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. |
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E.1.1.1 | Medical condition in easily understood language |
non-Hodgkin’s lymphoma (NHL) |
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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 | 19.0 |
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 | 100000004864 |
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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 of a subcutaneous (SC) formulation of rituximab in term of progression-free survival after randomization (PFSrand) to either prolonged rituximab maintenance until progression (Maintenance II) or observation in patients with relapsed or refractory, indolent non-Hodgkin’s lymphoma who responded to Induction and initial 2 years maintenance therapy (Maintenance I). |
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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 measured from the first Induction dose of rituximab (OSregist) and from the time of randomization to Maintenance II (OSrand), Overall Response Rate (ORR), Partial Response (PR) to Complete Response (CR) conversion rate at the end of Maintenance I, 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/administration-related reactions (IRRs/ARRs) and immunoglobulin (Ig) quantification. |
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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 the Time in Motion pharmacoeconomic sub-study that will assess Medical Care Utilization parameters. Details of the sub-study will be described in a separate protocol.
Protocol Title: Time and Motion Study of Rituximab (MabThera) Subcuteneous and Intraveneaous Formulations : M-10676.
Protocol Date and Version: February 27, 2012 Version 7.0. |
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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.
• Patients must have received, and must have relapsed or been refractory to, one or more lines of adequate therapy prior to enrolment, including at least one line consisting of immunotherapy and/or chemotherapy and/or radiotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 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.
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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 the first documented disease progression or death, whichever occurs first. |
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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 measured from day of first rituximab Induction dose (OSregist) and from randomization (OSrand), Overall Response Rate (ORR) at the end of the Induction Phase and PR to CR conversion rate at the end of Maintenance I. |
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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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 |
observation arm (no treatment) |
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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 | 2 |
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 |
Brazil |
Bulgaria |
Canada |
Colombia |
Ecuador |
Egypt |
France |
Germany |
Greece |
Hungary |
Italy |
Lithuania |
Norway |
Romania |
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 study (EOS) is defined as the last patient’s last visit in Maintenance II. The study will end when all patients randomized in Maintenance II have been followed for at least 15 months after randomization, or earlier if one of the following is documented for all patients: disease recurrence, withdrawal from the study, loss to follow-up or death.
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 69 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 69 |
E.8.9.2 | In all countries concerned by the trial days | 0 |