E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rhuematoid Arthritis |
Artritis Reumatoidea |
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E.1.1.1 | Medical condition in easily understood language |
Rhuematoid Arthritis |
Artritis Reumatoidea |
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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 | 20.0 |
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 main aim of this project is to test the hypothesis that the presence or absence of specific synovial cellular and molecular signatures (B cells and B cell-associated signatures), assessed following a synovial tissue biopsy, will enrich for response / non-response to the B cell depleting anti-CD20 monoclonal antibody (mAb) Rituximab.
The primary aim of this project is to show that in patients failing DMARD therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab and Etanercept (treated together for analysis) therapy. |
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E.2.2 | Secondary objectives of the trial |
In addition to the primary objective previously stated, we will address the following questions: 1) Can a diagnostic synovial biopsy showing a B-cell “rich/poor pathotype” define specific disease responsive/resistant subsets for patient stratification and help rationalize biologic drug choice? 2) Is clinical response associated with inhibition of B cell-linked pathways within the synovium and dependent on local B cell lineage depletion? 3) Is survival of auto-reactive B cells within “protected” synovial niches responsible for B-cell joint re-population and disease resistance-relapse?
For the B-cell-rich synovial pathotypes, we aim to compare the treatment effects of Rituximab to the other two treatment options (Tocilizumab and Etanercept, treated together for analysis). Finally, we aim to examine the interaction between treatments and B-cell status (rich and poor). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients will be recruited with active Rheumatoid Arthritis: 1. 2010 ACR / EULAR classification criteria for a diagnosis of Rheumatoid Arthritis * 2. Patients with DMARD failure and eligible for anti-TNF therapy according to UK NICE guidelines **Patients must have a minimum of 3 swollen joints – the joint selected for biopsy and a minimum of 2 from 28 joint count set, as assessed at biopsy visit 3. Selected joint for biopsy must be minimum grade 2 synovial thickening, as assessed at the biopsy visit 4. 18 years of age or over 5. Patients must be capable of giving informed consent and the consent must be obtained prior to any screening procedures 6. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures
* The ACR/EULAR classification for a diagnosis of RA could have been at any time in the patient’s disease history; the score does not need to be 6 or more at screening. **According to the UK National Institute for Health and Care Excellence (NICE) guidelines, the TNF-α inhibitors are recommended as options for the treatment of adults who have both of the following characteristics: 1) Disease is severe, that is, a disease activity score (DAS28) greater than 5.1 2) Disease has not responded to intensive therapy with a combination of conventional disease modifying antirheumatic drugs (DMARDs). Current NICE guidelines available at the following link: http://www.nice.org.uk/guidance/ta375. |
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E.4 | Principal exclusion criteria |
Patients will be excluded if they have any contraindication to Etanercept, Rituximab or Tocilizumab therapy:
1. Women who are pregnant or breast-feeding 2. Women of child-bearing potential or males whose partners are women of child-bearing potential, unwilling to use an effective method of contraception (recommend double contraception) throughout the trial and beyond the end of trial treatment for the duration as defined in the relevant SmPC; 12 months for Rituximab, at least 3 weeks for Etanercept, and at least 3 months for Tocilizumab. 3. History of or current primary inflammatory joint disease or primary rheumatological autoimmune disease other than RA (if secondary to RA, then the patient is still eligible). 4. Prior exposure to Rituximab, any anti-TNF, Tocilizumab, or any other biologic for treatment of RA 5. Treatment with any investigational agent ≤ 4 weeks prior to baseline or < 5 half-lives of the investigational drug (whichever is the longer) 6. Intra-articular or parenteral corticosteroids ≤ 4 weeks prior to screening visit. 7. Oral prednisolone more than 10mg/d or equivalent ≤ 4 weeks prior to baseline synovial biopsy. 8. Active infection 9. Known HIV, active Hepatitis B/C infection. Hepatitis B screening test must be performed at or in the preceding 3 months of screening visit. 10. Septic arthritis of a native joint within the last 12 months 11. Septic arthritis of a prosthetic joint within 12 months or indefinitely if the joint remains in situ 12. Latent TB infection unless they have completed adequate antibiotic prophylaxis 13. Malignancy (other than basal cell carcinoma) within the last 10 years 14. New York Heart Association (NYHA) grade III or IV congestive heart failure 15. Demyelinating disease 16. Known allergy to latex, Rituximab, Tocilizumab or Etanercept 17. Any other contra-indication to the study medications as detailed in the applicable SmPC including low IgG levels, at physician’s discretion 18. Receipt of live vaccine <4 weeks prior to first IMP infusion or dose 19. Major surgery in 3 months prior to first IMP infusion or dose 20. Presence of a transplanted organ (with the exception of a corneal transplant >3 months prior to screening). 21. Known recent substance abuse (drug or alcohol). 22. Poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period 23. Patients unable to tolerate synovial biopsy or in whom this is contraindicated including patients on anti-coagulants. Oral anti-platelet agents are permitted. 24. Patients currently recruited to other clinical trials. 25. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point will assess the difference in the ACR 20 response between Rituximab and other treatments (Tocilizumab and Etanercept therapy treated together for analysis) at 16 weeks from baseline in the B-cell poor pathotype sub-group. |
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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. Patients deemed treatment failures at 16 weeks, will be switched to the other therapeutic option. Such patients will be considered a new patient starting at week 0 with treatment response assessed again at 16 weeks for ACR20 response. 2. For the B-cell-rich synovial pathotype sub-group, we aim to compare the treatment effects of Rituximab to the other two treatment options (Tocilizumab and Etanercept, treated together for analysis) 3. To examine the interaction between treatments and B-cell status (rich and poor). |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | 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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | 3 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 | 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
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The end of the study will be triggered 6 months after the last patient completes their final study visit (Last Patient Last Visit LPLV; e.g. the post-treatment visit/call assessment). This additional 6 months will allow time for sample processing and image analysis. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |