Clinical Trials Register

Summary
EudraCT Number:	2015-001835-20
Sponsor's Protocol Code Number:	OZBS12.15060
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-12-22
Trial 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

Belgium - FPS Health-DGM

A.2

EudraCT number

2015-001835-20

A.3

Full title of the trial

Morphine intravenous vs. paracetamol intravenous after cardiac surgery in neonates and infants.

Morfine IV vs. paracetamol IV na cardiochirurgie in neonaten en kinderen

A.3.1

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

Morphine or paracetamol as pain medication in children after open heart surgery

Morfine of paracetamol als pijnstiller bij kinderen na open hart operaties.

A.3.2

Name or abbreviated title of the trial where available

Morphine IV vs paracetamol IV for analgosedation in neonates and infants after cardiac surgery

Morfine IV of paracetamol IV voor analgosedatie bij neonaten en kind na cardiochirurgie

A.4.1

Sponsor's protocol code number

OZBS12.15060

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	Erasmus MC
B.1.3.4	Country	Netherlands
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	Erasmus MC
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus MC
B.5.2	Functional name of contact point	Project leader
B.5.3	Address:
B.5.3.1	Street Address	Wytemaweg 80
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 CN
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31107036189n.a.
B.5.5	Fax number	n.a.n.a.n.a.n.a.
B.5.6	E-mail	e.wildschut@erasmusmc.nl

D. IMP Identification
D.IMP: 1
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	Morphine HCl 10 mg = 1 ml solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratoires Sterop 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	Morfine HCl-3-water
D.3.2	Product code	BE414346
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	Morphine
D.3.9.1	CAS number	52-26-6
D.3.9.3	Other descriptive name	MORPHINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB14596MIG
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	10
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	Paracetamol 10 ml/ml solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi
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	paracetamol
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	Yes
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	Paracetamol
D.3.9.3	Other descriptive name	PARACETAMOL
D.3.9.4	EV Substance Code	SUB09611MIG
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	10
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
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

congenital cardiac defects

Congenitale hartafwijkingen

E.1.1.1

Medical condition in easily understood language

Congental cardiac defects

Aangeboren hartafwijkingen

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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 outcome measure is the weight-adjusted cumulative morphine consumption (mcg/kg) in the first 48 hours post-operatively.

Vermindering van de cumulatieve morfine behoefte in de eerste 48 uur na cardiochirurgie in mck/kg

E.2.2

Secondary objectives of the trial

1. Incidence of adverse drug reactions
a. hemodynamically: hypotension or bradycardia, with the need for intervention by means of medication or a fluid bolus.
b. Decreased gastro-intestinal motility or intestinal obstruction not directly related to the underlying diagnosis and not previously existing, with the need for intervention.
c. Vomiting.
d. Number of re-intubations.
e. Pediatric delirium as measured by the SOS-PD-scale.
2. DNA analysis will be performed to evaluate the effect of gene polymorphisms on the PK of analgesic medication.
3. Concomitant use of sedatives.
4. The number of hours on ventilation.
5. The length of PICU stay.
6. To develop a population PKPD-based post-operative pain management algorithm based on the results of this trial.

1. incidentie van ongewenste bijwerkingen
a. hemodynamisch: hypotensie of bradycardie, met noodzaak tot interventie met medicatie of vocht bolus
b. verminder gastro-intestinale motiliteit of obstructie,niet direct gerelateerd aan de onderliggende diagnose and niet eerder bestaand, met noodzaak tot interventie
c. braken
d. incidentie van re-intubatie
e. delirium
2. DNA analyse om gen polymorfismen te bepalendie invloed hebben op de PK van analgetica.
3. gebruik van sedativa
4. duur van ventilatie in uren
5. ligduur op kinder IC
6. resultaten van de trial worden gebruik om een PKPD-based pain protocol te maken

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Informed consent,
Neonate / infant aged 0-36 months,
Cardiac surgery with the use of CPB.

Informed consent
Neonaat of kind in de leeftijd van 0 t/m 36 maanden
Cardiochirurgie met gebruik van de cardiopulmonale bypass

E.4

Principal exclusion criteria

No informed consent
Known allergy to or intolerance for paracetamol or morphine,
Administration of opioids in the 24 hours prior to surgery.
Hepatic dysfunction defined as three times the reference value of ALAT/ASAT.
Renal insufficiency defined as Pediatric RIFLE category - injury, defined as estimated creatinine clearance reduced by 50% and urine output <0.5 ml/kg/h for 16 hours.

Geen informed consent
Bekende allergie tegen of intollerantie voor morfine of paracetamol
toedienen van opioiden tot 24 uur voor de operatie
leverfunctiestoornissen, gedefineerd als drie keer de referentiewaarden van ALAT/ASAT
nierfunctiestoornissen, gedefineerd als 50% vermindering van klaring en urine output < 0.5 ml/kg/h gedurende 16 uur

E.5 End points

E.5.1

Primary end point(s)

Cumulative morphine dose over 48 hours in mcg/kg.

Cumulatieve morfine dosering gedurende 48 uur

E.5.1.1

Timepoint(s) of evaluation of this end point

48 hours after surgery

48 uur na einde van de operatie

E.5.2

Secondary end point(s)

1. Level of pain assessed by validated PD instruments until 48 hours after stop study medication
2. Incidence of adverse drug reactions
3. Incidence of concomitant use of sedative
4. Hours on ventilation
5. Incidence of over- and undersedation
6. Incidence of withdrawal syndrome and pediatric delirium
7. The length of PICU stay
8. Use of corticosteroids
9. Parents postoperative pain measurement two days after discharge
10. Bayley scales of infant and toddler development (one year after surgery)

1. pijnscore tot 48 uur na stop studie medicatie
2. incidentie van ongewenste bijwerkingen
3. incidentie van gebruik van sedativa
4. duur van ventilatie in uren
5. incidentie van over- en ondersedatie
6. incidentie van delier en onttrekkinsverschijnselen
7. ligduur op kinder IC
8. gebruik van corticosteroïden
9. pijnmeting door ouders 2 dagen na ontslag uit ziekenhuis
10. Bayley score voor ontwikkeling 1 jaar na operatie

E.5.2.1

Timepoint(s) of evaluation of this end point

1-8: 48 hours after stop study medication (96 hours after surgery)
9: 2 days after discharge from hospital
10: 1 year after surgery

1 t/m 8: 48 uur na stoppen van de studiemedicatie (96 uur na de operatie)
9: 2 dagen na ontslag uit het ziekenhuis
10: 1 jaar na de operatie

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

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

Yes

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

Insufficient effect of paracetamol as primary analgesic after cardiac surgery in children

Onvoldoende effect van paracetamol as primair analgeticum na cardiochirurgie in kinderen

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

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:

208

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

100

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)

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

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

children aged 0 - 36 months

kinderen in de leeftijd van 0 t/m 36 maanden

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

208

F.4.2.2

In the whole clinical trial

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)

None

Niet

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

2017-12-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-12

P. End of Trial
P.	End of Trial Status	Ongoing

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