Clinical Trials Register

Summary
EudraCT Number:	2013-001997-18
Sponsor's Protocol Code Number:	ACHN-490-007
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:	2013-12-11
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

2013-001997-18

A.3

Full title of the trial

A Phase 3, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Plazomicin Compared with Colistin in Patients with Infection due to Carbapenem-Resistant Enterobacteriaceae (CRE)

Studio Clinico di Fase 3, Multicentrico, Randomizzato, in Aperto, per valutare l’Efficacia e la Sicurezza di Plazomicina comparata con Colistina in Pazienti con Infezione dovuta a Enterobatteriacei Resistenti ai Carbapenemi (CRE)

A.3.1

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

A Study of Plazomicin Compared with Colistin when combined with a second antibiotic (either meropenem or tigcycline) in the treatment of Patients with blood stream Infection (BSI) or nosocomial pneumonia due to Carbapenem-Resistant Enterobacteriaceae (CRE). Therapeutic Drug Managment (TDM) will be used to ensure that Plazomicin exposures lie within an acceptable range of the target mean steady-state area the curve
(AUC).

A.4.1

Sponsor's protocol code number

ACHN-490-007

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01970371

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	Achaogen, Inc.
B.1.3.4	Country	United States
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	Achaogen, Inc.
B.4.2	Country	United States
B.4.1	Name of organisation providing support	US Department of Health and Human Services, Biomedical Advanced Research and Development Authority (BARDA)
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Achaogen, Inc.
B.5.2	Functional name of contact point	Clinical Trials Registration Group
B.5.3	Address:
B.5.3.1	Street Address	7000 Shoreline Court, Suite 371
B.5.3.2	Town/ city	South San Francisco, CA
B.5.3.3	Post code	94080
B.5.3.4	Country	United States
B.5.4	Telephone number	+1650800-3636
B.5.5	Fax number	+1650434-3765
B.5.6	E-mail	clinical-trials@achaogen.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	Plazomicin
D.3.2	Product code	ACHN-490
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous drip use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	To be determined
D.3.9.1	CAS number	1380078-95-4
D.3.9.2	Current sponsor code	ACHN-490
D.3.9.3	Other descriptive name	NO ACTIVE SUBSTANCE
D.3.9.4	EV Substance Code	SUB49728
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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: 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	Colistimethate for Injection
D.2.1.1.2	Name of the Marketing Authorisation holder	X-Gen Pharmaceuticals
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Colistimethate sodium
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 drip use (Noncurrent)
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	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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

Bloodstream infections (BSI) and nosocomial pneumonia due to carbapenem-resistant Enterobacteriaceae (CRE)

Trattamento delle infezioni sistemiche e della polmonite nosocomiale causata da Enterobatteriacee Resistenti ai Carbapenemi (CRE)

E.1.1.1

Medical condition in easily understood language

Infection due to Carbapenem Resistant Enterobacteriaceae (CRE)

Infezioni causate da Enterobatteriacee Resistenti ai Carbapenemi (CRE)

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	10018657
E.1.2	Term	Gram-negative bacterial infection NOS
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

The primary objective of this study is to demonstrate the superiority, in terms of all-cause mortality at 28 days, of a plazomicin-based regimen compared with a colistin-based regimen in the treatment of BSI or nosocomial pneumonia due to CRE.

L’obiettivo primario dello studio è dimostrare la superiorità, in termini di mortalità per tutte le cause a 28 giorni, di un regime a base di plazomicina rispetto a un regime a base di colistina nel trattamento delle BSI o della polmonite nosocomiale causata da CRE.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are:
- to compare additional efficacy outcomes and safety of a plazomicin-based regimen with a colistin-based regimen in the treatment of BSI or nosocomial pneumonia due to CRE
- to evaluate the PK of intravenous (IV) plazomicin in patients with CRE infection.
- to evaluate the clinical utility of TDM for plazomicin dose adjustment

-Confrontare gli esiti di efficacia aggiuntivi e la sicurezza di un regime a base di plazomicina con un regime a base di colistina nel trattamento di BSI o polmonite nosocomiale causata da CRE
-Valutare la farmacocinetica (PK) della plazomicina per via endovenosa (EV) in pazienti trattati con plazomicina
-Valutare l’utilità clinica del monitoraggio terapeutico del farmaco (Therapeutic Drug Management, TDM) per l’aggiustamento della dose di plazomicina

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Full Title: "Evaluation of the ARK™ Plazomicin Assay for the
Determination of Plazomicin Plasma Concentrations in the Phase 3
Clinical Study ACHN-490-007"
Date: 01Oct2013
Version: Original
Objective: "The objective of this study is to assess the correlation of the
plasma concentrations of plazomicin as measured by the ARK Plazomicin
Assay and the reference method, LC/MS/MS in patient plasma samples
collected prospectively from study ACHN-490-007."

Titolo: "Valutazione del test Plazomincina ARK™ per la determinazione delle concentrazioni plasmatiche di plazomicina nello studio clinico di fase III ACHN-490-007"
Data: 1 Ottobre 2013
Versione: originale
Obiettivo: valutare la correlazione tra concentrazioni plasmatiche di plazomicina misurate con il test ARK™ e quelle misurate con il metodo di riferimento LC/MS/MS nei campioni plasmatici raccolti ai pazienti partecipanti allo studio ACHN-490-007.

E.3

Principal inclusion criteria

•Male and female patients age 18 to 85 years, inclusive
•APACHE II score between 15 and 30, inclusive
•Presumptive identification of a carbapenem resistant-member of the Enterobacteriaceae as defined by rapid testing methods from an appropriate culture specimen ≤ 72 hours prior to study OR definitive identification of a carbapenem resistant-member of the Enterobacteriaceae as defined by local lab identification and susceptibility testing from an appropriate culture specimen ≤ 72 hours prior to study entry
•Diagnosis of BSI as defined by at least one positive blood culture meeting the above microbiological criteria associated with at least one of the following signs of infection: Fever or hypothermia; New onset arterial hypotension; Elevated total peripheral white blood cell (WBC) count > 10,000 cells/mm3, > 15% immature neutrophils (band forms) regardless of total peripheral WBC count, or leukopenia with total WBC count < 4500 cells/mm3
•Or, diagnosis of nosocomial pneumonia in a patient on mechanical ventilation, as defined by lower respiratory tract or pleural fluid culture meeting the above defined microbiological criteria, and associated with the following clinical signs of pneumonia: A chest X-ray or computed tomography (CT) scan with findings consistent with a diagnosis of pneumonia; Worsening gas exchange; Purulent deep respiratory specimen; AND one of the following: Elevated total peripheral WBC count > 10,000 cells/mm3, > 15% immature neutrophils (band forms) regardless of total peripheral WBC count, or leukopenia with total WBC count < 4500 cells/mm3; Fever or hypothermia

•Pazienti di ambo i sessi di età compresa fra i 18 e gli 85 anni inclusi
•Punteggio APACHE II compreso tra 15 e 30 inclusi
•Presuntiva identificazione di presenza di un membro della famiglia Enterobacteriaceae resistente ai carbapenemi, come definito da un rapido test di laboratorio, su un campione raccolto ≤ 72 ore prima della randomizzazione
oppure, definitiva identificazione di un membro della famiglia Enterobacteriaceae resistente ai carbapenemi come definita dal laboratorio locale su un campione raccolto ≤ 72 ore prima della randomizzazione
•Diagnosi di BSI definita da almeno un’emocoltura positiva che soddisfa i criteri microbiologici precedenti e associata ad almeno uno dei seguenti segni di infezione: febbre o ipotermia, nuova insorgenza di ipotensione arteriosa, aumentata conta totale dei leucociti (white blood cell, WBC) nel sangue periferico > 10.000 cellule/mm3, neutrofili immaturi > 15% (forme a banda) a prescindere dalla WBC totale nel sangue periferico o leucopenia con WBC totale < 4500 cellule/mm3.
•Polmonite nosocomiale in un paziente in ventilazione meccanica, come definito dalla coltura di campione del tratto respiratorio inferiore o del fluido pleurico che soddisfa i criteri microbiologici definiti precedentemente e associata ai seguenti segni clinici di polmonite misurati entro 24 ore prima o dopo il momento nel quale è stata ottenuta una coltura positiva:
-Una radiografia toracica o una tomografia computerizzata (TAC) con risultati compatibili con una diagnosi di polmonite
-Peggioramento dello scambio gassoso
-Campioni respiratori profondi purulenti •
-E almeno una delle situazioni seguenti:
aumentata conta WBC totale nel sangue periferico > 10.000 cellule/mm3, neutrofili immaturi > 15% (forme a banda) a prescindere dalla conta WBC totale nel sangue periferico o leucopenia con WBC totale < 4500 cellule/mm3, Febbre o ipotermia.

E.4

Principal exclusion criteria

•Patient has received more than 72 hours of empirical therapy
•Infection with CRE isolate with reduced susceptibilty to colistin
•Presence of refractory septic shock
•Objective clinical evidence for any of the following clinical syndromes that necessitates antimicrobial therapy for greater than 14 days: endovascular infection including endocarditis, osteomyelitis, prosthetic joint infection, meningitis and/or other central nervous system infections
•Objective clinical evidence of infectious involvement of intravascular material not intended to be removed within 4 calendar days of initial positive culture
•Pulmonary disease that precludes evaluation of therapeutic response including known bronchial obstruction or a history of post-obstructive pneumonia, tracheobronchitis, primary lung cancer or malignancies metastatic to the lung, bronchiectasis, known or suspected active tuberculosis
•Patients with severe liver disease (Child-Pugh score of Class C)
•Patients in acute renal failure or on intermittent hemodialysis (IHD) at the time of screening
•Patients with a history of seizure disorder and who are receiving anti-convulsive therapy
•Diagnosis of myasthenia gravis or any other neuromuscular disorder

•Il paziente ha ricevuto più di 72 ore di terapia empirica
•Infezione con isolato di CRE con ridotta suscettibilità alla colistina
•Presenza di shock settico refrattario
•Evidenze cliniche oggettive di una qualsiasi delle seguenti sindromi cliniche che richiedono terapia antimicrobica per più di 14 giorni: infezione endovascolare comprese endocardite, osteomielite, infezione di articolazioni protesiche, meningite e/o altre infezioni del sistema nervoso centrale
•Evidenze cliniche oggettive di coinvolgimento infettivo di materiale endovascolare per i quali non è prevista la rimozione entro 4 giorni di calendario dalla coltura positiva iniziale
•Patologie polmonari che precludono la valutazione della risposta terapeutica comprese: nota ostruzione bronchiale o un’anamnesi di polmonite post-ostruttiva, tracheobronchite, carcinoma polmonare primario o neoplasie metastatiche al polmone, bronchiettasie, nota o sospetta tubercolosi attiva.
•Pazienti con grave malattia epatica (punteggio Child-Pugh di classe C)
•Pazienti con insufficienza renale acuta o pazienti in emodialisi intermittente (intermittente hemodialysis, IHD) al momento dello screening
•Pazienti con un’anamnesi di disturbo convulsivo e che ricevono terapia anticonvulsiva
•Diagnosi di miastenia gravis o di qualsiasi altro disturbo neuromuscolare

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is all-cause mortality

L’endpoint di efficacia primario è la mortalità per tutte le cause

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days

28 giorni

E.5.2

Secondary end point(s)

Secondary efficacy parameters include time to death through Day 28; all-cause mortality at 14 days after randomization; assessment of clinical response (as determined by the adjudication committee) at end of treatment, test of cure, and end of study; overall incidence of adverse events; plazomicin PK parameters; and frequency with which the use of TDM leads to a dose adjustment of plazomicin.

Gli endpoint di efficacia secondari includono il tempo al decesso fino a 28 giorni, la mortalità per tutte le cause 14 giorni dopo la randomizzazione e la valutazione della risposta clinica (determinata da un comitato di aggiudicazione) alla fine del trattamento ed alla fine dello studio; incidenza di AE; parametri PK per la plazomicina; la frequenza con la quale l’uso di TDM porta a un aggiustamento della dose.

E.5.2.1

Timepoint(s) of evaluation of this end point

14 and 28 days

14 e 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

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

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

Brazil

Israel

Mexico

Ukraine

Korea, Republic of

Taiwan

Turkey

United States

Colombia

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

Last follow-up call for the last patient

Ultima telefonata di follow up dell'ultimo paziente dello studio

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:

179

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

179

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

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

200

F.4.2.2

In the whole clinical trial

358

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)

Both of the study treatments (trial drug, plazomicin and comparator, colistin) are intended for the short term treatment of bacterial infection. If the treatment fails, the investigators are expected to use an appropriate alternative standard of care treatment.

Ambedue i trattamenti (test e comparator) sono utilizzati come trattamento a breve terine della infezioni batteriche. Se il trattamento fallisce, lo sperimentatore userà in alternativa un' appropriata 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

2014-01-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-08-01

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IMP with orphan designation in the indication
Orphan Designation Number:
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