E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
rheumatoid arthritis |
reumatoïde artritis |
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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 | 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 |
To investigate non-inferiority of rituximab SC 336 mg to rituximab IV 200 mg, with the lower boundary of the 95% confidence interval of AUC0-6mnd,SC : AUC0-6mnd,IV exceeding the non-inferiority margin of 0.8. |
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E.2.2 | Secondary objectives of the trial |
1. To describe the relevant pharmacokinetic parameters of rituximab 336 mg SC compared to 200 mg IV: peak level, trough level, Cavg; 2. To evaluate the between group difference in changes in disease activity (DAS28-CRP) after 6 months, compared to a NI margin of 0.6; 3. To evaluate the between group differences on on B-cell counts; 4. To assess the differences in incidence of anti-drug antibodies (ADAs); 5. To assess the incidence of AEs in both groups; 6. To assess patient preferences for either SC or IV formulation.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Rheumatoid arthritis: either 2010 EULAR/ACR RA and/or 1987 ACR RA criteria and/or clinical diagnosis of the treating rheumatologist; 2. Patients using rituximab in ultra-low dose: either 200 mg or 500 mg as previous dose, given every 6 months, with or without concomitant methotrexate; 3. Having sufficient response to rituximab treatment, operationalized as a DAS28-CRP < 2.9 3-6 months after the last infusion and/or judgment of low disease activity by the treating rheumatologist; 4. ≥16 years old and mentally competent; 5. Ability to read and communicate well in Dutch.
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E.4 | Principal exclusion criteria |
1. Previous non-response to ultra-low dose rituximab (DAS28-CRP > 2.9); 2. Objection or contraindication to either of the treatment options;
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E.5 End points |
E.5.1 | Primary end point(s) |
The main study endpoint is non-inferiority of rituximab 336 mg SC to rituximab 200 mg IV, based on AUC0-6 months. The AUC will be calculated using the four samples with the trapezoid method. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months. |
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E.5.2 | Secondary end point(s) |
Additional PK parameters In addition to the AUC0-6months, the peak level, the trough level and the average concentration (Cavg) are considered relevant PK parameters to compare both formulas. Those parameters will be calculated using (some of) the four RTX samples drawn, analysed by the RTX assay of Sanquin.
Efficacy Disease activity will be measured at baseline, at three months and at six months, using the DAS28-CRP score. Therefore, we collect the following parameters: - Physical examination: swollen joint count, tender joint count; - Patient Global Assessment of disease activity (VAS); - Acute phase reactants: CRP.
B-cell count B-cell count will be performed at baseline, at three months and at six months. For this analysis, blood will be drawn in a 3 ml EDTA tube. B-cell count will be performed at the Radboudumc immunology laboratory. The percentages and absolute number of B-cells will be determined within 24 hours after blood collection by using a combination of fluorochrome-labelled monoclonal antibodies, CD45, CD3, CD19 and CD16/56 (Tetra 2 combi from Beckman Coulter). With the use of a fully standardized volumetric counting flow cytometer, the Aquios (Beckman Coulter), samples will be incubated with MoAbs, erythrocytes will be lysed and subsequently the analysis will be automatically performed. Samples will be calibrated using standardized fixed cells samples (Aquios Immuno-Trol cells, Beckman Coulter). Quality control assessment is performed by participating in the regular program of the UK Neqas (Sheffield), the Alternative Immunomonitoring Program (12 samples per year).
Anti-drug antibodies Presence of anti-drug antibodies against rituximab will be measured in the proportion of patients with undetectable rituximab levels. This means that in patients with rituximab levels < 0.1 mg/L anti-drug antibodies will be measured in serum. Samples will then be analysed using a validated ADA radio-immune assay at the bioanalytical laboratory of Sanquin.
Adverse Events The occurrence of adverse events during the study period will be registered using the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.21 AEs that can occur using rituximab IV or SC are an increased risk for infections and (skin) malignancies. AEs will be monitored throughout the study.
Patient preferences In the intervention group, patient preference for IV or SC RTX therapy will be assessed on the last visit in a small questionnaire, using a 7-point Likert-scale, with one end representing SC therapy and the other end IV therapy. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PK parameters: Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months. - Efficacy: at baseline, at 3 months and at 6 months - B-cell count: at baseline, at 3 months and at 6 months - Anti-drug antibodies: antibodies will be determined for low RTX serum levels. Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months. - Adverse Events: throughout the study - Patient preferences: for the SC group, at 6 months |
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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 | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | Yes |
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 | Yes |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |