Prospective, Controlled, Double-Blind, Randomized Multicentric Study On The Efficacy And Safety Of An Early Target Controlled Plasma Volume Replacement Therapy With A Balanced Gelatine Solution vs A Balanced Electrolyte Solution In Patients With Severe Sepsis
Phase: PHASE4
Conditions: Hypovolemia
Sponsor: B. Braun Melsungen AG

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Study Plan of 
PROSPECTIVE, RANDOMIZED, CONTROLLED, DOUBLE-BLIND, MULTI-
CENTRIC, INTERNATIONAL STUDY ON THE EFFICACY AND SAFETY OF AN 
EARLY TARGET CONTROLLED PLASMA VOLUME REPLACEMENT THERAPY 
WITH A BALANCED GELATIN SOLUTION VS A BALANCED ELECTROLYTE 
SOLUTION IN PATIENTS WITH SEVERE SEPSIS / SEPTIC SHOCK 
 
GENIUS (GELATIN IN ICU AND SEPSIS) 
 
STUDY IDENTIFICATION NO.: HC-G-H-1209 
NCT02715466 
Date of final applicable study plan: 16.06.2020 
 
Marketing Authorization Holder: 
 
B. Braun Melsungen AG 
Germany 
 
 
Organized and Financed by: 
 
B. Braun Melsungen AG 
Division Hospital Care 
Carl-Braun-Str. 1 
34212 Melsungen 
Germany 
 

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STUDY OVERVIEW 
 
Title of Study 
PROSPECTIVE, RANDOMIZED, CONTROLLED, DOUBLE-BLIND, 
MULTI-CENTRIC, INTERNATIONAL STUDY ON THE EFFICACY AND 
SAFETY OF AN EARLY TARGET CONTROLLED PLASMA VOLUME 
REPLACEMENT THERAPY WITH A BALANCED GELATIN 
SOLUTION VS A BALANCED ELECTROLYTE SOLUTION IN 
PATIENTS WITH SEVERE SEPSIS / SEPTIC SHOCK 
Acronym 
GENIUS (GELATIN IN ICU AND SEPSIS) 
Investigational Products 
(IPs)  
Investigational test product (gelatin group): 
Gelaspan (plasma adapted gelatin solution for infusion)  
 To be administered in combination with background medication (i.e. 
open-label Sterofundin ISO; a plasma adapted electrolyte solution) in a 
ratio of 1:1 (gelatin:electrolyte) 
 
Investigational reference product (crystalloid group): 
Sterofundin ISO (plasma adapted electrolyte solution)  
 To be administered in combination with background medication (i.e. 
open-label Sterofundin ISO; a plasma adapted electrolyte solution) in a 
ratio of 1:1 
Background Medication 
Open-label Sterofundin ISO (plasma adapted electrolyte solution) 
Phase
IV
Study Design 
Prospective, controlled, randomized, double-blind, international, multi-centric 
study with two parallel groups 
Number of Sites & 
Countries 
Multi-centric, international  
(Participating countries: Austria, Czech Republic, France, Germany, Spain) 
Up to 15 sites
Sample Size 
2 x 304 patients (in total 608 patients) 
Sample size re-calculation after 2 x 200 (in total 400) patients. 
Indication
Hypovolaemia in Severe Sepsis / Septic Shock
Primary Objective 
Investigate the efficacy of early goal directed fluid management of a 
combination of a gelatin and crystalloid regime in comparison to a pure 
crystalloid regime in achieving haemodynamic stability (HDS) in patients 
with severe sepsis / septic shock. 
Primary Variable 
Time until first / initial HDS is achieved (in minutes). 
Time measurement will start with first administration of IPs and will be 
continued until first HDS is achieved.
Secondary Objectives 
Investigation of safety and efficacy parameters of the applied fluid regimes. 
Secondary Variables 
 Safety 
Renal function 
 Serum creatinine (SCr) 
 Serum blood urea nitrogen (BUN) 
 Estimated glomerular filtration rate (eGFR) 
 Need and indication of renal replacement therapy (RRT)  

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 Urine output  
 Kidney Disease Improving Global Outcome (KDIGO) score 
 
Coagulation 
 Prothrombin time (PT) 
 Activated partial thromboplastin time (aPTT)  
 International norm ratio (INR) 
Site specific measurements (Innsbruck): 
 Fibrinogen  
 Antithrombin (AT)  
 Platelets absolute 
 
Hepatic function 
 Bilirubin 
 
Adverse Events 
 (Serious) adverse events ((S)AEs) / reactions ((S)ARs) 
 
Other 
 Number of red blood cell (RBC) units 
 Number of fresh frozen plasma (FFP) units 
 Number of other blood products 
 Vasopressor therapy 
 Inotropic therapy 
 
 Efficacy 
Fluid administration according to the volume algorithm 
 Volume needed to achieve first / initial HDS  
 Total volume until 48 h after randomization 
 Administered bottles 
 
Additional administered crystalloid solutions for further volume 
treatment 
 Drug and volume  
 
Fluid balance  
 Fluid intake  
 Fluid output  
 Fluid balance  
 
Haemodynamics 
 Volume responsiveness upon passive leg raising (PLR) or exogenous 
fluid challenge  
 Haemodynamic readings as required by the volume algorithm and 
haemodynamics from 48 h after randomization until ICU discharge or 
day 28, whatever occurs first 
 
Tissue oxygenation and acid base balance 
 Arterial blood gas analyses (BGA) 

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 Serum electrolytes 
 Base excess (BE) 
 Lactate / lactate decrease 
 Central venous BGA 
 Arterial oxygen content 
 Oxygen delivery  
 Outcome  
 Length of stay (LOS) in the intensive care unit (ICU) 
 Hospital LOS 
 Days on RRT  
 Number of infection free days 
 Number of antibiotic free days 
 Number of ventilator free days  
 Number of vasopressor free days  
 
 Follow-up 
 Last available SCr (day 28) 
 Colloid therapy (day 28) 
 Mortality & cause of death (if applicable) (day 28 & day 90) 
 Health-related quality of life (HRQoL) (day 90) 
 New RRT / kidney disease (day 90) 
 
 Other variables 
Demographic data  
 Age 
 Gender 
 Height 
 Weight 
 Race 
 Type of patient (e.g. trauma patient, surgical patient) 
 
Anamnesis  
 APACHE II & SOFA  score 
 Temperature 
 Fluid input in the 24 h prior to randomization 
 Origin of sepsis 
 Procalcitonin (optional) 
 Causative organism of infection 
 Medical history 
 
Concomitant medication 
 Antibiotic therapy 
 Nephrotoxic therapy  
 Contrast agents  
 Anticoagulation therapy 
 
Study termination 

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Patient Inclusion /  
Exclusion Criteria 
Inclusion criteria: 
 Male or female patients  18 years of age 
 Women of child bearing potential must test negative on standard 
pregnancy test (urine or serum) 
 Patients with body weight  140 kg  
 Patients diagnosed severe sepsis / septic shock (refer to section Fehler! 
Verweisquelle konnte nicht gefunden werden. for definitions) at 
admission on ICU who can be enrolled within 90 min after admission OR 
patients diagnosed severe sepsis / septic shock during ICU stay who can 
be enrolled within 90 min after diagnosis  
 Patients where antibiotic therapy has already been started (prior to 
randomization) 
 Patients who are fluid responsive. Fluid responsiveness is defined as 
increase of > 10% in mean arterial pressure (MAP) after PLR or fluid 
challenge (max. 250 ml crystalloid solution) 
 Signed informed consent by patient, legal representative or authorized 
person or deferred consent 
 
Exclusion criteria: 
 Administration of HES, dextrane solutions or > 500 ml of Gelatin 
solutions within the 24 h prior to randomization 
 Death expected within the next 48 h (moribund patients as defined by 
ASA ≥ class V) 
 Patients with confirmed acute SARS-CoV-2 (COVID-19) infection (as 
available from routine medical records/ patient chart) 
 Patients for whom the need of pressure infusions are expected 
 Requirement for renal support (either continuous or discontinuous 
techniques, including intermittent haemodialysis, haemofiltration and 
haemodiafiltration) 
 Patients receiving therapeutic heparin medication due to chronic 
coagulation disease / anticoagulation medication (i.e. partial 
thromboplastin time > 60 sec) 
 Acutely burned patients (refer to section Fehler! Verweisquelle konnte 
nicht gefunden werden.) 
 Renal failure with oliguria or anuria 
 Severe general oedema 
 Severe congestive cardiac failure 
 Hypersensitivity to the active substance or ingredients of the IPs 
 Hypersensitivity to galactose-α-1,3-galactose (alpha-Gal) or known 
allergy to red meat (mammal meat) and offal 
 Hypervolaemia / hyperhydration 
 Hyperkalaemia  
 Hypercalcaemia  
 Metabolic alkalosis 

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 Simultaneous participation in another interventional clinical trial (drugs or 
medical devices studies) 
Investigational Test 
Product 
Gelaspan: Plasma adapted gelatin solution for infusion 
Composition (1000 ml solution contain): 
Succinylated gelatin (= modified fluid gelatin) 
40.0 g 
Sodium chloride 
5.55 g 
Sodium acetate trihydrate 
3.27 g 
Potassium chloride 
0.30 g 
Calcium chloride dihydrate 
0.15 g 
Magnesium chloride hexahydrate 
0.20 g 
 
Excipients for pH-adjustment: 
Sodium hydroxide 40% 
0 – 0.133 g 
Hydrochloric acid 20% 
0 – 0.182 g 
 
Electrolyte concentrations 
Sodium 
151 mmol/l 
Chloride 
103 mmol/l 
Potassium 
4 mmol/l 
Calcium 
1 mmol/l 
Magnesium 
1 mmol/l 
Bicarbonate as Acetate 
24 mmol/l 
Molecular weight, weight average:  
30 000 Dalton 
Molecular weight, number average:  
23 200 Dalton 
Theoretical osmolarity:  
284 mOsm/l 
Investigational Reference 
Product 
 
 
 
Sterofundin ISO: Plasma adapted electrolyte solution for infusion 
Composition (1000 ml solution contain): 
Sodium chloride 
6.80 g 
Potassium chloride 
0.30 g 
Calcium chloride dihydrate 
0.37 g 
Magnesium chloride hexahydrate 
0.20 g 
Sodium acetate trihydrate 
3.27 g 
Malic acid 
0.67 g 
 
Electrolyte concentration 
Sodium  
145.0 mmol/l 
Potassium  
4.0 mmol/l 
Calcium  
2.5 mmol/l 
Magnesium  
1.0 mmol/l 
Chloride  
127.0 mmol/l 
Acetate  
24.0 mmol/l 
Malic acid 
5.0 mmol/l 
pH: 
5.1 – 5.9  
Theoretical osmolarity: 
309 mOsmol/l
Fluid Administration 
Method of Administration 
The administration of IPs and background medication is performed 
intravenously. 
 
 
Dosage  

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Dosing of IPs is individualized to the patient’s volume needs. Blinded IP 
volume applied should not exceed 30 ml/kg/day. 
In addition background medication is applied alternating with IPs in a 
ratio of 1:1. 
Fluids are administered according to the volume algorithm as long as the 
patient is fluid responsive. Fluid responsiveness is defined as an increase 
of 10% of MAP and / or stroke volume index (SVI) after endogenous or 
exogenous fluid challenge. An endogenous fluid challenge is achieved by 
means of PLR. An exogenous fluid challenge is achieved by infusing 500 
ml of fluid in 15 min. 
Refer to protocol section Fehler! Verweisquelle konnte nicht gefunden 
werden. for details on the fluid management strategy. 
Duration of Treatment 
Treatment with IPs starts directly with randomization and discontinues 
with the achievement of HDS, achievement of maximum daily dose (30 
ml/kg) or 48 h after randomization, whatever occurs first. 
Visit Schedule 
Prior randomization - 90 min window: 
 Verification of in- / exclusion criteria 
 RBC and antibiotic therapy prior randomization 
 Demographic data including pregnancy test in women of childbearing 
potential 
 Anamnesis & medical history 
At randomization 
 Blood samples for laboratory evaluations (renal function, coagulation, 
hepatic function, lactate, scores) - immediately before first IP 
administration  
Randomisation until 48 h thereafter: 
 Set of catheters (e.g. arterial line, central-venous line) 
 Set of urinary catheter 
 Assessment of HDS and primary endpoint ‘time to first / initial HDS’ 
(lactate, urine production, ScvO2) 
 SCr (every 6 h until 48 h after randomization) 
 Urine output (every 6 h until 48 h after randomization)  
 Blood samples for laboratory evaluations (renal function, coagulation, 
hepatic function) 
 Vasopressor therapy 
 Inotropic therapy 
 Fluid administration (i.e. IP and background medication acc. to volume 
algorithm) 
 Administered crystalloids for further volume treatment 
 Fluid intake & fluid output 
 Fluid responsiveness upon PLR or exogenous fluid challenges as required 
by the volume algorithm 
 Haemodynamic readings as required by the volume algorithm 

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 Tissue oxygenation and acid base balance (BGA within the first 6 h every 
2 h, then every 12 h until 48 h after randomization) 
 (Serious) adverse events / reactions 
 Applied blood products  
 Concomitant medications 
 SOFA score, temperature 
 Fulfilment of ICU discharge criteria 
 RRT including indication 
 Invasive mechanical ventilation 
48 h after randomization until ICU discharge or day 28 (whatever occurs 
first): 
 Blood samples for laboratory evaluations (renal function, coagulation, 
hepatic function) 
 Severe sepsis / septic shock (second, third,… hit) 
 Vasopressor therapy 
 Inotropic therapy 
 Administered crystalloids for further volume treatment 
 Fluid intake & fluid output 
 Urine output 
 Haemodynamic readings (minimum and maximum daily)  
 Tissue oxygenation and acid base balance  
 (Serious) adverse events / reactions 
 Applied blood products  
 Concomitant medications 
 SOFA score, temperature 
 Fulfilment of ICU discharge criteria 
 RRT including indication 
 Invasive mechanical ventilation 
 Several outcome parameters (hospital LOS, ICU LOS, number of 
ventilator free days, number of infection free days, number of antibiotic 
free days, number of vasopressor free days, days on RRT)  
 Study termination 
Day 28: 
 Last available SCr documented from ICU discharge until hospital 
discharge or day 28, whatever occurs first  
 Colloid therapy from ICU discharge until hospital discharge or day 28, 
whatever occurs first  
 Mortality & cause of death if applicable 
Day 90: 
 Mortality & cause of death if applicable 
 New RRT / kidney disease 

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 HRQoL questionnaire & appendix (if applicable) 
Duration of Study per 
Patient 
Start of study: With randomization 
Treatment period (administration of fluids according to the volume 
algorithm): 
 Start of administration: With randomization  
 Duration of administration:  
 Treatment with fluids according to the volume algorithm 
discontinues with the achievement of HDS or 48 h after 
randomization, whatever occurs first 
 Treatment with additional crystalloid solutions for further volume 
treatment only starts after achievement of HDS, achievement of 
max. daily dose or 48 h after randomization until ICU discharge or 
day 28, whatever occurs first  
End of study: ICU discharge or day 28, whatever occurs first 
Follow ups: day 28 & day 90
Study Schedule 
Planned start: Q1 / 2016 
Planned recruitment time: 5.5 years 
Planned last patient out: Q4 / 2021
Statistical Methods 
Sample size will be based on assumption of difference between the gelatin 
and the crystalloid group. 
Randomization / Blinding  
Randomized with the following strata: 
 Site 
 RBCs pre-treatment within 24 h prior to randomization  
Double-blinded
Data Safety Monitoring 
Board (DSMB)
A DSMB is appointed. 
 
 
 

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