety and Tolerability Analyses 
7 
6.8.1 
Adverse Events 
7 
6.8.2 
Laboratory Parameters 
7 
6.8.3 
Other Safety Data 
7 
6.9 
Subgroup Analysis 
7 
6.10 
Interim Analysis 
7 
6.11 
Deviation from Protocol and Amendment 
8 
7 
Software and Validation 
8 
8 
Attachments 
Error! Bookmark not defined. 
 
 


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List of Abbreviations 
ITT 
 
Intention-to Treat 
FAS 
 
Full Analysis Set 
PPS 
 
Per-Protocol Set 
LOS 
 
Listing Only Set 
ICU 
 
Intensive Care Unit 
SAP 
 
Systolic Blood Pressure 
MAP  
Mean Arterial blood Pressure 
DAP 
 
Diastolic Blood Pressure 
CVP 
 
Central Venous Pressure 
CO 
 
Cardiac output 
LOCF  
Last observation carried forward 
GCS  
Glascow Coma Scale 
AE 
 
Adverse Event 
DSUR  
Data Safety Update Report 
SMC   
Study Monitoring Committee 
 
1 
Study Background 
1.1 
Study Objective 
To investigate whether the replacement with albumin and the maintenance of its serum level 
above 30 g/L for 28 days improve survival in the patients with septic shock compared to 
resuscitation and volume maintenance without albumin. 
1.2 
Study Design 
Randomized Controlled Multicenter 
1.3 
Protocol Version and Amendments 
Final 3.0 from 18JUL2019 
2 
Analysis Sets 
2.1 
Full Analysis Set (FAS) 
The FAS includes all patients randomized, who have at least one data point after 
randomization. Patients will be analyzed as randomized (Intention-to Treat, ITT, principle) 
The primary efficacy analysis will be performed in the FAS. All data assessed will be 
analyzed in the FAS. 
2.2 
Per-Protocol Set (PPS) 
The Per-Protocol-Set includes all patients of the ITT without additional albumin application 
other than study medication, who have no major protocol deviations.  
A protocol deviation is defined as major, if it substantially influences the primary efficacy 
parameter 90 day mortality. 
In particular, application of albumin in addition to the study medication leads to exclusion 
from PPS, although allowed according study protocol for reasons of patient’s safety. 
Primary efficacy analysis will be repeated in the PPS as a sensitivity analysis. 
In case of differences between treatment randomized and applicated, a further sensitivity 
analysis will be performed „as treated“. 
2.3 
Safety 
The safety analysis will be performed for FAS, but patients will be analyzed as treated. 


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2.4 
Listing Only Set (LOS) 
Patients, excluded from FAS (screening failures) will be listed as far as available. Reasons 
for exclusion/non-inclusion will be analyzed as far as available. 
2.5 
Predictable Major Protocol Deviations 
Application of albumin in addition to the study medication leads to exclusion from PPS, 
although it is no protocol deviation. It is allowed according study protocol for reasons of 
patient’s safety, but substantially influences the study objective. 
3 
Study Centers 
40-50 Centers. Centers will be listed with number of recruited patients in the statistical report. 
4 
Study Variables 
4.1 
Population Characteristics and Baseline Data 
• 
Eligibility and consent 
• 
Age, weight, height, sex, type of admission, residence before admission to ICU and 
other demographic data 
• 
Diagnoses, comorbidities, data on infection,  
• 
Lactate 
• 
APACHE II-Score, SAPS-II-Score und SOFA-Score 
• 
Treatment application and compliance, albumin application in addition to study 
medication 
4.2 
Primary Endpoint 
• 
90-day-mortality 
4.3 
Secondary Endpoints 
• 
28- and 60-day-mortality 
• 
Mortality rate at ICU and in-hospital mortality 
• 
SOFA score 
• 
Duration of stay on ICU and duration of hospitalization, 
• 
Days not requiring artificial respiration, days without vasopressors 
• 
Assessment of amount of albumin applicated, other colloids and crystalloids 
• 
Overall fluid intake, overall fluid balance 
4.4 
Safety Variables 
4.4.1 Adverse Events 
• 
AEs, SAEs and sepsis related events 
4.4.2 Laboratory Parameters 
• 
Microbiology  
• 
Routine laboratory: hemoglobin, creatinine, bilirubin, C-reactive protein, procalcitonin, 
leukocytes, thrombocytes, lactate, arterial blood gas (paCO2, paO2, FiO2, SO2, pH, 
ScO2) 


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4.4.3 Other Safety Data  
• 
Clinical parameters: body temperature, respiratory rate, hemodynamic parameters 
(SAP, MAP, DAP, CVP, CO)  
• 
Anti-infective therapy  
• 
Adjunctive sepsis therapy 
• 
Intensive care (intubation, central venous catheter, arterial catheter, renal 
replacement therapy, ventilation, ECMO, hemodynamic monitoring) 
5 
Handling of Missing Values and Outliers 
5.1 
Missing Values 
Single day missing values in GCS (up to 3 consecutive) will be replaced by LOCF for 
evaluation of daily SOFA score. 
All other missing values will be treated as such and not replaced by estimates. Missing 
values for the primary efficacy parameter 90 day mortality will be respected in Kaplan Meier 
analysis of mortality. 
5.2 
Outliers 
No special procedures for outliers are planned. 
5.3 
Other Data Rules 
Amount of albumin applicated is defined as sum of volume therapy (human albumin 4% or 
5%*0.05 + Human albumin 20%*0.2) and study medication (Albutein® 200g/L OR Plasbumin 
20 *0.2) over 24h. 
 
Overall fluid intake, output and balance are defined as follows: 
Overall fluid intake  
 
= enteral fluid intake [24 h] + parenteral fluid intake [24 h] + volume therapy [24 h]  
 
+ study medication application volume sum for the respective 24 h 
Overall fluid output [1] 
 
= urine output [24 h] + other fluid loss  
 
 
 
 
(Feces, vomiting, stomach tube, perspiration, other). 
If perspiration is missing in more than 10% of visits in patients, the following definition [2] 
excluding perspiration will be used for main analysis. Analysis in subgroup with perspiration 
available will be performed as additional sensitivity analysis. 
Overall fluid output [2] 
 
= urine output [24 h] – other fluid loss  
 
 
 
 
(Feces, vomiting, stomach tube, other). 
Overall fluid balance  
 
= Overall fluid intake - Overall fluid output  
 
If values are given for a differing time frame, they will be normed to 24 h 
(value * 24 / [given different time frame] ). 
Values of the time window 6 h after randomization will be normed to 6 hours analogously. 
 
Physiological data: Baseline values assessed at randomization time frame will be compared 
to values assessed at time frame 6h ± 1 after randomization  
SOFA: Baseline values assessed 24h before randomization time frame will be compared to 
treatment days. 
 
Note: 


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MAP can be used only as given in CRF. Evaluation from Systolic and diastolic blood 
pressure is not possible, since worst values are assessed, hence values do not reflect same 
time point 
6 
Statistical Methodology 
6.1 
Sample Size Considerations 
1412 evaluable patients, 706 per arm planned. For details of sample size planning see study 
protocol. 
6.2 
General Principles 
All available data will be analyzed at least descriptively. Descriptive analysis includes at least 
number of available and missing data, mean, standard deviation, minimum, quartiles 
including median and maximum for metric data and number and % of patients per category 
for non-metric data. Day-wise descriptive statistics will include at least number of available 
data, mean, minimum, median and maximum  
All analyses will be performed by treatment group and in total. 
6.3 
Population Characteristics and Baseline Data 
Descriptive analysis 
6.4 
Previous and Concomitant Diseases and Therapies 
Frequency analysis 
6.5 
Exposition to Therapy / Compliance 
Descriptive analysis 
6.6 
Primary Analysis 
The primary efficacy variable 90 day mortality will be analyzed with a Generalized mixed 
model with fixed effects SAPS II score, baseline lactate, baseline-albumin-serum value, type 
of admission (surgical/non-surgical) and treatment group and random effect center; 
descriptive statistics will be presented. The primary analysis will take place in FAS according 
to ITT-principle; an additional sensitivity analysis in PPS will be performed. 
In addition, descriptive analysis of 90-day mortality in subgroups with respect to baseline-
lactate, baseline albumin, baseline SOFA, SAPS II und APACHE II will be performed. 
6.7 
Secondary Analyses 
28- and 60-day-mortality, mortality rate at ICU and in-hospital mortality will be analyzed 
descriptively. Overall mortality will be described by Kaplan Meier methods. 
SOFA score will be analyzed descriptively over time, for organ subscores frequency analysis 
will be presented. Number and % of patients with organ dysfunction defined as any subscore 
> 2 and number of patients with organ failure defined as any subscore >3 will be given.  
Duration of stay on ICU and duration of hospitalization, days not requiring artificial respiration 
and days without vasopressors will be analyzed descriptively. 
Amount of albumin applicated, other colloids and crystalloids will be analyzed descriptively 
over time. 
Overall fluid intake and overall fluid balance will be analyzed descriptively over time. 
Definition [1] for overall fluid output will be used, if 90% of perspiration values are given  If 
perspiration is missing in more than 10% of visits n patients, definition [2] excluding 
perspiration will be used for main analysis. Analysis in subgroup with perspiration available 
will be performed as additional sensitivity analysis. 


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6.8 
Safety and Tolerability Analyses 
6.8.1 Adverse Events 
For sepsis related AEs, frequency analysis with respect to categories 
cardiovascular / respiratory / hepatic / renal / hematological / neurological,  
will be presented. 
Respective entries of AEs possibly related to study medication in AE data base will be 
selected and presented separately. 
All AEs and serious AEs will be presented by incidence analysis of the pre-specified 
categories as well as intensity, relationship to study medication, measures with respect to 
study medication as well as other measures and outcome. Events of category “Other” will be 
listed. 
For infections, frequency analysis over types, grade and origin will be provided. 
Analysis of daily assessed data will be performed over the following time frames: Screening / 
6h after randomization / Day 1 / Day 2-7 / Day 8-28. 
6.8.2 Laboratory Parameters 
For microbiological analysis, incidence of pathogen by source and in total will be evaluated. 
For routine laboratory, descriptive analysis will be performed. Analysis of daily assessed data 
will be performed over the following time frames: Screening / 6h after randomization / Day 1 / 
Day 2-7 / Day 8-28. 
6.8.3 Other Safety Data 
Descriptive analysis 
Clinical parameters: body temperature, respiratorical frequency, hemodynamic parameters 
(SAP, MAP, DAP, CVP, CO) will be analyzed descriptively over time.  
For anti-infective therapy and adjunctive sepsis therapy, incidence analysis will be 
performed. 
For intensive care measures (intubation, central venous catheter, arterial catheter, renal 
replacement therapy, ventilation, ECMO, hemodynamic monitoring), frequencies will be 
presented. 
Analysis of daily assessed data will be performed over the following time frames: Screening / 
6h after randomization / Day 1 / Day 2-7 / Day 8-28. 
6.9 
Subgroup Analysis 
Descriptive analysis of 90 day mortality and Kaplan Meier analysis will be given in subgroups 
for 
Baseline-albumin (0..< 20g/l, 20..<25 g/l, 25..<30 g/l, ≥ 30g/l) 
Baseline-lactate (< / ≥ 8mmol/l, stratum of randomization) 
SOFA baseline value (0..<10, 10..<15, ≥15) 
SAPS II baseline value (0..<40, 40..<80, ≥80) 
APACHE II baseline value (0..<10, 10..<20, 20..<30, ≥30) 
 
If predefined cuts lead to any small subgroups (less than 10 patients), analysis using 
quartiles of study population for subgroup definition will be added for the respective 
parameter.  
6.10 Interim Analysis 
Not planned 


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6.11 Deviation from Protocol and Amendment 
Corresponding to recommendations of reviewers, subgroups with respect to SOFA, SAPS II 
and APACHE II baseline values are prespecified instead of using quartiles.  
7 
Software and Validation 
Analysis will be performed with SAS Version 9.4 or higher. 
 
Validation plan: 
All programs will be validated on either a basic or an enhanced validation level. Basic validation 
level means validation by the programmer according ZKS Jena SOP Bi06 and includes check 
of program code, check of log-file and check of output. Enhanced validation will be performed 
by an independent programmer and includes enhanced check of program code, log-file and 
output. Primary efficacy analysis will be validated by independent duplicate programming. 
Results of adverse events analysis will be cross-checked with the contents of the safety data 
base. 
Programms for DSUR and SMC reports will be validated on basic validation level by the 
respective programmer. 
 
Analysis 
Validation level 
Population characteristics and baseline data 
basic 
Previous and concomitant diseases and therapies 
basic 
Exposition to therapy / compliance 
basic 
Primary analysis 
enhanced 
Secondary analyses 
basic 
Adverse events 
basic 
Laboratory parameters 
basic 
Other safety data 
basic