Clinical Trials Register

Summary
EudraCT Number:	2015-004526-33
Sponsor's Protocol Code Number:	PDARCT1
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-12-03
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

Ireland - HPRA

A.2

EudraCT number

2015-004526-33

A.3

Full title of the trial

A Randomised Controlled Trial of Early Targeted Patent Ductus Arteriosus Treatment Using a Risk Based Severity Score

A.3.1

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

A Randomised Controlled Trial of Early Targeted Patent Ductus Arteriosus Treatment Using a Risk Based Severity Score

A.3.2

Name or abbreviated title of the trial where available

PDA RCT

A.4.1

Sponsor's protocol code number

PDARCT1

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	Royal College of Surgeons in Ireland
B.1.3.4	Country	Ireland
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	Health Research Board Clinical Trials Network
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Royal College of Surgeons in Ireland
B.5.2	Functional name of contact point	Afif EL-Khuffash
B.5.3	Address:
B.5.3.1	Street Address	Department of Neonatology
B.5.3.2	Town/ city	The Rotunda Hospital
B.5.3.3	Post code	Dublin 1
B.5.3.4	Country	Ireland
B.5.4	Telephone number	353876683387
B.5.5	Fax number	35318176870
B.5.6	E-mail	afifelkhuffash@rcsi.ie

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	Pedea 5 mg/ml solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Orphan Europe SARL
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Pedea 5 mg/ml solution for injection
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.3.8	INN - Proposed INN	IBUPROFEN
D.3.9.1	CAS number	57469-77-9
D.3.9.3	Other descriptive name	Pedea 5 mg/ml solution for injection
D.3.9.4	EV Substance Code	SUB08098MIG
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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Suspension for injection
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

Patent Ductus Arteriosus

E.1.1.1

Medical condition in easily understood language

Aorta to pulmonary artery duct

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10034130
E.1.2	Term	Patent ductus arteriosus
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

We aim to identify infants at high risk of developing CLD/Death by utilising the PDAsc, and randomise those infants to early treatment with Ibuprofen versus placebo. We hypothesise that:

• in preterm infants less than 29 weeks gestation;
• at high risk of developing CLD/Death (Primary outcome) based on a PDAsc ≥ 5.0;
• obtained using echocardiography carried out between 36 and 48 hours of life;

,early treatment with non-steroidal anti-inflammatory drugs (Ibuprofen) compared with placebo will result in a reduction of CLD/Death by 36 weeks post menstrual age (PMA). Infants with a PDAsc < 5 will not be enrolled in the study but will be followed up to discharge to confirm their low risk status.

E.2.2

Secondary objectives of the trial

We will collect information on important secondary outcomes including culture proven sepsis, inotrope and diuretic use, postnatal steroids administration, PDA treatment beyond day 14 of age (including PDA ligation), necrotizing enterocolitis (NEC) with radiological evidence of pneumatosis intestinalis; intraventricular haemorrhage , days on invasive ventilation/continuous positive airway pressure (CPAP)/ supplemental oxygen, hospital days, treated retinopathy of prematurity and periventricular leukomalacia.

In this pilot study we also aim to ascertain issues with recruiting infants and obtaining consent, compliance with the protocol, the rate (if any) of loss to follow up, and the general acceptability, feasibility and compliance of administering the intervention.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All infants less than 29 weeks admitted to the NICU with a PDA identified on echocardiography between 36 and 48 hours of life will be eligible for inclusion. A comprehensive assessment of PDA significance will be performed using echocardiography to derive a PDA risk score based on this following formula: Infants with a risk score ≥ 5.0 are deemed to be at high risk of developing CLD/Death and will be randomised to either arm

(Gestation in weeks × -1.304) + (PDA diameter in mm × 0.781) + (Left ventricular output in ml/kg/min × 0.008) + (maximum PDA velocity in m/s × -1.065) + (LV a` wave in cm/s × -0.470) + 41, where 41 is the constant of the formula.

E.4

Principal exclusion criteria

The following infants will be excluded:

• lack of consent or study investigators
• lethal congenital abnormality or obvious syndrome
• pulmonary hypoplasia
• active bleeding
• known or suspected NEC
• platelet count < 100/mm2
• creatinine > 100 µmol/L; neutropenia
• oliguria < 1ml/kg/hour
• congenital heart disease other than a PDA or a patent foramen ovale
• grade 3 or higher IVH

E.5 End points

E.5.1

Primary end point(s)

The primary outcome of the study is chronic lung disease defined as the need for oxygen at 36 weeks corrected age or and/or death before discharge.

E.5.1.1

Timepoint(s) of evaluation of this end point

This will be assessed prior to hospital discharge at 36 weeks corrected age.

E.5.2

Secondary end point(s)

The following secondary clinical outcomes will also be obtained: culture proven sepsis, inotrope and frusemide use, postnatal steroids administration, PDA treatment beyond day 14 of age (including PDA ligation), necrotizing enterocolitis (NEC) with radiological evidence of pneumatosis intestinalis; intraventricular haemorrhage assessed on day 7 of age and classified according to Papile Classification, days on invasive ventilation/continuous positive airway pressure (CPAP)/ supplemental oxygen, hospital days, treated retinopathy of prematurity and periventricular leukomalacia.

E.5.2.1

Timepoint(s) of evaluation of this end point

This will be assessed prior to hospital discharge at 36 weeks corrected age.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

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

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.8.4.1

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

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

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:

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Preterm infants < 29 weeks gestation.

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)

Additional therapy for the PDA will not be instituted over the first two weeks of age in line with the current PDA treatment practice. Medical treatment of a PDA in infants beyond the first two weeks will be performed using paracetamol as per unit policy. Infants who fail to close a PDA following paracetamol will be considered for PDA ligation.

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

2016-01-29

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-08-05

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