E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis: patients who are dual ACPA and HLA-DR4 positive |
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E.1.1.1 | Medical condition in easily understood language |
Rheumatoid Arthritis with specific bad prognostic markers (ACPA and HLA-DR4) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 is to characterize the impact of inhibition of costimulation (with abatacept) on the T cell mediated autoimmune response in ACPA+ RA patients. |
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E.2.2 | Secondary objectives of the trial |
The secondary goals are to: (i) identify biomarkers for response to costimulatory blockade in RA (ii) characterise the impact of abatacept on the phenotype and function of myeloid and dendritic cells in RA (iii) to correlate the foregoing with the changes observed in clinical parameters of disease.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects, aged > 18 years, 2. RA as defined by the 2010 EULAR/ACR classification criteria 3. Eligible for abatacept therapy according to local/national guidelines: a. Active RA defined by DAS28 score required by local guidelines for eligibility for abatacept b. Have previously failed (efficacy or tolerance) at least one DMARDs c. Have no contraindications to treatment with abatacept 4. Be able to tolerate methotrexate at dose of 10-25mg/week, either orally or subcutaneously 5. Anti-CCP positive 6. HLA-DRB1*0401 or 0404 positive 7. Able and willing to give written informed consent and comply with the requirements of the study protocol. Note: During screening, only patients who are HLA-DRB1*0401/0404 positive will proceed with the study, while DRB1*0401/0404 negative patients will be withdrawn from the study. |
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E.4 | Principal exclusion criteria |
• History of or current autoimmune rheumatic disease other than RA • Concomitant use of any biologic agent, including TNF inhibitors • Previous abatacept treatment • Patients requiring >10mg prednisolone daily or IM corticosteroids • Active infection. • Known HIV or hepatitis B/C infection • Latent TB infection • Malignancy (other than non-melanoma skin cell cancers) within 5 years • Women who are pregnant, women of child bearing potential who are unwilling to use appropriate contraception or breast-feeding • Inability to give informed consent |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change of the immunological phenotype in T cells following costimulatory blockade for 12 weeks compared with pre-therapy baseline. |
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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) |
1) Changes in immunological response at 4, 12 and 24 weeks measured by transcriptional profiling of relevant cell subsets. 2) Association of immunological responses with clinical outcome measures (including ACR20, DAS28) up to 24 weeks 3) T cell subpopulation profiles(e.g. Th1, Th2, Th17, Tregs and TFH; CD28, CD40L, ICOS, PD-1 profiles) at 12 and 24 weeks 4) Effects on broader antigen-specific T cell / B cell responses (including response to recall antigens such as tetanus and measurement of autoantibodies) 5) Impact on DC (CD11c+) phenotype, including MHC II expression 6) Epigenetic alterations that occur in cell subsets between base line and wk 24 (including microRNAs) 7) Preliminary biomarkers of response identified using urinary metabolomic and/or proteomic analysis.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 4, 12 and 24 weeks 2) up to 24 weeks 3) 12 and 24 weeks 4) 4, 12 and 24 weeks 5) 4, 12 and 24 weeks 6) 24 weeks 7) 12 and 24 weeks |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 0 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 20 |