Clinical Trials Register

Summary
EudraCT Number:	2012-000726-21
Sponsor's Protocol Code Number:	D4280C00006
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:	2013-02-26
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

2012-000726-21

A.3

Full title of the trial

An Open-Label, Randomized, Multicenter, Phase III Study of Ceftazidime Avibactam (CAZ-AVI, formerly CAZ104) and Best Available Therapy for the Treatment of Infections Due to Ceftazidime Resistant Gram Negative Pathogens

Uno studio di fase III multicentrico, randomizzato e in aperto su ceftazidima avibactam (CAZ-AVI, in precedenza CAZ104) e sulla migliore terapia disponibile per il trattamento di infezioni dovute a patogeni gram-negativi resistenti a ceftazidima.

A.3.1

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

Ceftazidime-Avibactam for the treatment of infections due to Ceftazidime Resistant Pathogens

Ceftazidima avibactam nel trattamento di infezioni dovute a patogeni ceftazidima resistenti.

A.4.1

Sponsor's protocol code number

D4280C00006

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 AB
B.1.3.4	Country	Sweden
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 Centre
B.5.3	Address:
B.5.3.1	Street Address	Room Tatnall Bldg, 1800 Concord Pike, PO Box 15437
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	DE 19850-5437
B.5.3.4	Country	United States
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 concentrate 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	1192491-61-4
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	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	Metronidazole
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter Healthcare Ltd
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.3.1	Product name	metronidazole
D.3.4	Pharmaceutical form	Solution for injection/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	METRONIDAZOLE
D.3.9.1	CAS number	443-48-1
D.3.9.4	EV Substance Code	SUB08922MIG
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: 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	Meronem
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca
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	Meropenem
D.3.4	Pharmaceutical form	Powder for solution for injection/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.3.9.4	EV Substance Code	SUB21617
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	1
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: 4
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	Colomycin Injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Forest Laboratories UK Limited
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.3.1	Product name	Colomycin
D.3.4	Pharmaceutical form	Powder for solution for injection/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	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	IU international unit(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	2000000
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: 5
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	Tygacil
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	tigecycline
D.3.4	Pharmaceutical form	Powder for solution for injection/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	TIGECYCLINE
D.3.9.1	CAS number	220620-09-7
D.3.9.4	EV Substance Code	SUB16467MIG
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	50
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: 6
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	Imipenem/Cilastatin 500 mg/500 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira UK Limited
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.3.1	Product name	Imipenem/Cilistatin
D.3.4	Pharmaceutical form	Powder for solution for injection/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	IMIPENEM MONOHYDRATE
D.3.9.1	CAS number	74431-23-5
D.3.9.4	EV Substance Code	SUB21472
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	530
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CILASTATIN SODIUM
D.3.9.1	CAS number	81129-83-1
D.3.9.4	EV Substance Code	SUB01295MIG
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	530
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: 7
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	Doribax
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	doripenem
D.3.4	Pharmaceutical form	Powder for solution for injection/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	DORIPENEM
D.3.9.1	CAS number	148016-81-3
D.3.9.4	EV Substance Code	SUB22196
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.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

cUTI, Complicated Urinary Tract Infection, cIAI, Complicated intra-abdominal infection

cUTI infezioni complicate del tratto urinario; cIAI, infezioni complicate intraddominali.

E.1.1.1

Medical condition in easily understood language

Urinary Tract Infection, abdominal infection

Infezioni complicate del tratto urinario; infezioni complicate intraddominali.

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	LLT
E.1.2	Classification code	10046574
E.1.2	Term	Urinary tract infection NOS
E.1.2	System Organ Class	100000004862

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	10056570
E.1.2	Term	Intra-abdominal infection
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

To estimate the per-patient clinical response to ceftazidime-avibactam and best available therapy at TOC in the treatment of selected serious infections caused by ceftazidime-resistant Gram negative pathogens.

• Valutare la risposta clinica per paziente alla ceftazidima avibactam (CAZ-AVI, già CAZ104) e la migliore terapia disponibile (BAT) alla Prova di cura (TOC) nel trattamento di una selezione di gravi infezioni dovute a patogeni gram-negativi resistenti a ceftazidima

E.2.2

Secondary objectives of the trial

•To further evaluate the clinical response to CAZ-AVI and BAT at different visits and in patient subgroups (including entry diagnosis, pathogen, resistance mechanism, and previously failed treatment class)
•To estimate the microbiological response to CAZ-AVI and BAT in the treatment of selected serious infections caused by ceftazidime-resistant Gram-negative pathogens
•To evaluate the reasons for treatment change and/or discontinuation for CAZ-AVI and BAT
•To estimate the 28-day, all-cause mortality among patients treated with CAZ-AVI and BAT
•To evaluate the safety and tolerability profile of CAZ-AVI and BAT for the treatment of selected serious infections caused by ceftazidime-resistant Gram-negative pathogens
•To evaluate the pharmacokinetics (PK) of the individual components of CAZ-AVI in this population with selected serious infections, and to characterize the relationship between the PK and clinical and microbiological response for CAZ-AVI

•Valutare ulteriormente la risposta clinica a CAZ-AVI e BAT in occasione di visite differenti e in diversi sottogruppi di pazienti (compresi diagnosi di ingresso, patogeno, meccanismo di resistenza e classe del precedente trattamento senza esito positivo)
•Valutare la risposta microbiologica a CAZ-AVI e BAT nel trattamento di una selezione di infezioni gravi causate da patogeni gram-negativi resistenti a ceftazidima
•Valutare i motivi per il cambio e/o l'interruzione del trattamento per CAZ-AVI e BAT
•Valutare la mortalità a 28 giorni dovuta a qualsiasi causa tra i pazienti trattati con CAZ-AVI e BAT
•Valutare la tollerabilità e la sicurezza di CAZ-AVI e BAT per il trattamento di una selezione di infezioni gravi causate da patogeni gram-negativi resistenti a ceftazidima
•Valutare la farmacocinetica (PK) dei singoli componenti di CAZ-AVI in questa popolazione con selezione di infezioni gravi e caratterizzare il rapporto tra PK e risposta clinica e microbiologica per CAZ-AVI

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.≥18 and ≤90 years of age
2.Female patients can participate if they are surgically sterile or completed menopause or females capable of having children and agree not to attempt pregnancy while receiving IV study therapy and for a period of 28 days after last infusion
3.Patient has a ceftazidime-resistant Gram negative pathogen that was isolated from an appropriate culture within 5 days prior to study entry (ie, the study-qualifying culture), which was determined to be the causative agent of the entry infection

1) L'età dei pazienti deve essere ≥ 18 e < 90 anni.
2) le pazienti femmine possono partecipare devono soddisfare i criteri elencati di seguito se sono state sterilizzate chirurgicamente o si trovano in post-menopausa o se potenzialmente fertili acconsentono a usare metodi contraccettivi, durante il trattamento e per almeno 28 giorni dopo l’ultima infusione della terapia sperimentale.
3) Il paziente presenta un agente patogeno Gram-negativo ceftazidima-resistente, isolato da una coltura appropriata nei 5 giorni precedenti l’ingresso nello studio (cioè la coltura di qualifica per lo studio) e identificato quale agente che causa l’infezione di ammissione.

E.4

Principal exclusion criteria

1.Patient has an APACHE II score >30
2.Patient has an infection due to Gram negative pathogen that is unlikely to respond to CAZ-AVI treatment (eg, Acinetobacter spp., Stenotrophomonas spp.)
3.Patient is receiving hemodialysis or peritoneal dialysis or had a renal transplant
4.Patient is immunocompromised
5.Patient has a rapidly progressive or terminal illness with a high risk of mortality due to any cause, including acute hepatic failure, respiratory failure or severe septic shock

1. Il paziente ha un punteggio APACHE II >30
2. Il paziente presenta un’infezione causata da agente batterico Gram-negativo, che con tutta probabilità non risponderà al trattamento CAZ-AVI (cioè Acinetobacter e sottospecie, Stenotrophomonas e sottospecie)
3. Il paziente viene sottoposto a emodialisi o dialisi peritoneale o trapianto renale
4. Il paziente è immunocompromesso.
5. Il paziente ha una patologia in rapida progressione o terminale, comprese insufficienza epatica acuta o insufficienza respiratoria con elevato rischio di mortalità per altre cause

E.5 End points

E.5.1

Primary end point(s)

The proportion of patients with clinical cure at the Test of Cure visit in the modified intent-to-treat analysis set.

La proporzione di pazienti con guarigione clinica alla visita del trattamento di guarigione

E.5.1.1

Timepoint(s) of evaluation of this end point

7-10 days after last infusion

Da 7 a 10 giorni dopo l'ultima infusione

E.5.2

Secondary end point(s)

1)The proportion of patients with clinical cure in the modified intent to treat analysis set.
2)The proportion of patients with clinical cure in the extended microbiologically evaluable analysis set.
3)The proportion of patients with clinical cure by pathogen (eg, E. coli, Klebsiella spp., Pseudomonas aeruginosa) in the modified intent to treat analysis set.
4)The proportion of patients with clinical cure by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the modified intent to treat analysis set.
5)The proportion of patients with clinical cure by entry diagnosis (complicated intra-abdominal infection/complicated urinary tract infection) in the modified intent to treat analysis set.
6)The proportion of patients with clinical cure by pathogen (eg, E. coli, Klebsiella spp., Pseudomonas aeruginosa) in the extended microbiologically evaluable analysis set.
7)The proportion of patients with clinical sure by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the extended microbiologically evaluable analysis set.
8)The proportion of patients with clinical cure by entry diagnosis (complicated intra-abdominal infection/complicated urinary tract infection) in the extended microbiologically evaluable analysis set.
9)The proportion of patients with clinical cure by previously failed treatment class (eg, quinolone, β lactam/β lactamase inhibitor, third- or fourth generation cephalosporin, carbapenem), in the modified intent to treat analysis set.
10)The proportion of patients with clinical cure by previously failed treatment class (eg, quinolone, β lactam/β lactamase inhibitor, third- or fourth generation cephalosporin, carbapenem) in the extended microbiologically evaluable analysis set.
11)The proportion of patients with favorable per-pathogen microbiological response in the modified intent to treat analysis set
12)The proportion of patients with favorable per-pathogen microbiological response in the extended microbiologically evaluable analysis set.
13)The proportion of patients with a favorable per-patient microbiological response in the modified intent to treat analysis set.
14)The proportion of patients with a favorable per-patient microbiological response in the extended microbiologically evaluable analysis set.
15)The proportion of patients with a favorable microbiological response by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the modified intent to treat analysis set.
16)The proportion of patients with a favorable microbiological response by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the extended microbiologically evaluable analysis set.
17)The proportion of favorable per-pathogen microbiologic response by minimum inhibitory concentration in the modified intent to treat analysis set.
18)The proportion of favorable per-pathogen microbiologic response by minimum inhibitory concentration in the extended microbiologically evaluable analysis set.
19)The reasons for treatment change and/or discontinuation in the modified intent to treat analysis set.
20)The 28-day mortality rate in the microbiological modified intent to treat analysis set.
21)The 28-day mortality rate in the extended microbiological evaluable analysis set.
22)The safety and tolerability by incidence and severity of adverse events and serious adverse events, vital signs, clinical laboratory tests, ECGs and physical exams.
23)Pharmacokinetics: maximum concentration (Cmax), minimum concentration, area under plasma concentration time curve at study state and terminal half-life.

1) La proporzione di pazienti con guarigione clinica nel gruppo
di analisi Intent-to-Treat modificato.
2) La proporzione di pazienti con guarigione clinica nel
gruppo esteso di analisi microbiologicamente valutabili .
3) La proporzione di pazienti con guarigione clinica in base a patogeni (per es. E. Coli,
Klebsiella spp., Pseudomonas aeruginosa) nel gruppo di analisi Intent-to-Treat
modificato.
4) la proporzione di pazienti con guarigione clinica in base a meccanismo di resistenza
(ad es. produttori di Klebsiella pneumoniae carbapenemasi,
produttori di β-lattamasi a spettro esteso) nel gruppo di analisi Intent-to-Treat
modificato.
5) La proporzione di pazienti con guarigione clinica in base alla diagnosi d'ingresso
(infezione intra-addominale complicata/infezione del tratto urinario complicata)
nel gruppo di analisi Intent-to-Treat modificato.
6) La proporzione di pazienti con guarigione clinica in base a patogeni (ad es. E. Coli,
Klebsiella spp., Pseudomonas aeruginosa) nel gruppo esteso di analisi
microbiologicamente valutabili .
7) La proporzione di pazienti con guarigione clinica in base a meccanismo di resistenza
(ad es. produttori di Klebsiella pneumoniae carbapenemasi,
produttori di β-lattamasi a spettro esteso) nel gruppo esteso di analisi microbiologicamente
valutabili .
8) La proporzione di pazienti con guarigione clinica in base alla diagnosi d'ingresso
(infezione intra-addominale complicata/infezione del tratto urinario complicata)
nel gruppo estesodi analisi microbiologicamente valutabili.
9) La proporzione di pazienti con guarigione clinica in base a classe di trattamento precedentemente non riuscita
(ad es. chinoloni, inibitori di β-lattame/β-lattamasi, cefalosporina di terza
o quarta generazione, carbapenemi), nel gruppo
di analisi Intent-to-Treat modificato.
10) La proporzione di pazienti con guarigione clinica in base a classe di trattamento precedentemente non riuscita
(ad es. chinoloni, inibitori di β-lattame/β-lattamasi, cefalosporina di terza o
quarta generazione, carbapenemi) nel gruppo esteso di analisi
microbiologicamente valutabili .
11) La proporzione di pazienti con risposta microbiologica per agente patogeno favorevole
nel gruppo di analisi Intent-to-Treat modificato.
12) La proporzione di pazienti con risposta microbiologica per agente patogeno favorevole
nel gruppo esteso di analisi microbiologicamente valutabili.
13) La proporzione di pazienti con risposta microbiologica per agente patogeno favorevole
nel gruppo di analisi Intent-to-Treat modificato.
14) La proporzione di pazienti con risposta microbiologica per agente patogeno favorevole
nel gruppo esteso di analisi microbiologicamente valutabili.
15) La proporzione di pazienti con risposta microbiologica
per meccanismo di resistenza favorevole (ad es. produttori di Klebsiella pneumoniae carbapenemasi, produttori di β-lattamasi a spettro esteso) nel gruppo di analisi
Intent-to-Treat modificato.
16) La proporzione di pazienti con risposta microbiologica
per meccanismo di resistenza favorevole (ad es. produttori di Klebsiella pneumoniae carbapenemasi,
produttori di β-lattamasi a spettro esteso) nel gruppo esteso di analisi
microbiologicamente valutabili .
17) La proporzione di risposta microbiologica per agente patogeno favorevole in base alla
concentrazione minima di inibitore nel gruppo di analisi Intent-to-Treat
modificato.
18) La proporzione di risposta microbiologica per agente patogeno favorevole in base alla
concentrazione minima di inibitore nel gruppo esteso di analisi microbiologicamente
valutabili .
19) Le ragioni per il cambio di trattamento e/o discontinuità nel
gruppo di analisi Intent-to-Treat modificato.
20) Il tasso di mortalità al giorno 28 nel gruppo di analisi Intent-to-Treat modificato.
21) Il tasso di mortalità al giorno 28 nel gruppo di analisi esteso microbiologicamente valutabili.
22) La sicurezza e tollerabilità in base all'incidenza e severità di eventi avversi
e gravi eventi avversi, segni vitali, test clinici di laboratorio,
ECG ed esami fisici.
23) Farmacocinetica: concentrazione massima (Cmax), concentrazione minima, area sotto la curva di concentrazione plasmatica-tempo
allo stato stazionario e all'emivita terminale.

E.5.2.1

Timepoint(s) of evaluation of this end point

(1, 2, 10-14, 17, 18) Within 24 hours after last infusion of study therapy, 21-35 days after randomization and 28-32 days after randomization
3-9, At 7-10,15,16 days after last infusion of study therapy
(19) Study duration [Day 1 through last follow up visit (up to 35 days)]
(20, 21) At 28 days after randomization
(22)At study duration (from screening visit (Day-1) through last follow up visit (up to 35 days)]
(23) At anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug

(1, 2, 10-14, 17, 18) entro 24 ore dopo l'ultima infusione della terapia dello studio,
da 21 a 35 giorni dopo la randomizzazione e da 28 a 32 giorni dopo la randomizzazione
(3-9) da 7 a -10 giorni, 15, 16 giorni dopo l'ultima infusione della terapia dello studio
(19) durata dello studio [dal giorno 1 fino all'ultima visita di follow-up (per un massimo di 35 giorni)]
(20, 21) a 28 giorni dopo la randomizzazione
(22) per la durata dello studio [(dalla visita di screening (giorno 1) fino all'ultima visita di
follow-up (per un massimo di 35 giorni)]
(23) in qualsiasi momento entro 15 minuti prima o dopo l'interruzione dell'assunzione del farmaco dello studio, in qualsiasi momento tra 30 e 90 minuti dopo l'interruzione dell'assunzione del farmaco ...., Vedere protocollo.

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

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

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

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

Australia

Brazil

Canada

Chile

China

India

Israel

Japan

Korea, Republic of

Mexico

Peru

Philippines

Russian Federation

South Africa

Taiwan

Turkey

Ukraine

United States

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:

256

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

144

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

F.3.3.6

Subjects incapable of giving consent personally

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

230

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)

Standard of care

Terapia standard

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

2013-03-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-24

P. End of Trial
P.	End of Trial Status	Completed

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Orphan Designation Number:
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