Clinical Trials Register

Summary
EudraCT Number:	2011-005722-21
Sponsor's Protocol Code Number:	D4280C00004
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-10-09
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2011-005722-21

A.3

Full title of the trial

A Phase III, Randomized, Multicenter, Double-Blind, Double Dummy, Parallel Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime-Avibactam (CAZ-AVI, formerly CAZ104) Versus Doripenem Followed by Appropriate Oral Therapy in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, With a Gram Negative Pathogen in Hospitalized Adults

Wieloośrodkowe, randomizowane, prowadzone w grupach równoległych metodą podwójnie ślepej i podwójnie pozorowanej próby porównawcze badanie fazy III oceniające skuteczność, bezpieczeństwo i tolerancję stosowania ceftazydymu-awibaktamu (CAZ-AVI, poprzednia nazwa: CAZ104) w porównaniu z doripenemem, z następczym leczeniem doustnym powikłanych zakażeń układu moczowego, w tym ostrego odmiedniczkowego zapalenia nerek, wywołanych patogenem Gram ujemnym u dorosłych wymagających hospitalizacji

A.3.1

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

Compare Ceftazidime-Avibactam vs Doripenem Followed by Oral Therapy for hospitalized adults with complicated UTIs

A.4.1

Sponsor's protocol code number

D4280C00004

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.5.4	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 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	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	Belgium
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 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	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.IMP: 3
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	Ciproxin
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer plc, Bayer Schering Pharma
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	Ciprofloxacin
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	85721-33-1
D.3.9.3	Other descriptive name	CIPROFLOXACIN
D.3.9.4	EV Substance Code	SUB07470MIG
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: 4
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	Septrin Forte
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen Pharma Trading Limited
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Sulfamethoxazole/Trimethoprim
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SULFAMETHOXAZOLE
D.3.9.1	CAS number	723-46-6
D.3.9.4	EV Substance Code	SUB10711MIG
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	800
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TRIMETHOPRIM
D.3.9.1	CAS number	738-70-5
D.3.9.4	EV Substance Code	SUB11310MIG
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	160
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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 injection/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

Complicated Urinary Tract Infections (cUTIs)

Powikłane zakażenie układu moczowego (pZUM)

E.1.1.1

Medical condition in easily understood language

Urinary Tract Infection

Zakażenie układu moczowego

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 noninferiority of ceftazidime-avibactam compared with doripenem with respect to symptomatic resolution of UTI-specific symptoms and resolution of, or improvement in, flank pain based on the patient-reported symptom assessment

Ocena co najmniej równoważności ceftazydymu-awibaktamu w porównaniu z doripenemem pod względem następujących równorzędnych głównych punktów końcowych w zmodyfikowanym zbiorze do analizy zdefiniowanym w oparciu o zamiar leczenia, dla którego dostępne są dane mikrobiologiczne:
Ustąpienie objawów (lub powrót do stanu sprzed choroby) w przypadku objawów swoistych dla ZUM, za wyjątkiem bólu w okolicy lędźwiowej (częstość/nagłe parcie/bolesne oddawanie moczu/ból okolicy nadłonowej) oraz ustąpienie lub zmniejszenie objawów dla bólu w okolicy lędźwiowej na podstawie samooceny odpowiedzi objawów przez pacjenta w czasie wizyty Dzień 5.
Dla każdego pacjenta eradykacja mikrobiologiczna i ustąpienie objawów (lub powrót do stanu sprzed choroby) w przypadku wszystkich objawów swoistych dla ZUM (częstość/nagłe parcie/bolesne oddawanie moczu/ból okolicy nadłonowej/ból w okolicy lędźwiowej) na podstawie samooceny odpowiedzi objawów przez pacjenta w czasie wizyty dotyczącej analizy wyleczeń.

E.2.2

Secondary objectives of the trial

•To deter. the efficacy(Ef) of CAZ-AVI compared w/ dori wrt the per pt & per-pathogen MR at the EoIVT,ToC,& LFU visits in pts who are in the mmITT,ME,& eME analysis sets(AS)
•To deter. the Ef of CAZ-AVI compared to dori wrt the symptomatic resolution of UTI-specific symptoms based on pt-reported symptom assessment at ToC, & LFU visits in mmITT AS
•To deter. the Ef of CAZ-AVI compared w/ dori wrt the investigator-determined CC at the EoIVT,ToC,& LFU visits in pts who are in the mmITT,ME,eME,& CE AS
•To eval the Ef of CAZ-AVI vs dori in pathogens resistant to ceftazidime
•To comp the time to 1st defervescence of CAZ-AVI vs dori in pts who are on IV study therapy & who have fever at study entry in the mmITT,ME,eME,& CE AS
•To eval the safety & toler. profile of CAZ-AVI compared w/ dori in the tx of pts w/ a cUTI in the safety AS
•To eval the pk of the ind. components of CAZ-AVI(avibactam & ceftazidime)
•To eval CAZ-AVI exposure & the antimicrobial response relationship

•Określenie skuteczności produktu CAZ AVI w porównaniu z doripenemem pod względem odpowiedzi mikrobiologicznej dla każdego pacjenta w czasie wizyty dotyczącej zakończenia leczenia dożylnego [EOT (IV)], TOC i późnej wizyty kontrolnej (LFU)
•Określenie skuteczności preparatu CAZ AVI w porównaniu z doripenemem pod względem ustąpienia objawów (lub powrotu do stanu sprzed choroby) w przypadku wszystkich objawów swoistych dla ZUM (nadmierna częstość/nagłe parcie/bolesne oddawanie moczu/ból okolicy nadłonowej/ból w okolicy lędźwiowej) na podstawie samooceny odpowiedzi objawów przez pacjenta w czasie wizyt TOC i LFU
•Określenie skuteczności preparatu CAZ AVI w porównaniu z doripenemem pod względem odpowiedzi mikrobiologicznej dla każdego patogenu w czasie wizyty EOT (IV), TOC i LFU u pacjentów w zbiorze do analizy mMITT, ME i poszerzonym zbiorze ME.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.18 to 90 years of age inclusive
2.Female patient is authorized to participate in this clinical study if she has been surgically sterilized or postmenopausal for at least 1 year orher sexual partner has had a vasectomy and must be willing, during treatment and for at least 7 days after last dose of IV study therapy, to practice highly effective methods of birth control
3.Has pyuria with >/= 10 WBCs and has a positive urine culture within 48 hours of enrollment containing >/=10 to the fifth CFU/ml of a recognized uropathogen known to be susceptible to IV study therapy (CAZ-AVI and doripenem)
4.Demonstrates either acute pyelonephritis or complicated lower UTI without pyelonephritis

1.Pacjent musi być w wieku od 18 do 90 lat włączenie.
2.Kobiety mogą wziąć udział w badaniu, jeżeli spełnią następujące kryteria: pacjentka została poddana chirurgicznej sterylizacji lub znajduje się w okresie pomenopauzalnym od przynajmniej 1 roku lub jej partner przeszedł zabieg wasektomii i wyraża zgodę na stosowanie wysoce skutecznych metod kontroli urodzin podczas otrzymywania badanego leczenia IV i przez okres co najmniej 7 dni od zakończenia przyjmowania badanego leczenia IV.
3.Pacjent choruje na ropomocz określony jako ≥10 białych krwinek w polu widzenia w próbce moczu pobranej ze środkowego strumienia lub z cewnika, w standardowym badaniu osadu moczu, lub ≥10 białych krwinek/ mm3 w nieodwirowanym moczu.
4.U pacjenta występuje ostre odmiedniczkowe zapalenie nerek lub powikłane zakażenie dolnego odcinka układu moczowego bez odmiedniczkowego zapalenia nerek

E.4

Principal exclusion criteria

1.Urine pathogen is a Gram-positive pathogen or a uropathogen resistant to CAZ-AVI or doripenem
2.Patient's urine culture at study entry isolates more than 2 microorganisms regardless of colony count or patient has a confirmed fungal UTI
3.Patient is receiving hemodialysis or peritoneal dialysis or had a renal transplant
4.Patient is immunocompromised.
5.Patient is considered unlikely to survive the 6- to 8-week study period or have a rapidly progressive or terminal illness, including septic shock that is associated with a high risk of mortality

1.W przypadku, gdy dostępny będzie wynik posiewu moczu, przynajmniej 1 Gram-ujemny uropatogen będzie odporny na preparat CAZ-AVI lub doripenem.
2.W przypadku, gdy dostępny będzie wynik posiewu moczu, posiew moczu pacjenta przy włączeniu do badania będzie izolował więcej niż 2 mikroorganizmy niezależnie od liczebności kolonii lub u pacjenta zostanie potwierdzone grzybicze zakażenie układu moczowego.
3.Pacjent otrzymuje hemodializę lub dializę otrzewnową lub u pacjenta wykonano przeszczep nerki.
4.U pacjenta występuje upośledzenie odporności
5.Uważa się za mało prawdopodobne, że pacjent przeżyje 6-8 tygodniowy okres badania albo u pacjenta wystąpiła gwałtowna progresja lub nieuleczalna choroba, w tym wstrząs septyczny, który jest związany z wysokim ryzkiem śmiertelności.

E.5 End points

E.5.1

Primary end point(s)

•The proportion of patients with resolved (or return to premorbid) UTI symptoms except flank pain and resolution or improvement in flank pain based on patient-reported symptom assessment response at Day 5 visit. Timeframe: Day 5 after study drug start
•The proportion of patients with a per patient microbiological eradication and resolution (or return to premorbid) of all UTI-specified symptoms based on patient-reported symptom assessment response. Timeframe: 21 to 25 days after study drug start

•Odsetek pacjentów, u których stwierdzono ustąpienie objawów (lub powrót do stanu sprzed choroby) w przypadku objawów swoistych dla ZUM na podstawie samooceny odpowiedzi objawów przez pacjenta w czasie wizyty w 5. dniu. Rama czasowa: dzień 5 od rozpoczęcia badanego leczenia
•Odsetek pacjentów, u których stwierdzono eradykację mikrobiologiczną oraz ustąpienie objawów w przypadku wszystkich objawów swoistych dla ZUM na podstawie samooceny odpowiedzi objawów przez pacjenta. Rama czasowa: 21 do 25 dni od rozpoczęcia badanego leczenia.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary Outcome measure 1 - Day 5 after start of study drug
Primary Outcome measure 2 - Day 21-25 after start of study drug

1. Pomiar wyniku pierwszorzędowego – 5. dzień od rozpoczęcia przyjmowania leku badanego
2. Pomiar wyniku pierwszorzędowego – 21. do 25. dzień po rozpoczęciu przyjmowania leku badanego

E.5.2

Secondary end point(s)

•The proportion of pts w/ a favorable per pt MR in the mmITT analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after study drug start(SDS)
•The proportion of pts w/ a favorable per pt MR in the ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after SDS
•The proportion of pts w/ a favorable per pt MR in the extended ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after SDS
•The proportion of pts w/ resolution (or return to premorbid) of all UTI-specific symptoms based on the pt-reported symptom assessment response in the mmITT analysis set. Outcome measured at the following timepoints: 21-25 days & 45-52 days after SDS
•The proportion of favorable per-pathogen MR in the mmITT analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after study drug start
•The proportion of favorable per-pathogen MR in the ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the start of study drug(SoSD)
•The proportion of favorable per-pathogen MR in the extended ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD
•The proportion of pts w/ an investigator-determined CC in the mmITT analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD
•The proportion of pts w/ an investigator-determined CC in the ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD
•The proportion of pts w/ an investigator-determined CC in the extended ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21 ~ 25 days & 45 ~ 52 days after the SoSD
•The proportion of pts w/ an investigator-determined CC in the CE analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD
•The favorable per pathogen MR by categories of minimum inhibitory concentration in the mmITT analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD
•The favorable per pathogen MR by categories of minimum inhibitory concentration in the ME analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25days & 45-52 days after the SoSD
•The favorable per pathogen MR by categories of minimum inhibitory concentration in the extended ME analysis set. Outcome measured at the following timepoints: 24 hrs after completion of study drug, 21-25 days & 45-52 days after the SoSD
•The proportion of pts w/ favorable investigator clinical response assessment in pts infected w/ a ceftazidime resistant pathogen in the mmITT analysis set. Outcome measured at the following timepoint: 21-25 days after study drug start
•The proportion of pts w/ an investigator-determined CC in pts infected w/ a ceftazidime resistant pathogen in the ME analysis set. Outcome measured at the following timepoint: 21-25 days after study drug start
•The proportion of pts w/ an investigator-determined CC in pts infected w/ a ceftazidime resistant pathogen in the extended ME analysis set. Outcome measured at the following timepoint: 21-25 days after study drug start
•The proportion of pts w/ favorable per-pt MR for pts infected w/ a ceftazidime resistant pathogen in the mmITT analysis set. Outcome measured at the following timepoint: 21-25 days after SDS
•The proportion of pts w/ favorable per-pt MR for pts infected w/ a ceftazidime resistant pathogen in the ME analysis set. Timeframe: 21-25 days after study drug start
•The proportion of pts w/ favorable per-pt MR for pts infected w/ a ceftazidime resistant pathogen in the extended ME analysis set. Timeframe: 21-25 days after study drug start
•The proportion of pts w/ symptomatic resolution (defined in the coprimary variables) for pts infected w/ a ceftazidime resistant pathogen in the mmITT analysis set. Outcome measured at the following timepoint: Day 5 & 21-25 days after study drug start
•The time to 1st defervescence while on IV study therapy in pts in the mmITT, ME, extended ME, and CE analysis sets who have fever at study entry. Timeframe: any time after start of study drug to end of IV study therapy
•Evaluation of the pk of the individual components of CAZ-AVI (avibactam & ceftazidime)
•The safety & tolerability by incidence & severity of adverse events & serious adverse events, vital signs, clinical laboratory tests, ECGs & physical exams. Outcome measured at the following timepoints: study duration (screening visit (Day -1) through last follow up visit (up to 52 days)

-Odsetek pacjentów z korzystną odpowiedzią mikrobiologiczną dla każdego pacjenta w zbiorze do analizy mMITT. Ramy czasowe: w ciągu 24 godzin od ostatniego dnia przyjmowania leku badanego, 21-25 oraz 45-52 dni po rozpoczęciu przyjmowania leku badanego
-Odsetek pacjentów, u których stwierdzono ustąpienie objawów w przypadku wszystkich objawów swoistych dla ZUM na podstawie samooceny odpowiedzi objawów przez pacjenta. Ramy czasowe: 21-25 oraz 45-52 dni po rozpoczęciu przyjmowania leku badanego
-Odsetek pacjentów z korzystną odpowiedzią mikrobiologiczną dla każdego patogenu w zbiorze do analizy mMITT, ME i poszerzonym zbiorze ME. Ramy czasowe: w ciągu 24 godzin od ostatniego dnia przyjmowania leku badanego, 21-25 oraz 45-52 dni po rozpoczęciu przyjmowania leku badanego
-Odsetek pacjentów ze wskaźnikiem wyleczeń klinicznych określanym przez badacza w zbiorze do analizy mMITT. Ramy czasowe: w ciągu 24 godzin od ostatniego dnia przyjmowania leku badanego, 21-25 oraz 45-52 dni po rozpoczęciu przyjmowania leku badanego
-Odsetek pacjentów z korzystną odpowiedzią mikrobiologiczną dla każdego patogenu względem kategorii najniższego stężenia hamującego (MIC) w zbiorze do analizy mMITT. Ramy czasowe: w ciągu 24 godzin od ostatniego dnia przyjmowania leku badanego, 21-25 oraz 45-52 dni po rozpoczęciu przyjmowania leku badanego
-Odsetek pacjentów z korzystną oceną odpowiedzi klinicznej przez badacza w zbiorze do analizy mMITT. Ramy czasowe: w ciągu 21 do 25 od rozpoczęcia przyjmowania leku badanego.
-Czas do stwierdzenia pierwszego ustąpienia gorączki w czasie przyjmowania leków stosowanych w badaniu podawanych dożylnie u pacjentów w zbiorze do analizy mMITT, u których stwierdzano gorączkę w czasie włączenia do badania. Ramy czasowe: w każdym momencie od rozpoczęcia przyjmowania leku badanego do zakończenia przyjmowania leków badanych podawanych dożylnie.
-Bezpieczeństwo i tolerancja będą oceniane na podstawie częstości i ciężkości zdarzeń niepożądanych (AE) i ciężkich zdarzeń niepożądanych (SAE), pomiaru parametrów życiowych, laboratoryjnych badań klinicznych, EKG oraz badania fizykalnego. Ramy czasowe: w okresie trwania badania (od wizyty przesiewowej do czasu ostatniej wizyty kontrolnej (do 50 dni))
-PK: stężenie minimalne/maksymalne / obszar pod krzywą stężenia leku w stanie równowagi oraz w okresie półtrwania. Ramy czasowe: 15 minut przed rozpoczęciem lub po zakończeniu podawania leku badanego, w okresie pomiędzy 30 a 90 minut oraz 300 i 360 minut po zakończeniu podawania leku badanego.

E.5.2.1

Timepoint(s) of evaluation of this end point

Listed in E.5.2

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Microbiology cultures

kultury mikrobiologiczne

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

Bulgaria

Canada

Croatia

Czech Republic

France

Germany

Greece

India

Israel

Italy

Korea, Republic of

Mexico

Peru

Poland

Romania

Russian Federation

Spain

Taiwan

Ukraine

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

The end of the study is defined as the last visit of the last patient participating in the study.

Ostatnia wizyta ostatniego pacjenta uczestniczącego w badaniu

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:

328

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

176

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

250

F.4.2.2

In the whole clinical trial

504

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

Zgodnie ze standardami opieki medycznej

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

2012-12-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-08-18

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