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    Summary
    EudraCT Number:2004-001756-36
    Sponsor's Protocol Code Number:PRIMA
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-05-05
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2004-001756-36
    A.3Full title of the trial
    A multicentre, phase III, open-label, randomized study in patients with advanced follicular lymphoma evaluating the benefit of maintenance therapy with rituximab (Mabthéra® ) after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicentre, phase III, open-label, randomized study in patients with advanced follicular lymphoma evaluating the benefit of maintenance therapy with rituximab (Mabthéra® ) after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy.
    A.3.2Name or abbreviated title of the trial where available
    PRIMA
    A.4.1Sponsor's protocol code numberPRIMA
    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 SponsorLYSARC
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF.Hoffmann-la Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLYSARC
    B.5.2Functional name of contact pointStéphane VINCENT
    B.5.3 Address:
    B.5.3.1Street AddressCentre Hospitalier Lyon-Sud Secteur Sainte Eugénie - Pavillon 6D
    B.5.3.2Town/ cityPIERRE-BENITE
    B.5.3.3Post code69495
    B.5.3.4CountryFrance
    B.5.4Telephone number+334 72 66 93 33
    B.5.5Fax number+334 72 66 38 57
    B.5.6E-mailstephane.vincent@lysarc.org
    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 Yes
    D.2.1.1.1Trade name MabThera 100 mg
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRituximab
    D.3.9.1CAS number 174722-31-7
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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.IMP: 2
    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 Yes
    D.2.1.1.1Trade name MabThera 500 mg
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRituximab
    D.3.9.1CAS number 174722-31-7
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    Follicular lymphoma
    E.1.1.1Medical condition in easily understood language
    Lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the benefit of maintenance therapy with rituximab as measured by progression-free survival (PFS) in comparison with no maintenance therapy after induction of response with chemotherapy plus rituximab in patients with high tumor burden follicular lymphoma
    E.2.2Secondary objectives of the trial
    To evaluate event-free survival (EFS), overall survival (OS), time to next anti-lymphoma treatment (TTNLT), time to next chemotherapy treatment (TTNCT), response rates at the end of maintenance treatment, transformation rate at first relapse and quality of life for three different chemotherapy regimens combined with rituximab, with or without maintenance rituximab, for first line treatment of high tumor burden,
    follicular lymphoma. To assess safety of rituximab maintenance therapy
    over 2 years as measured by the incidence of toxicity.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The PRIMA study represents a unique opportunity to collect biological samples from patients with follicular lymphoma at diagnosis that can be used to improve comprehension of the disease, better define the prognostic criteria in follicular lymphoma and identify new factors that influence treatments results and outcome. These scientific studies will be performed as ancillary studies based on the PRIMA protocol.
    E.3Principal inclusion criteria
    Histologically confirmed follicular lymphoma grade 1, 2 or 3a (biopsy ≤ 4 months).
    - Patients previously untreated.
    - Bulky disease at study entry according to the GELF criteria:
    - Age must be > 18 years.
    - Performance status < 2 on the ECOG scale (see appendix E1).
    - Adequate hematological function (unless those abnormalities are related to lymphoma extension) within 28 days prior to registration, including:
    • Hemoglobin ≥ 8.0 g/dL (5.0 mmol/L)
    • Absolute neutrophil count (ANC) ≥ 1.5 109/L
    • Platelet count ≥ 100 109/L
    - Women are not breast feeding, are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. Men agree not to father a child during participation in the trial and during the 12 months thereafter.
    - Having previously signed a written informed consent form.
    E.4Principal exclusion criteria
    - Transformation to high-grade lymphoma (secondary to “low-grade” follicular lymphoma).
    - Grade 3b follicular lymphoma.
    - Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis).
    - Patients regularly taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone.
    - Patients with prior or concomitant malignancies except non-melanoma skin cancer or adequately treated in situ cervical cancer.
    - Major surgery (excluding lymph node biopsy) within 28 days prior to registration.
    - Poor renal function: Serum creatinine > 2.0 mg/dL (197 μmol/L),
    - Poor hepatic function: total bilirubin > 2.0 mg/dL (34 μmol/L), AST (SGT) > 3 x the upper limit of normal unless these abnormalities are related to lymphoma.
    - Known HIV infection or active HBV or HCV infection ≤ 4 weeks at registration.
    - Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease). Judgment is up to the investigator.
    - Life expectancy < 6 months
    - Known sensitivity or allergy to murine products
    - Treatment within a clinical trial within 30 days prior to trial entry
    - Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS will be measured from the day of randomization to the date of first documented disease progression, relapse or death from any cause. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.
    E.5.2Secondary end point(s)
    Event-free Survival (EFS)
    Event-free survival will be measured from the date of randomization to the date of first documented progression, relapse, initiation of a new anti-lymphoma treatment or death by any cause. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.
    Time To Next Anti-Lymphoma Treatment (TTNLT)
    Time to next anti-lymphoma treatment will be measured from the date of randomization to the date of first documented administration of any new anti-lymphoma treatment (chemotherapy, radiotherapy, radioimmunotherapy, immunotherapy). Patients continuing in response or who are lost to follow-up will be censored on their last visit date. Patients who died (due to any cause) before having received a new anti-lymphoma treatment will be included in the statistical analysis with death being counted as an event.
    Time to next Chemotherapy Treatment (TTNCT)
    Time to next chemotherapy treatment will be measured from the date of randomization to the date of first documented administration of new chemotherapy or new cytotoxic agent. For any given patient, the TTNCT may be the same as TTNLT. Patients continuing in response or who are lost to follow-up will be censored on their last visit date. Patients who died (due to any cause) before having received a new chemotherapy treatment will be included in the statistical analysis with death being counted as an event.
    Overall Survival
    Overall survival will be determined from the date of randomization to the date of death regardless of cause. Patients who have not died at the time of the analysis (clinical cut-off) will be censored at the date of the last contact. If a patient was not assessed for survival within the last 3 months prior to the analysis an assessment within the next month is required.
    Overall Response Rate at the End of Maintenance Treatment
    Response rates will be assessed at the end of the 2 years maintenance treatment phase by the investigator. Assessment of response will be based on the International Workshop to Standardize Response Criteria for NHL (Criteria for evaluation of response in Non-Hodgkin’s lymphoma Cheson, 1999). A patient is defined as a responder if he has a complete response (CR/Cru) or partial response (PR) after the end of the maintenance treatment.
    Patients without response assessment (due to whatever reason) will be considered as non-responders.
    Transformation Rate at First Progression
    Histological transformation rate at first progression is defined by the appearance of diffuse areas of large lymphoma cells within a tumor site. For this purpose, a biopsy or a cytological examination should be obtained at progression, if possible. This material should be available for central pathological review. This analysis will be restricted to patients with a biopsy at first progression.
    Quality of Life Analysis
    QoL scale measurements using the FACT-G and QLQ-C30 questionnaires collected over time will be compared for patients receiving rituximab maintenance and those in the observation arm.
    E.5.2.1Timepoint(s) of evaluation of this end point
    EFS : from date of randomization to date of first documented progression, relapse, initiation of new anti-lymphoma treatment or death
    TTNLT: from date of randomization to date of first documented administration of any new anti-lymphoma treatment
    TTNCT from date of randomization to date of first documented administration of new chemotherapy or new cytotoxic agent
    OS: determined from date of randomization to date of death
    Overall Response Rate at the End of Maintenance Treatment
    assessed at the end of the 2 years maintenance phasePatients without response assessment (due to whatever reason) will be considered as non-responders.
    Transformation Rate at First Progression: should be obtained at progression
    Quality of Life Analysis: collected over time arm
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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.7.1.3.1Other 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    no therapy
    E.8.2.4Number of treatment arms in the trial2
    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 concerned23
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA95
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    China
    Colombia
    Croatia
    Czech Republic
    Denmark
    Finland
    France
    India
    Israel
    Netherlands
    New Zealand
    Peru
    Portugal
    Serbia
    Spain
    Thailand
    Turkey
    United Kingdom
    Uruguay
    Venezuela, Bolivarian Republic of
    E.8.7Trial 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
    Last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years12
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years12
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 600
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 600
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 900
    F.4.2.2In the whole clinical trial 1200
    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)
    Best medical care
    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 Decision2005-03-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-03-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-12-31
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