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    The EU Clinical Trials Register currently displays   37236   clinical trials with a EudraCT protocol, of which   6125   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2013-000647-12
    Sponsor's Protocol Code Number:ML28881
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-04-19
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-000647-12
    A.3Full title of the trial
    A single arm, multicentre, phase IIIb study to evaluate safety, efficacy and pharmacokinetic (PK) of subcutaneous (SC) rituximab administered during induction phase or maintenance in previously untreated patients with CD20+ diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A single arm, multicentre, phase IIIb study to evaluate safety, efficacy and pharmacokinetic (PK) of subcutaneous (SC) rituximab administered during induction phase or maintenance in previously untreated patients with CD20+ diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL)
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberML28881
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorROCHE S.p.A.
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRoche SpA
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSERGIO SCACCABAROZZI
    B.5.2Functional name of contact pointHEAD OF CLINICAL OPERATIONS
    B.5.3 Address:
    B.5.3.1Street AddressVIALE G.B. STUCCHI 110
    B.5.3.2Town/ cityMONZA
    B.5.3.3Post code20052
    B.5.4Telephone number00390392475070
    B.5.5Fax number00390392475085
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMabthera SC
    D.3.2Product code RO 45-2294/F04
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    CD20+ diffuse large B-cell lymphoma or CD20+ follicular non-Hodgkin’s lymphoma grade 1, 2 or 3a
    E.1.1.1Medical condition in easily understood language
    follicular non-Hodgkin’s lymphoma and diffuse large B-cell lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective for this Study is as follows:
     To evaluate the incidence of AARs following multiple doses of rituximab SC during Induction and/or Maintenance therapy in patients with CD20+ DLBCL or CD20+ follicular NHL, who have previously received at least one dose of rituximab IV.
    AARs are defined as all AEs occurring within 24 hours of rituximab SC administration and which are considered related to Study drug. AARs include IIRRs, injection-site reactions, administration site conditions and all symptoms thereof.
    E.2.2Secondary objectives of the trial
    •To evaluate the safety of rituximab SC
    •To evaluate the efficacy of rituximab SC
    •to evaluate the pharmacokinetic of rituximab SC: in FL and DLBCL patients:
    -population PK parameter, effects of subject characteristics on the rituximab population PK parameters, effects of the covariates related to disease at baseline, interindividual variability,relationship of Ctrough (pre-dose concentration) over time and CR/CRu at 4-8 weeks after the last dose of Induction treatment (concentration defined over time trial), and only for DLBDL patients also rituximab exposures (concentration over time) during the 2 different scheduling of rituximab SC R-CHOP14 or R-CHOP 21
    •Patient-reported outcome is measured using Rituximab Administration Satisfaction Questionnaire (RASQ-SC)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet the following criteria for Study entry:
    1. Signed, written informed consent form
    2. Age ≥ 18 and ≤ 80 years at time of enrolment
    Rituximab – Roche S.p.A.
    Protocol ML28881 (MABRELLA) - Version 1, 18 March 2013 45
    3. Histologically confirmed, CD20+ DLBCL or CD20+ follicular NHL grade 1, 2 or 3a, according to the WHO classification system
    4. Currently being treated with rituximab IV in the Induction or Maintenance setting, having received at least one full dose of rituximab IV, defined as standard full dose of rituximab IV 375 mg/m2 administered without interruption or early discontinuation because of tolerability issues
    5. Expectation and current ability for the patient to receive at least four additional cycles of treatment during the Induction phase or six additional cycles of treatment during the Maintenance phase (patients with follicular NHL)
    6. Induction only: An International Prognostic Index (IPI) score of 1-4 or IPI score of 0 with bulky disease, defined as one lesion ≥ 7.5 cm, or Follicular Lymphoma International Prognostic Index (FLIPI) (low, intermediate or high risk) (see Appendix 4)
    7. Induction only: At least one bi-dimensionally measurable lesion defined as ≥ 1.5 cm in its largest dimension on computed tomography (CT) scan
    8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 (see Appendix 4)
    E.4Principal exclusion criteria
    Patients who meet any of the following criteria will be excluded from Study entry:
    Cancer-Related Criteria
    1. Transformed lymphoma or follicular lymphoma (FL) IIIB
    2. Primary central nervous system lymphoma, histologic evidence of transformation to a Burkitt lymphoma, primary effusion lymphoma, primary mediastinal DLBCL, DLBCL of the testis, or primary cutaneous DLBCL
    3. History of other malignancy that could affect compliance with the protocol or interpretation of results. This includes a malignancy that has been treated but not with curative intent, unless the malignancy has been in remission without treatment for ≥ 5 years prior to dosing. Note: Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix are eligible for the Study.
    Prior or Concomitant Treatments
    4. Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent.
