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 | 19.0 |
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 mailnaim of this project is to test the hypothesis that the presence or absence of specific synovial cellular and molecular signatures (B cells and B cells-associated signatures), assesed 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 Tociluzumab therapy. |
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E.2.2 | Secondary objectives of the trial |
In addition to the primary objective previously started, 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 assosiated 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 to the guideline 'Doelmatig gebruik van biologicals bij reumatoide artritis, axiale spondyloartritis en artritis psoriatica' of the Dutch Society of Rheumatology (NVR)."
3. Patients should be receiving a stable dose Methotrexate for at least 4 weeks prior to biopsy visit.
4. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of Rheumatoid Arthritis.
5. Over 18 years of age
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
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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 12 months after stopping study treatment.
3. History of or current primary inflammatory joint disease or primary autoimmune disease other than RA.
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, whichever is the longer).
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 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 (e.g. patients on anti-coagulants).
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 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 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 cells-associated signatures), assesed 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 subgroup randomised to Rituximab or Tocilizumab; the primary endpoint measure is the proportion of patients achieving a CDAI response at 16 wks from baseline.
The primary analysis will focus on whether there is a superiority of Toculizumab 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 |
Timepoint for evaluation of the primary endpoint will be at 16 weeks from baseline. |
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E.5.2 | Secondary end point(s) |
1. For the B-cell rich synovial pathotypes, we aim to show non-inferiority of Rituximab compared to Tocilizumab.
2. 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.
3. Area under the curve (AUC) of mean improvement in DAS28 over time between 0, 16 and 48 weeks.
4. Percentage of patients with low disease activity (DAS28 < 3.2) at 12, 24, 36, 48, 96 weeks
5. Percentage of patients in remission (DAS28 < 2.6) at 16, 48 and 96 weeks
6. Percentage of patients with ACR 20, 50 and 70 response rates at 16, 48 and 96 weeks
7. Percentage of patients with a low clinical disease activity index score (CDAI)
8. Mean % change in DAS28 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 24 and 48 weeks.
14. Reduction in US 2D grey scale and power Doppler signal at 16, 48 and 96 weeks.
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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
| 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 | 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 their final study visit (Last Patient last Visit LPLV) at the 48 weeks assesment |
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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 | |
E.8.9.2 | In all countries concerned by the trial years | 4 |