A systematic review of the effectiveness of adalimumab

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24 Effectiveness change in modified total Sharp score from baseline to week 52 between the combination therapy and the methotrexate monotherapy only. Keystone and colleagues, 2004 (DE019) 114 This 52-week, double-blind, multicentre trial compared adalimumab 40 mg s.c. every other week, 20 mg s.c. every week and placebo in patients receiving concomitant methotrexate. Patients who either were rheumatoid factor positive or had at least one joint erosion on radiographs of the hands and feet were recruited. The primary end-points were ACR20 response at 24 weeks, change in modified Sharp score at week 52 and change in HAQ at week 52. STAR: Furst and colleagues, 2003 (DE031) 115 This 24-week, double-blind, multicentre safety trial compared adalimumab 40 mg s.c. every other week with placebo in RA patients who continued to receive their standard antirheumatic therapy (including DMARDs). Concomitant DMARDs were permitted if doses had been stable for at least 28 days before screening, and a single increase in DMARD dosage was allowed at week 12 or subsequent visits if a patient failed to meet or maintain ACR20 response. Eighty-three per cent of patients received at least one DMARD. The primary end-point, safety, was assessed by types and frequencies of adverse events, physical examination findings and standard laboratory test results. Meta-analyses of adalimumab trials The approaches to meta-analyses and data presentation are described in detail in the section ‘Data analysis’ (p. 14). The only adalimumab trial that recruited exclusively methotrexate-naïve patients with disease duration of less than 3 years was the PREMIER 102,109 trial and included three treatment arms which allow more than one comparison: adalimumab versus methotrexate and combination (adalimumab plus methotrexate) versus methotrexate. Adalimumab versus methotrexate The PREMIER 102,109 trial is the only trial that included head-to-head comparison between adalimumab and a DMARD (methotrexate). The results are summarised in Table 3. Efficacy The only effectiveness result reaching conventional levels of statistical significance between adalimumab and methotrexate is radiographic joint damage. Patients treated with adalimumab had a smaller increase in modified Sharp score compared with those treated with methotrexate (mean difference over 2 years –4.90, 95% CI [Commercial-in-confidence information removed]). Adalimumab appears to be marginally less effective than methotrexate in reducing disease activity as measured by other means, for example the ACR20 response (RR 0.88, 95% CI 0.75 to 1.03) and ACR50 response (RR 0.86, 95% CI 0.70 to 1.06). Tolerability No significant difference was found between adalimumab and methotrexate. Safety One death occurred in the methotrexate arm and four occurred in the adalimumab arm. The number of patients with malignancy was similar ([Commercial-in-confidence information removed] in the methotrexate arm and four in the adalimumab arm). More patients experienced SAEs in the adalimumab arm, although this did not reach statistical significance ([Commercial-inconfidence information removed]). [Commercialin-confidence information removed] patients had serious infections in the methotrexate arm compared with [Commercial-in-confidence information removed] in the adalimumab arm, but no difference was found in the risk of overall infection between the treatment groups. Adalimumab versus placebo Five trials 112–115,119 included a comparison of adalimumab with placebo at the licensed dose (or equivalent). Three additional trials 116–118 included this comparison at above or under licensed doses. The results of primary analyses (licensed dose only) for the comparison between adalimumab and placebo are summarised in Table 4. Forest plots for the ACR20, ACR50, ACR70, HAQ, SAEs and malignancy are shown in the upper parts of Figures 2–12. Efficacy Adalimumab at the licensed dose is significantly more effective than placebo for all the efficacy outcomes included in the meta-analyses. Tolerability Significantly [Commercial-inconfidence information removed] patients withdrew for any reasons and for lack of efficacy in the adalimumab group compared with the placebo group. Slightly more patients withdrew owing to adverse events in the adalimumab group, but these did not reach statistical significance. Safety Adalimumab is associated with a slight, but significantly increased, risk of any infection compared with placebo. It also appears to be associated with an increased risk of death,
malignancy and serious infections, although these did not reach statistical significance. No difference in the risk of serious adverse events was observed. Sensitivity analyses Results of sensitivity analyses that included the licensed dose and above, and all doses, are listed in Tables 70 and 71 (Appendix 4). The results are in the same direction and very similar to the primary analysis. The increase in serious infection became statistically significant. © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 42 TABLE 3 Summary of 2-year results from the PREMIER study: adalimumab s.c. licensed dose only (40 mg every other week) 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 531 RR (fixed) 0.88 (0.75 to 1.03) ACR50 responder 531 RR (fixed) 0.86 (0.70 to 1.06) ACR70 responder 531 RR (fixed) 0.99 (0.75 to 1.30) RD ACR20 responder 531 RD (fixed) –0.07 (–0.15 to 0.02) RD ACR50 responder 531 RD (fixed) –0.06 (–0.14 to 0.02) RD ACR70 responder 531 RD (fixed) 0.00 (–0.08 to 0.07) SJC, mean change from baseline Patient’s global assessment, mean change 335 WMD (fixed) [Commercial-in-confidence information removed] from baseline 329 WMD (fixed) [Commercial-in-confidence information removed] HAQ, mean change from baseline 328 WMD (fixed) 0.00 (–0.13 to 0.13) DAS28-4, mean change from baseline Modified van de Heijde–Sharp score, mean 319 WMD (fixed) [Commercial-in-confidence information removed] change from baseline 531 WMD (fixed) –4.90 [Commercial-inconfidence information removed]* Withdrawal for any reasons 531 RR (fixed) 1.14 (0.91 to 1.43) Withdrawal due to lack of efficacy 531 RR (fixed) 1.06 (0.74 to 1.52) Withdrawal due to adverse events 531 RR (fixed) 1.28 (0.73 to 2.26) Death 531 RR (fixed) 3.75 (0.42 to 33.35) SAEs 531 RR (fixed) [Commercial-in-confidence information removed] Malignancy: all 531 RR (fixed) [Commercial-in-confidence information removed] Malignancy: skin cancer excluding melanoma 531 RR (fixed) [Commercial-in-confidence information removed] Malignancy: all cancer excluding non-melanoma skin cancer 531 RR (fixed) 0.94 (0.24 to 3.71) Serious infection 531 RR (fixed) 0.40 (0.11 to 1.54) Any infection 531 RR (fixed) [Commercial-in-confidence information removed] * Statistically significant result (p < 0.05). Adalimumab plus methotrexate versus methotrexate alone Only the PREMIER 102,109 trial included this comparison in methotrexate-naïve, early RA patients, and the results are summarised in Table 5. The outcomes for ACR20, ACR50, ACR70, HAQ, SAEs, and malignancy are also displayed in the lower parts of Figures 2–12. Efficacy The combination of adalimumab plus methotrexate is more effective than methotrexate 25
Page 1 and 2: A systematic review of the effectiv
Page 3 and 4: A systematic review of the effectiv
Page 5 and 6: Objectives: This report reviews the
Page 7: Glossary and list of abbreviations
Page 10 and 11: viii Glossary and list of abbreviat
Page 13 and 14: Background Rheumatoid arthritis (RA
Page 15: increased risk of serious infection
Page 19 and 20: Summary RA is a common, chronic, in
Page 21 and 22: (IL-2) and interleukin-6 (IL-6), pr
Page 23 and 24: Assessment of response to DMARDs Re
Page 25 and 26: combination with methotrexate or al
Page 27: disease between clinic appointments
Page 30 and 31: 14 Effectiveness in juvenile arthri
Page 32 and 33: 16 Effectiveness adalimumab plus me
Page 34 and 35: 18 Effectiveness Monoclonal Antibod
Page 36 and 37: 20 TABLE 1 Description of included
Page 38 and 39: 22 TABLE 2 Quality of included RCTs
Page 42 and 43: 26 Effectiveness TABLE 4 Meta-analy
Page 44 and 45: 28 Effectiveness Review: Adalimumab
Page 46 and 47: 30 Effectiveness Review: Adalimumab
Page 48 and 49: 32 TABLE 6 Effectiveness Descriptio
Page 50 and 51: 34 TABLE 6 Effectiveness Descriptio
Page 52 and 53: 36 TABLE 7 Effectiveness Quality of
Page 54 and 55: 38 Effectiveness etanercept trials.
Page 56 and 57: 40 Effectiveness TABLE 9 Summary of
Page 58 and 59: 42 Effectiveness Review: Etanercept
Page 70 and 71: 54 Effectiveness TABLE 11 Summary o
Page 72 and 73: 56 TABLE 12 Description of included
Page 74 and 75: 58 TABLE 13 Quality of included RCT
Page 76 and 77: 60 Effectiveness per week and escal
Page 78 and 79: 62 Effectiveness significant advant
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Page 82 and 83: 66 Effectiveness Review: Infliximab
Page 84 and 85: 68 Effectiveness FIGURE 44 Malignan
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TABLE 20 Summary of published ICERs
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TABLE 21 Published etanercept econo
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TABLE 23 Published economic analyse
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TABLE 25 Treatment sequences: adali
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management of RA, i.e. 1st and 2nd
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To estimate the long-term consequen
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TABLE 32 TNF inhibitors as last act
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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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TABLE 85 Bansback et al., 2005 166
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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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TABLE 99 Variation 2: TNF inhibitor
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A systematic review of the effectiveness of adalimumab

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