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 macular edema (ME) |
Afectación visual debida a un edema macular (EM) causada por el factor de crecimiento endotelial vascular (VEGF) |
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E.1.1.1 | Medical condition in easily understood language |
Impaired vision due to increased accumulation of fluid in the back of the eye (macula) caused by an intrinsic substance, so-called vascular endothelial growth factor (VEGF) |
Afectación visual debida al acumulo de fluidos en el fondo del ojo (mácula) causado por una sustancia intrinseca llamada factor de crecimeinto del endotelio vascular |
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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 | PT |
E.1.2 | Classification code | 10025415 |
E.1.2 | Term | Macular oedema |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that an individualized regimen of intravitreal injection of 0.5 mg ranibizumab has superior efficacy compared to sham treatment in adult patients with visual impairment due to VEGF-driven ME. The primary objective will be assessed by the 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 un EM causado por VEGF. El objetivo principal se evaluará mediante el cambio de la AVMC desde la basal hasta el mes 2. |
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E.2.2 | Secondary objectives of the trial |
Evaluate efficacy of ranibizumab vs sham treatment by assessing ?BCVA change from baseline (BL) by visit to Mo 2 ?change in CSFT and CSFV (by OCT) from BL over time to Mo 2 ?presence of intra-/sub-retinal fluid (by OCT) and presence of active ME leakage (by FA) at Mo 2 ?rescue treatment requirement at Mo 1 Evaluate efficacy of ranibizumab by original treatment assignment by assessing ?average BCVA change from BL to Mo 1 through 12 ?change from BL in CSFT and CSFV (by OCT) by visit ?presence of intra-/sub-retinal fluid (by OCT) and presence of active ME leakage (by FA) at Mo 2,6 and 12 compared to BL ?proportion of patients with ?1, ?5, ?10 and ?15 letters gain or reaching 84 letters, at Mo 2, 6 and 12 ?proportion of patients with >1, >5,>10 and >15 letters loss at Mo 2,6 and 12 Assess number of ranibizumab (re)treatments by Mo 2,6 and 12 Evaluate: ?safety of ranibizumab (ocular and non-ocular AE) vs sham at Mo 2 and over time at Mo 6 and 12 ?reasons for treatment decision |
Evaluar la eficacia de ranibizumab en comparación con el tto simulado según: ? Cambio en la AVMC desde la basal hasta mes 2 ? Cambio en el GMC y en el VMC desde la basal hasta el mes 2 ? Presencia de líquido intra y/o subretiniano en mes 2 ? Necesidad de tratamiento de rescate en el mes 1
Evaluar la eficacia de ranibizumab como tto original según: ? Cambio medio en la AVMC desde la basal hasta el mes 1, 6 y 12. ? Cambio en el GMC y el VMC desde la basal. ? Presencia de líquido intra y/o subrretiniano en el mes 2, 6 y 12comparado con la basal. ? Aumento ? 1, ? 5, ? 10 y ? 15 letras o consecución de 84 letras, en el mes 2, 6 y 12. ? Pérdida ? 1, ? 5, ? 10 y ? 15 letras en el mes 2, 6 y 12. ? Tratamientos y retratamientos con ranibizumab en el mes 2, 6 y 12. ? Motivos de la decisión de tratamiento según criterio clínico y de la actividad de la enfermedad. ? Seguridad de ranibizumab por tipo, frecuencia y gravedad de los AEs en comparación con el sham en el mes 2, 6 y 12. |
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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 |
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E.3 | Principal inclusion criteria |
1. Diagnosis of treatment naïve (patient has not received any prior medication/ treatment for the ME lesion under study) active ME secondary to any causes (for adult patients: except DME and RVO); 2. BCVA must be between ? 24 and ? 83 letters tested at 4 meters starting distance using ETDRS-like visual acuity charts; 3. Visual loss should be only due to the presence of any eligible types of ME based on ocular clinical, as well as FA and OCT findings. |
1. Diagnóstico de un EM activo que no haya recibido tratamiento (el paciente no ha recibido ningún tratamiento/medicación anterior para la lesión de EM en estudio) secundario a cualquier causa (en pacientes adultos, salvo EMD y OVR) 2. La AVMC debe encontrarse entre ? 24 y ? 83 letras, comprobada a una distancia inicial del 4 metros mediante optotipos de agudeza visual del tipo ETDRS. 3. La pérdida visual solo deberá estar causada por la presencia de cualquier tipo elegible de EM (en pacientes adultos, salvo el EMD y la OVR) según exploraciones oculares clínicas y hallazgos en AF y OCT. |
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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 ME at screening; 5. Active diabetic retinopathy, active ocular/periocular infectious disease or active intraocular inflammation at screening; 6. Confirmed intraocular pressure (IOP) ? 25 mmHg for any reason at screening; 7. Neovascularization of the iris or neovascular glaucoma at screening; 8. ME secondary to DME or RVO (for adult patients only); 9. Use of any systemic anti-VEGF drugs within 6 months before baseline; 10. History of focal/grid laser photocoagulation with involvement of the macular area administered to treat ME at any time; 11. History of intraocular treatment with any anti-angiogenic drugs (including any anti-VEGF agents) or verteporfin photodynamic therapy (vPDT) 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 del EM 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. EM secundario al EMD u OVR (solo en pacientes adultos). Criterios de exclusión por medicación sistémica previa o actual 9. Uso de cualquier fármaco sistémico anti-VEGF durante los 6 meses anteriores a la basal (p. ej., sorafenib [Nexavar®], sunitinib [Sutent®], bevacizumab [Avastin®]). 10. Antecedentes de fotocoagulación focal/en rejilla con láser con afectación de la zona macular administrada para tratar el EM 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. |
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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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 ME leakage assessed by fluorescein angiography (FA) at Month 2 5) Requirement for rescue treatment at Month 1 6) Average BCVA change in study eye from baseline to Month 1 through Month 12 7) Change from baseline in CSFT and CSFV in study eye by visit 8) Presence of intra-/subretinal fluid in study eye at Month 2, Month 6, and Month 12 compared to Baseline 9) Presence of active ME leakage in study eye at Month 2, Month 6, and Mon th 12 compared to Baseline 10) Proportion of patients with 1 ? 5? 10 ? and 15 ? letters gain or reaching 84 letters, at Month 2, Month 6 and Month 12 11) Proportion of patients with > 1, > 5, > 10 and > 15 letters loss at Month 2, Month 6 and Month 12 12) Number of ranibizumab treatments and retreatments to study eye by Month 2, Month and Month 12 13) Type, frequency and severity of ocular and non-ocular adverse events in the study eye up Month 2, up to Month 6 and up to Month 12 |
1) Cambio de la MAVC desde basal a mes 2 en el ojo de estudio comparado con tratamiento simulado 2) Cambio en el GMC y VMC de basal a mes 2 3) Persencia de liquido intra-/subretiniano en el ojo de estudio en mes 2 4) Presencia de infiltrado debido a EM activo en mes 2 5) Requerimiento de medicacion de rescate en mes 1 6) Cambio medio en la MAVC en el ojo de estudio de mes 1 a 12 7) Cambio en el GMC y VMC por visita 8) Persencia de liquido intra-/subretiniano en el ojo de estudio en mes 2, 6 y 12 comparado a la basal 9) Presencia de infiltrado debido a EM activo en mes 2, 6 y 12 comparado con basal 10) Proporcion de pacientes que ganen 1 ? 5? 10 ? and 15 ? letras o que consigan 84 letras en el mes 2, 6 y 12 11) Proporcion de pacientes son una perdida de > 1, > 5, > 10 and > 15 letras en el mes 2, 6 y 12 12) Numbero de tratamientos y retratamientos con ranibizumab en el ojo de estudio en mes 2, 6 y 12 13) Tipo, frecuencia y gravedad de los AEs en el ojo de estudio en el mes 2, 6 y 12. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
grupo abierto para adolescentes |
open label group for adolescents |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
tratamiento simulado (solo adultos) |
sham injection (adults only) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 49 |
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 | No |
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 |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Ireland |
Israel |
Italy |
Korea, Republic of |
Latvia |
Netherlands |
Russian Federation |
Singapore |
Slovakia |
South Africa |
Spain |
Switzerland |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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
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LVLS |
Ultima visita del ultimo paciente |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |