Elsevier

The Lancet

Volume 388, Issue 10061, 3–9 December 2016, Pages 2763-2774
The Lancet

Articles
Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study

https://doi.org/10.1016/S0140-6736(16)31651-8Get rights and content

Summary

Background

To date, head-to-head trials comparing the efficacy and safety of biological disease-modifying antirheumatic drugs within the same class, including TNF inhibitors, in patients with active rheumatoid arthritis despite methotrexate therapy are lacking. We aimed to compare the efficacy and safety of two different TNF inhibitors and to assess the efficacy and safety of switching to the other TNF inhibitor without a washout period after insufficient primary response to the first TNF inhibitor at week 12.

Methods

In this 104-week, randomised, single-blind (double-blind until week 12 and investigator blind thereafter), parallel-group, head-to-head superiority study (EXXELERATE), eligible patients from 151 centres worldwide were aged 18 years or older with a diagnosis of rheumatoid arthritis at screening, as defined by the 2010 ACR/EULAR criteria, and had prognostic factors for severe disease progression, including a positive rheumatoid factor, or anti-cyclic citrullinated peptide antibody result, or both. Participants were randomly assigned (1:1) via an interactive voice and web response system with no stratification to receive certolizumab pegol plus methotrexate or adalimumab plus methotrexate. All study staff were kept masked throughout the study and participants were masked until week 12. At week 12, patients were classified as responders (by either achieving low disease activity [LDA] according to Disease Activity Score 28-erythrocyte sedimentation rate [DAS28-ESR] ≤3·2 or DAS28-ESR reduction ≥1·2 from baseline) or as non-responders. Non-responders to the first TNF inhibitor to which they were randomised were switched to the other TNF inhibitor with no washout period. Primary endpoints were the percentage of patients achieving a 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 12 and LDA at week 104 (week 12 non-responders were considered LDA non-responders). This study is registered with ClinicalTrials.gov, number NCT01500278.

Findings

Between Dec 14, 2011, and Nov 11, 2013, 1488 patients were screened of whom 915 were randomly assigned; 457 to certolizumab pegol plus methotrexate and 458 to adalimumab plus methotrexate. No statistically significant difference was observed in ACR20 response at week 12 (314 [69%] of 454 patients and 324 [71%] of 454 patients; odds ratio [OR] 0·90 [95% CI 0·67–1·20]; p=0·467) or DAS28-ESR LDA at week 104 (161 [35%] of 454 patients and 152 [33%] of 454 patients; OR 1·09 [0·82–1·45]; p=0·532) between certolizumab pegol plus methotrexate and adalimumab plus methotrexate, respectively. At week 12, 65 non-responders to certolizumab pegol were switched to adalimumab and 57 non-responders to adalimumab were switched to certolizumab pegol; 33 (58%) of 57 patients switching to certolizumab pegol and 40 (62%) of 65 patients switching to adalimumab responded 12 weeks later by achieving LDA or a DAS28-ESR reduction 1·2 or greater. 389 [75%] of 516 patients who received certolizumab pegol plus methotrexate and 386 [74%] of 523 patients who received adalimumab plus methotrexate reported treatment-emergent adverse events. Three deaths (1%) occurred in each group. No serious infection events were reported in the 70-day period after treatment switch.

Interpretation

These results show that certolizumab pegol plus methotrexate is not superior to adalimumab plus methotrexate. The data also show the clinical benefit and safety of switching to a second TNF inhibitor without a washout period after primary failure to a first TNF inhibitor.

Funding

UCB Pharma.

Introduction

Rheumatoid arthritis is a chronic inflammatory disease driven by various proinflammatory cytokines.1 Several biological disease-modifying anti-rheumatic drugs (bDMARDS) with different mechanisms of action, have been shown to be efficacious in the treatment of patients with rheumatoid arthritis.1, 2 Current treatment guidelines recommend escalating therapy to a combination of bDMARDs and methotrexate for patients with rheumatoid arthritis who have an inadequate response to conventional synthetic DMARDs (csDMARDs).3, 4 Indirect evidence from meta-analyses and direct evidence from a small number of head-to-head studies comparing TNF inhibitors to drugs with other mechanisms of action suggest that, on average, bDMARDs might be generally similar to one another in terms of efficacy and safety.5, 6, 7, 8 At present, the TNF inhibitors class of therapeutics are often the first biologics prescribed in clinical practice; however, a direct comparison of different TNF inhibitors has never been done. Direct head-to-head comparisons should provide the most rigorous evidence on the comparative effectiveness of different treatments.5, 6, 7, 9, 10 In the absence of data from direct head-to-head trials, different TNF inhibitors can only be indirectly compared, which is difficult given several limitations with methods.10, 11

Research in context

Evidence before this study

In 2010, before this study was initiated, a systematic literature review was done using search terms: anti-tumour necrosis factor (TNF), certolizumab pegol, infliximab, adalimumab, etanercept, golimumab, direct comparison, efficacy, and safety in the Ovid and PubMed database platforms. The results of this systematic literature review confirmed that no randomised controlled trials had directly compared the efficacy and safety of two TNF inhibitors. Therapy options for rheumatoid arthritis have progressed rapidly in recent years with the introduction of biological disease-modifying antirheumatic drugs (bDMARDs). EULAR and ACR recommendations for the management of rheumatoid arthritis suggest first treating patients with a conventional synthetic DMARD. If an adequate response is not achieved, it is then recommended to add a bDMARD. The TNF inhibitor class of bDMARD is often the first class of bDMARDs used. EULAR and ACR guidelines recommend switching patients to another TNF inhibitor or to a bDMARD with a different mechanism of action if they fail to respond to their first bDMARD by 3 months. To date, no direct head-to-head trials have compared the efficacy and safety of different TNF inhibitors. Furthermore, no studies have investigated the efficacy and safety of directly switching to a second TNF inhibitor following an inadequate response to the first TNF inhibitor. Evidence for the efficacy of switching from one TNF inhibitor to another has come from studies recruiting patients with a history of inadequate response to either primary or secondary treatment with a TNF inhibitor, for example the REALISTIC and GO-AFTER trials.

