Clinical Trials Register

Summary
EudraCT Number:	2012-005417-38
Sponsor's Protocol Code Number:	CRFB002G2301
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-10
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

Spain - AEMPS

A.2

EudraCT number

2012-005417-38

A.3

Full title of the trial

A 12-month, randomized, double-masked, sham-controlled, multicenter study to evaluate the efficacy and safety of 0.5mg ranibizumab intravitreal injections in patients with visual impairment due to vascular endothelial growth factor (VEGF)-driven choroidal neovascularization (CNV)

Estudio multicéntrico, aleatorizado, con doble enmascaramiento, con control simulado de 12 meses de duración para evaluar la eficacia y la seguridad de inyecciones intravítreas de 0,5 mg de ranibizumab en pacientes con afectación visual debida a una neovascularización coroidea (NVC) causada por el factor de crecimiento endotelial vascular (VEGF)

A.3.1

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

A 12-month study to evaluate the efficacy and safety of injections of 0.5 mg ranibizumab into the eye of patients with impaired vision which is caused by new vessels (neovascularization) in the choroid and for which ranibizumab may have a positive impact

Estudio de 12 meses de duración para evaluar la eficacia y seguridad de inyecciones de 0.5 mg de ranibizumab en el ojo de pacientes con visión afectada debrido a nuevos vasos en la coroide y para los que ranibizumab podria tener un impacto positivo

A.4.1

Sponsor's protocol code number

CRFB002G2301

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 Farmacéutica, S.A.
B.1.3.4	Country	Spain
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	Novartis Farmacéutica, S.A.
B.5.2	Functional name of contact point	Departamento Médico (ICRO)
B.5.3	Address:
B.5.3.1	Street Address	Gran Via de les Corts Catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34900353036
B.5.5	Fax number	+34932479903
B.5.6	E-mail	eecc.novartis@novartis.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 Europharm Limited
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	Lucentis
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	RFB002
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.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 vascular endothelial growth factor (VEGF) driven choroidal neovascularization (CNV)

Afectación visual debida a una neovascularización coroidea (NVC) causada por el factor de crecimiento endotelial vascular (VEGF)

E.1.1.1

Medical condition in easily understood language

Impaired vision due to abnormal growth of blood vessels in the choroid which is caused by an intrinsic substance, so-called vascular endothelial growth factor (VEGF)

Afectación visual debida al crecimiento anormal de vasos en la coroide que es causado por una sustancia intrinseca llamada factor de crecimeinto del endotelio vascular

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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10060837
E.1.2	Term	Choroidal neovascularization
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	PT
E.1.2	Classification code	10047571
E.1.2	Term	Visual impairment
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

To demonstrate that intravitreal injection of 0.5 mg ranibizumab, administered based on individual patient needs has superior efficacy compared to sham treatment in adult patients with visual impairment due to VEGF-driven CNV other than wAMD and PM. The primary objective will be assessed by the best corrected visual acuity (BCVA) change from baseline to Month 2.

Demostrar que una pauta individualizada de inyección intravítrea de 0,5 mg de ranibizumab tiene una eficacia superior en comparación con el tratamiento simulado en pacientes adultos con afectación visual debida a una NVC causada por VEGF. El objetivo principal se evaluará mediante el cambio de la AVMC desde la basal hasta el mes 2.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of ranibizumab as compared to sham treatment by assessing
? BCVA change over time to Month 2
? change in CSFT and CSFV (by OCT) from baseline (BL) over time to Month 2
? presence of intra-/sub-retinal fluid (by OCT) and presence of active chorioretinal leakage (by FA) at Month 2
To evaluate the efficacy of ranibizumab by original treatment assignment by assessing:
? average BCVA change from Month 1 to 6 from Month 1 to 12 compared to BL
? change from BL in CSFT and CSFV assessed by OCT by visit
? presence of intra-/subretinal fluid (by OCT) and presence of active chorioretinal leakage (by FA) at Month 2, 6 and 12 compared to BL
?proportion of patients with ? 1,? 5,? 10 and ? 15 letters gain or reaching 84 letters, at Month 2, 6 and 12
To assess the number of ranibizumab (re-)treatments by Month 2, 6 and 12
To evaluate the safety of ranibizumab as assessed by type, frequency and severity of
ocular and non-ocular AE up to months 2, 6 and 12

Evaluar la eficacia de ranibizumab en comparación con el tratamiento simulado según la valoración de los factores siguientes:
? Cambio en la AVMC al mes 2
? Cambio en el GMC y en el VMC desde la basal hasta el mes 2.
? Presencia de líquido intrarretiniano/subretiniano en el mes 2.

