Clinical Trials Register

Summary
EudraCT Number:	2016-002388-33
Sponsor's Protocol Code Number:	ZKSJ0086
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-08-15
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

Germany - BfArM

A.2

EudraCT number

2016-002388-33

A.3

Full title of the trial

Therapeutic drug monitoring (TDM) for personalized antibiotic treatment with piperacillin-tazobactam (PipTaz) in patients with febrile neutropenia after myelo-suppressive cytostatic chemotherapy

Therapeutisches Drug Monitoring (TDM) von Piperacillin bei Patienten mit Fieber in Neutropenie nach myelosuppressiver zytostatischer Chemotherapie

A.3.1

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

Measurement of the blood concentration of the antibiotic piperacillin and individual drug dosage in patients with febrile neutropenia after chemotherapy

Bestimmung der Konzentration des Antibiotikums Piperacillin im Blut bei Patienten mit Fieber in Neutropenie nach Chemotherapie mit individueller Dosisanpassung

A.3.2

Name or abbreviated title of the trial where available

Target-FN

A.4.1

Sponsor's protocol code number

ZKSJ0086

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	Friedrich-Schiller-University Jena
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	BMBF
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Jena University Hospital - Centre for Clinical Studies
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Salvador-Allende-Platz 27
B.5.3.2	Town/ city	Jena
B.5.3.3	Post code	07747
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4936419396652
B.5.5	Fax number	+4936419399969
B.5.6	E-mail	ZKS-Projektmangement@med.uni-jena.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Piperacillin/Tazobactam
D.3.2	Product code	Pip/Taz
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Piperacillin
D.3.9.1	CAS number	59703-84-3
D.3.9.3	Other descriptive name	PIPERACILLIN SODIUM
D.3.9.4	EV Substance Code	SUB03840MIG
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	4
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tazobactam
D.3.9.1	CAS number	89785-84-2
D.3.9.3	Other descriptive name	TAZOBACTAM SODIUM
D.3.9.4	EV Substance Code	SUB04682MIG
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	0,5
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

Patients with febrile neutropenia after myelo-suppressive chemotherapy treated with piperacillin/tazobactam

Patienten mit Fieber in Neutropenie nach myelo-suppressiver Chemotherapie, die mit Piperacillin/Tazobactam behandelt werden

E.1.1.1

Medical condition in easily understood language

Immunosuppressed patients with cancer and fever

Immunsupprimierte Krebs-Patienten mit Fieber

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

The primary goal of the study is to examine if and in which extent the effect of a dose adjusted administration of piperacillin/tazobactam after therapeutic drug monitoring has a benefit on a stable fever recovery without changing the anti infective therapy in patients with neutropenia after myelo-suppressive cytostatic chemotherapy

Das Primärziel der Studie soll feststellen, ob und inwieweit die dosisangepasste Gabe von Piperacillin/Tazobactam nach Therapeutic Drug Monitoring einen Vorteil hinsichtlich der stabilen Entfieberung ohne eine Umstellung der antiinfektiven Therapie bei Patienten in der Neutropeniephase nach myelosuppressiver zytostatischer Chemotherapie herbeiführen kann.

E.2.2

Secondary objectives of the trial

- 30 day mortality
- Infect associated 30 days mortality
- Duration and cumulative doses of antibiotic therapy of the current fever episode
- Number of dose adjustments/therapy cycle
- Duration of combination therapy with anti-infective in the current fever episode
- Days without antibiotics at hospital stay
- Need of intensive care unit
- Time spent in hospital
- Antibiotic therapy costs
- Occurrence of antibiotic resistant bacteria
- Pharmacokinetic / pharmacodynamic indices
- Days without antibiotics at stage of neutropenia
- Recovery of the infection
- Progression to SIRS/Sepsis
- Rate of superinfection with another pathogen
- Security (Side effects)

- 30-Tage Mortalität
- infektassoziierte 30 Tage-Mortalität
- Dauer und kumulative Dosis der Antibiotikatherapie der aktuellen Fieberepisode
- Anzahl Dosisanpassungen/Therapiezyklus
- Dauer der Kombinationstherapie mit Antiinfektiva in der aktuellen Fieberepisode
- antibiotikafreie Tage während des Krankenhausaufenthaltes
- Notwendigkeit eines Intensivstationsaufenthaltes
- Krankenhausverweildauer
- Kosten der Antibiotikatherapie
- Vorkommen von Antibiotika-resistenten Bakterien
- Pharmakokinetik (PK) / Pharmakodynamik (PD) - Indizes
- antibiotikafreie Tage während der Neutropeniephase
- Ausheilung der Infektion
- Progression in SIRS/Sepsis
- Rate Superinfektion mit einem anderen Erreger
- Sicherheit (Nebenwirkungen)

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

1. Biomarker, Version final 1, 01.08.2016
To evaluate serum-biomarker for predictive value of outcome of febrile neutropenia

2. Immunology, Version final, 01.08.2016
To evaluate changes in immune cells to predict outcome of febrile neutropenia

3. COST-Target-FN, Version final 1; 01.08.2016
To estimate additional costs caused by febrile neutropenia

1. Biomarker, Version final 1, 01.08.2016
Zur Evaluation von Serum-Biomarkern zur Outcome-Vorhersage der febrilen Neutropenie
2. Immunology, Version final, 01.08.2016
Zur Evaluation von Immunzellen zur Outcome-Vorhersage der febrilen Neutropenie
3. COST-Target-FN, Version final, 01.08.2016
Zur Abschätzung der zusätzlichen Kosten verursacht durch die febrile Neutropenie

E.3

Principal inclusion criteria

- Fever (temperature >38.3°C at one time or temperature >38.0°C twice in 2 hours) and existing neutropenia after myelo-suppressive cytostatic chemotherapy (leucocytes <1,0Gpt/l or netrophile granulocytes <0,5Gpt/l)
- Planned or started therapy with the antibiotic Piperacillin-Tazobactam
- Written consent of the Patient

- Fieber (definiert als Körpertemperatur einmalig >38,3°C oder zweimal >38,0°C inner-halb von 2 Stunden) und bestehende Neutropenie nach myelosuppressiver zytostatischer Chemotherapie (definiert als Leukozytenzahl <1,0Gpt/l bzw. neutrophile Granulozyten <0,5Gpt/l)
- geplante oder gestartete antimikrobielle Therapie mit Piperacillin-Tazobactam
- Schriftliche Einwilligung des Patienten

E.4

Principal exclusion criteria

- Age <18 years
- Pregnancy/breast feeding women
- Women in childbearing age, whithout women with following criteria:
o Post-menopausal (12 month normal amenorhoea or 6 month amenorhoea with FSH at serum >40mlU/ml)
o Postoperative (ovarectomy at both sides with or without hysterectomy)
o Regular use of a preventive measure
o Sexual abstinence
o Vasectomia of the partner
- Not able to give consent
- Known hypersensitivity against
o ß-Laktam antibiotica or other
o components oft he investigated substance (Pip/Taz)
- pretreatment with Pip/Taz >18g in the last 24h before randomisation
- if the patient is participating at other interventional clinical trials
- previous inclusion inTARGET-FN
- hepatic impairment (Child-Pugh C)
- Renal insufficiency (eGFR<40ml/min)
- Infection which needs specific anti-infective treatment (e.g. endocarditis or invasive fungal infection)
- Life expectancy <90 days due to other co-morbidities

- Alter < 18 Jahre
- Schwangerschaft / Stillzeit
- Frauen im gebärfähigen Alter, außer Frauen, die die folgenden Kriterien erfüllen:
o post-menopausal (12 Monate natürliche Amenorrhoe oder 6 Monate Amenorrhoe mit Serum-FSH > 40 mlU/ml)
o postoperativ (6 Wochen nach beidseitiger Ovarektomie mit oder ohne Hyster-ektomie)
o regelmäßige und korrekte Anwendung einer Verhütungsmethode mit Fehler¬quote < 1% pro Jahr
o sexuelle Enthaltsamkeit
o Vasektomie des Partners
- nicht bestehende Einwilligungsfähigkeit
- Anamnestisch bekannte Überempfindlichkeit gegen
o ß-Laktam Antibiotika oder gegen einen der sonstigen
o Bestandteile der Prüfsubstanz (Pip/Taz)
- Vorbehandlung mit Pip/Taz >18g innerhalb der letzten 24h vor Randomisierung
- Teilnahme des Patienten an einer anderen interventionellen klinischen Prüfung
- Vorherige Studienteilnahme (TARGET-FN)
- eingeschränkte Leberfunktion (Child-Pugh C)
- Niereninsuffizienz (eGFR<40ml/min)
- Infektion, die eine andere definierte antiinfektive Therapie erfordert (z.B. Endokarditis oder invasive Pilzinfektion)
- Lebenserwartung < 90 Tage aufgrund von Nebenerkrankungen

E.5 End points

E.5.1

Primary end point(s)

stable fever recovery (yes/no) defined as 5 consecutive days without fever without any changes in the antibacterial therapy. This proportion of patients without fever under TDM will be compared according to the proportion of the control group.

Stabile Entfieberung (ja/nein) definiert als 5 konsekutive fieberfreie Tage ohne Umstellung der antibakteriellen Therapie. Verglichen wird die Proportion fieberfreier Patienten unter TDM mit der entsprechenden Proportion unter der Kontrollbedingung.

E.5.1.1

Timepoint(s) of evaluation of this end point

Until the end of the therapy in accordance with the instructions of the treating physician or until 5 consecutive days without fever.

Bis Ende der Therapie nach Ermessen des behandelnden Arztes bzw. bis 5 konsekutive Tage ohne Fieber.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

During course of treatment with Pip / Taz and until day 30 or until discharge with a follow-up on day 30

Im Studienverlauf während der Therapie mit Pip/Taz und des Krankenhausaufenthaltes bis Tag 30 bzw. bis zur Entlassung und Follow-Up an Tag 30

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Vergleich von Standard-Therapie der Dosierung nach Fachinformation mit individueller Dosisanpassung

Comparison of standard therapy with dosage on prescription information with individual dose adjustm.

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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 Patient out (LPO)

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

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:

104

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

104

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

208

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)

No specific follow-up necessary. Within the present knowledge there is no evidence of the occurrence of late effects after treatment with the study medication

Keine spezifische Nachbetreuung nötig. Nach gegenwärtigem Kenntnisstand gibt es keinen Anhalt für das Auftreten von Spätfolgen nach einer Therapie mit der Prüfmedikation

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

2016-09-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-29

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-06-10

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