Clinical Trials Register

Summary
EudraCT Number:	2012-000165-20
Sponsor's Protocol Code Number:	OZUROFT01/12
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:	2012-01-31
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

Spain - AEMPS

A.2

EudraCT number

2012-000165-20

A.3

Full title of the trial

SEQUENTIAL CLINICAL TRIAL TO EVALUATE THE EFFECTIVENESS OF INTRAVITREAL BEVACIZUMAB AS RESCUE TREATMENT OF RECURRENT MACULAR EDEMA SECONDARY TO RETINAL VEIN OCCLUSION TREATED WITH OZURDEX

ENSAYO CLÍNICO SECUENCIAL PARA EVALUAR LA EFICACIA DE BEVACIZUMAB INTRAVÍTREO COMO TRATAMIENTO DE RESCATE DE LA RECIDIVA DEL EDEMA MACULAR SECUNDARIO A OCLUSION DE VENA DE RETINA TRATADO CON OZURDEX

A.3.1

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

Clinical trial to evaluate the results of intravitreal bevacizumab injections in cases of recurrence of macular edema secondary to retinal vein thrombosis previously treated with ozurdex

Ensayo Clínico para evaluar los resultados del tratamiento con inyecciones intravítreas de bevacizumab en los casos de recidiva del edema macular secundario a trombosis de vena de retina que ha sido tratado previamente con ozurdex

A.4.1

Sponsor's protocol code number

OZUROFT01/12

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	Fundación para la Investigación biomédica del Hospital Universitario Ramón y Cajal. Madrid
B.1.3.4	Country	Spain
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	Concedida ayuda a la investigación clínica independiente 2011.MSPI. EC11-136
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundación para la Investigación biomédica del Hospital Universitario Ramón y Cajal. Madrid
B.5.2	Functional name of contact point	Dra Moreno López
B.5.3	Address:
B.5.3.1	Street Address	Carretera de Colmenar Viejo Km 9.100
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28034
B.5.3.4	Country	Spain
B.5.4	Telephone number	34913368633
B.5.6	E-mail	mmorelop@gmail.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	AVASTIN
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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 infusion
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	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.25
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Macular edema secondary to retinal vein occlusion

Edema macular secundario a oclusiones venosas de retina

E.1.1.1

Medical condition in easily understood language

Visual loss due to Macular edema after retinal vein occlusion

La pérdida de visión por edema macular debido a trombosis venosa de la retina

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	PT
E.1.2	Classification code	10038907
E.1.2	Term	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

Visual acuity (VA) gain and foveal thickness reduction by OCT.

We define success in the following cases:

(a) Functional success: ≥ 3-lines gain in VA.

(b) Anatomical success (measured with OCT):

(b1) Full anatomical success: absence of LIR, abscence of LSR and foveal thickness less than or equal to 300 microns.
(b2) Partial anatomical success: ≥ 30% foveal thickness reduction from baseline.

Ganancia de agudeza visual (AV) y reducción del grosor foveal central por tomografía de coherencia óptica (OCT).

Definimos éxito en cualquiera de los siguientes supuestos:
(a) Éxito funcional: Pacientes que ganan ≥ 3 líneas de AV;
(b) Éxito anatómico (medido con OCT): (b1)Éxito anatómico absoluto: ausencia de LIR y LSR con grosor foveal menor igual a 300 µm; (b2)Éxito anatómico relativo: descenso ≥ 30% de grosor foveal.

E.2.2

Secondary objectives of the trial

1. To evaluate the reduction in the number of patients requiring a second Ozurdex implant.
2. To evaluate the number of intravitreal bevacizumab injections (IVB) that are required to stabilize the macular edema (ME).
3. To assess the safety of IVB in the treatment of ME due to retinal vein occlusion (RVO).
4. To identify positive predictor factors of IVB rescue treatment

a)Evaluar la reducción en el número de pacientes que precisen un segundo implante de Ozurdex.
b) Evaluar el número de inyecciones de bevacizumab que se precisan para estabilizar/ resolver el edema de mácula.
c) Evaluar la seguridad de bevacizumab intravítreo (IVB) en el edema macular de las oclusiones de vena de retina.
d) Identificar factores pronósticos de respuesta al rescate con IVB

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

(a) Patients ≥ 18 years of age;
(b) Who have been diagnosed with CRVO or BRVO of <1 year of evolution;
(c) Subjects who have been treated for ME secondary to RVO with a single Ozurdex implant within 6 months and who have recurrence or persistence of ME at 2 months following Ozurdex implant.
(d) Patients who have received thorough information on the design, the purpose of the study, the potential risks and understand their rigths to refuse to participate in the study at any time, and have signed the informed consent document.
(e) Patients who understand the purpose of the study and are available to make the necessary follow-up visits.
(f) Both in the case of female and male patients, the patient agrees to use
a double barrier method of contraception from the moment of signing
the informed consent until 6 months after the end of their participation
in the study
(g) negative pregnancy test

(a) Pacientes ≥ 18 años de edad;
(b) Estar diagnosticados de OVCR y ORVR de < 1 año de evolución;
(c) Haber sido tratados por EM secundario a OVR con un único implante de Ozurdex en los 6 meses previos y que presentan recidiva o persistencia del EM a partir del 2º mes del implante;
(d) Haber recibido información sobre el diseño, los fines del estudio, los posibles riesgos que de él pueden derivarse y de que en cualquier momento pueden denegar su colaboración y consentir por escrito en participar en el estudio;
(e) Entender el propósito del estudio y estar disponibles a realizar las visitas necesarias
(f) Las mujeres en edad fértil y los varones con pareja en edad fértil deben comprometerse (paciente y pareja) a utilizar un método anticonceptivo de gran eficacia (esterilización quirúrgica, método de barrera fiable, anticonceptivos orales o implantes hormonales contraceptivos) y a continuar utilizándolos hasta 6 meses después de la última dosis del fármaco en investigación
(g) test de embarazo negativo

E.4

Principal exclusion criteria

(f) Subjects who have received oral or intravitreal treatment for ME in the 4 months prior to Ozurdex implant.

(g) Subjects who have undergone laser ophthalmic treatment or eye surgery within 4 months prior to OZURDEX.

(h) Subjects having any systemic disease that prevents the use of BIV (pregnancy, lactation, uncontrolled hypertension, diabetic retinopathy or uncontrolled systemic disease).

(i) Subjects on topical prostaglandin analogues for ocular hipertension.

(j) Allergy to any component of Avastin.

(k) The presence of clinically significant vitreoretinal traction or macular epiretinal membrane on OCT.

(l) The presence of optic disc or retinal neovascularization, past or active choroidal neovascularization, active eye infection, aphakia or anterior chamber intraocular lens or significant media opacity.

(m) Any eye condition that to the investigator's discretion may prevent a ≥ 3- line gain in VA.

(n) Pregnancy o breast feeding
(o) To have contraindications or limitations to bevacizumab

(f) Sujetos que hayan recibido tratamiento oral o intravítreo dirigidos al EM en los 4 meses previos al implante de Ozurdex.
(g) Sujetos que hayan sido sometidos a cirugía ocular o láser en los 4 meses previos a OZURDEX.
(h) Padecer alguna enfermedad sistémica que contraindique el uso de BIV (embarazo, lactancia, hipertensión arterial no controlada; retinopatía diabética o cualquier enfermedad sistémica no controlada).
(i) Estar en tratamiento con análogos de prostaglandinas como hipotensores oculares tópicos.
(j) Alergia a algún componente de Avastin.
(k) Hallazgos en OCT de tracción vítreo-macular o presencia de membrana epirretiniana clínicamente significativa.
(l) Presencia de neovascularización de papila o de retina, neovascularización coroidea activa o pasada, infección ocular activa, afaquia o lente intraocular de cámara anterior u opacidad de medios clínicamente significativa.
(m) Cualquier condición en el ojo afecto que a criterio del investigador pueda impedir una ganancia ≥ 3 líneas de AV.
(n) Mujeres embarazadas o en periodo de lactancia
(o) Contraindicaciones o limitaciones al uso de bevacizumab

E.5 End points

E.5.1

Primary end point(s)

• Cuantitative evaluation of VA measured on a logarithmic scale.
• Foveal thickness (measured with OCT HD-Cirrus (Carl Zeiss Meditec).

• Evaluación cuantitativa de AV medida en escala logarítmica.
• Grosor foveal (medido con OCT HD-Cirrus (Carl Zeiss Meditec).

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 meses

E.5.2

Secondary end point(s)

• Safety of intravitreal bevacizumab in ME secondary to RVO treated with Ozurdex: systemic and ocular adverse events.
• Number of pacientes that need a second implant of Ozurdex.
• Number of IVB needed to stabilize the ME

• Seguridad de bevacizumab intravítreo en el EM de las ORV tratadas con Ozurdex: acontecimientos adversos oculares y sistémicos.
• Número de pacientes que precisan un segundo implante de Ozurdex.
• Número de BIV necesarias para estabilizar el EM en la visita del mes 6

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months

6 meses

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)

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

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.8.5

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

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

The study is considered completed when the last patient recruited
perform the last scheduled visit

El estudio finalizará cuando el última paciente reclutado realice la
última visita de estudio

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.1.1.1

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:

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.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)

Not applicable. Care will be the expected for that condition

No aplica. Seguirán tratamiento conforme a práctica clínica habitual

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

2012-04-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-12-16

P. End of Trial
P.	End of Trial Status	Completed

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