Evaluar la eficacia de ranibizumab como tratamiento original según la valoración de los factores siguientes:
? Cambio medio en la AVMC desde la basal hasta el mes 1 y mes 6, y hasta el mes 1 continuando hasta el mes 12.
? Cambio en el GMC y el VMC desde la basal analizado mediante OCT por visita.
? Aumento ? 1, ? 5, ? 10 y ? 15 letras o consecución de 84 letras, en el mes 2, el mes 6 y el mes 12.

Evaluar el número de tratamientos y retratamientos con ranibizumab en el mes 2, el mes 6 y el mes 12.

Evaluar la seguridad de ranibizumab por tipo, frecuencia y gravedad de los acontecimientos adversos oculares y no oculares hasta el mes 2, hasta el mes 6 y hasta el mes 12.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

To describe the efficacy and safety of ranibizumab in adolescent patients

Evaluar la eficacia y la seguridad de ranibizumab en pacientes adolescentes

E.3

Principal inclusion criteria

1. Diagnosis of treatment naïve active CNV secondary to any causes, except wAMD and PM in adults;
2. All types of CNV lesions present in the study eye;
3. BCVA must be between ? 24 and ? 83 letters in the study eye tested at 4 meters starting distance using ETDRS-like visual acuity charts;
4. Visual loss in the study eye should only be due to the presence of any eligible types of CNV based on ocular clinical, as well as FA and OCT images.

1. Diagnóstico de una NVC activa que no haya recibido tratamiento secundaria a cualquier causa, salvo DMAEh y MP en pacientes adultos
2. El ojo en estudio presenta al menos uno tipo de lesion
3. La AVMC debe encontrarse entre ? 24 y ? 83 letras en el ojo en estudio, comprobado a una distancia inicial de 4 metros mediante optotipos de agudeza visual del tipo ETDRS
4. La pérdida visual del ojo en estudio solo deberá estar causada por la presencia de cualquier tipo elegible de NVC (en pacientes adultos, salvo DMAEh y MP) según exploraciones oculares clínicas y hallazgos en AF y OCT.

E.4

Principal exclusion criteria

1. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment;
2. History of malignancy of any organ system within the past 5 years;
3. History of stroke less than 6 months prior to screening;
4. Active systemic inflammation or infection, related directly
to the underlying causal disease of CNV at screening;
5. Active diabetic retinopathy, active ocular/periocular infectious disease or active intraocular inflammation at screening
6. Confirmed intraocular pressure ? 25 mmHg for any reason at screening
7. Neovascularization of the iris or neovascular glaucoma at screening
8. CNV secondary to PM or wAMD
9. Use of any systemic anti-VEGF drugs within 6 months before baseline;
10. History of focal laser photocoagulation with involvement of the macular area
administered to treat CNV at any time;
11. History of intraocular treatment with any anti-angiogenic drugs or
verteporfin photodynamic therapy at any time;
12. History of intravitreal treatment with corticosteroids at any time;
13. History of vitreoretinal surgery at any time. Other
protocol-defined inclusion/exclusion criteria may apply.

1. Mujeres en edad fértil, definidas como toda mujer fisiológicamente capaz de quedarse embarazada, salvo que estén utilizando métodos anticonceptivos efectivos durante la administración del tratamiento del estudio.
2. Antecedentes de cáncer de cualquier sistema orgánico (salvo carcinoma cutáneo de células basales o escamosas localizado), tratado o no tratado, durante los últimos 5 años, independientemente de que existan o no pruebas de recurrencia local o metástasis.
3. Antecedentes de accidente cerebrovascular menos de 6 meses antes de la selección.
4. Inflamación sistémica activa o infección , relacionada directamente con la enfermedad subyacente causante de la NVC en la selección.
5. Retinopatía diabética activa, enfermedad infecciosa ocular/periocular activa o inflamación intraocular activa en la selección.
6. Presión intraocular confirmada (PIO) ? 25 mmHg por cualquier motivo en la selección.
7. Neovascularización del iris o glaucoma neovascular en la selección.
8. NVC secundaria a la MP o DMAEh (solo en pacientes adultos).
9. Uso de otros fármacos en investigación (excepto vitaminas y minerales) en el momento de la inclusión, o durante los 30 días o 5 semividas anteriores a la inclusión, aquello que sea más largo.
10. Antecedentes de fotocoagulación focal con láser con afectación de la zona macular administrada para tratar la NVC en cualquier momento.
11. Antecedentes de tratamiento intraocular con cualquier fármaco antiangiogénico (incluyendo cualquier agente anti-VEGF) o terapia fotodinámica verteporfina (TFDv) en cualquier momento.
12. Antecedentes de tratamiento intravítreo con corticosteroides en cualquier momento.
13. Antecedentes de cirugía intrarretiniana en cualquier momento.
ver protocolo para el resto de criterios

E.5 End points

E.5.1

Primary end point(s)

Best corrected visual acuity (BCVA) change from baseline to Month 2

Cambio en la Mejor Agudeza Visual Corregida (MAVC) desde la visita basal a mes 2

E.5.1.1

Timepoint(s) of evaluation of this end point

month 2

mes 2

E.5.2

Secondary end point(s)

1) BCVA change from baseline by visit up to Month 2 in study eye (ranibizumab as compared to sham treatment)
2) Change in central subfield thickness (CSFT) and central subfield volume (CSFV) in study eye from baseline over time to
Month 2
3) Presence of intra-/subretinal fluid in study eye at Month 2
4) Presence of active chorioretinal leakage assessed by FA at Month 2
5) Average BCVA change in study eye from baseline to Month 1 through Month 12
6) Change from baseline in CSFT and CSFV in study eye by visit
7) Presence of intra-/subretinal fluid in study eye at Month 2, Month 6 and Month 12 compared to Baseline
8) Presence of active chorioretinal leakage in study eye at Month 2, Month 6 and Month 12 compared to Baseline
9) Proportion of patients with ? 1, ? 5, ? 10 and ? 15 letters gain or reaching 84 letters in study eye, at Month 2, Month 6 and Month 12
10) Proportion of patients with > 1, > 5, > 10 and > 15 letters loss at Month 2, Month 6 and Month 12
11) Number of ranibizumab treatments and retreatments to study eye by Month 2, Month 6 and Month 12
12) Type, frequency and severity of ocular and non-ocular adverse events in the study eye up to Month 2, up to Month 6 and up to Month 12
13) Requirement for rescue treatment at Month 1

1) Cambio en la AVMC con respecto a la basal, a lo largo del tiempo, por visita hasta mes 2 en el ojo de estudio.
2) Cambio en el GMC y el MC con respecto a la basal, a lo largo del tiempo, por visita hasta mes 2.
3) Presencia de líquido intrarretiniano/subretiniano el el ojo de estudio en el mes 2.
4) Presencia de infiltrado cororetiniano valorado por AF en el mes 2
5) Cambio medio en la AVMC desde mes 1 a mes 12.
6) Cambio por visita desde basal en el GMC y VMC.
7) Presencia de líquido intrarretiniano/subretiniano el el ojo de estudio en el mes 2, 6 y 12 comparado al basal.
8) Presencia de infiltrado cororetiniano en el mes 2, 6 y 12 comparado con basal
9) Ganancia en la AVMC ? 1, ? 5, ? 10 y ? 15 letras o consecución de 84 letras con respecto a la basal, en el mes 2, el mes 6 y el mes 12.
10) Pérdida en la AVMC ? 1, ? 5, ? 10 y ? 15 letras en el mes 2, el mes 6 y el mes 12.
11) numero de tratamientos y retratamientos con ranibizumab en el ojo de estudio hasta mes 2, 6 y 12.
12) Tipo, frecuencia y severidad de los efectos adversos oculares y no ocularesen el ojo de estudiohasta mes 2, 6 y 12.
13) Requerimeinto de medicación de rescate en mes 1

E.5.2.1

Timepoint(s) of evaluation of this end point

see above

ver arriba

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

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

Yes

E.8.1.7.1

Other trial design description

grupo de tratamiento abierto para adolescentes

open label group for adolescents

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

simulacion de inyeccion (solo adultos)

sham injection (adults only)

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

Belgium

Brazil

Canada

Czech Republic

Denmark

France

Germany

Greece

Hong Kong

Hungary

India

Italy

Korea, Republic of

Latvia

Lithuania

Peru

Poland

Portugal

Russian Federation

Singapore

Slovakia

South Africa

Spain

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

Ultima visita del ultimo paciente

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:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

157

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

F.4.2.2

In the whole clinical trial

187

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)

None

Ninguno

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

2013-08-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-11-11

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IMP with orphan designation in the indication
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