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Note: This record shows only 22 elements of the WHO Trial Registration Data Set. To view changes that have been made to the source record, or for additional information about this trial, click on the URL below to go to the source record in the primary register.
Register: EUCTR
Last refreshed on: 13 October 2020
Main ID:  EUCTR2018-003877-91-DE
Date of registration: 26/02/2019
Prospective Registration: Yes
Primary sponsor: Universitätsklinikum Erlangen
Public title: 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
Scientific title: 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 - TOLERA
Date of first enrolment: 13/06/2019
Target sample size: 20
Recruitment status: Authorised-recruitment may be ongoing or finished
Study type:  Interventional clinical trial of medicinal product
Study design:  Controlled: yes
Randomised: yes
Open: yes
Single blind: no
Double blind: no
Parallel group: yes
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: no
Other: yes
Other specify the comparator: Standard treatment
Number of treatment arms in the trial: 2
Phase:  Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no
Countries of recruitment
Name: Medizinische Klinik 3   
Address:  Ulmenweg 18 91054 Erlangen Germany
Affiliation:  Universitätsklinikum Erlangen
Name: Medizinische Klinik 3   
Address:  Ulmenweg 18 91054 Erlangen Germany
Affiliation:  Universitätsklinikum Erlangen
Key inclusion & exclusion criteria
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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

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 hospital

Age minimum:
Age maximum:
Female: yes
Male: yes
Health Condition(s) or Problem(s) studied
Active rheumatoid arthritis with ACPA antibodies failing methotrexate
MedDRA version: 23.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders
Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Pharmaceutical Form: Concentrate for solution for infusion
CAS Number: 174722-31-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Trade Name: Orencia
Pharmaceutical Form: Solution for injection in pre-filled syringe
CAS Number: 332348-12-6
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 125-

Primary Outcome(s)
Main Objective: 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
Primary 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)
Secondary Objective: Not applicable

Timepoint(s) of evaluation of this end point: Week 52
Secondary Outcome(s)
Secondary 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
• 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.
Timepoint(s) of evaluation of this end point: Screening, Baseline, Week 8, Week 12, Week 24, Week 36, Week 48, Week 52
Secondary ID(s)
Source(s) of Monetary Support
Bristol-Myers Squibb GmbH & Co. KGaA
Deutsche Forschungsgemeinschaft
Secondary Sponsor(s)
Ethics review
Status: Approved
Approval date: 12/02/2019
Results available:
Date Posted:
Date Completed:
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