Clinical Trials Register

Summary
EudraCT Number:	2018-000196-32
Sponsor's Protocol Code Number:	METABOLICRESUS
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:	2018-10-01
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

2018-000196-32

A.3

Full title of the trial

PILOT STUDY ON THE USE OF HYDROCORTISONE, VITAMIN C AND THYAMINE IN PATIENT WITH SEPSIS AND SEPTIC SHOCK.

ESTUDIO PILOTO SOBRE EL USO DE HIDROCORTISONA, VITAMINA C Y TIAMINA EN PACIENTE CON SEPSIS Y SHOCK SEPTICO.

A.3.1

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

EFFECTS OF HYDROCORTISONE, VITAMIN C AND THYAMINE IN PATIENTS WITH GENERALIZED INFECTION

EFECTOS DE LA HIDROCORTISONA, VITAMINA C Y TIAMINA EN PACEINTES CON INFECCION GENERALIZADA

A.4.1

Sponsor's protocol code number

METABOLICRESUS

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	HU DE GIRONA DR JOSEP TRUETA
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	HUD E GIRONA DR JOSEP TRUETA
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HU DE GIRONA DR JOSEP TRUETA
B.5.2	Functional name of contact point	CRISTINA MARTINEZ
B.5.3	Address:
B.5.3.1	Street Address	PAVELLO GOVERN,PLANTA 3 DESAPCHO 330
B.5.3.2	Town/ city	GIRONA
B.5.3.3	Post code	17007
B.5.3.4	Country	Spain
B.5.4	Telephone number	00349729402002343
B.5.5	Fax number	0034972485422
B.5.6	E-mail	CMARTINEZ@IDIBGI.ORG

D. IMP Identification
D.IMP: 1
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	Hidrocortisone
D.2.1.1.2	Name of the Marketing Authorisation holder	TAKEDA FARMACÉUTICA ESPAÑA, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent) Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HYDROCORTISONE SODIUM PHOSPHATE
D.3.9.1	CAS number	6000-74-4
D.3.9.2	Current sponsor code	ACTOCORTINA
D.3.9.4	EV Substance Code	SUB02568MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	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	Ascorbic acid
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER HISPANIA, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ASCORBIC ACID
D.3.9.2	Current sponsor code	ASCORBIC ACID
D.3.9.4	EV Substance Code	SUB05579MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	36
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
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	Benerva
D.2.1.1.2	Name of the Marketing Authorisation holder	TEOFARMA S.r.l.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	THIAMINE
D.3.9.1	CAS number	59-43-8
D.3.9.4	EV Substance Code	SUB10969MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1600
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

sepsis and septic shock

sepsis y shock séptico

E.1.1.1

Medical condition in easily understood language

general infection

infección sistémica

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	HLT
E.1.2	Classification code	10040054
E.1.2	Term	Sepsis, bacteraemia, viraemia and fungaemia NEC
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

* Estimate and compare the hospital survival at 28 days of admission in patients with septic shock treated with the usual management and patients treated with ascorbic acid, thiamine and hydrocortisone added to the usual management
* Compare the mortality at 7, 14 and 28 days of admission in patients with septic shock treated with the usual management and patients treated with ascorbic acid, thiamine and hydrocortisone added to the usual management

* Estimar y comparar la supervivencia hospitalaria a los 28 días de ingreso en pacientes con shock séptico tratados con el manejo habitual y los pacientes tratados con acido ascórbico, tiamina e hidrocortisona adicionado al manejo habitual
* Comparar la mortalidad a los 7, 14 y a los 28 días de ingreso en pacientes con shock séptico tratados con el manejo habitual y los pacientes tratados con acido ascórbico, tiamina e hidrocortisona adicionado al manejo habitual

E.2.2

Secondary objectives of the trial

* Compare the days of admission to the ICU in patients with septic shock treated with the usual management and patients treated with ascorbic acid, thiamine and hydrocortisone added to the usual management.
* Compare the days of mechanical ventilation in patients with septic shock treated with the usual management and patients treated with ascorbic acid, thiamine and hydrocortisone added to the usual management.
* Compare the days of need for vasoactive drug requirements and doses in patients with septic shock treated with the usual management and patients treated with ascorbic acid, thiamine and hydrocortisone added to the usual management

* Comparar los días de ingreso en UCI en los pacientes con shock séptico tratados con el manejo habitual y los pacientes tratados con acido ascórbico, tiamina e hidrocortisona adicionado al manejo habitual.
* Comparar los días de ventilación mecánica en los pacientes con shock séptico tratados con el manejo habitual y los pacientes tratados con acido ascórbico, tiamina e hidrocortisona adicionado al manejo habitual.
* Comparar los días de necesidad de requerimientos de drogas vasoactivas y dosis en los pacientes con shock séptico tratados con el manejo habitual y los pacientes tratados con acido ascórbico, tiamina e hidrocortisona adicionado al manejo habitual.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

* Patients> 18 years of age with diagnosis of septic shock and multiple organ failure admitted to our Unit
* Admission in ICU once diagnosed of sepsis and / or septic shock. The first 24 hours after admission to the ICU will be established as the inclusion limit.
* Signed Informed consent form

* Pacientes > de 18 años con diagnóstico de shock séptico y fracaso multiorgánico ingresados en nuestra Unidad
* Ingreso en UCI una vez diagnosticado de sepsis y/o shock séptico. Se establecerá como límite de inclusión las primeras 24 horas tras el ingreso en UCI
* Consentimiento informado por escrito.

E.4

Principal exclusion criteria

* Patients under 18 years of age
* Pregnancy
* Coexistence of other types of shock at the time of admission
* Limitation of therapeutic effort or ICT (Conditioned Intensive Therapy) to admission to the ICU. It refers to patients in whom prior to admission to the ICU it has been decided not to perform any or some of the usual treatment measures of sepsis, or in which a time limit is established in which, in case of non-response, they would withdraw intensive measures. This limitation will be indicated by your treating doctor and if it exists, the patient would be excluded from the study.
* Patient with a history of previous intake of ascorbic acid, thiamin or corticosteroids in the month prior to admission to the ICU
* Patients considered immunodeficient (more than 10 mg of prednisone or its equivalent per day in the last 2 weeks, immunosuppressive therapy or diagnosis of acquired immunodeficiency syndrome).

* Pacientes menores de 18 años
* Embarazo
* Coexistencia de otros tipos de shock en el momento del ingreso
* Limitación del esfuerzo terapéutico o TIC (Terapia Intensiva Condicionada) al ingreso en UCI. Se refiere a los pacientes en los que previo al ingreso a UCI se ha decidido no realizar alguna o algunas de las medidas de tratamiento habituales de la sepsis, o en el que se establece un límite de tiempo en el cual en caso de no respuesta se retirarían medidas intensivas. Esta limitación estará indicada por su médico tratante y en caso de existir, el paciente seria excluido del estudio.
*Paciente con antecedentes de ingesta previa de ácido ascórbico, tiamina o corticosteroides en el mes previo al ingreso en UCI
* Pacientes considerados inmunodeficientes (Mas de 10 mg de prednisona o su equivalente por día en las ultimas 2 semanas, terapia inmunosupresora o diagnostico de síndrome de inmunodeficiencia adquirida).

E.5 End points

E.5.1

Primary end point(s)

Mortality 28 days after admission to the ICU.

Mortalidad a los 28 días de ingreso en UCI.

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days after admission

28 días de ingreso en UCI.

E.5.2

Secondary end point(s)

• Admission days in ICU: Number of days the patient has been admitted to the ICU due to sepsis
• Days of mechanical ventilation: Number of days the patient has required mechanical ventilation
• Days of vasoactive drugs: Number of days the patient required vasoactive drugs
• Maximum dose of vasoactive drugs per day: Maximum dose of vasoactive drugs daily during the first 7 days of treatment

• Días de admisión en UCI: Número de días que el paciente ha estado ingresado en UCI por sepsis
• Días de ventilación mecánica: Número de días que el paciente ha requerido ventilación mecánica
• Días de drogas vasoactivas: Número de días que el paciente ha requerido drogas vasoactivas
• Dosis máxima de drogas vasoactivas por día: Dosis máxima de drogas vasoactivas diaria durante los primeros 7 días de tratamiento

E.5.2.1

Timepoint(s) of evaluation of this end point

Discharge date or exitus

Hasta fecha del alta o exitus del paciente

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

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

End of trial ( last visit of the patinet) is after 28 days of inclusion (duration of patient in the study is 28 days).It is a pilot study in which patients will be included during 2 years

Ultima visita paciente (ens of study ) es tras 28 días de ingreso. Es un estudio piloto en el cual se inluirán lso pacientes durnate 2 años

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

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

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

patients admitted to the intensive care unit with a diagnosis of sepsis and septic shock

pacientes ingresado en unidad de cuidados intensivos con diagnostico de sepsis y shock septico

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

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

NONE, usual care

Ninguno, tratamiento convencional

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

2018-11-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-31

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

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