A systematic review of the effectiveness of adalimumab

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26 Effectiveness TABLE 4 Meta-analyses: adalimumab s.c. licensed dose only (40 mg every other week or equivalent) versus placebo (with or without ongoing conventional DMARDs), end of trial Comparison or outcome Studies N included Statistical method Effect size (95% CI) in analysis ACR20 responder 5112–115,119 1854 RR (fixed) 2.11 (1.84 to 2.42)* ACR50 responder 5112–115,119 1854 RR (fixed) 3.58 (2.81 to 4.58)* ACR70 responder 5112–115,119 1854 RR (fixed) 5.22 (3.45 to 7.89)* RD ACR20 responder 5112–115,119 1854 RD (fixed) 0.28 (0.24 to 0.32)* RD ACR50 responder 5112–115,119 1854 RD (fixed) 0.24 (0.20 to 0.27)* RD ACR70 responder 5112–115,119 1854 RD (random) 0.13 (0.09 to 0.17)* Swollen joint count, mean change from 5 112–115,119 baseline 1851 WMD (fixed) –5.14 (–6.07 to –4.21)* Patient’s global assessment, mean change 5 112–115,119 from baseline 1850 WMD (fixed) –1.62 (–1.89 to –1.35)* HAQ, mean change from baseline 5 112–115,119 1850 WMD (fixed) –0.31 (–0.36 to –0.26)* DAS28, mean change from baseline 2113,119 476 WMD (fixed) –1.12 (–1.37 to –0.86)* Modified van de Heijde–Sharp score, 1114 mean change from baseline 551 WMD (fixed) –2.20 (–3.33 to –1.07)* Withdrawal for any reasons 5 112–115,119 1861 RR (fixed) [Commercial-inconfidence information removed]* Withdrawal due to lack of efficacy 5 112–115,119 1861 RR (fixed) [Commercial-inconfidence information removed]* Withdrawal due to adverse events 5 112–115,119 1861 RR (fixed) 1.37 (0.87 to 2.16) Death 5112–115,119 1861 RR (fixed) 2.02 (0.42 to 9.59) SAEs 5112–115,119 1861 RR (fixed) 1.05 (0.78 to 1.41) Malignancy: all 5112–115,119 1861 RR (fixed) 3.44 (0.94 to 12.60) Malignancy: skin cancer excluding 5112–115,119 melanoma 1861 RR (fixed) 2.11 (0.55 to 8.06) Malignancy: all cancer excluding 5 112–115,119 non-melanoma skin cancer 1861 RR (fixed) 2.92 (0.50 to 17.13) Serious infection 5 112–115,119 1861 RR (fixed) 2.35 (1.00 to 5.53) Any infection 4112–115 1719 RR (fixed) 1.18 (1.07 to 1.29)* * Statistically significant result (p < 0.05). alone for all the efficacy outcomes included in the meta-analysis, although the difference did not reach statistical significance for [Commercial-inconfidence information removed] and HAQ change. Tolerability Compared with methotrexate alone, the combination was associated with significantly fewer withdrawals due to lack of efficacy and withdrawals for any reason. The combination was associated with a statistically non-significant increase in withdrawal due to adverse events. Safety The only statistically significant difference between the combination and methotrexate monotherapy among the safety outcomes metaanalysed was [Commercial-in-confidence information removed]. There was also a nonsignificant increase in serious infection in the combination group compared with the methotrexate group (RR [Commercial-inconfidence information removed]). Etanercept Description of included etanercept trials Eleven trials comprising a total of 3717 patients (3659 actually treated) were included. Clinical study reports were provided by Wyeth for ten of the studies: Moreland (three studies), 120–122 ERA, 123,124 Weinblatt, 125 ; Wajdula, 126 Codreanu, 103
