Clinical Trials Register

Summary
EudraCT Number:	2017-002124-24
Sponsor's Protocol Code Number:	ROPROP
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2017-09-25
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

Germany - BfArM

A.2

EudraCT number

2017-002124-24

A.3

Full title of the trial

Oral Propranolol for prevention of threshold retinopathy of prematurity

Orales Propranolol zur Prävention einer höhergradigen Frühgeborenen-Retinopathie

A.3.1

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

Oral Propranolol for prevention of threshold retinopathy of prematurity

Orales Propranolol zur Prävention einer höhergradigen Frühgeborenen-Retinopathie

A.3.2

Name or abbreviated title of the trial where available

ROPROP

A.4.1

Sponsor's protocol code number

ROPROP

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03083431

A.5.4

Other Identifiers

Name:	other Study ID No	Number:	01GM1703
Name:	DRKS No	Number:	00013730

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	Universität Zürich
B.1.3.4	Country	Switzerland
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	DFG and BMBF (BMBF/ DLR Projektträger)
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Swiss National Science Foundation (SNF)
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	the Scientific and Technological Research Council of Turkey (TÜBITAK)
B.4.2	Country	Türkiye
B.4.1	Name of organisation providing support	Ministry of Health (MoH) in Israel
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Tübingen
B.5.2	Functional name of contact point	Center for Pediatric Clinical Studi
B.5.3	Address:
B.5.3.1	Street Address	Frondsbergstraße 23
B.5.3.2	Town/ city	Tübingen
B.5.3.3	Post code	72076
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4970712981462
B.5.5	Fax number	+497071294857
B.5.6	E-mail	cpcs@med.uni-tuebingen.de

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	No
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	Propranolol-HCl
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Gastroenteral use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Propranolol hydrochloride
D.3.9.1	CAS number	318-98-9
D.3.9.4	EV Substance Code	SUB10119MIG
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	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	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	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Retinopathy of prematurity

E.1.1.1

Medical condition in easily understood language

Retinopathy of prematurity (ROP) is a disorder of the developing retina observed only in preterm infants that may lead to blindness.

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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety and efficacy of orally administered propranolol to reduce the risk of threshold retinopathy of prematurity in extremely preterm infants

E.2.2

Secondary objectives of the trial

To assess the safety and efficacy of orally administered propranolol to reduce the rate of extremely preterm infants requiring local interventions for severe retinopathy of prematurity

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Preterm infant born before 28 weeks gestation
• Birth weight below 1250 g
• Alive at 5 weeks of age
• Postmenstrual age 31 0/7 – 36 6/7 weeks
• Ophthalmoscopic evidence of incipient ROP (stage 1 or 2, with or without plus disease)
• Written informed consent by parents or legal guardian, including saving and propagation of pseudonymous medical data for study purposes, according to national requirements

E.4

Principal exclusion criteria

• ROP stage 3 at time of inclusion (endpoint already reached)
• Thyrotoxicosis, arterial hypertension or congenital heart diseases requiring open-label propranolol treatment (such as tetralogy of Fallot, paroxysmal supraventricular tachycardia, or long QT syndrome)
• Atrio-ventricular block grade 2 or 3 (contraindication for propranolol)
• Sinuatrial block (contraindication for propranolol)
• Uncontrolled heart failure or cardiogenic shock (contraindication for propranolol)
• Acute severe infection (inclusion may be postponed until infection has resolved)
• Bronchial asthma
• Major congenital malformations or known chromosomal anomalies
• Colobomas and other eye malformations
• PHACE syndrome (posterior fossa anomalies, large infantile hemangiomas of the face, neck, and/or scalp, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies) (risk of cerebrovascular complications)
• Very large hemangioma (risk of hyperkalemia), as judged by the attending physician
• Heart rate consistently (>1 h) < 100/min
• Noninvasive mean arterial pressure consistently (>1 h) <40 mmHg
• Medication of the infant or the mother if breastfeeding with clonidine, reserpine, angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists, or antiarrhythmic drugs including amiodarone, propafenone, lidocaine, digoxin/digitoxin, quinidine, verapamil, diltiazem, or bepridil (pharmacodynamic interaction)
• Medication of the infant with rifampicin or phenobarbitone (enhanced metabolic clearance)
• Concurrent treatment with insulin (risk of hypoglycemia)
• Severe liver dysfunction (GPT > 900 U/l)
• Chronic kidney impairment (creatinine > 1.3 mg/dl [100 µM])
• Persistent hypoglycemia (blood glucose < 36 mg/dl [2.0 mM] in 3 consecutive samples immediately preceding enrollment)
• Persistent hyperkalemia (venous serum potassium > 5.9 mM in 3 consecutive samples immediately preceding enrollment)
• Persistent neutropenia (absolute neutrophil counts <1,000/µL in 3 consecutive samples immediately preceding enrollment)
• Known hypersensitivity to propranolol or any of the excipients
• Prinzmetal’s angina, Raynaud’s phenomenon (severe peripheral arterial circulatory disturbance), or pheochromocytoma (contraindications for propranolol in adults, not occurring in newborn infants)
• Participation in another pharmacological interventional clinical trial
• Any circumstances that make the investigator believe that participation in the study leads to exceptional medical or organizational problems for the patient
• Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint:
Survival without threshold ROP (stage 3 or more severe ROP(including aggressive posterior ROP))

E.5.1.1

Timepoint(s) of evaluation of this end point

time frame: 48 weeks postmenstrual age

E.5.2

Secondary end point(s)

Secondary endpoints:
Survival without ROP treated with ablative laser surgery or intravitreal VEGF antagonists

E.5.2.1

Timepoint(s) of evaluation of this end point

time frame: 48 weeks postmenstrual age

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Switzerland

Israel

Germany

Türkiye

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

LPLV = Last-Participant-Out
Final examination at 48 (± 2) weeks postmenstrual age (Visit #5) - extended to 70 weeks PMA if treated with anti-VEGF antibodies.
Visit #5: Closeout Visit (outpatient or inpatient)

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

Number of subjects for this age range:

276

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:

276

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:

276

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

ROP is a disease specific for very preterm infants and does not occur in adults or children of more advanced age.

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

very preterm infants

F.4 Planned number of subjects to be included

F.4.1

In the member state

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

276

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)

Study medication is only given to patients treated in the neonatal unit. The study drug is reduced by 50% and discontinued the following day prior to discharge. After discharge, the patient will be subject to follow-up by the study until 48 weeks postmenstrual age. All infants are scheduled to undergo serial pediatric examinations throughout infancy and childhood, have further visits to their pediatrician as needed, and are invited to participate in standardized neurodevelopmental assessments.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Swiss Neonatal Network
G.4.3.4	Network Country	Switzerland

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

2017-12-21

P. End of Trial
P.	End of Trial Status	Restarted

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