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    Summary
    EudraCT Number:2018-003877-91
    Sponsor's Protocol Code Number:TOLERA
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-02-26
    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 ConcernedGermany - PEI
    A.2EudraCT number2018-003877-91
    A.3Full title of the trial
    Sequential B cell/T cell therapy to re-induce humoral immune tolerance in ACPA-positive Rheumatoid Arthritis (TOLERA): a prospective randomized controlled open-label single-centre clinical trial in adult subjects with active ACPA-positive Rheumatoid Arthritis failing Methotrexate
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    B cell therapy followed by T cell therapy to achieve immune tolerance in rheumatoid arthritis with ACPA antiboidies (TOLERA): an unblinded clinical trial in one centre with random assignment to treatment groups in adult patients who failed methotrexate therapy
    A.3.2Name or abbreviated title of the trial where available
    TOLERA
    A.4.1Sponsor's protocol code numberTOLERA
    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 SponsorUniversitätsklinikum Erlangen
    B.1.3.4CountryGermany
    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 supportDeutsche Forschungsgemeinschaft
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportBristol-Myers Squibb GmbH & Co. KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsklinikum Erlangen
    B.5.2Functional name of contact pointMedizinische Klinik 3
    B.5.3 Address:
    B.5.3.1Street AddressUlmenweg 18
    B.5.3.2Town/ cityErlangen
    B.5.3.3Post code91054
    B.5.3.4CountryGermany
    B.5.6E-mailgerhard.kroenke@uk-erlangen.de
    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.2.1.2Country 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 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 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.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 Orencia
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb
    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 Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNABATACEPT
    D.3.9.1CAS number 332348-12-6
    D.3.9.4EV Substance CodeSUB20635
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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 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.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
    Active rheumatoid arthritis with ACPA antibodies failing methotrexate
    E.1.1.1Medical condition in easily understood language
    Active rheumatoid arthritis showing anti-citrullinated protein antiboidies and without response to methotrexate
    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 23.1
    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 evaluate the effect of a sequential Rituximab/Abatacept treatment on auto-antibody production and thereby determine its potential to lower ACPA levels and to induce a potential seroconversion and thus an immunological remission
    E.2.2Secondary objectives of the trial
    Not applicable

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subject must be able to understand and communicate with the investigator and comply with the requirements of the study, must give a written and signed and dated informed consent before any study assessment is performed
    • Male or non-pregnant, non-lactating female subjects at least 18 years of age
    • Able to adhere to the study visits and protocol
    • Satisfy the ACR-EULAR 2010 classification criteria of Rheumatoid Arthritis at time point of diagnosis
    • SDAI > 11 at screening
    • ACPA positive (anti CCP2 antibody compulsory at screening) (+/- rheumatoid factor)
    • Completed vaccination for pneumococcus pneumoniae according to local guidelines at Baseline
    • Inadequate treatment response with highest tolerated dose after 3 months therapy and/or intolerance to cDMARDs specifically Methotrexate, Sulfasalzine, Hydroxychloroquine and Leflonumide or bDMARDs specifically TNF-alpha inhibitors or IL-6 receptor blockers.
    • Subjects who have previously been treated with other DMARDs will be allowed entry into study after appropriate wash-out period prior to baseline:
    o Etanercept: 4 weeks or longer
    o Infliximab: 8 weeks or longer
    o Adalimumab: 10 weeks or longer
    o Golimumab: 8 weeks or longer
    o Certolizumab: 8 weeks or longer
    o Tocilizumab: 8 weeks or longer
    o Baricitinib: 1 week or longer
    o Secukinumab: 20 weeks or longer
    For all other DMARDs not mentioned above the wash-out period should be five times the half-life of the DMARD concerned.
    • Sulfasalazin, Hydroxychloroquine and Leflunomide must be stopped during screening phase and be replaced by Methotrexate (if possible).
    •As csDMARD: only simultaneous therapy with Methotrexate allowed if tolerated
    • Maximum Glucocortidoiddose at Baseline: 20mg Prednisolone equivalent daily
    • JC-Virus DNA in Serum negative at screening
    E.4Principal exclusion criteria
    • Ongoing or previously treatment with Abatacept or Rituximab
    • Hypersensitivity to the active substance, mouse proteins (Rituximab), chinese hamster ovary cells (Abatacept) or other components
    • Contraindication for Rituximab or Abatacept treatment according to their SmPCs
    • Use of any other biologic immunomodulatory agent (monoclonal antibody) except insulin.