Added value of this study

In the absence of well-controlled clinical trial data, guidelines rely on indirect evidence from registries and meta-analyses. To the best of our knowledge, the EXXELERATE study is the first trial to compare two TNF inhibitors (certolizumab pegol and adalimumab) in a head-to-head setting and to assess the efficacy and safety of directly switching from one TNF inhibitor to another without a washout period following inadequate response to primary treatment with a TNF inhibitor.

Implications of all the available evidence

The results from EXXELERATE show, in a head-to-head setting, no significant difference between certolizumab pegol and adalimumab in combination with methotrexate in either short-term (12-week) or long-term (2-year) efficacy, and provide evidence supporting an initial treat-to-target principle, emphasising the importance of clinical decision making at week 12. By following this approach and using a second TNF inhibitor at week 12 (after an inadequate response to the first TNF inhibitor), clinicians can maximise, in a timely manner, the potential benefit of TNF inhibitor therapy for a patient. This also allows early identification of TNF inhibitor inadequate responder patients (within 6 months) who might potentially benefit from treatment that uses a different mechanism of action. Furthermore, EXXELERATE provides clinical evidence of comparable safety over 2 years between certolizumab pegol and adalimumab. Overall, these results support the use of TNF inhibitors in a methotrexate inadequate responder patient population and provide additional clinical evidence of the efficacy and safety of an immediate switch to a second TNF inhibitor in a primary TNF inhibitor inadequate responder population.

In addition to selecting the optimal first-line drug, current treatment guidelines for rheumatoid arthritis recommend switching patients to an alternative therapy if they have inadequate improvement by 3 months after the start of treatment (defined as not achieving a reduction of Disease Activity Score 28-erythrocyte sedimentation rate [DAS28-ESR] ≥1·2 or a >50% improvement in Clinical Disease Activity Index [CDAI] or Simplified Disease Activity Index [SDAI]),8, 12 or they do not achieve the treatment target (preferably remission or low disease activity [LDA], which is appropriate for patients with refractory disease) by 6 months.3, 4, 13 According to current American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) treatment recommendations,3, 4 patients who do not adequately respond to treatment with a first TNF inhibitor can switch to another TNF inhibitor or to a bDMARD with a different mechanism of action. There are five TNF inhibitors available for the treatment of rheumatoid arthritis: adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab. Results from the REALISTIC14 and GO-AFTER15 studies which enrolled inadequate responders to TNF inhibitors, suggest that using a second TNF inhibitor has at least some clinical benefit in this refractory patient population. However, the patients in these studies, as in studies of other mechanisms of action in inadequate-responder to TNF inhibitor populations, comprised a heterogeneous patient population, who had been treated with different TNF inhibitors for different durations, had different reasons for discontinuation, included both primary and secondary failures, and had inconsistent time periods between treatment with the previous TNF inhibitor and the new bDMARD.

We aimed to compare the efficacy and safety of two different TNF inhibitors and also to assess the efficacy and safety of switching to the other TNF inhibitor without a washout period, following insufficient response to the first TNF inhibitor at week 12. The study compared certolizumab pegol (a PEGylated, humanised, recombinant Fab' fragment with one TNF binding site16) in combination with methotrexate with adalimumab (a human monoclonal antibody with two TNF binding sites) in combination with methotrexate in patients who previously did not respond to methotrexate therapy.

Section snippets

Study design and participants

EXXELERATE (NCT01500278) was a 104-week (2-year) randomised, single-blind (double blind until week 12 and investigator blind thereafter), parallel-group, head-to-head superiority study comparing certolizumab pegol with adalimumab, both with background methotrexate (figure 1A). The study was done at 175 centres (of which 151 recruited patients) in Europe (Austria, Bulgaria, Czech Republic, France, Germany, Hungary, Ireland, Italy, Poland, Portugal, Romania, Spain, and Switzerland) Australia, and

Results

Between Dec 14, 2011, and Nov 11, 2013, 1488 patients were screened, of whom 915 were randomly assigned; 457 to certolizumab pegol plus methotrexate and 458 to adalimumab plus methotrexate. Of these, 457 participants assigned to certolizumab pegol plus methotrexate were included in the safety set and 457 participants assigned to adalimumab plus methotrexate were included in the safety set. 454 participants assigned to certolizumab pegol plus methotrexate and 454 assigned to adalimumab plus

Discussion

The EXXELERATE study is the first prospective, single blind (double blind to week 12 and investigator blind thereafter) trial, assessing the efficacy of one TNF inhibitor, certolizumab pegol, compared with another, adalimumab, with a primary superiority endpoint at 12 weeks and 2 years, among patients with rheumatoid arthritis receiving background methotrexate. In this study, despite differences in approved dosing (such as a loading dose for certolizumab pegol), the results in the predefined

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