Clinical Trials Register

Summary
EudraCT Number:	2020-000836-23
Sponsor's Protocol Code Number:	FentanylTH
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-10-21
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-000836-23

A.3

Full title of the trial

Continous fentanyl infusion in newborns with hypoxic ischemic encephalopathy treated with therapeutic hypothermia: pharmacokinetics study

Fentanile in infusione continua in neonati con encefalopatia ipossico ischemica trattati con ipotermia terapeutica: studio di farmacocinetica

A.3.1

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

Continous fentanyl infusion in newborns with hypoxic ischemic encephalopathy treated with therapeutic hypothermia: pharmacokinetics study

Fentanile in infusione continua in neonati con encefalopatia ipossico ischemica trattati con ipotermia terapeutica: studio di farmacocinetica

A.3.2

Name or abbreviated title of the trial where available

FentanylTH

A.4.1

Sponsor's protocol code number

FentanylTH

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	AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA
B.1.3.4	Country	Italy
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	Fondo Aziendale per la Ricerca - Azienda Ospedaliero-Universitaria di Modena
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Azienda Ospedaliero-Universitaria di Modena
B.5.2	Functional name of contact point	Clinical Trial Quality Team
B.5.3	Address:
B.5.3.1	Street Address	Via Del Pozzo 71
B.5.3.2	Town/ city	Modena
B.5.3.3	Post code	41124
B.5.3.4	Country	Italy
B.5.4	Telephone number	0594225868
B.5.5	Fax number	0594224369
B.5.6	E-mail	ricercainnovazione@aou.mo.it

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	fentanyl-hameln
D.2.1.1.2	Name of the Marketing Authorisation holder	Hameln pharma plus gmbh
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Fentanyl-hameln
D.3.2	Product code	[-]
D.3.4	Pharmaceutical form	Solution for injection
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.3.9.2	Current sponsor code	-
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Infants with perinatal asphyxiation and indication to hypothermic treatment with analgo-sedation performed with fentanyl

Neonati con asfissia perinatale e indicazione di trattamento ipotermico con analgo-sedazione eseguito con fentanil

E.1.1.1

Medical condition in easily understood language

Infants with perinatal asphyxiation and indication to hypothermic treatment with analgo-sedation performed with fentanyl

Neonati con asfissia perinatale e indicazione di trattamento ipotermico con analgo-sedazione eseguito con fentanil

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10070512
E.1.2	Term	Hypoxic-ischemic encephalopathy
E.1.2	System Organ Class	100000004852

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 evaluate pharmacokinetics of Fentanyl in asphyxiated infants treated with hypothermia, in a standard regimen of Fentanyl administration. Drug plasma concentrations at the end of the starting bolus, after 24-48-72 hours infusion and after 96 hours from starting bolus will be assessed. Maximun- minimun concentration (Cmax-min) and clearance of drug will be determined.

Valutare la farmacocinetica di Fentanil nei neonati con encefalopatia ipossico-ischemica trattati con ipotermia, in un regime standard di somministrazione di Fentanil. Saranno valutate le concentrazioni plasmatiche del farmaco alla fine del bolo iniziale, dopo 24-48-72 ore di infusione e dopo 96 ore dall'inizio del bolo. Saranno determinate la concentrazione massima-minima (Cmax-min) e la clearance del farmaco.

E.2.2

Secondary objectives of the trial

Valutare la sicurezza del regime di Fentanil (carico di 1-2 mcg / Kg di Fentanil seguito da una infusione continua di Fentanil alla dose di 0,5-1 mcg / kg / h per TH e fase di riscaldamento) registrando le reazioni al farmaco

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Any newborn eligible for hypothermic treatment according to Italian Recommendation for the treatment of perinatal asphyxia (SIN raccomandation 2012):
- a gestational age >= 35 weeks and a birth weight > 1.8 kg;
- with Apgar Score at 5 min <= 5 or with continued resuscitation at 10 min postnatal or with 1 h postnatal blood gas analysis pH<7.0 or base deficit>12
- clinical signs of encephalopathy
- moderate to severe aEEG anomalies or seizures
- neuroprotective treatment by controlled hypothermia <6 h postnatal life
- parental written informed consent for participation in the study obtained
- study analgesic treatment available

- Neonati con asfissia perinatale e indicazione al trattamento ipotermico
- Età gestionale >= 35 settimane e peso alla nascita >1,8 Kg
- con Apgar score al 5 minuto <= 5 o con necessità ddi rianimazione al 10 minuto post-natale o con emogasanalisi a 1 ora di vita con pH < 7,0 o deficit di basi > 12mmol/L
- segni clinici e aEEG di encefalopatia
- Trattamento ipotermico neuroprotettivo iniziato entro le 6 ore di vita post natale
Consenso informato dei genitori per lo studio
-Trattamento analgesico in studio
- posizionamento di linea venosa centrale

E.4

Principal exclusion criteria

Neonates will not be recruited into the study if at least one of the following criteria is found:
- Known genetic or chromosomal disorders or major malformation
- No central venous line placement
- No written parental consent to participate following informed consent interview

I neonati non saranno reclutati nello studio se viene trovato almeno uno dei seguenti criteri:
- Alterazioni cromosomiche e/o genetiche note o malformazioni maggiori
- Assenza di linea venosa a doppio lume
- Mancato consenso dei genitori alla partecipazione allo studio

E.5 End points

E.5.1

Primary end point(s)

Drug plasma concentrations at the end of the starting bolus, after 24-48-72 hours infusion and after 96 hours from starting bolus will be assessed. Maximun- minimun concentration (Cmax-min) and clearance of drug will be
determined.

Saranno valutate le concentrazioni plasmatiche del farmaco alla fine del bolo iniziale, dopo 24-48-72 ore di infusione e dopo 96 ore dall'inizio del bolo. Saranno valutate la concentrazione massima-minima (Cmax-min) e la Clearance del farmaco.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 24-48-72 hours infusion and after 96 hours from starting bolus

dopo 24-48-72 ore infusione e dopo 96 ore dall'inizio del bolo

E.5.2

Secondary end point(s)

To evaluate the safety of the Fentanyl regimen (load of 1-2 mcg/Kg of Fentanyl followed by a continuous infusion of Fentanyl at dosage of 0,5-1 mcg/kg/h for TH and heating fase) by recording drug side effect:
- Rate of mechanically ventilated newborns during TH
- Rate of apnea and/or need of respiratory support starting during TH
- Need of resuscitation during TH
- Need of opioid antagonist administration during TH
- Incidence of hypotension during TH, defined as blood pressure below 10th centile for gestational age and postnatal age
- Need of cardiovascular support drugs during TH
- Rate of delayed intestinal passage (abdominal distension, gastric retention, absent/delayed evacuation, minimal enteral feeding intolerance)
- Rate of bladdr globus, defined as loss of spontaneous urination with enlarged bladder and need for catheterisation
- Site and severity of cerebral lesions detected by cerebral MRI
The analgesic effect of Fentanyl administration, by the application of validated algometric scales for chronic pain (EDIN – Echelle Douleur Inconfort Nouveau-Nè) and acute pain (PIPP- Premature Infant Pain Profile).
Efficacy of analgesic therapy is evaluated by the registration of the average heart rate of newborn during hypothermia and the presence of tremors.
To evaluate drug plasma concentrations in relation to the degree of disease (moderate – severe asphyxia)

Per valutare la sicurezza del regime di Fentanil (carico di 1-2 mcg / Kg di Fentanil seguito da una infusione continua di Fentanil alla dose di 0,5-1 mcg / kg / h per TH e fase di riscaldamento) registrando l'effetto collaterale del farmaco:
- Tasso di neonati ventilati meccanicamente durante il TH
- Tasso di apnea e / o necessità di supporto respiratorio a partire dal TH
- Necessità di rianimazione durante TH
- Necessità di somministrazione di antagonisti degli oppioidi durante il TH
- Incidenza di ipotensione durante il TH, definita come pressione sanguigna inferiore al 10 ° centile per età gestazionale ed età postnatale
- Necessità di farmaci per il supporto cardiovascolare durante il TH
- Tasso di passaggio intestinale ritardato (distensione addominale, ritenzione gastrica, evacuazione assente / ritardata, minima intolleranza all'alimentazione enterale)
- Tasso di bladdr globus, definito come perdita di minzione spontanea con vescica allargata e necessità di cateterizzazione
- Sito e gravità delle lesioni cerebrali rilevate dalla risonanza magnetica cerebrale
Effetto analgesico della somministrazione di Fentanil, mediante l'applicazione di scale algometriche convalidate per il dolore cronico (EDIN - Echelle Douleur Inconfort Nouveau-Nè) e il dolore acuto (PIPP - Profilo del dolore infantile prematuro).
Efficacia della terapia analgesica valutata dalla registrazione della frequenza cardiaca media del neonato durante l'ipotermia e dalla presenza di tremori.
Valutare le concentrazioni plasmatiche del farmaco in relazione al grado di malattia (asfissia da moderata a grave)

E.5.2.1

Timepoint(s) of evaluation of this end point

during TH

Durante il trattamente ipotermico

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

Yes

E.7.1.3.1

Other trial type description

pharmacokinetics study

studio di farmacocinetica

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

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

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

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

Information not present in EudraCT

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

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

Yes

F.1.1.1

In Utero

F.1.1.2

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

Yes

F.1.1.2.1

Number of subjects for this age range:

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)

F.1.1.5

Children (2-11years)

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

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

newborns with hypoxic ischemic encephalopathy

Neonati con encefalopatia ipossico ischemica

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

F.4.2.2

In the whole clinical trial

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)

the best supportive therapy available

la migliore terapia di supporto disponibile al momento

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

2021-01-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-22

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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