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    Summary
    EudraCT Number:2011-005021-48
    Sponsor's Protocol Code Number:TL011-RA-301
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-02-15
    Trial 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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2011-005021-48
    A.3Full title of the trial
    A multicenter, double-blind, randomized, active controlled, parallel-group study to evaluate the efficacy, safety, tolerability and pharmacodynamic profiles of TL011 infusions compared with MabThera® (rituximab) in subjects with severe, active rheumatoid arthritis treated with methotrexate (MTX)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate and compare the efficacy, safety, tolerability and pharmacodynamic (biochemical and physiological effects of the drug) of TL011 and MabThera® (rituximab) in patients with severe, active rheumatoid arthritis treated with methotrexate (MTX)
    A.3.2Name or abbreviated title of the trial where available
    ALTO
    A.4.1Sponsor's protocol code numberTL011-RA-301
    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 SponsorTeva Pharmaceutical Industries
    B.1.3.4CountryIsrael
    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 supportTeva Pharmaceutical Industries
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTeva Pharmaceutical Industries
    B.5.2Functional name of contact pointDr. Ronit Haviv
    B.5.3 Address:
    B.5.3.1Street Address12 Hatrufa St.
    B.5.3.2Town/ cityNetanya
    B.5.3.3Post code42504
    B.5.3.4CountryIsrael
    B.5.4Telephone number+97298361152
    B.5.5Fax number+97298361364
    B.5.6E-mailronit.haviv@teva.co.il
    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 nameTL011
    D.3.2Product code TL011
    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 INNTL011
    D.3.9.2Current sponsor codeTL011
    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 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®, 100 mg concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    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.3.9.4EV Substance CodeSUB12570MIG
    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
    adult patients with severe, active rheumatoid arthritis patients treated with methotrexate (MTX)
    E.1.1.1Medical condition in easily understood language
    rheumatoid arthritis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    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 equivalence of the efficacy of TL011 in comparison with the reference product MabThera® (rituximab) in subjects with severe, active RA treated with MTX
    E.2.2Secondary objectives of the trial
    To assess the pharmacodynamics (PD), immunogenicity, safety, and tolerability of TL011 in comparison with MabThera® (rituximab) in subjects with severe, active RA treated with MTX
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Aged 18-80 years (inclusive) at screening.
    2. Rheumatoid arthritis for at least 6 months, as defined by the Revised Criteria ACR 1987 (adult onset RA).
    3. Severe, active, seropositive (plasma RF level of at least 20 IU/mL and/or ACPA/anti-CCP positive) disease as defined by the following, revealed in screening tests:
    • Active disease defined as presence of at least 8 swollen and 8 tender joints (at the screening visit).
    • A serum CRP level of >=15 mg/L (>=1.5 mg/dL) and/or an ESR (Westergren method) of >= 28 mm per hour at screening.
    4. Inadequate response or intolerance DMARDs other than MTX and/or TNFi therapies (1 or more).
    5. Treatment with MTX (10 to 25 mg/week) for at least 12 weeks prior to screening, with at least 4 weeks before screening at a stable dosage that will remain stable throughout the study period (up to Week 48).
    6. Willing and able to provide written informed consent prior to performing study procedures.
    7. Women or men of reproductive potential must use (or have his/her partner use) effective contraceptive methods starting from screening and until 12 months following the last infusion (acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner’s vasectomy or double-barrier method [condom or diaphragm with spermicide]).
    E.4Principal exclusion criteria
    1. Documented rheumatic autoimmune disease or inflammatory joint disease other than RA (eg, psoriatic arthritis or ankylosing spondylitis).
    2. Significant systemic involvement secondary to RA (eg, vasculitis, pulmonary fibrosis, or Felty’s syndrome) or American Rheumatism Association (ARA) functional class IV disease.
    3. Hypersensitivity to active ingredients, excipients (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections) and murine proteins.
    4. Active uncontrolled infection (viral, bacterial or fungal infection) requiring systemic therapy or clinically significant infection, at screening and/or at Day 1 (baseline), or a history of recurring or chronic infections or with underlying conditions that may, according to the Investigator’s judgment, further predispose subjects to serious infection.
    5. Known immunodeficiency syndrome, including total immunoglobulins (IgG, IgA and IgM) lower than the lower limit of normal (LLN).
    6. Positive human immunodeficiency virus (HIV) serology (in case of positive result an additional HIV RNA test should be performed), positive hepatitis B surface antigen or positive hepatitis C antigen (in case of positive result an additional hepatitis C virus [HCV] RNA test should be performed).
    7. History of cancer in the past 5 years prior to screening (except 8. Immunization with live viral vaccines less than 4 weeks prior to Day 1 (baseline) and/or planned live viral vaccination during the core
    9. Use of oral/intravenous/intramuscular systemic corticosteroids
    • Oral corticosteroids at a dose higher than 10 mg prednisone daily (or an equivalent dose of other oral steroids) within the 4 weeks prior to screening and between screening and Day 1 (baseline)
    OR
    • Oral corticosteroids at a dose equal to or lower than 10 mg prednisone daily (or an equivalent dose of other oral steroids) that were not kept at a stable dose within 4 weeks prior to screening and between screening and Day 1 (baseline).
    • Use of intravenous/intramuscular/intra-articular or parenteral glucocorticoids <4 weeks prior to screening.
    10. Use of any cytotoxic therapies and immunosuppressants, (except for allowed dosage of MTX) or other DMARDs within the 4 weeks prior to screening or between screening and Day 1 (baseline).
    11. Prior use of MabThera (rituximab) and/or participation in a previous clinical trial with the investigational study drug TL011.
    12. Use of TNFi and any other biological agent for the treatment of autoimmune diseases less than 8 weeks prior to Day 1 (baseline) or use of etanercept and anakinra less than 4 weeks prior to Day 1.
    13. Participation in a previous clinical trial and/or use of an investigational drug within 90 days of screening.
    14. Clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation based on the Investigator’s judgment. Conditions may include cardiovascular disease (including severe heart failure of New York Heart Association [NYHA] class IV or severe, uncontrolled cardiac disease) pulmonary, hepatic, renal, or neurological disease as determined by medical history, physical examination, laboratory tests, chest X-ray, or ECG.
    15. Likely to be non-compliant or uncooperative during the study in the judgment of the Investigator.
    16. History of tuberculosis, latent tuberculosis tested as required by the local regulations, and/or positive chest X-ray for tuberculosis at screening or within the previous 6 months.
    17. Pregnant, lactating, or intending to become pregnant during the study or within 12 months following the last infusion.
    18. History of and/or current drug and/or alcohol abuse.
    E.5 End points
    E.5.1Primary end point(s)
    Determination of therapeutic equivalence of TL011 to rituximab (MabThera®)
    Primary efficacy endpoint: proportion of subjects (%) who meet the ACR criteria for 20% improvement (ACR20) from baseline
    E.5.1.1Timepoint(s) of evaluation of this end point
    At week 24
    E.5.2Secondary end point(s)
    ACR20, ACR50, ACR70
    E.5.2.1Timepoint(s) of evaluation of this end point
    At week 24 and 48
    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 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.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 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.8.2.4Number 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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Bulgaria
    Czech Republic
    Georgia
    Germany
    Hungary
    Macedonia, the former Yugoslav Republic of
    Poland
    Romania
    Russian Federation
    Serbia
    Spain
    Ukraine
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months21
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months21
    E.8.9.2In all countries concerned by the trial 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: 354
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 190
    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 state58
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 228
    F.4.2.2In the whole clinical trial 544
    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)
    After completing the core study period (24 weeks in total, including 2-
    week treatment period and a further 22 weeks of follow-up) the
    patients will be followed up for additional 24-week follow-up period, including those who will need a repeat course of treatment (per Investigator’s medical judgment) at week 24.
    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 Decision2012-05-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-24
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2012-08-01
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