A systematic review of the effectiveness of adalimumab

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38 Effectiveness etanercept trials. The primary end-points were reduction in the number of swollen and tender joints from baseline to 12 weeks. Details of randomisation, allocation concealment and blinding were not described in the published paper and no trial report was made available. Keystone and colleagues, 2004 129 This 16-week multicentre RCT compared etanercept 50 mg s.c. once weekly, etanercept 25 mg twice s.c. weekly and placebo. Placebotreated patients received etanercept 25 mg twice weekly at 8 weeks and thus results from week 8 onwards were excluded from this review. Patients with at least six swollen joints and six tender joints were recruited. Patients were allowed to continue with stable doses of methotrexate (≤ 25 mg per week), but other DMARDs were not allowed. Approximately half of the patients in each treatment group were receiving concomitant methotrexate. The primary efficacy end-point was the ACR20 response. Etanercept 50 mg once weekly was compared with placebo at week 8 and the comparative efficacy of the two etanercept treatment regimens was also studied. Baumgartner and colleagues, 2004 104 This 16-week multicentre safety trial compared etanercept 25 mg s.c. twice weekly and placebo in adult RA patients, with at least one qualifying comorbid condition including diabetes, chronic obstructive pulmonary disease and recent infections. Randomisation was stratified by the presence of diabetes. Patients in this trial were older than those in other etanercept trials. Concomitant DMARDs (except for azathioprine, ciclosporin and cyclophosphamide) and NSAIDs were allowed and their use could be altered during the study. The overall prior and concurrent DMARD use was not reported, but 52% of all patients received concomitant methotrexate during the study. The primary end-point was the incidence of medically important infections, defined as infections that result in hospitalisation or treatment with intravenous antibiotics. No efficacy outcomes were measured. The initial study plan aimed to recruit 1000 patients, which allows an 84% power to detect a two-fold difference between the treatment groups (10% versus 20%). The study was, however, terminated early owing to the low incidence of medically important infections observed in the study (3% overall) and the slow recruitment of patients. Meta-analyses of etanercept trials The principles of analysis and data presentation of the etanercept trials are the same as those for adalimumab and are described in the section ‘Data analysis’ (p. 14). Two trials (TEMPO 110,127 and Codreanu 103 ) included three treatment arms, which allow more than one comparison. Etanercept versus conventional DMARD Three trials (ERA, 123 TEMPO 110,127 and Codreanu 103 ) included comparisons between etanercept and a conventional DMARD. Only the ERA trial, however, allows a genuine head-to-head comparison between etanercept and methotrexate in early RA patients who were naïve to both treatments. Around 40% of patients in TEMPO had previously taken methotrexate without experiencing treatment failure due to lack of efficacy or toxicity. This, in theory, could introduce bias in favour of methotrexate. These patients, however, had not continued the methotrexate treatment for at least 6 months before the study. The reasons for this and their potential impact on study results are not clear. The investigators performed subgroup analyses and found no significant interaction between previous use of methotrexate and treatment effects in terms of ACR responses, DAS and total Sharp score. 127 The trial by Codreanu and colleagues 103 recruited patients who had had an inadequate response to sulfasalazine, and thus this trial should not be regarded as a head-tohead comparison. This section therefore focuses on the results from ERA (Table 8) and TEMPO (Table 9). The outcomes for ACR20, ACR50, ACR70, HAQ, SAEs, and malignancy from all three trials are also shown in the lower parts of Figures 13–23. Efficacy Although the mean disease duration for the patients was only 1 year in ERA compared with over 6 years in the TEMPO, the results from these two studies are remarkably similar – no statistical heterogeneity between the studies was found in any of the outcomes that were meta-analysed. Overall, the results demonstrate that etanercept monotherapy is marginally more effective than methotrexate in improving RA symptoms and physical function. The differences between etanercept and methotrexate for ACR20 response and modified Sharp score were statistically significant in both studies, while the difference for ACR50 response was significant only in the TEMPO trial. Tolerability Etanercept monotherapy appears to be better tolerated than methotrexate monotherapy. Fewer patients withdrew either owing to lack of efficacy or because of adverse events in etanercepttreated groups.
