Clinical Trials Register

Summary
EudraCT Number:	2012-004819-31
Sponsor's Protocol Code Number:	1787/12
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:	2012-10-25
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

2012-004819-31

A.3

Full title of the trial

Multicenter open-label RCT to compare colistin alone vs. colistin plus meropenem

Trial randomizzato controllato multicentrico per la valutazione dell'efficacia di colistina rispetto a colistina e meropenem nel trattamento delle infezioni severe da batteri gram negativi multi resistenti

A.3.1

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

Multicenter open-label RCT to compare colistin alone vs. colistin plus meropenem

Trial randomizzato controllato multicentrico per la valutazione dell’efficacia di colistina rispetto a colistina e meropenem nel trattamento delle infezioni severe da batteri gram negativi multi resistenti

A.3.2

Name or abbreviated title of the trial where available

AIDA

A.4.1

Sponsor's protocol code number

1787/12

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	RADBOUD UNIVERSITY NIJMEGEN MEDICAL CENTER
B.1.3.4	Country	Netherlands
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	Comunità 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	Ist. di malattie infettive
B.5.3	Address:
B.5.3.1	Street Address	Lgo 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	0630154945
B.5.6	E-mail	etacconelli@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	MERREM 500*IM FL 500MG+F 2ML
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 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	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	6
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	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	COLISTIN
D.3.9.1	CAS number	1066-17-7
D.3.9.4	EV Substance Code	SUB01429MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	9000000
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	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	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	COLISTIN
D.3.9.1	CAS number	1066-17-7
D.3.9.4	EV Substance Code	SUB01429MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	9000000
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

INFECTIONS DUE TO CARBAPENEM RESISTENT GRAM NEGATIVE BACTERIA

INFEZIONE DA BATTERI GRAM NEGATIVI RESISTENTI AI CARBAPENEMICI

E.1.1.1

Medical condition in easily understood language

INFECTIONS DUE TO CARBAPENEM RESISTENT GRAM NEGATIVE BACTERIA

INFEZIONE DA BATTERI GRAM NEGATIVI RESISTENTI AI CARBAPENEMICI

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	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10004047
E.1.2	Term	Bacterial infections 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

Clinical success, defined as a composite of all of the following, all measured at 14 days:
• Patient alive
• Systolic blood pressure >90 mmHg without need for vasopressor support
• Stable or improved SOFA score, define as:
o for baseline SOFA ≥ 3: a decrease of at least 30%;
o for baseline SOFA <3: stable or decreased SOFA score
• For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved
• For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile

Miglioramento clinico a 14 giorni, definito come:
• paziente in vita E
• pressione arteriosa sistolica > 90 mmHg, senza necessità di sostegno farmacologico tramite vasopressore E
• punteggio SOFA stabile o in miglioramento, definito come segue: per SOFA al baseline ≥ 3 una riduzione di almeno il 30%; per SOFA al baseline <3 punteggio stabile o ridotto; E
• per i pazienti con HAP / VAP, rapporto PaO2/FiO2 stabile o in miglioramento; OPPURE
• per i pazienti con batteriemia, emocolture negative per il batterio target a 14 giorni, nel caso in cui il paziente sia ancora febbrile.

E.2.2

Secondary objectives of the trial

• 14 and 28-day all-cause mortality
• Clinical success, as defined above, but any modification to the antibiotic treatment not permitted by protocol will also be considered as failure. This will include any change or addition of antibiotics not permitted by study protocol. Early discontinuation of antibiotic treatment will not be considered as failure.
• Time to defervescence, defined as time to reach a temperature of <38°C with no recurrence for 3 days

• mortalità (qualsiasi causa) a 14 e 28 giorni;
• successo clinico come definito precedentemente, ma senza alcuna modifiche di trattamento. In questo caso, l’aggiunta di antibiotici non consentiti dal protocollo di studio verrà considerata come fallimento clinico. Invece, l’interruzione precoce di terapia non verrà considerata fallimento;
• tempo di defervescenza, definito come il tempo per raggiungere una temperatura <38 ° C senza recidiva per 3 giorni consecutivi;

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

We will include adult inpatients ≥18 years with clinically-significant infections as defined below caused by carbapenem-resistant and colistin-susceptible Gram-negative bacteria: Acinetobacter sp., P. aeruginosa or any Enterobacteriaceae (including but not limited to K. pneumoniae, E. coli and Enterobacter sp.). Patient recruitment will occur only after microbiological documentation and susceptibility testing. Patients will be included within 96 hours of the time the index culture was taken, regardless of the antibiotic treatment administered during this time period.

Pazienti adulti (≥ 18 anni) con infezioni clinicamente significative, in base alle definizioni di seguito riportate, causate da batteri gram-negativi (Acinetobacter sp, P. aeruginosa o qualsiasi Enterobacteriaceae) carbapenemico-resistenti (CR) e colistina-sensibili. L'arruolamento dei pazienti avrà luogo solo dopo la conferma dell’isolamento tramite esami microbiologici e test di sensibilità, che dovrà avvenire entro 96 ore dalla raccolta del campione, e indipendentemente dal trattamento antibiotico somministrato durante questo periodo di tempo.

E.4

Principal exclusion criteria

• Previous inclusion in the trial. Patients will be included in the RCT only once for the first identified episode of infection
• Pregnant women
• Epilepsy or prior seizures
• Known allergy to colistin or a carbapenem

• inclusione precedente: i pazienti saranno inclusi nello studio una sola volta corrispondente al primo episodio di infezione identificato;
• stato di gravidanza;
• storia di epilessia o convulsioni;
• allergia nota a colistina o carbapenemici;

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

14 days

14 giorni

E.5.2

Secondary end point(s)

14 and 28-day all-cause mortality
• Clinical success, as defined above, but any modification to the antibiotic treatment not permitted by protocol will also be considered as failure. This will include any change or addition of antibiotics not permitted by study protocol. Early discontinuation of antibiotic treatment will not be considered as failure.
• Time to defervescence, defined as time to reach a temperature of <38°C with no recurrence for 3 days

mortalità (qualsiasi causa) a 14 e 28 giorni;
• successo clinico come definito precedentemente, ma senza alcuna modifiche di trattamento. In questo caso, l’aggiunta di antibiotici non consentiti dal protocollo di studio verrà considerata come fallimento clinico. Invece, l’interruzione precoce di terapia non verrà considerata fallimento;
• tempo di defervescenza, definito come il tempo per raggiungere una temperatura <38 ° C senza recidiva per 3 giorni consecutivi;

E.5.2.1

Timepoint(s) of evaluation of this end point

14-28 days

14-28 giorni

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

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Israel

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

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:

162

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

162

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 2012-10-25.

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 in intensive care unit

Soggetti in rianimazione

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

264

F.4.2.2

In the whole clinical trial

324

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)

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

2013-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-18

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

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