Patients attending hospital-based rheumatology outpatient departments throughout the UK, who had been diagnosed with RA, were receiving MTX, had not responded to (at least two) csDMARD therapy (including MTX) and had experienced an inadequate response to treatment with one TNFi were invited to be screened for eligibility in the trial if they:
l were male or female and aged≥18 years
l had a diagnosis of RA as per the ACR/EULAR 2010 classification criteria confirmed at least 24 weeks prior to the screening visit
l failed csDMARD therapy according to NICE/BSR guidelines,101that is failure of at least two csDMARDs
l had persistent RA disease activity despite having been treated with a current initial TNFi agent for at least 12 weeks. Active RA was defined as:
¢ primary non-response defined as failing to improve DAS28 by>1.2 units or failing to achieve a DAS28 of≤3.2 units within the first 12–24 weeks of starting the initial TNFi treatment (this may include patients who have shown a reduction in DAS28 of>1.2 units but still demonstrate an unacceptably high disease activity in the physician’s judgement with evidence of an overall DAS28 of≥3.2 units) OR
¢ secondary non-response defined as lack of efficacy of the first TNFi treatment (having
demonstrated prior satisfactory response) as per clinician judgement, with the reason for cessation of the first TNFi treatment other than intolerance
l were MTX dose stable for 4 weeks prior to the screening visit and to be continued for the duration of the study
l were on non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids (oral prednisolone not exceeding 10 mg daily), on an unchanged regimen for at least 4 weeks prior to the screening visit and were expected to remain on a stable dose until the baseline assessments have been completed
l provided written informed consent prior to any trial-specific procedures.
Patients were excluded if they met any one of the following criteria.
l They had had major surgery (including joint surgery) within 8 weeks prior to the screening visit or planned major surgery within 52 weeks following randomisation.
l They had 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.
l They had received doses of prednisolone of>10 mg/day within the 4 weeks prior to the screening visit.
l They had received intra-articular or intramuscular steroid injections within 4 weeks prior to the screening visit.
l They had previously received more than one TNFi drug OR any other bDMARD for the treatment of RA.
l They were 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, ciclosporin, azathioprine, leflunomide, sulfasalazine) prior to the start of protocol treatment.
l They had been treated with any investigational drug in the last 12 weeks prior to the start of protocol treatment.
l They had other comorbidities 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 functional classification system102), 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 them at risk if they participated in the study or would make implementation of the protocol difficult.
l They had experienced any major episode of infection requiring hospitalisation or treatment with intravenous antibiotics within 12 weeks of start of the treatment protocol or oral antibiotics within 4 weeks of start of the protocol treatment.
l They were at significant risk of infection that, in the opinion of the investigator, would put them at risk if they participated in the study [e.g. leg ulceration, indwelling urinary catheter, septic joint within 52 weeks (or ever if a prosthetic joint is still in situ)].
l They had known active current or a history of recurrent bacterial, viral, fungal, mycobacterial or other infections including herpes zoster [for tuberculosis (TB) and hepatitis B and C, see below], but excluding fungal infections of nail beds as per clinical judgement.
l They had untreated active current or latent TB. Patients should have been screened for latent TB (as per BSR’s guidelines) within 24 weeks prior to the screening visit and, if positive, treated following local practice guidelines prior to the start of protocol treatment.
l They had 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.
l The had primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.
l In the case of women, they were pregnant or lactating or were women of child-bearing potential (WCBP) who were unwilling to use an effective birth control measure while receiving treatment and after the last dose of protocol treatment, as indicated in the relevant summary of product
characteristics (SmPC) or investigator’s brochure (IB).
l In the case of men, their partners were WCPB who were unwilling to use an effective birth control measure while receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC/IB.
DOI: 10.3310/hta22340 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 34
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l They were known to have significantly impaired bone marrow function as a result of, for example, significant anaemia, leucopenia, neutropenia or thrombocytopenia, defined by the following laboratory values at the time of the screening visit:
¢ haemoglobin level of<8.5 g/dl
¢ platelet count of<100 × 109/l
¢ white blood cell count of<2.0 × 109/l
¢ neutrophil count of<1 × 109/l
l They were known to have severe hypoproteinaemia at the time of the screening visit as a result of, for example, nephrotic syndrome or impaired renal function, defined by:
¢ a serum creatinine concentration of>150 µmol/l.
The eligibility criteria were based on BSR’s guidelines on the use of TNFi.101Important exclusion criteria that
are adhered to in clinical practice were applied in this study.
Patients were approached during standard clinic visits for the management of their RA, or were identified by waiting lists, registries or reviews of case records, and sent a personalised letter inviting them to participate. Patients were provided with verbal and written details about the trial and had as long as they required to consider participation. Assenting patients provided written consent before being registered into the trial and formally assessed for eligibility. Patients at Chapel Allerton Hospital also had the option of giving informed consent for blood and tissue samples to be taken for the SWITCH trial biobank for future scientific research. The participant information sheet and consent forms are provided inAppendix 1.