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    The EU Clinical Trials Register currently displays   41189   clinical trials with a EudraCT protocol, of which   6743   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2010-021184-32
    Sponsor's Protocol Code Number:GP13-201
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-09-13
    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 ConcernedFrance - ANSM
    A.2EudraCT number2010-021184-32
    A.3Full title of the trial
    A randomized, double-blind, controlled study to evaluate pharmacokinetics, pharmacodynamics, safety and efficacy of GP2013 and rituximab in patients with rheumatoid arthritis refractory or intolerant to standard DMARDs and one or two anti- TNF therapies
    A.4.1Sponsor's protocol code numberGP13-201
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorHexal AG
    B.1.3.4CountryGermany
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.2.5The 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 nameNA
    D.3.2Product code GP2013
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeGP2013
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000 to mg
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 RoleComparator
    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
    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.3.1Product nameMabthera
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000 to mg
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    Refractory rheumatoid arthritis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To demonstrate bioequivalence between GP2013 and rituximab in combination with MTX in patients with active RA who have not responded adequately, or have shown intolerance, to DMARDs, including MTX, and one or two anti-TNF therapies. Bioequivalence is defined as AUC(0-) and Cmax of blood concentrations of the drugs being comparable, i.e. the 90% confidence interval for the ratio of the geometric means (GP2013/rituximab) estimated based on non-compartmental analysis based on assessments up to week 24 must be within the standard bioequivalence limits 0.8 to 1.25.
    E.2.2Secondary objectives of the trial
    PK/PD
    • To evaluate pharmacokinetic parameters after the administration of two intravenous infusions of 1000 mg GP2013 and rituximab, respectively: AUC(0-24), clearance, volume of distribution and t1/2.
    • To evaluate the extent and kinetics of the depletion of peripheral blood B cells in response to GP2013 or rituximab, respectively, defined as AUECs of the relative change of the peripheral blood B cell count from baseline following the first infusion of GP2013 or rituximab, until the time of the second infusion.
    • Efficacy
    - To compare the proportion of patients with an ACR20 response at week 24 in response to treatment with GP2013 or rituximab, respectively.
    • Safety
    - Overall safety and tolerability of GP2013 and rituximab up to 24 and 52 weeks
    For additional secondary and exploratory objectives please see full protocol pages 20-21.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must give written informed consent before any study-related assessment is performed.
    2. Patients must be ≥18 years of age.
    3. Patients must have a diagnosis of Rheumatoid Arthritis, based on the ACR 1987 criteria. At least 4 of the following 7 criteria must be fulfilled to confirm the diagnosis of RA:
    • joint morning stiffness of at least one hour
    • swelling of joints in at least in three joint areas, diagnosed by a doctor
    • swelling of MCP and wrist joints, diagnosed by a doctor
    • bilateral, symmetric swelling of joints in the same joint areas, diagnosed by a doctor
    • rheumatoid nodule
    • rheumatoid factor seropositivity
    • positive findings in hand radiographs.
    4. Patients must have had the diagnosis of RA for at least 6 months.
    5. Patients must have active RA at baseline:
    • ≥ 6 swollen joints (of 66 joints assessed)
    • ≥ 6 tender joints (of 68 joints assessed)
    • CRP ≥ 10 mg/L
    OR ESR ≥ 28mm/1st hour
    Note: If one of the criteria is not met at baseline, the patient is not eligible for randomization at this timepoint. Rescreening (i.e. a second baseline visit) is at the discretion of the investigator.
    6. Patients must be seropositive for rheumatoid factor (RF) and/or have antibodies to cyclic citrullinated peptide (anti-CCP).
    7. Patients must have inadequate response or intolerance to non-biologic DMARDs, including MTX, and one or two TNF antagonists:
    • infliximab (≥ 3 mg/kg, ≥ 4 infusions),
    • adalimumab (40 mg biweekly ≥ 3 months),
    • etanercept (25 mg twice weekly or 50 mg weekly ≥ 3 months),
    • certolizumab pegol (400 mg every 2 weeks ≥ 3 months),
    • or golimumab (50 mg every 4 weeks ≥ 4 months),
    and discontinued the biological treatment due to lack of efficacy, or due to being intolerant to at least 1 administration of these agents.
    8. Patients may have previously received hydroxychloroquine, chloroquine, steroids, sulfasalazine, leflunomide, gold, cyclosporin but NEITHER any alkylating agents or azathioprine, NOR rituximab, abatacept, tocilizumab, anakinra or other biological treatments, apart from TNF antagonists, for RA.
    9. Patients must be on a stable dose of MTX (10-25 mg per week). They must have received MTX for at least 4 months with 25 mg/week as the maximal dose, and with a stable dose for 4 weeks prior to randomization.
    10. Patients must be on a stable dose of folic acid or equivalent (≥ 5 mg per week). They must have received folic acid or equivalent for at least 4 months and with a stable dose for 4 weeks prior to randomization.