Review: Adalimumab for rheumatoid arthritis 2006 Comparison: 03 Adalimumab s.c. licensed dose only (40 mg every other week or equivalent) vs placebo, end of trial Outcome: 01 ACR20 responder Study or subcategory Adalimumab n/N Control n/N 01 With (+) or without (–) concurrent, ongoing conventional DMARDs van de Putte, 2003119 [12 weeks] (–) van de Putte, 2004113 [26 weeks] (–) STAR115 [24 weeks] (±) ARMADA112 [24 weeks] (+) Keystone, 2004114 [52 weeks] (+) Subtotal (95% CI) Total events: 582 (adalimumab), 195 (control) Test for heterogeneity: 2 = 24.63, df = 4 (p < 0.0001), I2 36/71 7/70 96/225 21/110 167/315 110/315 45/67 9/62 238/419 48/200 1097 757 = 83.8% Test for overall effect: z = 10.70 (p < 0.00001) 02 With concurrent, newly initiated MTX (adalimumab + MTX vs MTX) PREMIER 102,109 [104 weeks] (+) Subtotal (95% CI) Total events: 186 (adalimumab), 144 (control) Test for heterogeneity: NA Test for overall effect: z = 3.12 (p = 0.002) 186/268 144/257 268 257 Subtotal (95% CI) Total events: 768 (adalimumab), 339 (control) Test for heterogeneity: 2 = 51.98, df = 5 (p < 0.00001), I2 1365 1014 = 90.4% Test for overall effect: z = 11.04 (p < 0.00001) © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 42 RR (fixed) (95% CI) 0.1 0.2 0.5 1 2 5 10 Favours control Favours adalimumab Weight (%) 1.92 7.69 30.00 2.55 17.73 59.90 40.10 40.10 100.00 FIGURE 2 ACR20 RR: adalimumab licensed dose versus placebo (including adalimumab plus MTX versus MTX) Review: Adalimumab for rheumatoid arthritis 2006 Comparison: 03 Adalimumab s.c. licensed dose only (40 mg every other week or equivalent) vs placebo, end of trial Outcome: 01 ACR20 responder Study or subcategory Adalimumab n/N Control n/N 01 With (+) or without (–) concurrent, ongoing conventional DMARDs van de Putte, 2003119 [12 weeks] (–) van de Putte, 2004113 [26 weeks] (–) STAR115 [24 weeks] (±) ARMADA112 [24 weeks] (+) Keystone, 2004114 [52 weeks] (+) Subtotal (95% CI) Total events: 582 (adalimumab), 195 (control) Test for heterogeneity: 2 = 23.64, df = 4 (p < 0.0001), I2 36/71 7/70 96/225 21/110 167/315 110/315 45/67 9/62 238/419 48/200 1097 757 = 83.1% Test for overall effect: z = 10.70 (p < 0.00001) 02 With concurrent, newly initiated MTX (adalimumab + MTX vs MTX) PREMIER 102,109 [104 weeks] (+) Subtotal (95% CI) Total events: 186 (adalimumab), 144 (control) Test for heterogeneity: NA Test for overall effect: z = 3.20 (p = 0.001) 186/268 144/257 268 257 Subtotal (95% CI) Total events: 768 (adalimumab), 339 (control) Test for heterogeneity: 2 = 34.78, df = 5 (p < 0.00001), I2 1365 1014 = 85.6% Test for overall effect: z = 12.70 (p < 0.00001) RD (fixed) (95% CI) –1 –0.5 0 0.5 1 Favours control Favours adalimumab Weight (%) 6.23 13.07 27.86 5.70 23.94 76.80 23.20 23.20 100.00 FIGURE 3 ACR20 RD: adalimumab licensed dose versus placebo (including adalimumab plus MTX versus MTX) RR (fixed) (95% CI) 5.07 (2.42 to 10.62) 2.23 (1.48 to 3.38) 1.52 (1.26 to 1.82) 4.63 (2.47 to 8.66) 2.37 (1.82 to 3.07) 2.11 (1.84 to 2.42) 1.24 (1.08 to 1.42) 1.24 (1.08 to 1.42) RD (fixed) (95% CI) 0.41 (0.27 to 0.54) 0.24 (0.14 to 0.33) 0.18 (0.10 to 0.26) 0.53 (0.38 to 0.67) 0.33 (0.25 to 0.40) 0.28 (0.24 to 0.32) 0.13 (0.05 to 0.22) 0.13 (0.05 to 0.22) 27
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
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Page 23 and 24: Assessment of response to DMARDs Re
Page 25 and 26: combination with methotrexate or al
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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
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Page 46 and 47: 30 Effectiveness Review: Adalimumab
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Page 52 and 53: 36 TABLE 7 Effectiveness Quality of
Page 54 and 55: 38 Effectiveness etanercept trials.
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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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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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