Clinical Trials Register

Summary
EudraCT Number:	2011-002350-31
Sponsor's Protocol Code Number:	CRFB002E2401
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-06
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-002350-31

A.3

Full title of the trial

A 24-month, phase IIIb, open-label, single arm, multicenter study assessing the efficacy and safety of an individualized, stabilization criteria-driven PRN dosing regimen with 0.5-mg ranibizumab intravitreal injections applied as monotherapy in patients with visual impairment due to macular edema secondary to central retinal vein occlusion (CRVO).

Studio di fase IIIb, in aperto, a braccio singolo, multicentrico, della durata di 24 mesi per valutare l'™efficacia e la sicurezza di un regime di dosaggio individualizzato, somministrato al bisogno (PRN) secondo criteri di stabilizzazione con iniezioni intravitreali di ranibizumab 0,5 mg applicate come monoterapia in pazienti con diminuzione visiva dovuta ad edema maculare secondario ad occlusione della vena centrale della retina (CRVO).

A.3.1

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

Ranibizumab treatment of visual impairment caused by occluded vessels (veins) that lead to swelling of the retina in the back of the eye.

Ranibizumab nel trattamento della diminuzione visiva causata dall'occlusione venosa che porta ad un rigonfiamento della retina nella parte posteriore dell'occhio.

A.3.2

Name or abbreviated title of the trial where available

Crystal

A.4.1

Sponsor's protocol code number

CRFB002E2401

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	NOVARTIS PHARMA AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PPD
B.5.2	Functional name of contact point	Project Management
B.5.3	Address:
B.5.3.1	Street Address	3900 Paramount Parkway
B.5.3.2	Town/ city	Morrisville
B.5.3.3	Post code	27580
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 919 5613005
B.5.5	Fax number	+1 919 6549184
B.5.6	E-mail	marie.hanssen@ppdi.com

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 Pharma Stein AG
D.2.1.2	Country which granted the Marketing Authorisation	Switzerland
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.3.4	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.3.9.2	Current sponsor code	RFBOO2
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB22314
D.3.10	Strength
D.3.10.1	Concentration unit	µl microlitre(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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

Visual impairment due to macular edema secondary to central retinal vein occlusion (CRVO)

Diminuzione visiva dovuta a edema maculare secondario all'occlusione della vena centrale retinica (CRVO)

E.1.1.1

Medical condition in easily understood language

Visual impairment caused by occluded vessels (veins) that lead to swelling of the retina in the back of the eye

Diminuzione visiva dovuta ad occlusione venosa che porta al rigonfiamento della retina nella parte posteriore dell'occhio.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10007972
E.1.2	Term	Central retinal vein occlusion
E.1.2	System Organ Class	10015919 - Eye 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

The primary objective is to evaluate the efficacy of an individualized stabilization criteria-driven PRN dosing regimen with 0.5 mg ranibizumab as assessed by the mean BCVA change at Month 12 compared to Baseline.

L’obiettivo primario è di valutare l’efficacia di un regime di dosaggio individualizzato, somministrato al bisogno secondo criteri di stabilizzazione con ranibizumab 0,5 mg, valutata mediante la variazione media della miglior acuità visiva corretta (BCVA) misurata al Mese 12 rispetto alla Baseline.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of PRN dosing of 0.5-mg ranibizumab injections as assessed by: • the mean change in BCVA • the mean average change in BCVA • the proportion of patients achieving: - BCVA improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 letters - reaching BCVA values of ≥73 letters (approximate 20/40 Snellen chart equivalent) - with a BCVA loss of <15 letters • the mean change in central reading center (CRC)-assessed central subfield thickness (CSFT) • the patient-reported outcomes by the NEI-VFQ-25 composite score and subscales To evaluate the mean average change in BCVA from the timepoint of the first treatment interruption (if due to BCVA stabilization) To evaluate the mean change in BCVA by visit from the timepoint of the first treatment interruption (if due to BCVA stabilization) To evaluate the safety of ranibizumab injections as assessed by the type, frequency,..

Gli obiettivi secondari di questo studio sono i seguenti: 1. Valutare l’efficacia di iniezioni di Ranibizumab a regime di dosaggio PRN di 0.5 mg, valutata da: - la variazione media dell’acuità visiva corretta al meglio (BCVA) dal Mese 1 al mese 24 rispetto alla Baseline - la media della variazione media dell’acuità visiva corretta al meglio (BCVA) dal Mese 1 al mese 12 e al mese 24 rispetto alla Baseline - la proporzione di pazienti che raggiungeranno un miglioramento dell’acuità visiva corretta al meglio (BCVA) di ≥1, ≥5, ≥10, ≥15 e ≥30 lettere dal Baseline al mese 12 e al mese 24. - la proporzione di pazienti che raggiungeranno valori dell’acuità visiva corretta al meglio (BCVA) di ≥ 73 lettere (approssimato a 20/40 dell’equivalente tavola di Snellen) - la proporzione di pazienti con una perdita di acuità visiva corretta al meglio (BCVA) di <15 lettere dal Baseline .....

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Written informed consent must be obtained before any study assessment is performed- Male or female patients must be at least 18 years of age - Diagnosis of visual impairment exclusively due to ME secondary to central retinal vein occlusion (CRVO) - Best-corrected visual acuity at Screening and Baseline must be between 73 and 19 letters Early Treatment Diabetic Retinopathy Study (ETDRS), inclusively (approximate Snellen chart equivalent of 20/40 and 20/400)

Criteri di inclusione principali: • Il consenso informato scritto deve essere ottenuto prima dell’esecuzione di qualsiasi valutazione dello studio • Pazienti di sesso maschile o femminile di età ≥ 18 anni • Diagnosi di diminuzione visiva esclusivamente dovuta a edema maculare secondario a CRVO • Punteggio BCVA allo Screening e alla Baseline compreso tra 73 e 19 lettere utilizzando le tavole di acuità visiva ETDRS (Early Treatment Diabetic Retinopathy Study), estremi inclusi (all’incirca equivalente a 20/40 e 20/400 con la tavola di Snellen)

E.4

Principal exclusion criteria

Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test • Stroke or myocardial infarction less than 3 months prior to Screening • Uncontrolled blood pressure defined as systolic value of >160 mm Hg or diastolic value of >100 mm Hg at Screening or Baseline. Antihypertensive treatment can be initiated and has to be taken for at least 30 days after which the patient can be assessed for study eligibility a second time • Any active periocular or ocular infection or inflammation (eg, blepharitis, conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) at Screening or Baseline in either eye • Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication or according to investigator's judgment) at Screening or Baseline or diagnosed within 6 months prior to Baseline in either eye • Neovascularization of the iris or neovascular glaucoma in either eye • Use of any systemic anti-vascular endothelial growth factor (VEGF) drugs within 6 months prior to Baseline (eg, sorafenib [Nexavar], sunitinib [Sutent], bevacizumab [Avastin]) • Prior treatment with any anti-angiogenic drugs (including any anti- VEGF agents) within 3 months prior to Baseline in either eye (eg, pegaptanib [Macugen], ranibizumab [Lucentis], bevacizumab [Avastin]) • Panretinal laser photocoagulation within 3 months prior to Baseline or anticipated or scheduled within the next 3 months following Baseline in the study eye • Focal or grid laser photocoagulation within 4 months prior to Baseline in the study eye • Use of intra- or periocular corticosteroids (including sub-Tenon) within 3 months prior to Screening in the study eye • Any use of intraocular corticosteroid implants (eg, dexamethasone [Ozurdex], fluocinolone acetonide [Iluvien]) in the study eye.

Criteri di esclusione principali: • Donne in stato di gravidanza o in allattamento, dove la gravidanza è definita come lo stato di un soggetto di sesso femminile dopo il concepimento e fino al termine della gestazione confermato mediante positività al test di laboratorio sulla gonadotropina corionica umana (hCG) • Ictus o infarto miocardico avvenuto meno di 3 mesi prima dello Screening • Pressione sanguigna non controllata definita come valore sistolico >160 mm Hg o valore diastolico >100 mm Hg allo Screening o alla Baseline. In questo caso è possibile iniziare un trattamento con antipertensivo e questo deve essere assunto per almeno 30 giorni, prima che il paziente possa essere valutato una seconda volta per l’inclusione nello studio • Qualsiasi infezione o infiammazione perioculare od oculare attiva (ad es. blefarite, congiuntivite, cheratite, sclerite, uveite, endoftalmite) allo Screening o alla Baseline in uno degli occhi • Glaucoma non controllato (pressione intraoculare [IOP] ≥30 mm Hg durante l’assunzione del farmaco o secondo il giudizio dello sperimentatore) allo Screening o alla Baseline o diagnosticato nei 6 mesi precedenti la Baseline in uno degli occhi • Neovascolarizzazione dell’iride o glaucoma neovascolare in uno degli occhi • Uso di qualsiasi fattore di crescita endoteliale anti-vascolare (VEGF) sistemico nei 6 mesi precedenti la Baseline (ad es. sorafenib [Nexavar], sunitinib [Sutent], bevacizumab [Avastin]) • Precedente trattamento con qualsiasi farmaco antiangiogenico nei 3 mesi prima della Baseline in uno degli occhi (ad es. pegaptanib [Macugen], ranibizumab [Lucentis], bevacizumab [Avastin])) • Fotocoagulazione laser panretinica nei 3 mesi precedenti la Baseline o prevista o programmata nei 3 mesi successivi la Baseline nell’occhio oggetto dello studio. • Fotocoagulazione laser focale o a griglia nei 4 mesi precedenti la Baseline nell’occhio oggetto dello studio • Uso di corticosteroidi intraoculari o perioculari (compresi i sottotenoniani) nei 3 mesi precedenti lo Screening nell’occhio oggetto dello studio • Qualsiasi uso di impianti di corticosteroidi intraoculari (ad es. desametasone [Ozurdex], fluocinolone acetonide [Iluvien]) nell’occhio oggetto dello studio.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is the mean change in BCVA at Month 12 compared to Baseline.

La variabile primaria di efficacia è la variazione media di BCVA al mese 12 rispetto al baseline.

E.5.1.1

Timepoint(s) of evaluation of this end point

At Month 12 compared to Baseline.

Al mese 12 rispetto al baseline.

E.5.2

Secondary end point(s)

The following secondary efficacy endpoints will be evaluated for the study eye: • the mean change in BCVA from Month 1 through Month 24 compared to Baseline, by visit • the mean change in BCVA from Month the timepoint of the first treatment interruption (due to BCVA stabilization) through Month 24, by visit • the mean average change in BCVA from Month 1 through Month 12 and from Month 1 through Month 24 compared to Baseline • the mean average change in BCVA from the timepoint of the first treatment interruption (due to BCVA stabilization) through Month 12 and/or Month 24 • the number and proportion of patients with a BCVA improvement of ≥ 1, ≥5, ≥10, ≥15, and ≥30 letters from Baseline to Month 12 and Month 24, by visit • the number and proportion of patients with a BCVA value of ≥73 letters (approximate 20/40 Snellen chart equivalent) at Month 12 and Month 24, by visit • the number and proportion of patients with a BCVA loss of <15 letters from Baseline up to Month 12 and Month 24, by visit • the mean change in CRC-assessed CSFT from Month 1 through Month 12 and Month 24 compared to Baseline • the mean change in patient-reported outcomes in NEI-VFQ-25 score (composite score and subscales) at Month 12 and Month 24 compared to Baseline

I seguenti endpoints secondari di efficacia saranno valutati per lo studio sull’occhio: - la variazione media dell’acuità visiva corretta al meglio (BCVA) dal Mese 1 al mese 24 rispetto alla Baseline, attraverso la visita. - la variazione media dell’acuità visiva corretta al meglio (BCVA) dal mese preciso della prima interruzione del trattamento (causato dalla stabilizzazione dell’acuità visiva corretta al meglio – BCVA-) fino al Mese 24, attraverso la visita - la media della variazione media dell’acuità visiva corretta al meglio (BCVA) dal mese 1 fino al Mese 12 e dal mese 1 fino la mese 24 rispetto al Baseline - la media della variazione media dell’acuità visiva corretta al meglio (BCVA) dal momento preciso della prima interruzione del trattamento (causato dalla stabilizzazione dell’acuità visiva corretta al meglio – BCVA-) fino al Mese 12 e/o al Mese 24 - il numero e la proporzione di pazienti con un miglioramento dell’acuità visiva corretta al meglio (BCVA) pari a ≥1, ≥5, ≥10, ≥15 e ≥30 lettere dal Baseline al mese 12 e al mese 24, attraverso la visita - il numero e la proporzione di pazienti con un valore dell’acuità visiva corretta al meglio (BCVA) pari a ≥ 73 lettere (approssimato all’equivalente 20/40 della tavola di Snellen), attraverso la visita - il numero e la proporzione di pazienti con una perdita di acuità visiva corretta al meglio (BCVA) di <15 lettere dal Baseline fino al mese 12 e mese 24, attraverso la visita - la variazione media dello spessore del sottocampo centrale (CSFT) valutato tramite il centro di lettura centrale (CRC) dal mese 1 al mese 12 e mese 24, rispetto al Baseline - la variazione media dei risultati riportati dal paziente nel punteggio del questionario NEI-VFQ-25 (punteggio composito e sottoscale) al mese 12 e al mese 24 rispetto al Baseline.

E.5.2.1

Timepoint(s) of evaluation of this end point

From Month 1 through Month 12 and from Month 1 through Month 24 compared to Baseline

Dal mese 1 al mese 12 e dal mese 1 al mese 24, rispetto al baseline.

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Australia

Canada

Switzerland

Turkey

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

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)

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)

Yes

F.1.2.1

Number of subjects for this age range:

105

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

245

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

Yes

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

Legal representative (legally authorized to act as personal representative to sign for patient) may sign ICF

Il Rappresentante Legale (legalmente autorizzato a firmare per il paziente come personale rappresentante) può firmare il consenso informato.

F.3.3.7

Others

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

310

F.4.2.2

In the whole clinical trial

350

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)

There are no plans after the end of treatment. Standard of care.

Non è stato pianificato alcun trattamento altermine dello studio. I pazienti saranno trattati con la terapia standard per la patologia.

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

2012-03-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-04-23

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