A systematic review of the effectiveness of adalimumab

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30 Effectiveness 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: 12 HAQ, mean change from baseline Study or subcategory N Adalimumab mean (SD) N 01 With (+) or without (–) concurrent, ongoing conventional DMARDs van de Putte, 2003 119 [12 weeks] (–) van de Putte, 2004 113 [26 weeks] (–) STAR 115 [24 weeks] (±) ARMADA 112 [24 weeks] (+) Keystone, 2004 114 [52 weeks] (+) Subtotal (95% CI) Test for heterogeneity: 2 = 4.90, df = 4 (p = 0.30), I 2 = 18.4% Test for overall effect: z = 12.41 (p < 0.00001) TEMPO, 127,128 Keystone, 129 and Baumgartner. 104 Additional data from these reports were included in this systematic review. The report by Lan and colleagues 130 was only available as a published paper. A list of these trials, including comparators and baseline patient characteristics, is shown in Table 6. Quality assessments of these trials, which are generally of high quality, are summarised in Table 7. In all trials, except for Baumgartner, 104 Control mean (SD) 71 –0.45 (0.46) 70 –0.04 (0.37) 225 –0.38 (0.61) 110 –0.07 (0.49) 312 –0.51 (0.56) 314 –0.26 (0.48) 67 –0.62 (0.63) 62 –0.27 (0.57) 419 –0.60 (0.56) 200 –0.25 (0.56) 1094 756 02 With concurrent, newly initiated MTX (adalimumab + MTX vs MTX) PREMIER102,109 [104 weeks] (+) 201 –1.00 (0.70) 166 –0.90 (0.60) Subtotal (95% CI) 201 166 Test for heterogeneity: NA Test for overall effect: z = 1.47 (p = 0.14) Total (95% CI) Test for heterogeneity: 2 = 13.65, df = 5 (p = 0.02), I2 1295 922 = 63.4% Test for overall effect: z = 12.14 (p < 0.00001) WMD (fixed) (95% CI) –1 –0.5 Favours 0 0.5 1 Favours adalimumab control Weight (%) 11.40 14.67 32.37 5.04 24.30 87.78 12.22 12.22 100.00 FIGURE 8 HAQ change: adalimumab licensed dose versus placebo (including adalimumab plus MTX versus MTX) FIGURE 9 SAE RR: adalimumab licensed dose versus placebo (including adalimumab plus MTX versus MTX) [Commercial-in-confidence information removed]. FIGURE 10 SAE RD: adalimumab licensed dose versus placebo (including adalimumab plus MTX versus MTX) [Commercial-in-confidence information removed]. FIGURE 11 Malignancy RR: adalimumab licensed dose versus placebo (including adalimumab plus MTX versus MTX) [Commercial-in-confidence information removed]. FIGURE 12 Malignancy RD: adalimumab licensed dose versus placebo (including adalimumab plus MTX versus MTX) [Commercial-in-confidence information removed]. WMD (fixed) (95% CI) –0.41 (–0.55 to –0.27) –0.31 (–0.43 to –0.19) –0.25 (–0.33 to –0.17) –0.35 (–0.56 to –0.14) –0.35 (–0.44 to –0.26) –0.31 (–0.36 to –0.26) –0.10 (–0.23 to 0.03) –0.10 (–0.23 to 0.03) patients had active disease defined according to a number of tender and swollen joints and other parameters such as ESR and CRP. All patients met agreed disease classification criteria. Stable doses of oral prednisolone (≤ 10 mg per day) and NSAIDs were allowed. With the exception of the trial by Baumgartner and colleagues, 104 patients with a recent history of infection and significant comorbidity were excluded. Only one trial, ERA, 123,124 recruited exclusively early RA patients. Key features for each of the studies are described below. Moreland and colleagues, 1996 120 Results from this study are not included in the meta-analyses because of very small patient numbers (three or four patients in each treatment group), short duration and imbalances in baseline patient characteristics (Table 6). Moreland and colleagues, 1997 121 This double-blind, multicentre RCT compared three doses of etanercept (0.25, 2 or 16 mg m –2 body surface area s.c. twice weekly) with placebo for three months. Patients who had failed up to four DMARDs and had at least ten swollen joints and 12 tender joints were included. Primary efficacy measures were percentage change from baseline to 3 months in swollen joint count, tender joint count and total count of swollen or tender joints.
Moreland and colleagues, 1999 122 This 6-month double-blind, multicentre RCT compared etanercept 10 or 25 mg s.c. twice weekly with placebo. Patients who had failed up to four DMARDs were recruited. At least ten swollen joints and 12 tender joints were required at entry. The primary efficacy end-points were ACR20 and ACR50 response at 3 and 6 months. © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 42 TABLE 5 Summary of 2-year results from PREMIER study: combination of adalimumab s.c. licensed dose (40 mg every other week or equivalent) plus MTX 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 525 RR (fixed) 1.24 (1.08 to 1.42)* ACR50 responder 525 RR (fixed) 1.38 (1.16 to 1.64)* ACR70 responder 525 RR (fixed) 1.64 (1.30 to 2.07)* RD ACR20 responder 525 RD (fixed) 0.13 (0.05 to 0.22)* RD ACR50 responder 525 RD (fixed) 0.16 (0.08 to 0.25)* RD ACR70 responder 525 RD (fixed) 0.18 (0.10 to 0.26)* SJC, mean change from baseline 369 WMD (fixed) [Commercial-in-confidence information removed] Patient’s global assessment, mean change 366 WMD (fixed) [Commercial-infrom baseline confidence information removed]* HAQ, mean change from baseline 367 WMD (fixed) –0.10 (–0.23 to 0.03) DAS28, mean change from baseline 352 WMD (fixed) [Commercial-in-confidence information removed]* Modified van de Heijde–Sharp score, 525 WMD (fixed) –8.50 [Commercial-inmean change from baseline confidence information removed]* Withdrawal for any reasons 525 RR (fixed) 0.71 (0.54 to 0.93)* Withdrawal due to lack of efficacy 525 RR (fixed) 0.27 (0.15 to 0.49)* Withdrawal due to adverse events 525 RR (fixed) 1.62 (0.94 to 2.77) Death 525 RR (fixed) 0.96 (0.06 to 15.25) SAEs 525 RR (fixed) [Commercial-in-confidence information removed] Malignancy: all 525 RR (fixed) [Commercial-in-confidence information removed] Malignancy: skin cancer excluding 525 RR (fixed) [Commercial-inmelanoma confidence information removed] Malignancy: all cancer excluding non-melanoma skin cancer 525 RR (fixed) 0.48 (0.09 to 2.60) Serious infection 525 RR (fixed) [Commercial-in-confidence information removed] Any infection 525 RR (fixed) [Commercial-in-confidence information removed]* * Statistically significant result (p < 0.05). Weinblatt and colleagues, 1999 125 This 24-week, double-blind, multicentre RCT compared etanercept 25 mg s.c. twice weekly with placebo. Patients who had at least six swollen joints and six tender joints despite at least 6 months of methotrexate treatment were included. All patients remained on stable doses of methotrexate (15–25 mg per week). The primary end-point was ACR20 response at 24 weeks. 31
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
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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
Page 38 and 39: 22 TABLE 2 Quality of included RCTs
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Page 54 and 55: 38 Effectiveness etanercept trials.
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Page 58 and 59: 42 Effectiveness Review: Etanercept
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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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Extensive sensitivity analysis was
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TABLE 96 Variation 1: TNF inhibitor
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A systematic review of the effectiveness of adalimumab

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