E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Lupus Nephritis |
NEFRITIS LÚPICA |
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E.1.1.1 | Medical condition in easily understood language |
Lupus Nephritis is an inflammation of the kidney caused by systemic lupus erythematosus (SLE), a disease of the immune system |
Nefritis lúpica es una inflamación del riñón causada por lupus eritematoso sistemico (LES), una enfermedad del sistema inmunitario |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
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 evaluate the efficacy of obinutuzumab compared with placebo in patients with International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Class III or IV Lupus Nephritis (LN) as measured by complete renal response (CRR) at 52 weeks |
- Evaluar la eficacia de obinutuzumab comparado con placebo en pacientes con nefritis lúpica (NL) de clase III o IV de la International Society of Nephrology (ISN)/Renal Pathology Society (RPS) medida por la respuesta renal completa (RRC) a las 52 semanas |
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E.2.2 | Secondary objectives of the trial |
? To assess the ability of obinutuzumab to induce overall renal response and to improve time-to-response over the course of 52 weeks ? To evaluate the safety of obinutuzumab compared with placebo in patients with Class III or IV LN ? To characterize the immunogenic potential of obinutuzumab by measuring human anti-drug antibodies and assessing their relationship with other outcome measures ? To fully characterize adverse events of special interest, including infusion reactions, infections, thrombocytopenia, and neutropenia ? To compare changes in CD19+ B cells in the peripheral blood following treatment with obinutuzumab versus placebo ? To characterize the pharmacokinetics of obinutuzumab in the LN population and assess potential PK interactions between obinutuzumab and concomitant medications ? To assess the change from baseline of the patient?s general health over the course of the study by use of the Patient?s Global Assessment |
-Evaluar la capacidad de obinutuzumab de inducir respuesta renal global y de mejorar el tiempo hasta la respuesta a lo largo de 52 semanas. -Evaluar la seguridad de obinutuzumab comparado con placebo en pacientes con NL de clase III o IV. -Caracterizar la capacidad inmunógena de obinutuzumab midiendo anticuerpos antifármaco humanos y examinando su relación con otros criterios de valoración. -Caracterizar por completo los AA de interés especial, como las reacciones a la infusión, las infecciones, la trombocitopenia y la neutropenia. -Comparar las variaciones de los linfocitos B CD19+ en la sangre periférica después del tratamiento con obinutuzumab en comparación con placebo. -Caracterizar la FC de obinutuzumab en la población con NL y evaluar las posibles interacciones FC entre obinutuzumab y fármacos concomitantes. - Evaluar la variación de la salud general del paciente durante el estudio con respecto al momento basal empleando la Evaluación global por el paciente. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
? Age 18?75 years ? Diagnosis of SLE, according to current American College of Rheumatology criteria ? Diagnosis of ISN/RPS 2003 Class III or IV LN as evidenced by renal biopsy performed within 6 months prior to screening. Patients may co-exhibit Class V disease in addition to either Class III or Class IV disease. ? Patients must demonstrate active urinary sediment as evidenced by >=10 red blood cells/high power field or the presence of red cell casts. ? Proteinuria (urine protein to creatinine ratio) >1.0 ? For women who are not postmenopausal (>=12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of <1% per year, during the treatment period and for at least 18 months after the last dose of study drug ? For men: agreement to remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for at least 12 months after the last dose of study drug and agreement to refrain from donating sperm during this same period |
- 18-75 años de edad - Diagnóstico de lupus eritematoso sistémico (LES), según los criterios vigentes del ACR - Diagnóstico de NL de clase III o IV de la ISN/RPS 2003 demostrado por la biopsia renal realizada en los 6 meses previos a la selección. Los pacientes pueden presentar también enfermedad de clase V además de la enfermedad de clase III o clase IV. - Los pacientes deben presentar un sedimento urinario activo, demostrado por la existencia de >= 10 eritrocitos/CGA o cilindros de eritrocitos. - Proteinuria (cociente proteínas/creatinina en orina) > 1,0 - Las mujeres que no sean posmenopáusicas ( >=12 meses de amenorrea no inducida por fármacos) ni quirúrgicamente estériles (ausencia de los ovarios o el útero): deberán comprometerse a no mantener relaciones sexuales o a usar dos métodos anticonceptivos adecuados, incluyendo al menos uno con una tasa de fallos anual < 1% al año, durante el período de tratamiento y durante al menos 18 meses después de la última dosis del fármaco del estudio. -Los varones deben comprometerse a no mantener relaciones sexuales o a utilizar un preservativo y otro método anticonceptivo que en conjunto tengan una tasa de fallos< 1% al año durante el periodo de tratamiento y durante al menos 12 meses después de la última dosis del fármaco del estudio, y deben comprometerse también a no donar semen durante ese mismo periodo. |
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E.4 | Principal exclusion criteria |
? Retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia, or dementia that is currently active and resulting from SLE ? Presence of rapidly progressive glomerulonephritis ? Severe renal impairment as defined by estimated GFR <30 milliliter per minute or the need for dialysis or renal transplant ? Greater than 50% of glomeruli with sclerosis on renal biopsy ? Treatment with cyclophosphamide or calcineurin inhibitors within the 3 months prior to randomization ? Unstable disease with thrombocytopenia or at high risk for developing clinically significant bleeding or organ dysfunction requiring therapies such as plasmapheresis or acute blood or platelet transfusions ? History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion ? Significant or uncontrolled medical disease in any organ system not related to SLE or LN, which, in the investigator?s opinion, would preclude patient participation ? Concomitant chronic conditions, excluding SLE, (e.g., asthma, Crohn?s disease) that required oral or systemic steroid use in the 52 weeks prior to screening ? History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ (except basal cell carcinomas of the skin that have been treated or excised and have resolved) |
- Retinitis, trastorno convulsivo mal controlado, estado de confusión agudo, mielitis, ictus o síndrome ictal, ataxia cerebelosa o demencia activa en la actualidad y secundaria al LES. - Presencia de glomerulonefritis rápidamente progresiva. - Insuficiencia renal grave, definida como una FG estimada < 30 ml/min o la necesidad de diálisis o trasplante renal. - Presencia de esclerosis en más del 50% de los glomérulos en la biopsia renal - Tratamiento con ciclofosfamida o inhibidores de la calcineurina en los 3 meses previos a la aleatorización. - Enfermedad inestable con trombocitopenia o con alto riesgo de sufrir una hemorragia o una disfunción orgánica clínicamente importantes que precisen tratamientos como plasmaféresis o transfusiones inmediatas de sangre o plaquetas. - Antecedentes de reacciones alérgicas o anafilácticas graves a anticuerpos monoclonales o hipersensibilidad conocida a cualquier componente de la infusión de obinutuzumab. - Enfermedad física significativa o no controlada en algún órgano o sistema no relacionada con LES o NL que, en opinión del investigador, impida la participación del paciente -Enfermedades crónicas concomitantes, excluido el LES (p. ej., asma, enfermedad de Crohn), que requieran el uso de esteroides orales o sistémicos en las 52 semanas previas a la selección. - Antecedente de cáncer, incluidos tumores sólidos, neoplasias malignas hematológicas y carcinoma in situ (excepto carcinomas basocelulares de la piel tratados o extirpados y que se hayan resuelto). |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Number of patients who achieve complete renal response (CRR) at Week 52 |
1. Número de pacientes que consigan una RRC en Semana 52. |
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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. Number of patients who achieve overall response at Week 52 2. Number of patients who achieve partial renal response (PRR) at Week 52 3. Time to first overall response over the course of 52 weeks 4. Number of patients who achieve CRR at Week 24 5. Percent change from baseline in biomarkers of LN disease activity 6. Time to CRR over the course of 52 weeks 7. Number of patients who achieve a modified CRR (mCRR1) at Week 52 8. Number of patients who achieve a second mCRR (mCRR2) at Week 52 9. Change in Patient's Global Assessment from baseline to Week 52 |
1. Número de pacientes que consigan una respuesta global en la semana 52. 2. Número de pacientes que logren una respuesta renal parcial (RRP) en semana 52. 3. Tiempo transcurrido hasta la RRC a lo largo de 52 semanas. 4. Número de pacientes que logren una RRC en la semana 24. 5. Cambio en porcentage con respecto al momento basal de biomarcadores de la actividad de la NL. 6. Tiempo transcurrido hasta la RRC a lo largo de 52 semanas. 7. Número de pacientes que logren una RRC modificada (RRCm1) en la semana 52. 8. Número de pacientes que logren una segunda RRCm (RRCm2) en la semana 52. 9. Cambios en la Evaluación Global de la actividad de la enfermedad por el paciente desde basal a semana 52. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 52 2. Week 52 3. Baseline (Day 1) to Week 52 4. Week 24 5. At screening (Day -28 to -1), Week 1 (before infusion), Week 2, Week 4, Week 12, Week 24 (before infusion), Week 36, Week 52, Week 76, and Week 104 6. Baseline (Day 1) to Week 52 7. Week 52 8. Week 52 9. Baseline (Day 1), Week 4, Week 12, Week 24, Week 36, Week 52 |
1. Semana 52 2. Semana 52 3. Basal (Día 1) a Semana 52. 4. Semana 24. 5. En selección (Día -28 a -2), Semana 1 (antes de infusión), Semana 2, Semana 4, Semana 12, Semana 24 (antes de infusión), Semana 36, Semana 52, Semana 76 y Semana 104. 6. Basal (día 1) a Semana 52. 7. Semana 52 8. Semana 52 9. Basal (Día 1), Semana 4, Semana 12, Semana 24, Semana 36, Semana 52. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Brazil |
Colombia |
France |
Germany |
Israel |
Italy |
Mexico |
Spain |
United States |
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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
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The end of this study is defined as LPLV at Week 104. This has been selected to enable 76 weeks of safety follow-up for obinutuzumab to assess the occurrence of AEs and to enable an assessment of peripheral blood CD19+ B cell return. Additional B-cell follow-up (BCFU) visits will occur in relevent patients until they have achieved their baseline CD19 level or LLN of CD19+ B cells for this lupus population, whichever occurs first. |
El final del estudio se define como la UVUP en la semana 104. Se ha determinado así para hacer un seguimiento de la seguridad de obinutuzumab durante 76 semanas a fin de evaluar la incidencia de AA y la recuperación de linfocitos B CD19 en sangre periférica. Se realizarán más visitas de seguimiento de los linfocitos B hasta que los pacientes alcancen su concentración basal de CD19 o el límite inferior de la normalidad de los linfocitos B CD19 en esta población con lupus, lo que ocurra primero. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |