Clinical Trials Register

Summary
EudraCT Number:	2015-000057-20
Sponsor's Protocol Code Number:	HC-G-H-1209
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-08-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2015-000057-20

A.3

Full title of the trial

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

ENSAYO PROSPECTIVO, ALEATORIZADO, CONTROLADO, DOBLE CIEGO, MULTICÉNTRICO, INTERNACIONAL SOBRE LA EFICACIA Y LA SEGURIDAD DE UN TRATAMIENTO PRECOZ DE SUSTITUCIÓN DE VOLUMEN PLASMÁTICO CON OBJETIVO CONTROLADO CON UNA SOLUCIÓN DE GELATINA EQUILIBRADA EN COMPARACIÓN CON UNA SOLUCIÓN ELECTROLÍTICA EQUILIBRADA EN PACIENTES CON SEPSIS GRAVE O CHOQUE SÉPTICO

A.3.1

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

Controlled, international study conducted in several centres on the therapeutic effect and safety of an early controlled plasma volume replacement treatment with a balanced gelatin solution tested against a balanced salt solution in patients with severe sepsis / septic shock

Estudio controlado, internacional realizado en varios centros sobre el efecto terapéutico y la seguridad de un tratamiento temprano controlado de reemplazo de volumen de plasma con una solución equilibrada de gelatina probada contra una solución equilibrada de sal en pacientes con sepsis grave/ choque séptico

A.3.2

Name or abbreviated title of the trial where available

GENIUS (GELATIN IN ICU AND SEPSIS)

GENIUS (GELATINA EN UCI Y SEPSIS)

A.4.1

Sponsor's protocol code number

HC-G-H-1209

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	B. Braun Melsungen AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	B. Braun Melsungen AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Grupo B.Braun Espana
B.5.2	Functional name of contact point	Jefe Departamento Medico
B.5.3	Address:
B.5.3.1	Street Address	Carretera de Terrassa, 121
B.5.3.2	Town/ city	Rubi
B.5.3.3	Post code	08191
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34935902283
B.5.6	E-mail	ricard.rosique@bbraun.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Gelafundin ISO 40 mg/ml Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	B. Braun Melsungen AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Gelaspan
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SUCCINYLATED GELATIN
D.3.9.1	CAS number	8000049276
D.3.9.3	Other descriptive name	SUCCINYLATED GELATIN
D.3.9.4	EV Substance Code	SUB22228
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40.0
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SODIUM CHLORIDE
D.3.9.1	CAS number	7647-14-5
D.3.9.3	Other descriptive name	SODIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12581MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5.55
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SODIUM ACETATE TRIHYDRATE
D.3.9.1	CAS number	6131904
D.3.9.3	Other descriptive name	SODIUM ACETATE TRIHYDRATE
D.3.9.4	EV Substance Code	SUB15266MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.27
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POTASSIUM CHLORIDE
D.3.9.1	CAS number	7447-40-7
D.3.9.3	Other descriptive name	POTASSIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12559MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.30
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CALCIUM CHLORIDE DIHYDRATE
D.3.9.1	CAS number	19935-04-8
D.3.9.3	Other descriptive name	CALCIUM CHLORIDE DIHYDRATE
D.3.9.4	EV Substance Code	SUB12664MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.15
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MAGNESIUM CHLORIDE HEXAHYDRATE
D.3.9.1	CAS number	0
D.3.9.3	Other descriptive name	MAGNESIUM CHLORIDE HEXAHYDRATE
D.3.9.4	EV Substance Code	SUB12526MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Isotonic colloidal volume substitute
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Sterofundin ISO Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	B. Braun Melsungen AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Sterofundin ISO
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SODIUM CHLORIDE
D.3.9.1	CAS number	7647-14-5
D.3.9.3	Other descriptive name	SODIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12581MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6.80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SODIUM ACETATE TRIHYDRATE
D.3.9.1	CAS number	6131904
D.3.9.3	Other descriptive name	SODIUM ACETATE TRIHYDRATE
D.3.9.4	EV Substance Code	SUB15266MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.27
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POTASSIUM CHLORIDE
D.3.9.1	CAS number	7447-40-7
D.3.9.3	Other descriptive name	POTASSIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12559MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.30
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CALCIUM CHLORIDE DIHYDRATE
D.3.9.1	CAS number	10035-04-8
D.3.9.3	Other descriptive name	CALCIUM CHLORIDE DIHYDRATE
D.3.9.4	EV Substance Code	SUB12664MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.37
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MAGNESIUM CHLORIDE HEXAHYDRATE
D.3.9.1	CAS number	0
D.3.9.3	Other descriptive name	MAGNESIUM CHLORIDE HEXAHYDRATE
D.3.9.4	EV Substance Code	SUB12526MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MALIC ACID
D.3.9.1	CAS number	6915-15-7
D.3.9.3	Other descriptive name	MALIC ACID
D.3.9.4	EV Substance Code	SUB14455MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.67
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hypovolaemia in Severe Sepsis / Septic Shock

Hipovolemia en caso de sepsis grave o choque séptico

E.1.1.1

Medical condition in easily understood language

Volume replacement in Severe Sepsis / Septic Shock

Reemplazo de volumen en Sepsis grave/ Choque séptico

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10040070
E.1.2	Term	Septic shock
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10040047
E.1.2	Term	Sepsis
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

Investigar la eficacia del manejo precoz de líquidos dirigido a un objetivo de una combinación terapéutica con gelatina y cristaloide en comparación con un tratamiento de cristaloide puro para alcanzar la estabilidad hemodinámica (EHD) en pacientes con sepsis grave o choque séptico.

E.2.2

Secondary objectives of the trial

Investigation of safety and efficacy parameters of the applied fluid regimes.

Investigación de los parámetros de seguridad y eficacia de las terapias con líquidos administradas.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or female patients ≥ 18 and ≤ 85 years of age
• Women of child bearing potential must test negative on standard pregnancy test (urine or serum)
• Patients with body weight ≥ 55 kg and ≤ 140 kg and body mass index (BMI) ≥ 18 kg/m2
• Patients diagnosed severe sepsis / septic shock (refer to section 7.2.1 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)
• Patient who are fluid responsive. Fluid responsiveness is defined as increase of > 10% in mean arterial pressure (MAP) after PLR
• Signed informed consent by patient, legal representative or authorized person or deferred consent

-Pacientes de ambos sexos  18 años de edad y  85 años
- Las mujeres en edad fértil deben dar negativo en la prueba de embarazo estándar (en orina o suero)
-Pacientes con peso corporal  55 kg y  140 kg e índice de masa corporal (IMC)  18 kg/m2
- Los pacientes diagnosticados de sepsis grave o choque séptico (véanse las definiciones en el apartado 7.2.1.) al ser ingresados en la UCI que pueden ser incluidos en un plazo de 90 min desde el ingreso O BIEN pacientes diagnosticados de sepsis grave o choque séptico durante su estancia en la UCI que pueden ser incluidos en un plazo de 90 min después del diagnóstico
- Pacientes en los que el tratamiento antibiótico ya se ha iniciado (antes de la asignación aleatoria)
- Pacientes que responden a los fluidos. El grado de respuesta a los fluidos se define como un incremento de > 10% en la presión arterial media (PAM) después de la PLR
- Consentimiento informado firmado por el paciente, representante legal o persona autorizada o consentimiento aplazado

E.4

Principal exclusion criteria

• Administration of HES, dextrane solutions or > 500 ml Gelatin solution within the 24 h prior to randomization
• Death expected within the next 48 h (moribund patients as defined by ASA ≥ class V)
• Patients whose medical condition does preclude the PLR manoeuvre
• 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:
Burns are defined as having any of the following before the administration of investigational products:
1. Burns ≥ 10 % of body surface area classified as “major burns": third-degree burns (syn. full thickness burns) of any size or second-degree burns > 2 inches (ca. 5 cm) wide or second-degree burns on the hands, feet, face, groin, buttocks, or a major joint
2. Burned area not yet re-epithelialised
• Renal failure with oliguria or anuria
• Severe general oedema
• Severe congestive cardiac failure
• Hypersensitivity to the active substance or ingredients of the IPs
• Hypervolaemia / hyperhydration
• Hyperkalaemia
• Hypercalcaemia
• Metabolic alkalosis
• Simultaneous participation in another interventional clinical trial (drugs or medical devices studies)

-Administración de HES, soluciones de dextrano o > 500 ml de soluciones de gelatina en las 24 h anteriores a la asignación aleatoria
- Muerte esperada en las próximas 48 h (pacientes moribundos definidos por ASA ≥ clase V)
- Pacientes cuya situación médica impide realizar la maniobra PLR
- Pacientes en los que se espera que necesiten perfusiones a presión
- Necesidad de apoyo renal (ya sean técnicas continuas o discontinuas, incluyendo hemodiálisis intermitente, hemofiltración y hemodiafiltración)
- Pacientes que reciben medicación con heparina terapéutica debido a una enfermedad de coagulación crónica / anticoagulantes (esto es, tiempo de tromboplastina parcial > 60 s)
- Pacientes quemados agudos
Las quemaduras se definen como las que tienen cualquiera de las siguientes condiciones antes de la administración de los productos de investigación:
1. quemaduras ≥ 10% de la superficie corporal clasificados como "quemaduras graves": quemaduras de tercer grado (quemaduras de todo el grosor) de cualquier tamaño o quemaduras de segundo grado> 2 pulgadas (aproximadamente 5 cm) de ancho o de segundo grado Quemaduras en las manos, pies, cara, ingle, nalgas o una articulación
2. Área quemada aún no reepitelizada

- Insuficiencia renal con oliguria o anuria
- Edema general grave
- Insuficiencia cardiaca congestiva grave
- Hipersensibilidad al principio activo o a los ingredientes de los PI
- Hipervolemia / hiperhidratación-
- Hiperpotasemia
- Hipercalcemia
- Alcalosis metabólica
- Participación simultánea en otro ensayo clínico de intervención (estudios con fármacos o productos sanitarios)

E.5 End points

E.5.1

Primary end point(s)

Time until first / initial HDS is achieved (in minutes).

Tiempo hasta alcanzar la primera EHD o la EHD inicial (en minutos).

E.5.1.1

Timepoint(s) of evaluation of this end point

Time measurement will start with first administration of IPs and will be continued until first HDS is achieved.

La medición del tiempo comenzará con la primera administración de los PI y continuará hasta que se alcance la primera EHD.

E.5.2

Secondary end point(s)

• Safety
-Renal function
Serum creatinine (SCr)
Serum blood urea nitrogen (BUN)
Urine creatinine
Estimated glomerular filtration rate (eGFR)
Creatinine clearance
Need and indication of renal replacement therapy (RRT)
Urine output
Kidney Disease Improving Global Outcome (KDIGO) score
-Coagulation
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
International norm ratio (INR)
ROTEM (optional)
-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)
Serum electrolytes
Base excess (BE)
Lactate / lactate decrease
Phosphate
Magnesium
Central venous BGA
Arterial oxygen content
Oxygen delivery
Perfusion index (optional)
pCO2 gap (optional)
• 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, SAPS 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

 Seguridad
Función renal
 Creatinina sérica (SCr)
 Nitrógeno ureico en suero sanguíneo (BUN)
 Creatinina en orina
 Tasa de filtración glomerular estimada (eGFR)
 Aclaramiento de creatinina
 Necesidad de indicación de tratamiento renal sustitutivo (TRS)
 Diuresis
 Puntuación del Kidney Disease Improving Global Outcome (KDIGO)
Coagulación
 Tiempo de protrombina (TP)
 Tiempo de tromboplastina parcial activado (TTPa)
 Índice internacional normalizado (INR)
 ROTEM (opcional)
Mediciones específicas de los centros (Innsbruck):
 Fibrinógeno
 Antitrombina (AT)
 Plaquetas absolutas
Función hepática
 Bilirrubina
Acontecimientos adversos
 Acontecimientos (AA(G)) y reacciones (RA(G)) adversas (graves)
Otros
 Número de unidades de eritrocitos (RBC)
 Número de unidades de plasma fresco congelado (FFP)
 Número de otros productos sanguíneos
 Tratamiento vasopresor
 Tratamiento inotrópico
 Eficacia
Administración de líquidos según el algoritmo volumétrico
 Volumen necesario para conseguir la primera EHD o la EHD inicial
 Volumen total hasta 48 h después del asignación aleatoria
 Frascos administrados
Soluciones de cristaloide adicionales administradas para terapia de volumen posterior
 Fármaco y volumen
Balance hídrico
 Aporte hídrico
 Salida hídrica
 Balance hídrico
Hemodinámica
 Grado de respuesta del volumen ante elevación pasiva de las piernas (PLR) o sobrecarga líquida exógena
 Lecturas hemodinámicas según requiere el algoritmo volumétrico y la hemodinámica de 48 h después de la asignación aleatoria hasta el alta de la UCI o el día 28, lo que ocurra primero
Oxigenación tisular y equilibrio ácido-base
 Análisis de gases en sangre arterial (BGA)
 Electrolitos séricos
 Exceso de base (EB)
 Lactato / disminución de lactato
 Fosfato
 Magnesio
 BGA en sangre venosa central
 Contenido de oxígeno arterial
 Aporte de oxígeno
 Índice de perfusión (opcional)
 Diferencia pCO2 (opcional)
Respuesta
 Duración de la estancia (LOS) en la unidad de cuidados intensivos (UCI)
 LOS en el hospital
 Días con TRS
 Número de días sin infección
 Número de días sin antibiótico
 Número días sin respirador
 Número de días sin vasopresor
 Seguimiento
 Último valor de SCr disponible (día 28)
 Terapia con coloides (día 28)
 Mortalidad y causa de la muerte (si procede) (día 28 y día 90)
 Calidad de vida relacionada con la salud (HRQoL) (día 90)
 Nuevo TRS / enfermedad renal (día 90)
 Otros criterios de valoración
Datos demográficos
 Edad
 Sexo
 Estatura
 Peso
 Raza
 Tipo de paciente (p. ej. paciente con traumatismo, paciente quirúrgico)
Antecedentes
 Puntuaciones APACHE II, SAPS II y SOFA
 Temperatura
 Aporte hídrico en las 24 h anteriores a la asignación aleatoria
 Origen de la sepsis
 Procalcitonina (opcional)
 Organismo causante de la infección
 Historia clínica
Medicación concomitante
 Tratamiento antibiótico
 Tratamiento nefrotóxico
 Medios de contraste
 Tratamiento de anticoagulación
Finalización del ensayo

E.5.2.1

Timepoint(s) of evaluation of this end point

See section E.5.2

Ver sección E.5.2

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Completion of last follow up of last patient.

Finalización del último seguimiento del último paciente.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

304

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

304

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2017-08-10.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Study indication is severe sepsis or septic shock, therefore patients are in an emergency situation. In the setting of emergency situation, requiring ICU admission / immediate medical treatment, the patients will not be able to consent personally.

La indicación del estudio es sepsis grave o choque séptico, los pacientes están en una situación de emergencia. En una situación de emergencia, que requiere la admisión en la UCI / tratamiento médico inmediato, los pacientes no podrán consentir

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

608

F.4.2.2

In the whole clinical trial

608

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not different from the expected normal treatment of that condition.

No es diferente del tratamiento normal esperado de esa afección.

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-08-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-13

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

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