    • Active ongoing inflammatory diseases other than RA that might confound the evaluation of the benefit of the therapy (including SLE, PSS, MCTD, SpA, Behcet disease, vasculitis or autoimmune hepatitis)
    • Active systemic infections during the last two weeks prior to baseline (exception: common cold)
    • History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection as defined by a positive QuantiFERON TB-Gold test. If presence of latent tuberculosis is established then treatment according to local country guidelines must have been initiated but patient cannot take part in the study.
    • Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process, obtained within 3 months prior to screening and evaluated by a qualified physician
    • Known active or past infection with hepatitis B or hepatitis C at screening or baseline as defined by Antibody positivity and/or positive DNA/RNA levels of hepatitis B/C
    • History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed)
    • Uncontrolled severe concomitant disease (including diabetes with plasma glucose >11.1 mmol/l rsp. 200 mg/dl, heart insufficiency >= NYHA III, COPD with severity >= GOLD 3, asthma according to GINA classification >= step 3)
    • Patients with weakened immune system defined as diagnosis of CVID, HIV and or total IgG levels lower than 600 mg/dl)
    • Requirement for immunization with live vaccine during the study period or within 4 weeks preceding baseline.
    • Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions which in the opinion of the investigator immunocompromises the subject and/or places the subject at unacceptable risk for participation in an immunomodulatory therapy
    • Evidence of severe renal dysfunction defined as eGFR < 30 ml/min/1,73 m2 (calculated using the MDRD formula) at screening (Visit 1)
    • History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests such as SGOT (AST) ≥ 3 fold upper limit of normal (ULN), SGPT (ALT) ) ≥ 3 fold ULN, alkaline phosphatase ≥ 3 fold ULN, or serum bilirubin ≥ 2 fold ULN .
    • Screening total WBC count <3,000/µL, or platelets <100,000/µL or neutrophils <1,500/µL or haemoglobin <8.5 g/dL (85g/L)
    • Subjects taking high potency opioid analgesics (e.g. methadone, hydromorphone, morphine)
    • Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results
    • Prior history of suicide attempt at any time in the subject's life time prior to screening and baseline, or major psychiatric illness requiring hospitalization within the last 3 years
    • Planned or ongoing pregnancy status or breast-feeding
    • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unwilling to use effective contraception during the study and for a minimum of 12 months after stopping treatment. Effective contraception is defined as either:
    o Barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicide (where available). Spermicides alone are not a barrier method of contraception and should not be used alone
    o The following methods are considered more effective than the barrier method and are also acceptable:
    o Total abstinence: When this is in line with the preferred and usual lifestyle of the subject [Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]
    o Female sterilization: have had a surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Participation in an interventional clinical trial with an IMP within the last 4 weeks prior to screening.
    • Patients who possibly are dependent on the Sponsor, the Principal Investigator or Investigator (e.g. family members)
    E.5 End points
    E.5.1Primary end point(s)
    • Proportion of anti CCP2 antibody seroconversions in anti-CCP2-positive RA patients at week52 (defined as lowering of anti-CCP2 antibodies below 5RE/ml)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 52
    E.5.2Secondary end point(s)
    • Change in anti CCP2 antibody levels (RE/ml)
    • Change in anti CCP2 antibodies Levels (RE/ml) in HLA-defined subgroups
    • Change in total IgG, IgA, IgM and IgG subclasses
    • Glycosylation profile of total IgG and ACPA
    • Change in B cell numbers
    • Change in numbers of CCP2-specific B-cells
    • SDAI, DAS28 CRP/ESR, CDAI
    • Number of patients in DAS28 CRP/ESR; CDAI, SDAI, Boolean remission at week 52
    • ACR 20, 50, 70 response at week 52
    • Number of flares in each group between week 8 and week 52: Flare as defined as loss of remission or low-disease activity (measured by a composite score (SDAI/DAS28 CRP or ESR)) lasting longer than on a daily variation of complaints.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Screening, Baseline, Week 8, Week 12, Week 24, Week 36, Week 48, Week 52
    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 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) 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 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
    Standard treatment
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state20
    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)
    Standard of 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 Decision2019-06-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-06-28
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