Safety No significant differences between etanercept and methotrexate were found. Malignancy occurred in five patients with etanercept and two patients with methotrexate in TEMPO, while equal numbers of patients (five each) developed cancer in the two treatment arms in ERA. Subgroup analyses In addition to the subgroup analyses of prior use of methotrexate, extensive analyses were performed in TEMPO to explore potential interactions between disease duration and treatment effects. The outcomes in the early RA cohort (disease duration ≤ 3 years at baseline), which accounted for one-third of all patients in the trial, were generally similar to the overall study results. For example, the mean HAQ changes from baseline at 2 years © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 42 TABLE 8 Summary of 2-year results from ERA study: etanercept s.c. licensed dose alone (25 mg twice weekly) versus MTX alone in MTX-naïve patients, 2-year results Comparison or outcome N included Statistical method Effect size (95% CI) in analysis ACR20 responder 424 RR (fixed) 1.22 (1.06 to 1.40)* ACR50 responder 424 RR (fixed) 1.16 (0.94 to 1.44) ACR70 responder 424 RR (fixed) 1.23 (0.89 to 1.70) RD ACR20 responder 424 RD (fixed) 0.13 (0.04 to 0.22)* RD ACR50 responder 424 RD (fixed) 0.07 (–0.03 to 0.16) RD ACR70 responder 424 RD (fixed) 0.05 (–0.03 to 0.14) SJC, end of study result 424 WMD (fixed) –1.50 (–3.44 to 0.44) Patient’s global assessment, end of study result 424 WMD (fixed) 0.00 (–0.46 to 0.46) HAQ, end of study result 424 WMD (fixed) –0.10 (–0.23 to 0.03) DAS, end of study result 424 Not estimable No data available Modified van de Heijde–Sharp score, mean change from baseline (1-year result) 417 WMD (fixed) –0.97 (–1.65 to –0.29)* Withdrawal for any reasons 424 RR (fixed) 0.63 (0.48 to 0.84)* Withdrawal due to lack of efficacy 424 RR (fixed) 0.73 (0.40 to 1.34) Withdrawal due to adverse events 424 RR (fixed) 0.58 (0.32 to 1.06) Death 424 RR (fixed) 3.14 (0.13 to 76.75) SAEs 424 RR (fixed) No data available Malignancy: all 424 RR (fixed) 1.05 (0.31 to 3.57) Malignancy: skin cancer excluding melanoma 424 RR (fixed) 1.05 (0.15 to 7.37) Malignancy: all cancer excluding non-melanoma skin cancer 424 RR (fixed) 1.05 (0.21 to 5.14) Serious infection 424 RR (fixed) 0.82 (0.31 to 2.15) Any infection 424 RR (fixed) 0.99 (0.90 to 1.09) * Statistically significant result (p < 0.05). were –0.7, –0.7 and –1.0 for methotrexate alone, etanercept alone and the combination group, respectively, for both the early RA cohort (baseline HAQ = 1.6) and the late RA cohort (baseline HAQ = 1.8). Codreanu, 2003 103 The comparison between etanercept and sulfasalazine in sulfasalazine partial responders/non-responders is summarised in Table 72 (Appendix 4). The results resemble those observed in trials comparing etanercept and placebo (described in the following section), which show that etanercept is significantly more effective and better tolerated. Significantly more patients in the etanercept arm had infections compared with patients in the sulfasalazine arm (RR 1.76, 95% CI 1.05 to 2.93). 39
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A systematic review of the effectiv
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Page 5 and 6: Objectives: This report reviews the
Page 7: Glossary and list of abbreviations
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Page 13 and 14: Background Rheumatoid arthritis (RA
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TABLE 34 Basic structure of the mod
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een quit on grounds of toxicity, ad
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TABLE 39 Strategy set: adalimumab a
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TABLE 43 Beta distributions for HAQ
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TABLE 44 Early cessation of DMARDs:
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TABLE 46 Unit costs for tests and v
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following properties, according to
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TABLE 52 Base case: TNF inhibitors
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TABLE 54 Base case: TNF inhibitors
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TABLE 59 Third TNF inhibitor follow
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TABLE 65 Sensitivity analyses: TNF
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TABLE 67 Sensitivity analyses: TNF
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The substantial economic impact of
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Summary Effectiveness: principal fi
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inhibitors, although the incrementa
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introduce bias which generally exag
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Adalimumab, etanercept and inflixim
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1. Jobanputra P, Barton P, Bryan S,
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46. Young A, Dixey J, Cox N, Davies
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tumor necrosis factor therapy in th
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arthritis: a 12-week, double-blind,
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171. Geborek P, Crnkic M, Petersson
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216. Schotte H, Willeke P, Mickholz
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The Health Assessment Questionnaire
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Cochrane Library (CENTRAL) 2005 Iss
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Appendix 3 © Queen’s Printer and
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TABLE 69 Studies excluded from clin
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148 Appendix 4 TABLE 71 Meta-analys
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150 Appendix 4 TABLE 73 Meta-analys
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152 Appendix 4 Infliximab versus pl
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154 Appendix 4 Infliximab plus MTX
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Ovid MEDLINE(R) 1966 to February we
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Appendix 8 © Queen’s Printer and
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TABLE 79 Wong et al., 2002 161 © Q
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TABLE 80 Kobelt et al., 2003 162 (c
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TABLE 82 Brennan et al., 2004 160
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176 Appendix 9 TABLE 89 Strategy se
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Extensive sensitivity analysis was
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TABLE 96 Variation 1: TNF inhibitor
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