    Note: (i) patients receiving corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must be on a documented stable dose of at least 4 weeks duration prior to randomization; (ii) a pre-phase of high dose prednisolone (e.g. 100 mg/day for 3 to 5 days) is acceptable for patients with aggressive NHL.
    Laboratory Assessments at Screening
    5. Inadequate renal function, defined as:
    - Creatinine > 1.5 times the upper limit of normal (ULN) (unless normal creatinine clearance), or calculated creatinine clearance < 40 mL/min (using the Cockcroft-Gault formula)
    6. Inadequate hematologic function, defined as:
    - Haemoglobin < 9 g/dL
    - Absolute neutrophil count < 1.5 x 109/L
    - Platelet count < 75 x 109/L
    7. Inadequate hepatic function, defined as:
    - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN
    - Total bilirubin ≥ 1.5 x ULN. Note: patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 x ULN
    Other Prior or Current Medical Conditions or Treatments
    8. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
    9. For patients with DLBCL - Contraindication to any of the individual components of CHOP (cyclophosphamide, vincristine, doxorubicin and prednisone), including prior receipt of anthracyclines
    10. Other serious underlying medical conditions, which, in the Investigator‘s judgment, could impair the ability of the patient to participate in the Study (e.g., significant cardiovascular disease, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease)
    11. Recent major surgery (within 4 weeks prior to dosing, other than for diagnosis
    12. Active and/or severe bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics except if for tumour fever) within 4 weeks prior to dosing
    13. Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (must be ruled out during screening):
    - Positive test results for chronic hepatitis B infection (defined as positive HBsAg serology)
    Patients with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody [HBcAb] and negative or positive HBsAg with HBV DNA undetectable) may be included. These patients must be followed closely.
    Patients need to receive antiviral therapy according to the local clinical practice.
    - Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
    Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
    14. History of human immunodeficiency virus (HIV) seropositive status
    General Criteria
    15. Inability to provide informed consent and comply with protocol requirements.
    16. Life expectancy of less than 6 months
    17. Pregnant or breastfeeding patients. A negative serum pregnancy test is required for women of childbearing potential within 7 days prior to dosing or within 14 days if with a confirmatory urine pregnancy test within 7 days prior to dosing. Women of childbearing potential are defined as pre-menopausal women or women who are < 2 years after the onset of menopause and are not surgically sterile
    18. Fertile men or women of childbearing potential who do not agree to use a highly effective measure of contraception (such as oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) throughout the Study and for at least 12 months after the last dose of rituximab.
    E.5 End points
    E.5.1Primary end point(s)
    -safety endpoint:AARs, including IIRRs, AEs, AEs of grade ≥ 3, SAEs, routine laboratory parameters, vital signs, concomitant medications, premature withdrawal from the Study and from Study medication due to AEs and ECOG performance status.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Timepoint of safety endpoints: at every visit

    E.5.2Secondary end point(s)
    -efficay endpoint:the efficacy of rituximab SC will be evaluated during Induction and/or Maintenance in terms of EFS, PFS, CR/Cru, DFS and OS and will be analysed for the FAS and for the Per Protocol populations.
    -PK endpoint: Descriptive statistics (mean, standard deviation, median and minimum and maximum values), will be computed for all PK parameters: Ctrough, AUC, Cmax, , and CL/F (clearance/fraction of absorbed drug).
    -patient satisfaction outcome endpoint:Patient-assessed satisfaction will be evaluated using the Rituximab Administration Satisfaction Questionnaire (RASQ-SC).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoint of efficacy enpoints: at baseline visit, final staging and end of study visit.
    Timepoint of PK endpoints:
    DLBCL patients:
    Induction Collection timelines:
    1.Baseline: pre-dose of rituximab SC administration
    2.Cycle 7 – Day 1: pre-dose of rituximab SC administration
    3.Cycle 7 – Day 7 (± 3 days)
    4.Cycle 7 – Day 14 (± 3 days)
    4.Cycle 8 – Day 1: pre-dose of rituximab SC administration
    FL patients:
    Induction Collection timelines:
    1.Baseline: pre-dose of rituximab SC administration
    2.Cycle 8 – Day 1: pre-dose of rituximab SC administration

    Maintenance Collection timelines:
    1.Baseline = pre-dose of rituximab SC administration
    2.Cycle 12 – Day 1: pre-dose of rituximab SC administration
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Patient satisfaction outcome
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.4.1Number of sites anticipated in Member State concerned40
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    The end of the Study is defined as the date when the last patient, last visit (LPLV) occurs. LPLV is expected to occur maximum 49 months after the last patient is enrolled; the study could be end in advance if there aren safety risks for the patients.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 130
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state160
    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)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-04
    P. End of Trial
    P.End of Trial StatusOngoing
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