Clinical Trials Register

Summary
EudraCT Number:	2017-004281-10
Sponsor's Protocol Code Number:	PT/11/2017
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-12-06
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

Denmark - DHMA

A.2

EudraCT number

2017-004281-10

A.3

Full title of the trial

Pharmacokinetics and pharmacodynamics of Piperacillin-Tazobactam (PT) in pediatric oncology patients with fever and neutropenia

Farmakokinetiske og farmakodynamiske studier af Piperacillin-Tazobactam (PT) til behandling af børn med cytostatika-induceret febril sygdom

A.3.1

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

Investigation on how children with cancer and fever metabolise the antibiotic, Piperacillin-tazobactam (PT) for the purpose of optimising the antibiotic treatment in this group of patients.

Undersøgelse af, hvordan børn med kræft og feber omsætter et antibiotikum, Piperacillin-tazobactam (PT) med henblik på at optimere antibiotikabehandlingen hos denne gruppe

A.4.1

Sponsor's protocol code number

PT/11/2017

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	Department of Pediatric oncology, Aarhus University hospital
B.1.3.4	Country	Denmark
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	Danish childhood Cancer foundation
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Pediatric Oncology, Aarhus University Hospital, Skejby
B.5.2	Functional name of contact point	Sabine Frølich Maarbjerg
B.5.3	Address:
B.5.3.1	Street Address	Palle Juul-Jensens Boulevard 99
B.5.3.2	Town/ city	Aarhus N
B.5.3.3	Post code	8200
B.5.3.4	Country	Denmark
B.5.6	E-mail	sabine.froelich@midt.rm.dk

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.2.1.1.1	Trade name	Tazocin
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Denmark
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Tazocin: Piperacillin/Tazobactam
D.3.4	Pharmaceutical form	Concentrate and solvent 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	Tazobactam
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Piperacillin
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.3.11 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

Pediatric oncology patients with fever

Børn med cancer og kemoinduceret feber

E.1.1.1

Medical condition in easily understood language

Children with cancer and fever

Børn med kræft og feber under kemoterapi

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10051312
E.1.2	Term	Neutropenic fever
E.1.2	System Organ Class	100000004851

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10076734
E.1.2	Term	Chemotherapy induced neutropenia
E.1.2	System Organ Class	100000004851

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007050
E.1.2	Term	Cancer
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of the PhD study is to optimize the dosing regimen of empiric Tazocin treatment in pediatric oncology patients with fever.

In sub-study 3, the main purpose is to determine whether continuous Tazocin infusion provide antibiotic concentrations associated with maximal activity in relation to MIC-levels. Furthermore, we want to find the most optimal dosing schedule.

Det overordnede formål med dette PhD-projekt er at optimere dosis og indgiftsmetode for den empiriske Tazocin-behandling til børneonkologiske patienter ud fra farmakokinetiske og – dynamiske studier af Tazocin hos denne gruppe børn.

Det primære formål med delstudie 3 er at undersøge om kontinuerlig infusion af Tazocin giver en mere optimal antibiotikaprofil sammenlignet med det nuværende bolusregime. Vi ønsker at bestemme den dosis af Tazocin givet som kontinuerlig infusion efter en bolusindgift af stoffet, der resulterer i den mest optimale antibiotikaprofil i relation til MIC-værdierne.

E.2.2

Secondary objectives of the trial

We conducted a clinical trial to describe the pharmacokinetics of Tazocin in the present Tazocin bolus regimen in children with cancer and fever (sub-study 2). Our preliminary results show that the children have Tazocin concentrations below the target range in above 50% of the time. The results also indicate that continuous Tazocin infusion would be more optimal.
Therefore, in sub-study 3, we want to investigate whether continuous infusion of Tazocin can optimize the antibiotic treatment in this group of children by providing a more stable Tazocin level above MIC.

Vi har udført et studie (delstudie 2) omkring farmakokinetik for det nuværende standardregime hvor Tazocin indgives som bolusinfusion 3 gange i døgnet til børn med cancer og feber. Vores foreløbige resultater fra delstudie 2 (fra 56 feberepisoder) peger på, at den nuværende behandling med bolusindgift af Tazocin ikke er optimal. Børnene har kun anbitiotikakoncentrationer i det optimale niveau i under halvdelen af tiden. I stedet tyder data på, at kontinuerlig infusion af Tazocin på infusionspumpe over 24 timer vil medføre en mere optimal antibiotika-behandling.
I delstudie 3 vil vi derfor undersøge, om kontinuerlig infusion giver en mere optimal antibiotikadækning med Tazocin-koncentrationer over MIC.

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

The PhD study is divided into three sub-studies. With this application we apply for approval of the third sub-study. The second sub-study has already been approved and we will soon finish the data collection in this sub-study.

Sub-study 1

Title:"Determination of Minimal Inhibitory Concentration (MIC) of Tazocin in the most pathogenic bacteria in pediatric oncology patients" Version 3, 02-19-2016

Objective: Determination of MIC-levels of the most pathogenic bacteria in blood cultures from children with cancer and febrile neutropenia who have been admitted to the department of Pediatric Oncology, Aarhus University Hospital from 2000-2015. The MIC-levels will form the basis of the target Tazocin concentration I the two subsequent studies.

Sub-study 2

Title: Pharmacokinetics of Piperacillin-Tazobactam (Tazocin) in the present bolus regimen in children with cancer and fever

Objective: We want to determine whether the present Tazocin dosing program achieves concentrations associated with maximal antibiotic activity in relation to MIC-levels. We want to perform pharmacokinetic analysis and make a population model.

PhD studiet består af tre delstudier. Med denne ansøgning søger vi om godkendelse af det tredje delstudie. Delstudie 2 er allerede blevet godkendt og vi nærmer os afslutningen af dataindsamlingen.

Delstudie 1
Titel: "Minimal Inhibitorisk Concentration (MIC) for isolater af patogene bakteriestammer dyrket fra blodet hos børn med cancer", version 3, 2016.02.19

Formål: Formålet med første delstudie er bestemmelse af MIC-niveauer for de mest patogene bakteriestammer, der er dyrket fra blodet hos børn med cancer og febril neutropeni. På baggrund af MIC-værdierne vil vi undersøge, hvilken koncentration af Tazocin i blodet, man skal stile mod for at opnå maksimal effekt af stoffet hos børn i behandling med empirisk Tazocin.

Delstudie 2

Titel: Farmakokinetik af bolusinjektion af Piperacillin-tazobactam (Tazocin) til børn med cancer og feber

Formål: I det andet delstudie er formålet at analysere, om det nuværende behandlingsregime med bolusinjektion af Tazocin 100 mg/kg 3 gange i døgnet er forbundet med en hensigtsmæssig farmakokinetisk profil af stoffet.
Det primære outcome i dette delstudie er at undersøge, hvor stor en andel af børnene, der opnår Tazocin-koncentrationer > 4 x MIC i > 50% af doseringsintervallet eller > 1 x MIC i 100 % af tiden

E.3

Principal inclusion criteria

- Children with cancer and fever who get admitted to the paediatric oncology department and start Tazocin treatment
- 6 months - 18 years
- All cancer types can be included
- A child can participate a maximum of 3 times in case of several fever episodes

- Børn med cancer, som bliver indlagt på Børneonkologisk afdeling, A20, AUH med kemoinduceret feber og opstartes i empirisk antibiotikabehandling med Tazocin.
- Alderskriterium: 6 måneder – 18 år
- Alle cancertyper kan indgå
- Et barn kan indgå flere gange i forbindelse med en ny antibiotikabehandlingsperiode og kan indgå selvom barnet får anden type antibiotika samtidigt. Hvert barn kan max. indgå i studiet 3 gange.

E.4

Principal exclusion criteria

- Babies that are only breast or bottle feed
- Not possible to take blood samples from the child's central venuous catheter
- Weight < 8 kg

- Småbørn, der ammes fuldt
- Hvis det ikke er praktisk muligt at tage blodprøver fra barnets CVK
- Vægt < 8 kg

E.5 End points

E.5.1

Primary end point(s)

For continuous infusion of Tazocin, our primary endpoint is to investigate if the children reach Tazocin levels > 4 x MIC for the most pathogenic bacteria in > 50% of the dosing interval or > 1 x MIC i 100 % of the dosing interval. We want to determine, if continuous infusion of this drug provides a more stable antibiotic concentration above MIC compared to the current bolus regimen.
So, the overall endpoint is to optimize the Tazocin treatment in this group of children.

Dvs. at vores primære endpoint er at undersøge om børnene, med kontinuerlig infusion af Tazocin opnår koncentrationer > 4 x MIC for de mikroorganismer, der er beskrevet i delstudie 1 i > 50% af doseringsintervallet eller > 1 x MIC i 100 % af doseringsintervallet. Vi vil således undersøge, om kontinuerlig infusion af stoffet resulterer i staibile antibiotika koncentrationer over MIC og dermed optimal effekt af stoffet.

E.5.1.1

Timepoint(s) of evaluation of this end point

The timepoint of evaluation of this endpoint is spring/summer 2019. By this
time all blood samples should be gathered and analyzed.

Data forventes indsamlet og analyseret i løbet af forår/sommer 2019.

E.5.2

Secondary end point(s)

In sub-study 3, we want to determine if continuous infusion of this drug provides a more stable antibiotic concentration above MIC compared to the current bolus regimen. Furthermore,
I det trejde delstudie ønsker vi at undersøge, om kontinuerlig infusion af Tazocin resulterer i en mere optimal antibiotikaprofil i henhold til MIC- værdierne. Vi vil endvidere bestemme hvilken dosis af Tazocin givet som bolus efterfulgt af kontinuerlig infusion, der giver den mest optimale farmakokinetiske profil i relation til MIC værdierne for de patogene mikroorganismer beskrevet i delstudie 1. we will determine the most optimal dosing of Tazocin administered as continous infusion.

I det trejde delstudie ønsker vi at undersøge, om kontinuerlig infusion af Tazocin resulterer i en mere optimal antibiotikaprofil i henhold til MIC- værdierne for de patogene mikroorganismer beskrevet i delstudie 1. Vi vil endvidere bestemme hvilken dosis af Tazocin givet som bolus efterfulgt af kontinuerlig infusion, der giver den mest optimale farmakokinetiske profil i relation til MIC værdierne .

E.5.2.1

Timepoint(s) of evaluation of this end point

Spring/summer 2019

Forår/sommer 2019

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

E.6.4

Safety

E.6.5

Efficacy

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)

Yes

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)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Longitudinelt observationsstudie

Observational study

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

Farmakokinetisk studie af Tazocin hos børn med cancer og feber

We investigate the pharmacokinetics of Tazocin in pediatric oncology patients

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

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

Sidste besøg/feberepisode afslutter forsøget

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

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The trial subjects include children < 15 years who are not allowed to give informed consent themselves.
The parents or guardians have to give consent on behalf of the child.

Børn under 15 år kan ikke selv give samtykke, idet de er mindreårige. Derfor er deltagelse i forsøget betinget af informeret samtykke fra begge indehavere af forældremyndigheden

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

None. The study participants will be treated according to the standard treatment for this patient group.

Ingen. De inkluderede patienter vil modtage standardbehandlingen efter deltagelse i projektet.

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

2018-01-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-01-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-06-30

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