    11. Patients must have stopped DMARDs for at least 4 weeks. In case of leflunomide it has to be discontinued for 8 weeks prior to randomization (unless a cholestyramine washout is performed, than randomization can happen 4 weeks after). Antimalarial drugs (hydroxychloroquine, chloroquine) or sulfasalazine which are permitted in combination with MTX should be taken at least for 4 months prior to randomization and at a stable dose for at least 4 weeks prior to randomization.
    12. Patients must have stopped etanercept, certolizumab pegol and adalimumab for at least 4 weeks, infliximab and golimumab for at least 8 weeks before randomization.
    13. If taking glucocorticoids, patients must be on stable dose of maximally 10 mg/day prednisone or equivalent over the past 2 weeks before randomization and continue this therapy during the trial.
    14. Patients requiring vaccination should be vaccinated according to current local guidance or practice at least 4 weeks prior to administration of study drugs.
    15. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen/low strength opioids as part of their RA therapy are required to be on a stable dose for at least 4 weeks before randomization.
    16. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen/low strength opioids PRN within 4 weeks before randomization have to stop their medication at least 24 hours before an ACR visit (i.e. visits 1, 2, 8 to 14 and in case of retreatment).

    For additional inclusion criteria, please refer to section 4.1 of the protocol.
    E.4Principal exclusion criteria
    1. RA patients with functional status class IV classified according to the ACR 1991 revised criteria.
    2. Patients with levels of serum IgG, IgM and IgA below LLN.
    3. Patients with systemic manifestations of RA, with the exception of Sjögren’s syndrome.
    4. Patients taking high potency opioid analgesics (e.g. methadone, hydromorphone, morphine).
    5. Female patients nursing (lactating / breast-feeding), pregnant or planning of pregnancy within 12 months after the last infusion of study drug, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
    6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives and intrauterine devices (IUDs)). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable.
    7. Patients who have had any therapy with intra-articular injections (e. g. corticoid) required by a flare up to 4 weeks before randomization.
    8. Patients with underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, infectious or gastrointestinal conditions, which in the opinion of the investigator immunocompromizes the patient and/or places the patient at unacceptable risk by receiving immunomodulatory therapy within the study – especially patients with clinical history of Felty’s Syndrome.
    9. Patients with significant medical problems, including but not limited to the following: uncontrolled hypertension (≥ 160/95 mmHg), congestive heart failure (New York Heart Association status of class III or IV).
    10. Patients with screening total WBC count < 3000/µL, platelets < 100,000/µL, neutrophils < 1,500/µL or hemoglobin < 8.5 g/dL.
    11. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests such as AST, ALT, or alkaline phosphatase. Any single parameter may not exceed 3 x upper limit of normal (ULN). A single parameter elevated up to and including 3 x ULN should be re-checked once more as soon as possible, and in all cases, at least prior to randomization.
    12. Patients with history of renal trauma, glomerulonephritis, a single kidney or a creatinine level exceeding 1.5 mg/dL.
    13. History of lymphoproliferative disease or any known malignancy or history of malignancy within the past 5 years (except non-melanoma skin cancer which has been treated with no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix, polyps (removed) in the colon with non-invasive malignancy).
    14. Patients who have lost or donated  400 mL blood in the 8 weeks prior to randomization.
    15. Inability or unwillingness to undergo repeated venepuncture (poor tolerability or lack of access to veins).
    16. Patients with plans to receive live vaccines during the study or 4 weeks prior to randomization.
    17. Known infection with HIV according to patient history.
    18. Active or latent hepatitis B (HBsAg positive) or hepatitis C at screening.
    19. Patients with other inflammatory diseases which might confound the evaluation of the efficacy (e.g. Crohn’s disease, ulcerative colitis).
    20. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection as defined by either a positive PPD skin test (the size of induration will be measured after 48-72 hours, and a positive result is defined as an induration of ≥ 5 mm or according to local guidelines) or a positive QuantiFERON TB-Gold test. Patients with evidence of latent tuberculosis may enter the study after evaluation by an appropriate specialist and after sufficient treatment has been initiated according to local medical practice.
    21. Active systemic infections during the two weeks (exception: common cold) prior to randomization.
    22. History of allergy (medication history) to any of the compounds used in the study.
    23. Hypersensitivity to any of the study medication excipients or to murine proteins.
    24. Concurrent therapy with any other investigational medicinal product within 30 days or 5 times the half-life, which ever is longer, prior to randomization.

    For additional exclusion criteria, please refer to section 4.2 of the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    PK bioequivalence is defined as AUC and Cmax of the drugs being comparable, i.e. the two-sided 90% confidence interval is within the predefined bioequivalence limits of 0.8 to 1.25. AUC and Cmax will be regarded as co-primary endpoints.
    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 Yes
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.6.13.1Other scope of the trial description
    Immunogenicity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study Yes
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.3.1Comparator description
    Rituximab
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    A patient will be considered to have completed the study when all scheduled study
    assessments and procedures up to and including Visit 14 (week 52) or, in case of retreatment with another course of study medication, his/ her 26 weeks safety, efficacy and PD follow-up visit, whichever is later, have been concluded.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    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.1.3Elderly (>=65 years) Yes
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 116
    F.4.2.2In the whole clinical trial 164
    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 Decision2010-10-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-10-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-11-10
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