Clinical Trials Register

Summary
EudraCT Number:	2010-023310-31
Sponsor's Protocol Code Number:	1325/11
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-12-28
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

2010-023310-31

A.3

Full title of the trial

Randomized, open label, multicenter trial to compare safety and efficacy of colistin vs. meropenem for empirical treatment of ventilator-associated pneumonia

Studio clinico in aperto randomizzato multicentrico volto a confrontare l'efficacia e la sicurezza del meropenem vs la colistina nel trattamento delle polmoniti acute

A.3.1

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

Randomized, open label, multicenter trial to compare safety and efficacy of colistin vs. meropenem for empirical treatment of ventilator-associated pneumonia

Ottimizzazione del trattamento delle polmoniti da vantilatore (VAP) causate da germi gram-negativi multiresistenti come Acinetobacter baumanni e Pseudomonas aeruginosa, mediante l’utilizzo di antibitici “off-patent”

A.3.2

Name or abbreviated title of the trial where available

MagicBullet

A.4.1

Sponsor's protocol code number

1325/11

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	CONSORCIO DE APOYO A LA INVESTIGACION BIOMEDICA EN RED (CAIBER)
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	Comunita' Europea
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Policlinico Gemelli
B.5.2	Functional name of contact point	Istituto di Anestesia Rianimazione
B.5.3	Address:
B.5.3.1	Street Address	L.go Gemelli 8
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	0630154490
B.5.5	Fax number	063013450
B.5.6	E-mail	m.antonelli@rm.unicatt.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	COLIMICINA*IM FL 1000000U4ML+F
D.2.1.1.2	Name of the Marketing Authorisation holder	UCB PHARMA SpA
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.3.4	Pharmaceutical form	Powder and solvent 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	COLISTIMETHATE SODIUM
D.3.9.1	CAS number	8068-28-8
D.3.9.4	EV Substance Code	SUB06801MIG
D.3.10	Strength
D.3.10.1	Concentration unit	million IU million international units
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	9
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	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	MERREM 250*EV FL 250MG+SAC.100
D.2.1.1.2	Name of the Marketing Authorisation holder	ASTRAZENECA SpA
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.3.4	Pharmaceutical form	Powder for 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	MEROPENEM
D.3.9.1	CAS number	96036-03-2
D.3.9.4	EV Substance Code	SUB08778MIG
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	3
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

VAP PATIENTS AT RISK FOR GRAM-NEGATIVE MDR PATHOGENS ISOLATION

PAZIENTI AFFETTI DA POLMONITE DA VENTILATORE A RISCHIO PER L' ISOLAMENTO DI GRAM NEGATIVI MULTIRESISTENTI

E.1.1.1

Medical condition in easily understood language

PATIENTS AFFECTED BY VAP, LIKELY CAUSED BY GERMS THAT ARE RESISTANT TO COMMON ANTIBIOTICS

PAZIENTI AFFETTI DA POLMONITE DA VENTILATORE, VEROSIMILMENTE CAUSATA DA BATTERI RESISTENTI AI COMUNI ANTIBIOTICI

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10035701
E.1.2	Term	Pneumonia gram-negative bacterial NOS
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 demonstrate that colistin iv. is not inferior to meropenen in the
empirical treatment of VAP regarding to the primary end-point: 28-day
all-cause mortality.

• Dimostrare che la colistina non è inferiore al meropenem per il trattamento empirico delle VAP, per ciò che riguarda l’”end point” primario: la mortalità complessiva (“all cause”) a 28 giorni

E.2.2

Secondary objectives of the trial

-To demonstrate that colistin is not inferior to meropenen the empirical
treatment of VAP regarding efficacy:
oClinical treatment response in patients clinically evaluated.
oMicrobiological treatment response.
-To compare the safety profile of colistin vs meropenen in VAP, and
ecological impact.
oTo study the abilities of two different antibiotic regimens, used in the
clinical trial, to select changes in the intestinal microbiome of patients.
-To Describe the pharmacokinetics of colistin in patients affected by VAP

• Valutazione dell’efficacia clinica al termine del trattamentO
• Valutazione dell’efficacia microbiologica al termine del trattamento
• Valutazione del profilo di sicurezza. Tale valutazione verrà effettuata attraverso la raccolta ed immediata notifica di tutti gli eventi avversi osservati durante lo studio
• Valutazione della selezione di eventuali germi colonizzanti MDR
• Analisi dei meccanismi di resistenza agli antibiotici
• Valutazione del profilo farmacocinetico (AUC, Cmax, Tmax, Cmax/AUC)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age ≥ 18 years
-To be included, each patient must fulfill the following criteria:
1.Consecutive adults who had received mechanical ventilation in the ICU
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for at least 4 days.
2.Clinical and radiological criteria of VAP.
3.Suspicion of multi-resistant gram-negative bacillus as cause of the
VAP.
4.Clinical Pulmonary Infection Store (CPIS) > 6.
5.Respiratory secretion sample obtained from the respiratory tract by
means of bronchoscope with broncoalveolar washing (BAL) or bronchial
aspirates, both quantitatively processed obtained in the 24 h. previous to
the beginning of antimicrobial treatment of the study.
6.The women of childbearing age (not surgically sterilized and in the
period between menarche and 1 year after the menopause) must have a
negative test of pregnancy in urine at the time of recruitment.
7.The patient or his/her legal representative must sign a document of
informed consent approved by the Ethics Review Committee.

o età>18aa
o ventilazione meccanica in Terapia Intensiva da almeno 96 ore
o diagnosi clinico-radiologica di VAP
o ospedalizzazione >4 gg
o punteggio CPIS>6
o esame microbiologico quantitativo delle secrezioni respiratorie effettuato nelle 24 precedenti l’inizio del trattamento
o sospetto coinvolgimento di GNB-MDR
o acquisizione del consenso informato
o test di gravidanza negativo (per le donne in età fertile).

E.4

Principal exclusion criteria

-Renal insufficiency in substitute treatment.
-Corporal weight <40 kg or >150 kg.
-Patients currently included in another clinical trial.
-Refractory shock or another disease that, according to the researcher,
presents a life expectancy inferior to 48 hours, after the recruitment.
-Known allergy or hyper sensibility to meropenem or any excipients
-Known allergy or hyper sensibility to any carbapenem
-Serious hyper sensibility (anaphylactic reaction or serious skin
reaction) to any betalactam (peniciline or cephalosporins)
-Known allergy or hyper sensibility to colistine
-Colistin reduces pre-synaptic release of acetylcholine at the
neuromuscular junction; this is why it should not be administered in
patients with Miastenia Gravis.
-

o nota allergia o ipersensibilità ad uno dei due antibiotici in studio (inclusi tutti i betalattamici)
o insufficienza renale in trattamento sostitutivo
o peso corporeo<40kg />150Kg
o paziente già arruolato in un altro trial
o aspettativa di vita inferiore alle 48 ore dal momento dell’arruolamento (es. stato di shock non responsivo al trattamento con amine)
o Miastenia gravis

E.5 End points

E.5.1

Primary end point(s)

mortality

la mortalità complessiva (“all cause”) a 28 giorni.

E.5.1.1

Timepoint(s) of evaluation of this end point

28 dies

28 GIORNI

E.5.2

Secondary end point(s)

Evaluation of clinical treatment response will be classified as, Clinical cure, failure or recurrence at the end of the treatment.
oClinical cure is defined as complete resolution of all signs and
symptoms of pneumonia.
oFailure as persistence or progression of signs and symptoms.
oRecurrence, as recurrence of signs, symptoms and/or new radiographic
evidence of pneumonia after final treatment. (Attached as annex, CRD
with the variables to record in each visit of the trial).
-Evaluation of microbiological response will be classified as eradication,
failure or recurrence by the researcher at the end of the treatment.
oEradication is defined as eradication of the bacterium causing VAP
during the treatment.
oFailure as persistence of the bacterium causing VAP during the
treatment.
oRelapse is defined as the recurrence of signs, symptoms or new
radiographic evidences of pneumonia present in the last evaluation and
isolation of the initial pathogen.

• Dimostrare che la colistina non è inferiore al meropenem per il trattamento empirico delle VAP, in termini di efficacia:
o Risposta clinica al trattamento
o Risposta microbiologica al trattamento
• Confrontare il profilo di sicurezza dell’utilizzo della colistina vs meropenem e il relativo impatto ecologico:
o Valutazione dell’effetto dell’utilizzo di colistina e meropenem sulla selezione di resistenze nella flora residente intestinale.
• Descrivere il profilo farmacocinetico della colistina nei pazienti con VAP.

E.5.2.1

Timepoint(s) of evaluation of this end point

every visit until end of the trial

ogni visita fino alla fine del trial

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

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

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

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

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

Number of subjects for this age range:

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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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 2011-12-28.

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

farmacologicl coma

pz in sedazione farmacologica

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

400

F.4.2.2

In the whole clinical trial

400

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)

it is not different from the normal care of that condition

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

2012-08-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-12-23

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