Principal findings - Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or ritux

Primary outcome

Owing to the early termination of the trial by the funders, the‘SWITCH’study was substantially underpowered in its objective to demonstrate non-inferiority of either alternative TNFi or abatacept to rituximab in terms of a reduction in the DAS28 at 24 weeks post randomisation. In the context of the low number of patients, alternative TNFi was non-inferior to rituximab in the ITT patient population, in that the estimate of the treatment effect excluded the non-inferiority margin of–0.6 units, but non-inferiority was not demonstrated in the PP population, which was our prespecified requirement for demonstrating non-inferiority overall. Non-inferiority of abatacept to rituximab was not demonstrated in either patient population; the 95% CI did not exclude the non-inferiority margin of–0.6 units and is therefore a plausible value.

As the trial was not permitted to recruit the target number of patients, the main interpretation of the results is based on the estimated treatment effect and corresponding precision. In the ITT patient population, the estimated mean difference in the reduction in the DAS28 after 24 weeks between

alternative TNFi and rituximab was 0.30 units (95% CI–0.45 to 1.05 units); the corresponding estimate for the difference between abatacept and rituximab was 0.04 units (95% CI–0.72 to 0.79 units). Hence, the treatment effect in the ITT patient population is estimated with a precision of±0.75 units (corresponding to the half-width of the 95% CI).

Following exclusion of patients according to the prespecified criteria, the number of patients included in the PP population resulted in the treatment effect for both interventions compared with rituximab being estimated with very low precision. The estimated treatment effect for alternative TNFi compared with rituximab was–0.58 units (95% CI–1.72 to 0.55 units) and for abatacept was–0.15 units (95% CI–1.27 to 0.98 units) for the DAS28 at 24 weeks. Therefore, the treatment effect was estimated with a precision of±1.13 units, so there is large uncertainty in the estimate of the treatment effect in the PP population.

Exploratory subgroup analysis

Subgroup effect estimates in this underpowered study should be interpreted cautiously; however, this component of the study was particularly novel and important clinically.

The suggestion of an association between negative serological status and poorer response to rituximab was consistent with meta-analyses,3–84_{a recent RCT of the first-line use of a bDMARD (as opposed to}

following first TNFi failure as with the‘SWITCH’study) in which non-inferiority of rituximab compared with a TNFi in seropositive patients142_{was observed and observational registry data.}82_{The dependency of}

individual CCG receptiveness to secure such agreements, however, increases the potential for regional inconsistency in prescribing options and approach. Complete SWITCH data could have pushed for inclusion in future technology appraisals.

Primary and secondary non-response to an initial TNFi is well recognised and an important marker of the mechanisms for treatment failure, with secondary non-response suggesting a pharmacokinetic basis for failure and primary non-response suggesting the wrong target.143_{The results suggest that primary}

non-response may benefit from a change in class of bDMARD, whereas secondary non-response can be circumvented by use of alternative TNFi; these are consistent with other published literature, albeit from uncontrolled cohort studies.

DOI: 10.3310/hta22340 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 34

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Secondary outcomes

Rheumatoid arthritis is a chronic disease that in the main requires long-term DMARD therapy. RCTs usually comprise a primary end point at week 24 (or earlier) that provides guidance only on short-term outcome whereas, in practice, reassurance on the maintenance (durability) of response is equally relevant. The secondary outcomes at weeks 36 and 48 go some way to providing this additional context. In the‘SWITCH’ study, there was evidence of a greater improvement in disease activity (via the DAS28) at week 36 for alternative TNFi than for rituximab, although this difference was not maintained at week 48. There was no evidence of a difference in the DAS28 between abatacept and rituximab at any time point. However, when assessing disease activity in terms of the odds of achieving a DAS28 response (≥1.2 units), there was no evidence of a difference for either intervention compared with rituximab at any of the time points.

Moreover, there was no evidence of a difference in the odds of achieving an ACR20 response at 24 weeks post randomisation for either intervention relative to rituximab.

In addition to demonstrating a reduction in the DAS28, the overall disease activity status and setting of a target of at least low disease activity (if not remission) is now established as an important goal, which is coined as part of a‘treat to target’management approach of RA.144_{In the}_‘_SWITCH_’_{study, the proportions}

of patients on alternative TNFi and rituximab who achieved DAS28 low disease activity or remission at 24 weeks were similar, whereas the proportion of patients who achieved low disease activity or remission on abatacept was lower. Furthermore, among patients on alternative TNFi, the proportion achieving low disease activity or remission continued to increase to week 48, whereas among those on abatacept and rituximab this proportion fell between 24 and 48 weeks.

Functional and quality-of-life patient-reported outcome measures remain important indicators of patient well-being. Overall, a general improvement in HAQ-DI, RAQoL and the Patient Global Assessment of General Health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the Patient Global Assessment of Pain and Patient Global Assessment of Arthritis at 12 weeks across all three treatment groups. Small improvements in the HADS anxiety and depression scores over the 48-week period were observed in patients treated with alternative TNFi or abatacept, whereas no notable improvement was apparent in those receiving rituximab.

The safety profile was similar for all three treatments. Ten SAEs were reported in nine patients, of which three events in three patients were considered to be related to trial medications. There were no SUSARs reported. Two patients died, in both cases following the development of a SAE (one each in the rituximab and abatacept groups). Ten patients experienced toxicity resulting in a permanent cessation of treatment (four patients on alternative TNFi, two on abatacept and four on rituximab).

The most common protocol deviations related to receiving steroid treatment within 6 weeks of an end-point assessment, not being compliant with treatment to 24 weeks and receiving additional contraindicated treatment, all of which were likely to have contributed to a less conservative estimate of the mean treatment effect relative to the ITT patient population.

Strengths and weaknesses

The principal strength of the‘SWITCH’study design was its emphasis on evaluation of a more defined and refined patient population, in keeping with the overall ambitions of the medical community for a more precise, tailored approach to medicine. This in itself, however, posed its own challenges, such as in recruitment. To date, almost all TNFi failure studies (RCTs and observationa studiesl) have included any cause of failure (inefficacy and toxicity/intolerance), limiting the strength in application of the data on an individual patient level and also the potential mechanistic insights that can be drawn from clinical studies (‘reverse translation’). The SWITCH study permitted the enrolment of only patients in whom TNFi had been found to be ineffective; although this is the predominant reason for failure, it will have limited the eligible patient pool. In addition, evaluating only patients on concomitant MTX (to recognise MTX synergy with bDMARD) will have limited the available recruitment pool further. In hindsight, accepting a less precise approach by including all patients (any cause of TNFi failure and TNFi with/without MTX combination) with

sensitivity analysis adjusting for MTX combination would have been more pragmatic and reduced some of the challenges in recruitment.

Nevertheless, the scientific design and rigorous conduct of this, albeit small, trial means that the SWITCH study will contribute to the evidence base for future research in RA, including in meta-analyses, and, hopefully, encourage future study design to address the factors such as those included in our exploratory subgroup analysis.

The obvious major weakness was the early termination, which resulted in a small number of patients recruited into the study. This naturally led to uncertainty in providing definitive conclusions. Despite this, the study identifies some indicators of response, which, although not definitive, provide support for, in particular, alternative TNFi rather than rituximab as a second-line bDMARD therapy in the management of RA. Furthermore, although an exploratory outcome, further diminished with the small sample size, the absence of a response to rituximab in the seronegative population is consistent with the published meta-analyses in efficacy trials.84_{These results, thus, further support that the hypothesis that an alternative}

bDMARD to rituximab may be preferable if a patient is seronegative. Moreover, if secondary non-response has resulted from a first TNFi, then it may also be more appropriate to consider a second TNFi.

It is important to emphasise, however, that no single treatment (or sequence) is appropriate for all patients and no single study will be able to address this completely. Although these and other complementary data may not provide definitive evidence on tailoring therapy, they do provide initial evidence to support a clinical judgement and increase the chance of treatment success on which subsequent studies can build. This approach to stratification of treatment would represent an advance to the current status of generally prescribing rituximab to all patients, thereby dismissing the potential benefits of switching to alternative therapies in patients who fail TNFi.

A further limitation of the design was the open-label nature of the study. Although blinding patients and treating clinicians to the allocated intervention would have reduced the risk and impact of any assessment bias, it would have been impractical to implement: each of the seven distinct bDMARDs in the SWITCH study involved a different route of delivery and dosing regimen, thus requiring multiple dummy infusions (necessitating additional inpatient attendance) and injections to maintain the blind. Such a treatment schedule was given careful consideration by our PPI advisor, and it was concluded that it would have imposed considerable burden on patients and was unethical, potentially either reducing recruitment further or increasing the rate of attrition throughout the study. However, the fact that all patients received an active therapy may have attenuated any bias introduced by the lack of blinding.

When the SWITCH study was designed, it included all three classes of bDMARD available for evaluation as second-line therapies when taken in combination with MTX, thereby reflecting the full range of therapies available. After the trial design and initiation, tocilizumab was approved as a first-line bDMARD and, hence, represented an additional option for the TNFi-inadequate response RA patient cohort. In addition, NICE has also approved the use of tocilizumab as a monotherapy, broadening the available therapies when given as monotherapy (without concomitant MTX).

The trial design allowed a pragmatic approach with clinician choice of the monoclonal antibody if the patient previously received etanercept. Moreover, a fourth monoclonal antibody, golimumab, was introduced into the alternative TNFi arm during the recruitment phase, thereby allowing further clinician choice across all available TNFis and ensuring further generalisability of the trial results to clinical practice. Although this pragmatic design may have introduced some heterogeneity into the results, it reflected current practice in the NHS and ensured that the EULAR guidance, recommending discussion between patient and treating clinician in the choice of bDMARD, was adhered to; this was considered important in order to maximise recruitment.

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In document Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT (Page 97-100)