Clinical Trials Register

Summary
EudraCT Number:	2018-000488-98
Sponsor's Protocol Code Number:	PPI-SepsisTrial
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-01-07
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-000488-98

A.3

Full title of the trial

Proton pump inhibitors (PPI) as a new strategy for therapy in sepsis: clinical trial to reduce severity of organ failure and in vitro experiments to search specific hallmarks in monocytes from septic patients and to characterize the mechanism of action of PPI (PPI-SEPSIS)

Inibitori di Pompa Protonica (PPI) come nuova strategia terapeutica per la sepsi: trial clinico per ridurre la gravità della disfunzione organica ed esperimenti in vitro per individuare hallmarks specifici nei monociti di pazienti settici e per caratterizzare il meccanismo d’azione dei PPI (PPI-SEPSIS).

A.3.1

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

Clinical trial to reduce the severity of organ dysfunction and in-vitro experiments to identify specific hallmarks in septic patients’ monocytes and to characterize the mechanism of action of PPI (PPI-SEPSIS)

Studio per ridurre la gravità della disfunzione organica ed esperimenti in vitro per individuare hallmarks specifici nei monociti di pazienti settici e per caratterizzare il meccanismo d’azione dei PPI (PPI-SEPSIS)

A.3.2

Name or abbreviated title of the trial where available

PPI-Sepsis Trial

A.4.1

Sponsor's protocol code number

PPI-SepsisTrial

A.5.4

Other Identifiers

Name:

Number:

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	OSPEDALE SAN RAFFAELE
B.1.3.4	Country	Italy
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	GRANT MINISTERIALE
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS Ospedale San Raffaele
B.5.2	Functional name of contact point	Anestesia e Rianimazione Cardio-Tor
B.5.3	Address:
B.5.3.1	Street Address	Via Olgettina, 60
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.4	Telephone number	0226436155
B.5.5	Fax number	0226436152
B.5.6	E-mail	landoni.giovanni@hsr.it

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	LUCEN - 40 MG POLVERE PER SOLUZIONE INIETTABILE/PER INFUSIONE 10 FLACONCINI POLVERE
D.2.1.1.2	Name of the Marketing Authorisation holder	ISTITUTO FARMACOBIOLOGICO MALESCI S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	ESOMEPRAZOLO
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Powder for solution for injection
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	ESOMEPRAZOLO MAGNESIO TRIIDRATO
D.3.9.1	CAS number	161796-78-7
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	8
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Sepsis is a severe disease with a high mortality rate and lack of efficacious therapies

La sepsi è una grave malattia con alta mortalità e mancanza di efficaci terapie.

E.1.1.1

Medical condition in easily understood language

Sepsis is a severe disease with a high mortality rate and lack of efficacious therapies

La sepsi è una grave malattia con alta mortalità e mancanza di efficaci terapie.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	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

To ascertain if high dose of esomeprazole safely reduces the incidence and severity of organ dysfunction as compared to placebo in adult patients with sepsis or septic shock, with reference to the mean SOFA score in the two groups

Accertarsi che l’alta dose di esomeprazolo riduca senza rischi l’incidenza e la severità della disfunzione di organo rispetto al placebo in pazienti adulti con sepsi o shock settico, con riferimento al punteggio medio di SOFA nei due gruppi.

E.2.2

Secondary objectives of the trial

Identifying new diagnostic or prognostic markers by analyzing functional traits in monocytes from critically ill patients with sepsis: definition of redox state and intra and extracellular pH, quantification of the levels of secreted ATP and cytokines (TNF, IL-1, HMGB1) at baseline and following in vitro TLR stimulation;
Understanding the molecular mechanism(s) underlying the therapeutic effects of PPI in acute sepsis: identification of the changes induced in the above parameters by treatment with esomeprazole vs placebo.

Identificare nuovi marcatori diagnostici o prognostici analizzando i tratti funzionali nei monociti provenienti da pazienti malati critici con sepsi; comprendere i meccanismi molecolari sottostanti gli effetti terapeutici degli IPP nella sepsi acuta; caratterizzazione della presenza di modifiche nei monociti dei pazienti sopravvissuti, trattati con esomeprazolo o placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age = 18 years old
2. Admitted to intensive care unit or emergency department
3. Sepsis or septic shock¿(Sepsis defined as acute change in total SOFA score=2 points consequent to the infection. The baseline SOFA score can be assumed to be zero in patients not known to have preexisting organ dysfunction. Septic shock defined as sepsis plus persisting hypotension requiring vasopressors to maintain MAP =65mmHg and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate volume resuscitation)
4. Able to express informed consent as requested by Ethical Committee

1. Avere almeno 18 anni
2. Essere ammessi in terapia intensiva –TI- o Pronto soccorso –PS-
3. Essere affetti da sepsi o shock settico
4. Essere capaci di esprimere il consenso informato o come richiesto dal comitato etico

E.4

Principal exclusion criteria

1. Able to express informed consent and deny it
2. Known allergy or intolerance to study drug
3. Little chance of survival, as defined by a SAPS II score more than 65 point¿
4. Concomitant acquired immunodeficiency syndrome (AIDS, Stage 3 HIV infection according to CDC)
5. On immunosuppressant or long-term corticosteroid therapy (more than 0.5 mg/kg/day of prednisone or equivalent for over 30 days)
6. Receiving lifesaving drugs known to have a strong interference with esomeprazole
7. Sepsis or septic shock since over 36 hours¿
8. Severe hepatic dysfunction
9. Pregnant or breastfeeding

1. Essere capaci di esprimere il consenso informato e rifiutarlo
2. Avere note allergie o intolleranze al farmaci in studio
3. Avere poca possibilità di sopravvivenza, come definito da un punteggio SAPS II di più di 65 punti
4. Avere una concomitante immunodeficienza acquisita
5. Avere ricevuto farmaci immunosoppressori o terapia corticosteroidea a lungo termine
6. Ricevere farmaci salva vita noti per avere una forte interferenza con l’esomeprazolo
7. Avere sepsi o shock settico da più di 36 ore
8. Avere una severa disfunzione epatica
9. Gravidanza/allattamento

E.5 End points

E.5.1

Primary end point(s)

Reduction of organ dysfunction measured though SOFA score

Riduzione del danno d’organo misurato con il punteggio SOFA.

E.5.1.1

Timepoint(s) of evaluation of this end point

During hospital stay

Per tutto il tempo di ricovero

E.5.2

Secondary end point(s)

Death from any cause; Antibiotic-free days; Adjusted ICU-free; Single organ failure severity, evaluated by mean difference in each different category of SOFA score.

Morte dovuta a qualsiasi causa, giorni liberi da antibiotici, giorni liberi dalla Ti, severità di una singola insufficienza d’organo valutato tramite una differenza media in ciascuna categoria del punteggio SOFA.

E.5.2.1

Timepoint(s) of evaluation of this end point

During hospital stay at days 30, 90, 180 after randomization

Durante il ricovero ospedaliero, 30, 90 e 180 giorni dalla data di randomizzazione.

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

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

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Information not present in EudraCT

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

LVLS

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:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

150

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 2021-01-07.

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

Patients unconscious and unable to give their consent

Pazienti incoscienti e incapaci di rilasciare il proprio consenso

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

290

F.4.2

For a multinational trial

F.4.2.1

In the EEA

300

F.4.2.2

In the whole clinical trial

300

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)

Standard of care

Normale pratica clinica

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

2018-07-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-05

P. End of Trial
P.	End of Trial Status	Ongoing

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