Background
TNF-inhibitors
Switching between TNF-inhibitors
Alternative bDMARD therapies
Methods/Design
Trial aims and objectives
Primary objective
Secondary objectives
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To compare alternative-mechanism-TNFi and abatacept to rituximab in terms of disease response, quality of life, toxicity, safety, structural and bone density outcomes (in terms of plain radiography and bone densitometry score) over a 12-month (48 weeks) period.
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To undertake an evaluation of the cost-effectiveness of switching patients to an alternative-mechanism TNFi, abatacept or rituximab.
Exploratory objectives
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To determine the optimal sequence of treatments by assessing whether response to the second treatment in patients with RA is related to the initial failed TNFi (TNFi monoclonal or TNF receptor fusion protein).
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To evaluate whether the response to the second treatment (alternative mechanism TNFi, abatacept or rituximab) is related to whether the patient was a primary (no initial response) or secondary (loss of an initial) response failure to their initial TNFi.
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To ascertain whether seropositive and seronegative (to rheumatoid factor +/- anti-citrullinated peptide antibody) RA patients behave differently in their response and disease outcome measures in the three treatment arms, particularly in the comparisons with rituximab.
Trial design
Eligibility
INCLUSION CRITERIA | |
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1 | Male and female subjects aged ≥18 years at the time of signing the Informed Consent Form. |
2 | Patients with a diagnosis of rheumatoid arthritis as per the ACR/EULAR 2010 classification criteria confirmed at least 24 weeks prior to the screening visit. |
3 | Patients who have failed conventional DMARD therapy as per NICE/BSR Guidelines i.e. failure of at least 2 DMARDS including methotrexate. |
4 | Patients with persistent RA disease activity despite having been treated with a current initial TNFi agent for at least 12 weeks. Active RA defined as*: a. Primary non-response: failing to improve DAS28 by > 1.2 or failing to achieve DAS28 ≤ 3.2 within the first 12 to 24 weeks of starting the initial TNFi. |
● This may include patients that have shown a reduction in DAS28 of >1.2 but still demonstrate unacceptably high disease activity in the physician’s judgement with evidence of an overall DAS28 of ≥3.2. | |
OR
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b. Secondary non-response: defined as inefficacy to first TNFi (having demonstrated prior satisfactory response) as per clinician judgement; with intolerance not the reason for cessation of first TNFi. | |
5 | Methotrexate dose stable for 4 weeks prior to the screening visit and to be continued for the duration of the study. |
6 | Patients on NSAIDs and/or corticosteroids (oral prednisolone not exceeding 10 mg daily) who have been on an unchanged regimen for at least 4 weeks prior to the screening visit and are expected to remain on a stable dose until the baseline assessments have been completed. |
7 | Provided written informed consent prior to any trial-specific procedures. |
*These criteria are consistent with BSR guidelines | |
EXCLUSION CRITERIA
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General
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1 | Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 52 weeks following randomisation. |
Study Specific
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2 | Patients with inflammatory joint disease of different origin, mixed connective tissue disease, Reiter’s syndrome, psoriatic arthritis, systemic lupus erythematosus, or any arthritis with onset prior to 16 years of age. |
3 | Patients receiving doses of prednisolone > 10 mg/day within the 4 weeks prior to the screening visit. |
4 | Patients receiving intra-articular or intra-muscular steroid injections within 4 weeks prior to the screening visit. |
Excluded Previous or Concomitant Therapy:
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5 | Patients who have previously received more than 1 TNFi drug OR any other biological therapy for the treatment of RA. |
6 | Patients unable or unwilling to stop treatment with a prohibited DMARD (i.e. synthetic DMARD aside from MTX e.g. oral or injectable gold, chloroquine, hydroxychloroquine, cyclosporine, azathioprine, leflunomide, sulphasalazine) prior to the start of protocol treatment. |
7 | Treatment with any investigational drug in the last 12 weeks prior to the start of protocol treatment. |
Exclusions for general safety - These criteria should be considered in the context of BSR guidance[44].
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8 | Patients with other co-morbidity including acute, severe infections, uncontrolled diabetes, uncontrolled hypertension, unstable ischaemic heart disease, moderate/severe heart failure (Class III/IV of the New York Heart Association (NYHA) functional classification system), active bowel disease, active peptic ulcer disease, recent stroke (within 12 weeks before the screening visit), or any other condition which, in the opinion of the investigator, would put the patient at risk to participate in the study or would make implementation of the protocol difficult. |
9 | Patients with any major episode of infection requiring hospitalization or treatment with IV antibiotics within 12 weeks of start of treatment protocol or oral antibiotics within 4 weeks of start of protocol treatment. |
10 | Patients at significant risk of infection, which in the opinion of the investigator would put the patient at risk to participate in the study (e.g. leg ulceration, indwelling urinary catheter, septic joint within 52 weeks (or ever if prosthetic joint still in situ)). |
11 | Patients with known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections including herpes zoster (for tuberculosis and Hepatitis B and C see below), but excluding fungal infections of nail beds as per clinical judgement. |
12 | Patients with untreated active current or latent tuberculosis (TB). Patients should have been screened for latent TB (as per BSR guidelines) within 24 weeks prior to the screening visit and, if positive, treated following local practice guidelines prior to the start of protocol treatment. |
13 | Patients with active current hepatitis B and/or C infection. Patients should have been screened for hepatitis B and C within 24 weeks prior to the screening visit and if positive, excluded from the study. |
14 | Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation. |
15 | Pregnancy, lactation or women of child-bearing potential (WCBP) unwilling to use an effective birth control measure whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant Summary of Product Characteristics (SmPC)/Investigator Brochure (IB). |
16 | Men whose partners are of child-bearing potential but who are unwilling to use an effective birth control measure whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC/IB. |
Laboratory value exclusions
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17 | Patients with known significantly impaired bone marrow function as for example significant anaemia, leukopaenia, neutropaenia or thrombocytopaenia as shown by the following laboratory values at the time of the screening visit: |
● Haemoglobin < 8.5 g/dl | |
● Platelet count < 100 x 109/L | |
● White blood cell count < 2.0 x 109/L | |
● Neutrophil count < 1 x 109/L | |
18 | Patients with known severe hypoproteinaemia at the time of the screening visit, e.g. in nephrotic syndrome or impaired renal function, as shown by: |
● Serum creatinine > 150 umol/L |
Recruitment
Consent to the switch trial BioBank
Screening and registration
Randomisation
Trial Intervention
TREATMENT ARM | TREATMENT DESCRIPTION | |
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Rituximab | Single dose of 1 g as an intravenous infusion to be administered at days 0 (week 0) and 15 (week 2; +5 days). | |
In line with standard practice, a participant who loses an initial 6 month (week 24) response as per NICE guidance may receive a further cycle of rituximab after a minimum of 6 months following the first dose. The second cycle of rituximab will be given at a dose of 1 g x 2 intravenous infusions will be administered at a 2-week interval (+5 days). | ||
Abatacept | Abatacept solution for subcutaneous injection: 125 mg/syringe (125 mg/mL). Abatacept will be given at a dose of 125 mg by subcutaneous injection at week 0 and once weekly thereafter for a minimum of 24 weeks. | |
Supplied by Bristol-Myers Squibb free of charge. Trial supplies to be ordered by individual sites which will be responsible for ring-fencing abatacept upon receipt. | ||
Alternative mechanism anti-TNF | Etanercept | Single dose of 50 mg etanercept by subcutaneous injection weekly for a minimum of 24 weeks (unless not tolerated). |
Adalimumab | Single dose of 40 mg adalimumab by subcutaneous injection every 2 weeks for a minimum of 24 weeks (unless not tolerated). | |
Infliximab | Infliximab will be given at a dose of 3 mg/kg per intravenous infusion, administered on a day-case unit or equivalent. The intravenous infusions will be administered at week 0, 2 (+/- 2 days), 6 (+/- 2 days) and then 8-weekly thereafter (+/- 7 days) for a minimum of 24 weeks. | |
Certolizumab Pegol | Single dose of 400 mg by subcutaneous injection at weeks 0, 2, 4 and then at a dose of 200 mg every 2 weeks thereafter for a minimum of 24 weeks. | |
Certolizumab pegol will be available free of charge for the first 12 weeks of protocol treatment if supplied by UCB Pharma through their RA Patient Access Scheme. |
Assessments, samples and data collection
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Screening visit: All patients will undergo screening within 4 weeks prior to the baseline assessment.
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Baseline visit: Baseline assessments are to be performed to confirm that the participant is still eligible for the study and to undertake randomisation to study treatment.
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Clinical assessment visits: Randomised participants attend these visits as part of the interventional (weeks 12, 24, 36 and 48) and the observational (weeks 60, 72, 84 and 96) phases of the study.
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Infusion visits: Participants allocated to Rituximab or Infliximab will undergo additional standard assessments for safety purposes on the infusion dates.Biological samples from participants consenting to the SWITCH Trial BioBank sub-study will be collected prior to commencement of trial treatment and at weeks 2/4, 12, 24, 48 and at the time of early discontinuation if it occurs outside of these time-points (see Figures 2,3 &4). The samples will be sent to a central Switch Trial Biobank. These samples will be used for a range of studies of direct relevance to the treatment of RA.
Outcomes
Sample size
Statistical analysis
Primary outcome analyses
Secondary outcome analyses
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DAS28: Multi-level repeated measures analysis, including minimisation factors and baseline DAS28 in addition to treatment.
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Markers of achieving DAS28 reduction of greater than 1.2 without toxicity, DAS28 LDAS and remission rates, ACR/EULAR Boolean remission and ACR response rates: Binary logistic regression analysis including the minimisation factors and baseline DAS28 in addition to treatment.
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EULAR response scores, SDAI and CDAI scores: Ordinal logistic regression analysis including the minimisation factors and baseline DAS28 in addition to treatment.
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RAQoL, HADS, HAQ-DI: Linear regression analysis will fitted to the change in QoL scores between baseline and 6 months including the minimisation factors and baseline DAS28 in addition to treatment.
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Safety and Toxicity: The proportion of participants experiencing toxicity will be summarised by treatment received. Adverse events (including serious adverse events (SAEs), serious suspected adverse reactions and suspected unexpected serious adverse events) will be summarised by treatment group and the relationship between events and study treatment or underlying RA will be assessed. Expected SAEs common to all treatments include injection site/infusion reactions, blood dyscrasias, serious infections, toxic epidermal necrolysis, Stevens-Johnson syndrome, pulmonary fibrosis, renal failure, neurological impairment, and new autoimmunity. In addition, intolerance to protocol treatment will be summarised by treatment received.