Clinical Trials Register

Summary
EudraCT Number:	2017-001768-39
Sponsor's Protocol Code Number:	SURFABRON
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-11-04
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

2017-001768-39

A.3

Full title of the trial

Randomized multicentre-controlled, placebo-controlled (1: 1) study to evaluate the efficacy and safety of Curosurf in patients under 12 months of age with moderate or severe acute respiratory distress syndrome (ARDS) Bronchiolitis, with the need for invasive mechanical ventilation.

Studio multicentrico randomizzato, controllato con placebo (1:1), in cieco, per valutare l’efficacia e la sicurezza del Curosurf nei pazienti di età inferiore ai 12 mesi affetti da sindrome da distress respiratorio acuto (ARDS) moderata o severa in corso di bronchiolite, con necessità di ventilazione meccanica invasiva.

A.3.1

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

Placebo-controlled study to evaluate the efficacy and safety of Curosurf in patients under 12 months of age with moderate or severe acute respiratory distress syndrome during bronchiolitis with the need for invasive mechanical ventilation

Studio controllato con placebo, in cieco, per valutare l’efficacia e la sicurezza del Curosurf nei pazienti di età inferiore ai 12 mesi affetti da sindrome da distress respiratorio acuto moderata o severa in corso di bronchiolite, con necessità di ventilazione meccanica invasiva

A.3.2

Name or abbreviated title of the trial where available

SURFABRON

A.4.1

Sponsor's protocol code number

SURFABRON

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 OSPEDALIERA UNIVERSITARIA INTEGRATA VERONA
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	Chiesi Farmaceutici spa
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 OSPEDALIERA INTEGRATA UNIVERSITARIA DI VERONA
B.5.2	Functional name of contact point	Unità Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	PIAZZALE STEFANI 1
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37126
B.5.3.4	Country	Italy
B.5.4	Telephone number	0458127043
B.5.5	Fax number	0458122814
B.5.6	E-mail	supporto.noprofit@aovr.veneto.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	CUROSURF - 80 MG/ML SOSPENSIONE PER INSTILLAZIONE ENDOTRACHEOBRONCHIALE 1 FLACONCINO 3 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	CHIESI FARMACEUTICI S.P.A.
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	CUROSURF
D.3.2	Product code	[028221024]
D.3.4	Pharmaceutical form	Endotracheopulmonary instillation, solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Endotracheopulmonary use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FRAZIONE FOSFOLIPIDICA DA POLMONE SUINO
D.3.9.2	Current sponsor code	FRAZIONE FOSFOLIPIDICA DA POLMONE SUINO
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	80
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

Acute severe hypoxic bronchiolitis

Bronchiolite acuta ipossiemica grave

E.1.1.1

Medical condition in easily understood language

Acute bronchiolitis

Bronchiolite acuta

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10000686
E.1.2	Term	Acute bronchiolitis
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

To evaluate whether treatment with Curosurf is effective compared to placebo (air) in reducing the duration of invasive mechanical ventilation during the first 14 days of admission, in children under 12 months of acute hypoxic bronchiolitis, viral origin, admitted to therapy intensive.

Valutare se il trattamento con Curosurf è efficace rispetto al placebo (aria) nel ridurre la durata della ventilazione meccanica invasiva nei primi 14 giorni di ricovero, in bambini affetti da bronchiolite acuta ipossiemica di origine virale, di età inferiore ai 12 mesi, ricoverati in terapia intensiva.

E.2.2

Secondary objectives of the trial

Assess whether the treatment is effective compared to placebo in reducing the duration of non-invasive mechanical ventilation in post-extubation; is effective compared to placebo in reducing the number of cases requiring new intubation after previous extubation in 14 days from randomization; compared to placebo in reducing days of stay in IT; reduce hospital days; reduce the duration of oxygen dependence;
improve oxygenation and ventilation of pts compared to placebo; Improve oxygenation parameters during invasive mechanical ventilation support; reduce the need to repeat treatment within 24h from the first; reduce the use of other unconventional therapies during treatment; the effectiveness in terms of mortality within the first 14 days of admission to IT and in any case by the discharge from the hospital; security and tolerability.

Valutare se il trattamento: è efficace rispetto al placebo nel ridurre la durata della ventilazione meccanica non invasiva in fase post-estubazione; è efficace rispetto al placebo nel ridurre il numero di casi che necessitano di nuova intubazione dopo precedente estubazione nei14giorni a partire dalla randomizzazione; rispetto al placebo nel ridurre i giorni di degenza in TI; ridurre i giorni di degenza in ospedale; ridurre la durata di ossigenodipendenza;
migliorare l’ossigenazione e la ventilazione dei pz rispetto al placebo; migliorare i parametri ventilatori durante supporto ventilatorio meccanico invasivo; ridurre la necessità di ripetere il trattamento entro 24h dal primo; ridurre l'utilizzo di altre terapie non convenzionali durante il trattamento; l'efficacia in termini di mortalità entro i primi 14gg di ricovero in TI e comunque entro la dimissione dall' ospedale; la sicurezza e la tollerabilità.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age> 40 weeks (correct gestational age) and <12 months.
2. Patient intubated and mechanically ventilated for at least 6 hours, with ventilation support requirements of at least 24 hours.
3. Clinical framework strongly suggestive of acute bronchiolitis (fever of probable viral origin, creeping rantules, prolonged exhalation, inflammation of the pulmonary arteries in chest x-rays)
4. Moderate or severe pediatric acute respiratory distress syndrome (OI)> Oxygenation Index (OI)> 8 or Oxygen Saturation Index (OSI)> 7.5
5. Written informed consent obtained by both parents

1. Età compresa tra > 40 settimane (età gestazionale corretta) e < 12 mesi.
2. Paziente intubato e ventilato meccanicamente da almeno 6 ore, con fabbisogno previsto di supporto ventilatorio di almeno 24 ore.
3. Quadro clinico fortemente suggestivo per bronchiolite acuta (febbre di probabile origine virale, rantoli crepitanti, espirio prolungato, iperespansione dei campi polmonari alla radiografia del torace)
4. Sindrome da distress respiratorio acuto pediatrico (Pediatric acute respiratory distress syndrome) moderata o severa, definita da un Oxygenation Index (OI) > 8 o un Oxygen Saturation Index (OSI) > 7.5
5. Consenso informato scritto ottenuto da entrambi i genitori

E.4

Principal exclusion criteria

1. Severe premature prematurity (gestational age <32 weeks)
2. Recent Oxygen Dependence (Oxygen Supplement Need to Keep SatO2> 95% in the Four Weeks Prior to Pediatric Intensive Care)
3. Mechanical invasive ventilation for more than 24 hours.
4. Oxygenation index - OI> 30
5. Congenital Cyanopathic Cardiopathies
6. Untreated pneumothorax
7. Neuromuscular Diseases
Severe neurological alterations
9. Other serious congenital anomalies
10. Indication not to try resuscitation
11. Patient already recruited for other clinical trials

1. Grave prematurità pregressa (Età gestazionale < 32 settimane)
2. Recente fase di ossigenodipendenza (necessità di supplementazione di ossigeno per mantenere satO2 > 95% nelle quattro settimane precedenti il ricovero in Terapia Intensiva Pediatrica)
3. Ventilazione meccanica invasiva per più di 24 ore.
4. Indice di Ossigenazione (Oxygenation index) - OI > 30
5. Cardiopatie congenite cianotizzanti
6. Pneumotorace non trattato
7. Malattie neuromuscolari
8. Gravi alterazioni neurologiche
9. Altre gravi anomalie congenite
10. Indicazione a non tentare la rianimazione
11. Paziente già reclutato per altri studi clinici

E.5 End points

E.5.1

Primary end point(s)

Number of free days of invasive mechanical ventilation from randomization to day 14, considering the first successful extubation (at least 48 hours without reintroduction)

Numero di giorni liberi da ventilazione meccanica invasiva dalla randomizzazione al giorno 14, considerando la prima estubazione riuscita con successo (almeno 48 ore senza necessità di reintubazione)

E.5.1.1

Timepoint(s) of evaluation of this end point

From randomization to day 14

dalla randomizzazione al giorno 14

E.5.2

Secondary end point(s)

Number of days off mechanical ventilation
noninvasive, from randomization to day 14.; Necessity of new intubation, after previous
extubation, within 14 days from
randomization;
(1) Number of days free from intensive care,
from randomization to day 14;
(2) Total number of days of hospital stay in TIP from
randomization;
(1) Number of free days from hospital stay,
from randomization to day 14;
(2) Total number of days of hospital stay
by randomization;; Number of free days from oxygen supplementation, from randomization to day 14;; Values of oxygenation indices (Oxygenation Saturation Index, Oxygenation Index) and ventilation indices (PaCO2, End Tidal CO2) detected 15 minutes before treatment and remote administration of 2, 6, 12, 24, 36 and 48 hours (for indexes of oxygenation if present arterial line);; Values of mechanical ventilation parameters, such as current volume (Vt), positive pressure of
end exhalation (PEEP), peak pressure inspiratory (PIP), respiratory rate, FiO2, inspirational time (Ti) and average pressure in the streets (MAP), detected 15 minutes before administration of the treatment and at a distance of 2,6, 12, 24, 36 and 48 hours after treatment; Number of Patients Repeated treatment (medication or placebo) within 24 hours of first treatment; Number of patients undergoing therapy not
Conventional (HFOV, ECMO, Nitric Oxide)
during the first 14 days; (1) Mortality during the first 14 days of hospitalization
hospital
(2) Mortality within discharge from the hospital; number of severe desaturation episodes (SatO2 <75%) during treatment; number of severe bradycardia episodes (FC <80 / min) during administration of
treatment; number of extreme bradycardia episodes or cardiac arrest that need chest compressions and / or administration of resuscitation drugs (eg adrenaline) during treatment; number of episodes of pulmonary haemorrhage;
number of pneumothorax episodes

Numero di giorni liberi da ventilazione meccanica
non invasiva, dalla randomizzazione al giorno 14. ; Necessità di nuova intubazione, dopo precedente
estubazione, nei 14 giorni a partire dalla
randomizzazione; (1) Numero di giorni liberi da terapia intensiva,
dalla randomizzazione al giorno 14;
(2) Numero totale di giorni di degenza in TIP dalla
randomizzazione; (1) Numero di giorni liberi da degenza in ospedale,
dalla randomizzazione al giorno 14;
(2) Numero totale di giorni di degenza ospedaliera
dalla randomizzazione;; Numero di giorni liberi da supplementazione di ossigeno, dalla randomizzazione al giorno 14;; Valori degli indici di ossigenazione (Oxygenation Saturation Index e Oxygenation Index) e degli indici di ventilazione (PaCO2, End Tidal CO2) rilevati 15 minuti prima della somministrazione del trattamento e a distanza di 2, 6, 12, 24, 36 e 48 ore (per gli indici di ossigenazione se presente linea arteriosa);; Valori dei parametri della ventilazione meccanica, quali volume corrente (Vt), pressione positiva di fine espirazione (PEEP), picco di pressione
inspiratoria (PIP), frequenza respiratoria, FiO2, tempo inspiratorio (Ti) e pressione media nelle vie aeree (MAP), rilevati 15 minuti prima della somministrazione del trattamento e a distanza di 2, 6, 12, 24, 36 e 48 ore dal trattamento; Numero di pazienti sottoposti a ripetizione del trattamento (farmaco o placebo) entro le 24 ore dal primo trattamento; Numero di pazienti sottoposti a terapie non convenzionali (HFOV, ECMO, Ossido nitrico) durante i primi 14 giorni; (1) Mortalità durante i primi 14 giorni di degenza
ospedaliera
(2) Mortalità entro la dimissione dall’ospedale; numero di episodi di desaturazione grave (SatO2 < 75%) durante la somministrazione del trattamento ; numero episodi di bradicardia severa (FC <
80/min) durante la somministrazione del
trattamento
; numero episodi bradicardia estrema o arresto cardiaco con necessità di compressioni toraciche e/o somministrazione di farmaci per la rianimazione (ad esempio adrenalina) durante la somministrazione del trattamento ; numero di episodi di emorragia polmonare; numero episodi di pneumotorace

E.5.2.1

Timepoint(s) of evaluation of this end point

from randomization to day 14.; Within 14 days from
randomization; (1) from randomization to day 14;
(2) by randomization; (1) from randomization to day 14;
(2) by randomization; from randomization to day 14; Ventricular and ventilation indices detected 15 minutes prior to treatment and at 2, 6, 12, 24, 36 and 48 hours distance; Values detected 15 minutes before
administration of the treatment and at a distance of 2,
6, 12, 24, 36 and 48 hours after treatment; within 24 hours of first treatment; during the first 14 days; (1) durante i primi 14 giorni di degenza ospedaliera
(2) entro la dimissione dall’ospedale; within 48 hours of treatment; within 48 hours of treatment; within 48 hours of treatment; during and within 48 of treatment; within 48 hours of treatment

dalla randomizzazione al giorno 14. ; Nei 14 giorni a partire dalla
randomizzazione; (1) dalla randomizzazione al giorno 14;
(2) dalla randomizzazione; (1) dalla randomizzazione al giorno 14;
(2) dalla randomizzazione;; dalla randomizzazione al giorno 14; Indici di ossigenazione e di ventilazione rilevati 15 minuti prima della somministrazione del trattamento e a distanza di 2, 6, 12, 24, 36 e 48 ore ; Valori rilevati 15 minuti prima della
somministrazione del trattamento e a distanza di 2,
6, 12, 24, 36 e 48 ore dal trattamento; entro le 24 ore dal primo trattamento; durante i primi 14 giorni; (1) durante i primi 14 giorni di degenza ospedaliera
(2) entro la dimissione dall’ospedale; entro le prime 48 ore dal trattamento; entro le prime 48 ore dal trattamento; entro le prime 48 ore dal tr

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

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Aria ambiente

Air

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

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

"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)

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:

122

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

patients under 12 months of age

pazienti di età inferiore a 12 mesi

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

172

F.4.2

For a multinational trial

F.4.2.1

In the EEA

172

F.4.2.2

In the whole clinical trial

172

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)

Patients after their participation in the study will be assisted according to normal clinical practice.

I pazienti al termine della loro partecipazione allo studio saranno assistiti secondo normale pratica clinica.

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

2018-03-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-04

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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IMP with orphan designation in the indication
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