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    Summary
    EudraCT Number:2009-013316-12
    Sponsor's Protocol Code Number:ML22497
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-10-21
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2009-013316-12
    A.3Full title of the trial
    A multi-center, randomized, double blind, placebo controlled study to evaluate remission in DMARD and biological naïve early reumatoid arthritis (RA) subjects treated with tocilizumab (TCZ) plus tight control methotrexate (MTX) treatment, TCZ monotherapy or tight control MTX monotherapy.
    A.3.2Name or abbreviated title of the trial where available
    U-Act-Early
    A.4.1Sponsor's protocol code numberML22497
    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 SponsorRoche Nederland B.V.
    B.1.3.4CountryNetherlands
    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 Yes
    D.2.1.1.1Trade name RoActemra
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited U.K.
    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 Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous 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) 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 Yes
    D.3.11.13.1Other medicinal product typeIL6-receptor inhibitor, humanised monoclonal antibody
    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 Methotrexate 'Lederle' 2,5mg tablets
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rheumatoid Arthritis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    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 compare the number of patients with early RA who achieve sustained remission with three different regimens: tocilizumab combined with tightly controlled MTX, tightly controlled MTX as monotherapy and tocilizumab as monotherapy. The main focus is the contrast between the combination therapy and the MTX monotherapy followed by the contrast between the two monotherapy treatments.
    E.2.2Secondary objectives of the trial
    To compare the progression of radiographic characteristics of joint damage among the three treatment strategies by use of the change in SharpvanderHeijde score.

    To compare clinical efficacy between the three treatment strategies by use of the ACR and EULAR response criteria.

    To study safety in the context of the three treatment strategies, including the:
    - occurrence of serious adverse events leading to withdrawal.
    - occurrence of serious infections
    - number of patients who are unable to use adequate dosage of MTX due to increase of liver enzymes

    To study differences in changes in functional disability, fatigue, quality of life and cost effectiveness in the three treatment strategy groups by use of the: Dutch consensus HAQ, the FACIT-fatigue, the IPQR, the SF-36, VAS pain and general wellbeing Questionnaires, a Dutch Healthcare resource use and work participation questionnaire, and the EuroQol (EQ5D) questionnaire.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or non-pregnant, non-nursing female
    2. ≥ 18 years of age
    3. Early RA (disease symptoms <1 year) according to the revised 1987 ACR and/or ACR/EULAR classification criteria of 2010 for RA
    4. Disease activity measured by DAS28 ≥ 2,6
    5. Patients able and willing to give written informed consent and comply with the requirements of the study protocol
    6. Immunization status current for pneumovax, influenza as assessed according to standard of care for RA patients receiving a biological agent
    E.4Principal exclusion criteria
    1.Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis. Patients with interstitial pulmonary fibrosis and still able to tolerate MTX therapy are permitted. Sjögren’s Syndrome with RA is permitted
    2.Current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease)
    3. Glucocorticoids used for RA < 6 weeks prior to baseline (NB: inhaled glucocorticoids are allowed)
    4.Immunization with a live/attenuated vaccine within 4 weeks prior to baseline
    5.Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before screening
    6.Previous treatment with any biologic drug that is used in the treatment of RA
    7.Previous treatment with any DMARD that is used in the treatment of RA
    8.Any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation
    9.Treatment with IV gamma globulin, plasmapheresis or Prosorba® column within 6 months before baseline
    10.Serum creatinine > 142 μmol/L in female patients and > 168 μmol/L in male patients or an active renal disease
    11.ALT or AST > 1.5 x ULN (if initial sample yields ALT or AST > 1.5 x ULN, a second sample may be taken and tested during the screening period)

    12.Platelet count < 100 x 109/L (100,000/mm3)
    13.Hemoglobin < 1.5 mmol/l below LLN for gender
    14.WBC < 4.0 x 109/L (4000/mm3),
    15. Absolute neutrophil count < 1.0 x 109/L (1000? 500/mm3)
    16.Absolute lymphocyte count < 0.5 x 109/L (500/mm3)
    17.Positive HBsAg or HCV antibody
    18.Triglycerides > 10 mmol/L (> 900 mg/dL) at screening (fasted)
    19.Pregnant women or nursing (breastfeeding) mothers
    20.Females of child-bearing potential who are not using reliable means of contraception (such as physical barrier [patient and partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device)
    21.History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
    22.Chest X-ray (CXR) at screening showing evidence of any clinically significant abnormality
    23.Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or GI disease
    24.In patients with a history of complicated diverticulitis, the treating physician needs to consider the benefit-risk ratio
    25.A known history of chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforations
    26. Active TB requiring treatment within the previous 3 years. Patients with a positive purified protein derivative tuberculin skin test (PPD) at screening as per local guidelines are not eligible for the study unless they complete treatment for latent TB and have a negative CXR at enrollment. Patients treated for tuberculosis with no recurrence in 3 years are permitted
    27.Known uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral glucocorticoids
    28.Current liver disease as determined by investigator. Patients with prior history of ALT elevation are not excluded
    29. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to atypical mycobacterial disease, clinically significant abnormalities on CXR as determined by the investigator, hepatitis B and C, and herpes zoster for which systemic treatment is needed, but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
    30.History of, or currently active, primary or secondary immunodeficiency, such as HIV or AIDS
    31.Evidence of active malignant disease, malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors, except non-melanoma skin cancer that has been excised and cured)
    32.History of alcohol, drug, or chemical abuse within the 6 months prior to screening
    33. Neuropathies or other painful conditions that might interfere with pain evaluation
    34.Patients with lack of peripheral venous access
    35. Patients with documented lactose intolerance


    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint of the present study is the sustained remission rate (SRR), i.e. the proportion of patients with early RA who achieve sustained remission.
    In individual patients, sustained remission is considered to be achieved if an uninterrupted period of approximately 6 months (at least 23 weeks) can be identified, over which:
    •At least 6 DAS28 values are available, including one at the beginning and one at the end of the period
    •All values are <2.6, with the exception of up to 2 values which can be between 2.6 and 3.2 provided that the investigator considers the patient to be in clinical remission for RA and documents the reason for the RA-unrelated elevation of DAS28 (such as an infection)
    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 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 Yes
    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 concerned24
    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 Information not present in EudraCT
    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 of the last visit of the last participating subject in this study
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    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 months0
    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.1.3Elderly (>=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 state300
    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)
    Both IMP's are commercial available. The patients physician has to decide which therapy is most suitable for each individual patient.
    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 Decision2009-10-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-11-10
    P. End of Trial
    P.End of Trial StatusCompleted
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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