E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients with ACPA-positieve active RA |
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E.1.1.1 | Medical condition in easily understood language |
patients with ACPA-positieve active RA |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003268 |
E.1.2 | Term | Arthritis rheumatoid |
E.1.2 | System Organ Class | 100000004859 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to assess the impact of filgotinib treatment on the presence and functional activation state of ACPA-expressing B cells in RA patients, compared to a control intervention. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are designed to define the changes to the auto-reactive B cell compartment induced by filgotinib versus control treatment in relation to the clinical context and to define/elucidate the mode of action of filgotinib with regard to these changes. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria. Each patient must:
- have a diagnosis of RA and must have fulfilled the revised 2010 EULAR/ACR criteria for classification of RA prior to initiation of first-line treatment. - have a positive test for the presence of anti-citrullinated protein antibodies (ACPA) in serum as determined by routine clinical assay. - have an ACPA serum level of at least 200 AU/ml, as determined by routine clinical assay. - have moderate to highly active disease defined by a disease activity score evaluating 28 joints (DAS28) ≥ 3.2 or, correspondingly, an sDAI score of > 11. - have used methotrexate monotherapy at a stable, oral dose of 15 mg once weekly for at least 3 months; concomitant glucocorticoid therapy is allowed if at a stable dose of ≤ 7.5 mg prednisolon equivalent within 30 days prior to entry in the study. - have adequate hematologic function (ANC ≥ 4000 cells/µL, platelet count ≥ 150000/µL, and haemoglobin ≥ 10 g/dL (corresponding to 6.2 mmol/L) - have serum creatinine concentrations < 1.5 mg/dl and/or a normal creatinine clearance - be at least 18 years of age - if female and of childbearing potential, agree to: comply with effective contraceptive measures, use adequate contraception since the last menses and use adequate contraception during the study - be willing to undergo pre-treatment screening for latent tuberculosis infection by chest X-ray and Mantoux testing as well as serological screening for chronic viral hepatitis infection in the case of randomization in the filgotinib treatment arm. - be able and willing to give written informed consent prior to entry in the study |
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study. Any patient who:
- has ever been treated with rituximab or another B-cell depleting agent - has been treated with a biological DMARD (except rituximab) or a targeted synthetic DMARD within 6 months prior to entry in the study - has received intra-articular or systemic glucocorticoid injections within 30 days prior to baseline or requires narcotic analgesics other than those accepted by the investigator for analgesia (e.g. paracetamol, NSAIDs, codeine, tramadol) - receives concomittant treatment with a csDMARD other than methotrexate − has been tested negative for ACPA − is in clinical remission as defined by a disease activity score evaluating 28 joints (DAS28) ≤ 2.6 or, correspondingly, an sDAI ≤ 3.3 − has evidence of prior thrombo-embolic events (e.g. deep-venous thrombosis, pulmonary embolism) − has evidence of poorly controlled diabetes, history of clinically significant pulmonary disease including methotrexate-induced lung disease, poorly controlled asthma or a history of severe life-threatening asthma attacks, history of active tuberculosis or history of latent tuberculosis without adequate medical treatment, liver cirrhosis or fibrosis, significant active infection or any underlying diseases that could predispose the subject to an unacceptable risk of infections. − has liver function abnormality (AST and/or ALT ≥ 3 x upper limit of normal range) − has concurrent treatment with an experimental drug or who has participated in another clinical trial with an investigational drug within 30 days prior to study entry − has pre-existing sensory or motor polyneuropathy ≥ Grade 2 according to NCI CTCAE − has past or current history of solid or haematological neoplasms, except for curatively treated non-melanoma skin cancer, adequately treated in situ carcinoma of the cervix or another cancer curatively treated and with no evidence of disease for at least 10 years − has significant cardiac disease, cardiac arrhythmia (Lown Grade ≥ III), uncontrolled hypertension or recent history of myocardial ischemia − is pregnant or a currently nursing woman − is, female and of childbearing potential, unwilling to use adequate contraceptive measures during the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the change from baseline in the frequency of ACPA-expressing B cells secreting ACPA-IgG in ex-vivo PBMC cultures at the 6 month time-point compared between the two treatment arms. Outcome measure for the primary end-point: assessment of the percentage of ACPA-IgG positive cell culture wells, as determined by ELISA, obtained from ex-vivo PBMC cultures
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoint is the change from baseline in disease activity (assessed as simplified disease activity index (sDAI)) at the 6 month time point. The sDAI is based on an assessment of 28 joints and calculated as the sum of the tender joint count (TJC28), the swollen joint count (SJC28), a patient global assessment on an visual analogue scale (PtGA), an evaluator global assessment (EGA) and the C-reactive Protein level in serum. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
immunology, mode of action.
The primary objective of the study is to assess the impact of filgotinib treatment on the presence and functional activation state of ACPA-expressing B cells in RA patients, compared to a control intervention. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |