E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 anti-TNF therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab 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?
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients will be recruited with active RA: 1. Patients who have failed anti-TNF therapy (inadequate responders – ir). Note: this includes patients that have failed anti-TNF therapy because of reactions. 2. Who are eligible for Rituximab therapy according NICE guidlines* 3. Patients should be receiving a stable dose Methotrexate for at least 4 weeks prior to the biopsy visit. 4. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of Rheumatoid Arthritis. 5. 18 years of age or over 6. Patient must be capable of giving informed consent 7. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures
*Reference to NICE guidelines: 1.1 Rituximuab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other disease-modifying anti-rheumatic drugs (DMARDS), including treatment with at least one tumour necrosis factor alpha (TNF alpha) inhibitor therapy. |
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E.4 | Principal exclusion criteria |
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 effective contraception during the study and for at least 6 months after stopping study treatment. 3.History of or current primary rheumatological inflammatory joint disease or primary autoimmune disease other than RA (if secondary to RA, then the patient is still eligible) 4. Prior exposure to Rituximab or Tocilizumab for the treatment of RA 5.Treatment with any investigational agent ≤ 4 weeks prior to baseline or < 5 half lives of the investigational drug 6.Intra articular or parenteral corticosteroids ≤ 4 weeks prior to biopsy visit (Visit 2) 7. Oral Prednisolone more than 10mg per day or equivalent ≤ 4 weeks prior to biopsy visit (Visit 2) 8.Active infection 9.Septic arthritis within a native joint within the last 12 months 10.Sepsis of a prosthetic joint within 12 months or indefinitely if the joint remains in situ 11.Known HIV or active hepatitis B/C infection. Hepatitis B screening test must be performed at or in the preceding 3 months of screening visit. 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 3 or 4 congestive cardiac failure 15.Demyelinating disease 16.Latex allergy or allergy to any excipients of Rituximab or Tocilizumab 17.Any other contra-indication to the study medications as detailed in their summaries of product characteristics (SmPC) including low IgG levels at clinician's discretion 18.Receipt of live vaccine <4 weeks prior to first infusion 19. Major surgery in 3 months prior to first infusion 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 trial(s) involving an investigational medicinal product (except any observational follow-up periods not involving an IMP). 25. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgement of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgement 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 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.
Therefore, while this study can be thought of as three distinct clinical trials in separate synovial histomorphological phenotypes (1. B cell rich, 2. B cell poor and 3. Germinal centres)with each sub group randomised to Rituximab or Tocilizumab; the Primary outcome measure is the proportion of patients achieving a CDAI (Clinical disease activity index) response at 16 weeks from baseline.
The primary analysis will focus on whether there is a superiority of Tocilizumab over Rituximab in histologically defined ‘B cell poor patients’.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The timepoint for evaluation of the primary end point will be at 16 weeks from baseline. |
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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 primary response. Treatment difference before and after switch will be compared in B cell poor and B cell rich. 2. For the B-cell rich synovial pathotypes, we aim to show non-inferiority of Rituxumab compared to Tocilizumab. The same analysis as for the primary endpoint will be repeated. 3. Area under the curve (AUC) of mean improvement in DAS28 over time between 0 and 16 weeks and between 0 and 48 weeks 4. Percentage of patients with low disease activity (DAS28 < 3.2) at 16, 24, 36, 48, 96 weeks 5. Percentage of patients in remission (DAS28 < 2.6) at 16 and 48 weeks 6. Percentage of patients with a low clinical disease activity index score (CDAI) at 16, 48 and 96 weeks 7. Mean % change in DAS28 between baseline and 16, 48 and 96 weeks 8. Mean % change in SF-36 score between baseline and 16, 48 and 96 weeks 9. Mean % change in clinical disease activity index score (CDAI) between baseline and 16, 48 and 96 weeks 10. Mean change in HAQ score between baseline and 16, 48 and 96 weeks 11. Change in Fatigue score between baseline and 16, 48 and 96 weeks 12. Serious adverse events over 12 months; the rate of serious adverse events in the 16 week period following a switch from one technology to the other will be compared 13. Mean change in erosive score by the van der Heijde/Sharp scoring system at baseline and week 24. 14. Reduction in US 2D grey scale and power Doppler signal at baseline, 16 and 48 weeks. 15. Mean change in synovial immune cell infiltrate determined immunohistologically (C20, CD68, CD138, CD3) between baseline, 16 and 48 weeks 16. Mean change in synovial gene expression between baseline, 16 weeks and 48 weeks 17. EULAR response based on DAS28 (good and moderate responder/non-responders)
Exploratory endpoint:
Germinal Centre pathotypes will constitute an exploratory component to the trial as insufficient power will be generated to show a significant difference in clinical response between each treatment.
1. Association between disease outcome, treatment group and synovial histology 2. Association between disease outcome, treatment group and Ultrasound measure of inflammation 3. Association between disease outcome treatment group and Disability
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The timepoints for evaluation of secondary end points will be up to 96 weeks from baseline. |
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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) | 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
| 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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 (data collection period) will be triggered when the last recruited patient completes the treatment phase of the trial at 48 weeks + 30 days (post-treatment Safety Follow-up Visit/ phone call) (Last Patient Last Visit LPLV). Up to an additional 6 months may be added to this timeline to allow time for completion of sample processing and image scoring as required. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 | 30 |