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    Summary
    EudraCT Number:2010-021430-64
    Sponsor's Protocol Code Number:RR10/9389
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-11-04
    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 ConcernedUK - MHRA
    A.2EudraCT number2010-021430-64
    A.3Full title of the trial
    A randomised double blind placebo controlled clinical trial of anti B-cell therapy in patients with primary Sjögren’s syndrome.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to show whether there is an improvment in symptoms after the administration of rituximab in patients with primary Sjögren’s syndrome.
    A.3.2Name or abbreviated title of the trial where available
    TRACTISS (Rituximab / Placebo in Sjogren's Syndrome) Version 1.0
    A.4.1Sponsor's protocol code numberRR10/9389
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN65360827
    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 SponsorUniversity of Leeds
    B.1.3.4CountryUnited Kingdom
    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 supportArthritis Research UK
    B.4.2CountryUnited Kingdom
    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 MabThera (rituximab)
    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 (Rituximab)
    D.3.2Product code N/A
    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.3.9.2Current sponsor coden/a
    D.3.9.3Other descriptive nameRituxan (US, Canada, Japan), MabThera (rest of world)
    D.3.9.4EV Substance CodeAS2
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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.3.11.13.1Other medicinal product typeGenetically engineered chimeric mouse/human monoclonal antibody.
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary Sjögren’s syndrome (PSS).
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10040767
    E.1.2Term Sjogren's syndrome
    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 assess the extent to which rituximab improves symptoms of fatigue and oral dryness in patients with primary Sjögren's syndrome.
    E.2.2Secondary objectives of the trial
    SECONDARY OBJECTIVES
    To assess whether rituximab:
    •Increases salivary and lachrymal flow.
    •Produces improvement in serological and peripheral blood inflammatory features.
    •Improves quality of life and disease activity indices.
    •Is cost effective.
    •Produces improvement in systemic features.
    •To further validate questionnaires measuring disease activity and patient symptoms currently in development for use in the assessment of Sjögren’s Syndrome.


    SUBSTUDY OBJECTIVES:
    •Central analysis to assess whether rituximab has a positive effect on glandular histology.
    •Central review of ultrasound imaging as an effective tool in determining treatment response

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Local and systemic T cell abnormalities in Primary Sjogren's Syndrome and their response to B cell depletion:
    • To compare peripheral blood T-cell transcriptional signatures in PSS patients with healthy and disease controls.
    • To compare peripheral blood T-cell transcriptional signatures in PSS patients pre- and post- B cell depletion
    • To characterise tissue distribution, phenotype, and gene expression of lesional T cells in PSS patients pre- and post-B-cell depletion.
    E.3Principal inclusion criteria
    Eligibility waivers to inclusion/exclusion criteria are not permitted.
    1. Aged between 18 and 80 years of age.
    2. A confirmed diagnosis of primary Sjögren’s syndrome by AECG criteria (see Appendix B).
    3. Positive for anti-Ro auto-antibodies.
    4. Patients with a diagnosis of primary Sjögren’s syndrome (by AECG criteria) with more than 10 years disease duration must have at least one systemic feature of:
    • Hypergammaglobulinaemia (IgG over 16)*, or
    • Low complement C4*, or
    • Cryoglobulinaemia
    OR
    • Active/past history since diagnosis of the following (ascribed to Sjögren’s Syndrome):
    o purpura/cutaneous vasculitis,
    o lymphadenopathy,
    o persistent parotid salivary gland swelling not due to infection,
    o peripheral neuropathy (previously documented by nerve conduction tests),
    o interstitial lung disease confirmed by HRCT,
    o renal tubular acidosis requiring treatment,
    o CNS disease ascribed to Sjögren’s syndrome (confirmed by MRI),
    o myositis (CPK>2N and EMG or biopsy evidence of myositis),
    o inflammatory arthritis
    5. An unstimulated salivary flow rate greater than 0ml in 15 minutes.
    6. Symptomatic oral dryness (≥ 5/10 on patient-completed Likert**).
    7. Symptomatic fatigue (≥ 5/10 on patient-completed Likert**).
    8. Patients on corticosteroids, NSAIDS, antidepressants, DMARDs (e.g. methotrexate, hydroxychloroquine, azathioprine, MMF, leflunomide, ciclosporin etc.), or pilocarpine*** must have been on a stable dose for 4 weeks prior to receiving the first infusion of study medication and expected to remain on this dose throughout the study. If they have stopped any of these drugs they should have been off it for at least 4 weeks weeks prior to receiving study medication.
    9. Given their written informed consent to participate in the trial and expected to be able to adhere to the study visit schedule and other protocol requirements.

    *Anti-Ro antibody test, IgG, RF and C4 assays performed within 6 months of screening may be used to confirm eligibility. If greater than 6 months repeats should be performed locally at screening to confirm eligibility.

    ** LIKERT range 0-10 with 10 corresponding to worst severity.

    *** Pilocarpine or drugs with similar pharmacological action should not be used within 12 hours of the assessment visits at screening, baseline, week 16, week 24, week 36 and week 48 (end of study).
    E.4Principal exclusion criteria
    Patients will be excluded from the trial for the following reasons:

    1. Diagnosis of secondary Sjögren’s syndrome.
    2. Pregnancy, lactation or women of child-bearing potential (WCBP) unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment has finished.
    3. Men whose partners are of child-bearing potential but who are unwilling to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment has finished.
    4. Patient has active or prior hepatitis B or C, known HIV positivity or known history of tuberculosis.
    5. Immunodeficiency or neutropaenia <1.5 x 109/l (unless a diagnosis of benign ethnic neutropaenia has been confirmed in which case the neutrophil count must be > 0.9 x 109/l at screening for Jamaican and Afro-Caribbean populations (60)).
    6. Any AECG exclusion criteria not covered elsewhere (graft versus host disease, primary lymphoma excluding PSS, sarcoidosis).
    7. Any malignancies that would normally preclude the use of rituximab within the past 5 years, including solid tumours, haematological malignancies and carcinoma in situ (except basal cell or squamous cell carcinoma of the skin that has been excised and cured)
    8. Participation in a clinical study involving administration of an investigational drug within the past 4 weeks prior to the first infusion.
    9. A history of major surgery within 3 months prior to first infusion or planned surgery during the study.
    10. Receipt of live/attenuated vaccine within 4 weeks prior to the first infusion.
    11. Previous exposure to rituximab or any other monoclonal antibody within the past 5 years.
    12. History of recurring or chronic infections or underlying conditions which may further predispose patients to serious infection.
    13. History of moderate to severe congestive heart failure according to the New York Heart Association (NYHA) functional classification system (see Appendix C) or other uncontrolled heart disease, or who have a clinically significant abnormal ECG at the time of screening.
    14. History of receiving human/murine recombinant products or known allergy or anaphylactic reaction to a biologic agent or any component of the active substance or any of its excipients or murine components.
    15. Patients with fibromyalgia or a diagnosis of significant depression or anxiety that in the opinion of the clinician would confound the interpretation of the study results.
    16. Current or a history of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease (including demyelinating diseases such as multiple sclerosis).
    17. Any history of organ transplant (with the exception of a corneal transplant >3 months prior to study entry).
    18. Presence of a clinically significant illness or mental disorder within 4 weeks of the start of the trial where the safety of the individual might be at risk by entry into the trial, or where the individual does not have the capacity to consent or where the outcome of the therapy cannot be assessed by virtue of the illness or disorder. Each patient will be assessed individually and no person who wishes to participate will be unreasonably excluded by virtue of the illness or disorder.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is the achievement of a 30% reduction at 48 weeks from baseline in either oral dryness or fatigue measured using patient-completed visual analogue scales (VAS - Range 0-100mm).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluation at week 48 from baseline.
    E.5.2Secondary end point(s)
    Fatigue (VAS Score – Range 0-100mm)
    Oral Dryness (VAS Score – Range 0-100mm)
    Ocular Dryness (VAS Score – Range 0-100mm)
    Patient global assessments (VAS Score – Range 0-100mm)
    Physician global assessments (VAS Score – Range 0-100mm)
    Salivary Flow (Stimulated and Unstimulated Salivary flow)
    Lachrymal Flow (Schirmers I test of ocular function)
    Quality of Life - ESSPRI (EULAR Sjögren’s Syndrome Patient Reported Index)
    Quality of Life, Disease Damage and Disease Activity Indices (ESSDAI, SF-36, PROFAD-SSI)
    Serological and Peripheral Blood Inflammatory Features (Haematology biochemistry, serology and immunology assays)
    Incremental Cost-effectiveness Ratio (EQ-5D, Health Economics)
    Systemic disease activity features (SCAI, SSDAI, SSDDI, SSDI)
    Validity of questionnaires, assessments and disease indices
    Glandular Histology (Labial Gland Biopsy)
    Glandular composition (Salivary Gland Ultrasound Scan)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluated at Baseline and weeks 16, 24, 36 and 48:
    Fatigue, Oral Dryness, Ocular Dryness, Patient global assessments,
    Physician global assessments, Salivary Flow, Lachrymal Flow, Quality of Life ESSPRI, Serological and Peripheral Blood Inflammatory Features (Haematology biochemistry, serology and immunology assays); Validity of questionnaires, assessments and disease indices

    Evaluated at baseline, 24 and 48 Weeks:
    Quality of Life, Disease Damage and Disease Activity Indices (ESSDAI, SF-36, PROFAD-SSI); Incremental Cost-effectiveness Ratio (EQ-5D, Health Economics); Systemic disease activity features (SCAI, SSDAI, SSDDI, SSDI).

    Evaluated from samples/scans performed at baseline, 16 and 36 weeks:
    Glandular Histology (Labial Gland Biopsy);Glandular composition (Salivary Gland US)
    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 No
    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 Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned20
    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 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
    The end of the trial is defined as the date of the last patient’s last treatment visit (week 26) plus 30 days. Long term follow up for purposes of the Main REC and Research Governance is to the last patient’s last trial follow up visit (week 48) which constitutes the non-interventional phase of the trial.
    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 years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days14
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 35
    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 state110
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 110
    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)
    The therapy is used to induce remission of symptoms and individual patients with Sjogren's would only receive 2 cycles (4 doses) of treatment in the trial. Further continued similar therapy would not be given to patients and thus no provision for continued therapy is necessary or appropriate. Patients will receive standard care as determined by their local treating clinician once the trial has ended.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR Comprehensive Clinical Research Network (CCRN)
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-10-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-01-16
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