Clinical Trials Register

Summary
EudraCT Number:	2012-004006-96
Sponsor's Protocol Code Number:	D4281C00001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-01-11
Trial results	View 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

2012-004006-96

A.3

Full title of the trial

A Phase III, Randomized, Multicentre, Double-blind, Double-dummy, Parallel-group Comparative Study to Determine the Efficacy, Safety And Tolerability of Ceftazidime-Avibactam Versus Meropenem in the Treatment of Nosocomial Pneumonia Including Ventilator-Associated Pneumonia in Hospitalized Adults

Studio comparativo di fase III, randomizzato, multicentrico, doppio cieco, doubble-dummy, a gruppi paralleli, per determinare l'efficacia, la sicurezza e la tollerabilita' di Ceftazimide-Avibactam (CAZ-AVI) rispetto a Meropenem nel trattamento di pazienti adulti ospedalizzati con polmonite nosocomiale inclusa polmonite associata a ventilazione meccanica (VAP).

A.3.1

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

A study comparing Ceftazidime-Avibactam versus Meropenem in hospitalized adults with nosocomial pneumonia

Studio di confronto dell'assocazione ceftazidima-Avibactam verso Meropenem in adulti ospedalizzati con polmonite nosocomiale.

A.3.2

Name or abbreviated title of the trial where available

REPROVE (CAZ-AVI)

CAZ-AVI

A.4.1

Sponsor's protocol code number

D4281C00001

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	ASTRAZENECA
B.1.3.4	Country	Italy
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	Astrazeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Astrazeneca
B.5.2	Functional name of contact point	Information Center
B.5.3	Address:
B.5.3.1	Street Address	....
B.5.3.2	Town/ city	.....
B.5.3.3	Post code	......
B.5.3.4	Country	United States
B.5.4	Telephone number	.....
B.5.5	Fax number	.......
B.5.6	E-mail	information.center@astrazeneca.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	No
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	ceftazidime avibactam
D.3.2	Product code	CAZ-AVI
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	CEFTAZIDIME PENTAHYDRATE
D.3.9.1	CAS number	78439-06-2
D.3.9.4	EV Substance Code	SUB01134MIG
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	2000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AVIBACTAM
D.3.9.1	CAS number	1192500-31-4
D.3.9.2	Current sponsor code	AVIBACTAM
D.3.9.3	Other descriptive name	AVIBACTAM
D.3.9.4	EV Substance Code	SUB72111
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	500
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	Meronem
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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 TRIHYDRATE
D.3.9.1	CAS number	119478-56-7
D.3.9.2	Current sponsor code	MEROPENEM
D.3.9.4	EV Substance Code	SUB21617
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	1000
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
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

nosocomial pneumonia (NP), ventilator-associated pneumonia (VAP)

polmonite nocosomiale (NP) inclusa polmonite associata a ventilazione meccanica (VAP)

E.1.1.1

Medical condition in easily understood language

lung infection

Infezione Polmonare

E.1.1.2

Therapeutic area

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

MedDRA Classification

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 assess the non-inferiority of ceftazidime-avibactam compared to meropenem with respect to clinical cure at the test of cure visit in patients in the clinically modified intent-to-treat population and patients in the clinically evaluable population

• Valutare la non-inferiorità della associazione ceftazidime- avibactam (CAZ-AVI) verso meropenem rispetto alla guarigione clinica valutata mediante verifica della negativizzazione della coltura batterica (visita al 21 ° giorno dalla randomizzazione) nei pazienti inseriti nella intent-to-treat clinicamente modificata (cMITT) e nella totalità dei pazienti clinicamente valutabili (CE).

E.2.2

Secondary objectives of the trial

To determine the efficacy of CAZ-AVI compared to meropenem with respect to the clinical cure at end of treatment in the clinically modified intent-to-treat, clinically evaluable, microbiologically modified intent-totreat, microbiologically evaluable and extended microbiologically evaluable populations and at test of cure in the microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable populations.

• Determinare l'efficacia di CAZ-AVI verso meropenem per quanto riguarda la guarigione clinica a fine trattamento (EoT) nei pazienti inseriti nella intent-to-treat clinicamente modificata (cMITT), nella totalità dei pazienti clinicamente valutabili (CE), nei pazienti inseriti nella intent-to-treat microbiologicamente modificata (mMITT), nei pazienti microbiologicamente valutabili (ME) e nella popolazione estesa di pazienti microbiologicamente valutabili (extended-ME) & alla visita di valutazione della guarigione clinica (ToC) nei pazienti inseriti nella intent-to-treat microbiologicamente modificata (mMITT), nei pazienti microbiologicamente valutabili (ME) e nella popolazione estesa di pazienti microbiologicamente valutabili (extended-ME)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• 18 to 90 years of age inclusive • Females can participate if surgically sterile or completed menopause; if able to have children, must have negative serum pregnancy test, agree not to attempt pregnancy and use acceptable contraception while receiving study therapy and for 1 week after • Onset of symptoms ≥48 hours after admission or <7 days after discharge from an inpatient acute or chronic care facility • New or worsening infiltrate on chest X-ray obtained within 48 hours prior to randomization • At least 1 of the following systemic signs: - Fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C) - White blood cell count >10,000 cells/mm3, or White blood cell count<4500 cells/mm3, or >15% band forms

• Adulti tra i 18 e i 90 anni di età.
• Le pazienti di sesso femminile possono partecipare allo studio se chirurgicamente sterili o se in menopausa completa; se potenzialmente fertili devono avere il test di gravidanza sierico negativo, essere d’accordo a non pianificare gravidanze e utilizzare un metodo contraccettivo accettabile per tutto il periodo di trattamento con il farmaco di studio e per la settimana successiva.
• Insorgenza dei sintomi oltre le 48 ore dal ricovero o entro 7 giorni dalla dimissione dalla struttura ospedaliera.
• Nuovo infiltrato o infiltrato in peggioramento ai raggi X al torace entro 48 ore dalla randomizzazione
• Almeno una delle seguenti manifestazioni sistemiche:
- Febbre (temperatura > 38°C) o ipotermia (temperatura rettale/centrale <35 °C)
- Conta dei globuli bianchi (WBC) > 10000 cellule/mm3 o conta WBC < 4500 cellule/mm3 o >15% cellule a banda

E.4

Principal exclusion criteria

• Pulmonary disease that precludes evaluation of therapeutic response (including, but not limited to, lung cancer, active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary infection or recent pulmonary embolism). • Patients with lung abscess, pleural empyema or post obstructive pneumonia. • Patients with an estimated creatinine clearance <16ml/min by Cockcroft Gault formula or patients expected to require haemodialysis or other renal support while on study therapy. • Acute hepatitis in the prior 6 months, cirrhosis, acute hepatic failure or acute decompensation of chronic hepatic failure. • Patients receiving hemodialysis or peritoneal dialysis.

• Patologie polmonari che precludono la valutazione della risposta terapeutica (inclusi, ma non solo, tumore polmonare, tubercolosi attiva, fibrosi cistica, malattia granulomatosa, infezione polmonare fungina o recente embolia polmonare)
• Pazienti con ascessi polmonari, empiema pleurico o polmonite post ostruttiva.
• Pazienti con una clearance della creatinina stimata <16 ml/min secondo la formula di Cockcroft Gault o pazienti per i quali si prevede una necessaria emodialisi o altri supporti renali durante il trattamento di studio.
• Epatite acuta nei 6 mesi precedenti, cirrosi, insufficienza epatica acuta o scompenso acuto da insufficienza epatica cronica.
• Pazienti in emodialisi o dialisi peritoneale.

E.5 End points

E.5.1

Primary end point(s)

The proportion of patients with clinical cure in the clinically modified intent-to-treat and clinically evaluable analysis sets (co-primary analyses)

. La percentuale di pazienti con guarigione clinica nella popolazione di pazienti cMITT e CE (analisi co-primaria).

E.5.1.1

Timepoint(s) of evaluation of this end point

at test of cure visit

alla Visita ''Test of Cure''

E.5.2

Secondary end point(s)

• The proportion of patients with clinical cure in the microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets • The proportion of patients with clinical cure in clinically modified intent-to-treat, clinically evaluable, microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets • The proportion of patients with a favorable per-patient microbiologic response in microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets • The proportion of favorable per-pathogen microbiologic responses in microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets • The proportion of favorable per-pathogen microbiologic responses by minimum inhibitory concentration categories in microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets • The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime in clinically evaluable, clinically modified intent to-treat, microbiologically evaluable analysis sets • Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime in microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets • The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime in microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets • The proportion of patients with death due to any cause (all-cause mortality) in the clinically evaluable, clinically modified intent-to-treat and microbiologically modified intent-to-treat analysis sets

 La percentuale di pazienti con guarigione clinica nella popolazione di pazienti mMITT, ME e extended ME.  La percentuale di pazienti con guarigione clinica nella popolazione di pazienti cMITT e CE mMITT, ME ed extended ME  La percentuale di pazienti con una risposta microbiologica per-paziente favorevole in pazienti mMITT, ME ed extended-ME (derivata da risposta microbiologica per patogeno).  La percentuale di pazienti con una risposta microbiologica per-patogeno favorevole in pazienti mMITT, ME ed extended-ME  La percentuale di risposte microbiologiche per-patogeno favorevole in pazienti mMITT, ME ed extended-ME  La percentuale di risposte microbiologiche per-patogeno favorevole alla minima concentrazione inibente (minimum inhibitory concentration (MIC)) nelle popolazioni di pazienti mMITT, ME e extended-ME  La percentuale di pazienti con giuarigione clinica nei pazienti con patogeni resistenti alla ceftazidima nelle popolazioni CE, cMITT e ME  La percentuale di pazienti con risposta microbiologica per-paziente favorevole nei pazienti con patogeni resistenti alla ceftazidima nelle popolazioni mMITT, ME e extended ME (derivata da risposta microbiologica per patogeno)  La percentuale di risposte microbiologiche per-patogeno favorevole nei pazienti con patogeni resistenti alla ceftazidima nelle popolazioni mMITT, ME e extended ME  La percentuale di pazienti morti per qualsiasi causa (all cause mortality) nella popolazione CE, cMITT e mMITT

E.5.2.1

Timepoint(s) of evaluation of this end point

at end of treatment visit and test of cure visit

alla visita di fine trattamento e alla visita ''Test of Cure''

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

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

Yes

E.6.13.1

Other scope of the trial description

Microbiology cultures

Colture microbiologiche

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

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

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

Argentina

Brazil

Chile

China

India

Japan

Mexico

Peru

Russian Federation

South Africa

Turkey

Ukraine

Vietnam

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:

961

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

553

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

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 may require intubation with subsequent sedation and
therefore not capable of providing consent.

I pazienti possono necessitare di intubazione con sedazione e quindi possono non essere in grado di fornire il consenso.

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

479

F.4.2.2

In the whole clinical trial

1494

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

2013-02-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-03-12

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

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