E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with relapsed or refractory CD20+ follicular non-Hodgkin's lymphoma (NHL) Grade 1, 2 or 3a, or other CD20+ indolent NHL (Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma, marginal zone lymphoma), according to the WHO classification system, or other not further classified low malignant lymphoma by immunohistochemistry. |
Pacientes con linfoma no Hodgkin (LNH) folicular CD20+, recurrente o refractario, de grado 1, 2 o 3a, u otro tipo de LNH indolente CD20+ (macroglobulinemia de Waldenström o linfoma linfoplasmacítico, linfoma de la zona marginal) de acuerdo con el sistema de clasificación de la OMS, u otros linfomas malignos de grado bajo no clasificados de forma específica en inmunohistoquímica. |
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E.1.1.1 | Medical condition in easily understood language |
non-Hodgkin's lymphoma (NHL) |
Linfoma no Hodgkin (LNH) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067070 |
E.1.2 | Term | Follicular B-cell non-Hodgkin's lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 evaluate the efficacy in term of progression-free survival after randomization (PFSrand) of a subcutaneous (SC) formulation of rituximab in patients who responded to Induction and initial 2 years maintenance therapy (Maintenance I), and were randomized to either prolonged rituximab maintenance until progression (Maintenance II) or observation. |
Evaluar la eficacia con respecto a la supervivencia libre de progresión tras la randomización (SLPrand) de una formulación subcutánea (SC) de rituximab en pacientes con linfoma no Hodgkin indolente, recurrente o refractario, que han respondido a tratamiento de inducción y a tratamiento de mantenimiento inicial de 2 años (mantenimiento I) y han sido randomizados para recibir tratamiento de mantenimiento continuado con rituximab hasta la progresión de la enfermedad (mantenimiento II) o ser sometidos a observación. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy and safety of SC rituximab during Induction, initial 2-year maintenance (Maintenance I) and randomized treatment period (Maintenance II). Efficacy will be evaluated in terms of Event- Free Survival (EFS), Time to Next Lymphoma Treatment (TNLT), Overall survival (OS), Overall Response Rate (ORR), Partial Response (PR) to Complete Response (CR) conversion rate, and PFS measured from the first Induction dose of rituximab (PFSregist). Safety assessments will include frequency of adverse events (AEs), serious adverse events (SAEs), and infusion/injection-related reactions (IRRs) and immunoglobulin (Ig) quantification. |
Evaluar la eficacia y la seguridad de rituximab SC durante los períodos de tratamiento de inducción, de tratamiento de mantenimiento inicial de 2 años (mantenimiento I) y de tratamiento randomizado (mantenimiento II). La eficacia se evaluará basándose en la supervivencia libre de acontecimientos (SLA), el tiempo hasta el siguiente tratamiento para el linfoma (TSTL), la supervivencia global (SG), el índice de respuesta global (IRG), el índice de conversión de respuesta parcial (RP) a respuesta completa (RC) y la SLP determinada desde la administración de la primera dosis de rituximab en el período de tratamiento de inducción (SLPregist). Las evaluaciones de seguridad incluirán la incidencia de acontecimientos adversos (AA), acontecimientos adversos graves (AAG) y reacciones relacionadas con la infusión/inyección (RRI) y la cuantificación de inmunoglobulinas (Ig). |
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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 |
Select sites will also participate in a Time in Motion pharmacoecenomic sub-study that will assess Medical Care Utilization (MCU) parameters. Details of the sub-study will be described in a separate protocol. |
Estudio Time and Motion de las formulaciones subcutánea (SC) e intravenosa (IV) de rituximab (MabThera) para el tratamiento del linfoma no Hodgkin indolente (LNHi). Versión 6.0 del 05 julio 2011 (inglés del 29 junio 2011). Para evaluar los parámetros de utilización de recursos médicos (URM), que permitirá recoger datos sobre la duración de la infusión y el uso de recursos y estará basado en un protocolo que se llevará a cabo solo en determinados centros. Detalles en protocolo independiente. |
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E.3 | Principal inclusion criteria |
- Age ? 18 years. - Histologically confirmed, CD20+ follicular NHL Grade 1, 2 or 3a, or other CD20+ indolent NHL (Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma, marginal zone lymphoma) according to the WHO classification system, other not further classified low malignant lymphoma by immunohistochemistry. - Patients must have received and must have relapsed or been refractory to one or more lines of adequate induction therapy prior to enrolment, including at least one line consisting of immunotherapy and/or chemotherapy. - Eastern Cooperative Oncology Group (ECOG) performance status < or = 2. |
- Edad > o igual a 18 años. - LNH folicular CD20+ de grado 1, 2 o 3a, confirmado histológicamente, u otros tipos de LNH indolente CD20+ (macroglobulinemia de Waldenström o linfoma linfoplasmacítico, linfoma de la zona marginal), de acuerdo con el sistema de clasificación de la OMS, u otros linfomas malignos de grado bajo no clasificados de forma específica en inmunohistoquímica. - Los pacientes deben haber manifestado recidiva o haber sido refractarios a una o más líneas de tratamiento de inducción previo adecuado, incluyendo al menos una línea de inmunoterapia y/o quimioterapia, antes de su inclusión en el estudio. - Estado funcional del Eastern Cooperative Oncology Group (ECOG) < o igual a 2. |
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E.4 | Principal exclusion criteria |
- Transformation to high-grade lymphoma. - Patients with aggressive lymphoma (e.g. mantle cell lymphoma). - Presence or history of central nervous system (CNS) lymphomatous disease (e.g., CNS lymphoma or lymphomatous meningitis). - Other malignancy within 5 years prior to enrolment, with the following exceptions (as long as curatively treated): carcinoma in situ of the cervix, squamous cell carcinoma of the skin, or basal cell skin cancer. Cervical carcinoma stage 1B or less, breast cancer in situ, or localized prostate cancer stage T1c or less may be considered, provided that the patient was treated with curative intent and has been relapse- and metastasis-free for at least 2 years prior to enrolment. - Inadequate hepatic or renal function prior to the first rituximab induction dose. - Known human immunodeficiency virus (HIV) infection. |
- Transformación a linfoma de grado alto. - Pacientes con linfoma agresivo (p. ej. linfoma de células del manto). - Presencia o antecedentes a enfermedad linfomatosa del sistema nervioso central (SNC) (p. ej. linfoma del SNC o meningitis linfomatosa). - Otras neoplasias malignas en los 5 años previos a la inclusión en el estudio, con las siguientes excepciones (siempre que se hayan tratado con intención curativa): carcinoma in situ de cervix, carcinoma de piel escamocelular o basocelular. Se puede considerar la inclusión de pacientes con carcinoma de cervix en estadio 1B o inferior, cáncer de mama in situ o cáncer de próstata localizado en estadio T1c o inferior, siempre que el paciente haya sido tratado con intención curativa y haya estado libre de recidiva y metástasis, como mínimo, en los 2 años previos a la inclusión en el estudio. - Función hepática o renal inadecuada antes de administrar la primera dosis de rituximab en el tratamiento de inducción. - Infección confirmada por el virus de inmunodeficiencia humana (VIH). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of the study is PFSrand. It is defined as the time from day of randomization to maintenance phase II to the first documented disease progression or death, whichever occurs first. |
Variable principal de eficacia del estudio es SLPrand: se determinará desde el día de la randomización hasta la fecha en que se documenta por primera vez la progresión de la enfermedad o la muerte, lo que ocurra primero. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1 every 8 weeks [56 ± 7 days] until PD |
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E.5.2 | Secondary end point(s) |
Progression free survival (PFS) measured from the day of first rituximab Induction dose (PFSregist), Event-free survival (EFS), Time to next lymphoma treatment (TNLT), Overall survival (OS), Overall Response Rate (ORR) and PR to CR conversion rate at the end of Induction and end of Maintenance I. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time Frame: Week 24 (cycle 8) |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
QUALITY OF LIFE (QOL) |
Calidad de vida |
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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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 130 |
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 |
Albania |
Argentina |
Austria |
Bosnia and Herzegovina |
Brazil |
Bulgaria |
Canada |
Colombia |
Ecuador |
Egypt |
France |
Germany |
Greece |
Hungary |
India |
Italy |
Norway |
Russian Federation |
Slovakia |
Slovenia |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
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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 the study is defined as the date of the final analysis of the primary endpoint. |
La terminación del estudio se define como la fecha del análisis final de la variable principal. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |