Clinical Trials Register

Summary
EudraCT Number:	2013-002539-13
Sponsor's Protocol Code Number:	CARE-ROP
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2013-12-30
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

Germany - PEI

A.2

EudraCT number

2013-002539-13

A.3

Full title of the trial

Multicenter randomized double masked parallel design exploratory study to assess safety and efficacy of two different doses of intravitreal anti-VEGF treatment with ranibizumab (0.12 mg vs. 0.20 mg) in infants with retinopathy of prematurity (ROP)

Eine multizentrische, randomisierte, doppelblinde, zweiarmige explorative Studie zur vergleichenden Beurteilung der Sicherheit und Wirksamkeit zweier unterschiedlicher Dosen intravitrealer Ranibizumab-Injektionen (0,12 mg vs. 0,20 mg) bei Kindern mit Frühgeborenenretinopathie (ROP)

A.3.1

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

Comparing Alternative Ranibizumab dosages for safety and Efficacy in Retinopathy Of Prematurity

Vergleich von zwei verschiedenen Ranibizumab-Dosierungen hinsichtlich Sicherheit und Wirksamkeit bei Frühgeborenenrethinopathie

A.3.2

Name or abbreviated title of the trial where available

CARE-ROP

A.4.1

Sponsor's protocol code number

CARE-ROP

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	University Medical Center Freiburg
B.1.3.4	Country	Germany
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	University Medical Center Freiburg
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Eye Hospital Greifwald
B.5.2	Functional name of contact point	medical director
B.5.3	Address:
B.5.3.1	Street Address	Ferdinand Sauerbruch Straße
B.5.3.2	Town/ city	Greifswald
B.5.3.3	Post code	17475
B.5.3.4	Country	Germany
B.5.6	E-mail	andreas.stahl@uni-greifswald.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	Yes
D.2.1.1.1	Trade name	Lucentis
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd
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	Ranibizumab
D.3.2	Product code	RFB002
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RANIBIZUMAB
D.3.9.1	CAS number	347396-82-1
D.3.9.4	EV Substance Code	SUB22314
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	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	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	Yes
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	Lucentis
D.2.1.1.2	Name of the Marketing Authorisation holder	Genentech Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Ranibizumab
D.3.2	Product code	RFB002
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RANIBIZUMAB
D.3.9.1	CAS number	347396-82-1
D.3.9.4	EV Substance Code	SUB22314
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	6
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	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	Yes
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

retinopathy of prematurity

Frühgeborenenretinopathie

E.1.1.1

Medical condition in easily understood language

Impairment of visual function due to excessive blood vessel growth inside the eye

Beeinträchtigung der Sehfunktion aufgrund erhöhter Bildung von Blutgefäßen im Augeninneren

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

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	10038974
E.1.2	Term	Retrolental fibroplasia
E.1.2	System Organ Class	100000004853

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 objective is to assess clinical efficacy of ranibizumab in children with ROP. Efficacy is determined by the number of infants without need for rescue treatment up to week 24 post first injection. Re-injection of study dose is not considered rescue treatment if applied after an initial response to treatment and after at least 4 weeks post injection.

Primäres Studienziel ist die Beurteilung der klinischen Wirksamkeit von Ranibizumab bei Kindern mit Frühgeborenenretinopathie. Diese wird anhand der Anzahl der Kinder ermittelt, die keine Rescue-Behandlung (zusätzliche Injektion von 0,20 mg Ranibizumab oder eine zusätzliche Laserbehandlung innerhalb von weniger als 4 Wochen nach der studienspezifischen Injektion) bis zur Woche 24 nach der ersten Injektion benötigen.

E.2.2

Secondary objectives of the trial

- To assess regression of plus disease during core study
- To assess regression of preretinal vascularized ridge during core study
- To assess progression of peripheral intraretinal vascularization beyond ridge during core study
- Safety determined by number and kind of AEs and SAEs per group during core study
- To compare the changes in vascular endothelial growth factor (VEGF) levels in the systemic circulation during core study
- To assess the number of re-injections of study dose during core study
- To assess the number of patients progressing to stage 4 or 5 ROP during core study
- To assess the number of patients with complete vascularization of the peripheral retina to within one disc diameter of the ora serrata during core study

- Rückgang der Gefäßschlängelungen im Verlauf der Studie
- Rückgang des prominenten Walls im Verlauf der Studie
- Fortschreiten der Gefäßneubildungen über den Wall hinaus im Verlauf der Studie
- Anzahl und Art der unerwünschten Ereignisse (UEs) und schwerwiegenden unerwünschten Ereignisse (SUEs) pro Gruppe im Verlauf der Studie
- Vergleich der Änderungen in den systemischen VEGF- Spiegeln (Plasmaproben)
- Anzahl der Re-Injektionen (Studiendosis) im Verlauf der Studie
- Anzahl der Kinder, bei denen es im Verlauf der Studie zum Voranschreiten der ROP zu Stadium 4 oder 5 kommt
- Anzahl der Kinder mit einer kompletten intraretinalen Vaskularisation der Retina bis zur Ora serrata im Verlauf der Studie

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Bilateral ROP in zone I (stage 1+, 2+, 3+/-, AP-ROP) or ROP in central (=posterior) zone II (stage 3+, AP-ROP). Zone I is defined as twice the distance from the optic disc to the fovea measured temporally, posterior zone II is defined as three times the distance from the optic disc to the fovea measured temporally. Treatment zones will be documented with a RetCam (if available).
2. Legal representatives or their designates willing and able to attend regular study visits with the study infant.
3. Written informed consent to participate in the study (signed by all patient’s legal representatives)

1. Bilaterale ROP in Zone I (Stadium 1+, 2+, 3+/-, Aggressive posteriore ROP) oder bilaterale ROP in posteriorer Zone II (Stadium 3+, Aggressive posteriore ROP). Zone I wird definiert als zweifacher Abstand von Papille (Sehnerv) zur Fovea auf temporaler Seite. Die posteriore Zone II wird definiert als dreifacher Abstand von Papille zur Fovea auf temporaler Seite. Die Behandlungszonen werden mit Hilfe einer RetCam, falls eine RetCam vorhanden ist, dokumentiert.
2. Bereitschaft der gesetzlichen Vertreter nach Krankenhausentlassung zusammen mit ihrem Kind an den Studienvisiten teilzunehmen.
3. Schriftliche Einwilligungserklärung durch die gesetzlichen Vertreter des Patienten zur Teilnahme an der Studie.

E.4

Principal exclusion criteria

1. Pediatric conditions rendering the infant ineligible to anti-VEGF treatment or to repeated blood draws as evaluated by a neonatal ICU specialist and a study ophthalmologist.
2. Congenital brain lesions significantly impairing optic nerve function.
3. Severe hydrocephalus with significantly increased intracranial pressure.
4. Advanced stages of ROP with partial or complete retinal detachment (ROP stage 4 and 5).
5. ROP involving only the peripheral retina (i.e. peripheral zone II or zone III).
6. Known hypersensitivity to the study drug or to drugs with similar chemical structures.
7. Contraindications for an intravitreal injection as listed in ranibizumab SmPC.
8. Systemic use of anti-VEGF therapeutics.
9. Use of other investigational drugs - excluding vitamins and minerals - at the time of enrollment, or within 30 days or 5 half-lives prior to enrollment, whichever is longer.

1. Gesundheitliche Verfassung, die eine anti-VEGF Behandlung oder vermehrte Blutentnahmen ausschließt. Die Beurteilung erfolgt durch einen Neonatologen der neonatologischen Intensivstation gemeinsam mit einem Ophthalmologen der Prüfgruppe.
2. Angeborene Gehirnverletzungen, die die Sehnervenfunktion deutlich beeinträchtigen.
3. Stark ausgeprägter Hydrocephalus mit deutlich erhöhtem Schädelinnendruck.
4. Fortgeschrittenes Stadium der ROP mit teilweiser oder kompletter Ablatio Retinae (Stadium 4 oder 5).
5. Frühgeborenenretinopathie nur im peripheren Bereich der Retina (periphere Zone II oder Zone III).
6. Bekannte Überempfindlichkeit gegenüber der Studienmedikation oder gegenüber anderen Medikamenten mit ähnlicher chemischer Struktur.
7. Kontraindikation für eine intravitreale Injektion entsprechend der Fachinformation für Ranibizumab
8. Systemische Anwendung von anti-VEGF Medikamenten.
9. Anwendung anderer Studienmedikamente – außer Vitamine und Mineralien – zum Zeitpunkt des Einschlusses oder innerhalb von 30 Tagen bzw. 5 Halbwertszeiten vor Einschluss, je nachdem welcher Zeitraum länger ist.

E.5 End points

E.5.1

Primary end point(s)

number of infants without need for rescue treatment

Anzahl der Kinder die keine Notfall-Behandlung benötigen

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24

Woche 24

E.5.2

Secondary end point(s)

- Number of infants with regression of plus disease, regression of preretinal vascularized ridge, and progression of peripheral intraretinal vascularization beyond ridge during core study
- Number of patients progressing to stage 4 or 5 ROP during core study
- Number of patients with complete vascularization of the peripheral retina to within one disc diameter of the ora serrata during core study
- The number of ranibizumab regular (re-)injections during the core study as well as the time to (regular) re-injections

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 24

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

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

different dosage of same product

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

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

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)

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 born infants

Frühgeborene

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)

After the trial there will be an additional 4.5 years observational follow-up phase (opthalmologic examination 1 and 5 years after trial start, paediatric examination 2 and 5 years after trial start). The Treatment of the patients after end of the Trial lies within discretion of the treating physician.

Nach Abschluss der klinischen Prüfung schließt sich eine zusätzliche 4.5-jährige Nachbeobachtungsperiode an (augenärztliche Untersuchung 1 und 5 Jahre nach Studienstart, kinderärztliche Untersuchung 2 und 5 Jahre nach Studienstart). Die Behandlung der Patienten nach Abschluss der klinischen Prüfung liegt im Ermessen des Prüfarztes.

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

2014-04-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-24

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

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