A systematic review of the effectiveness of adalimumab

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46 Effectiveness Review: Etanercept for rheumatoid arthritis 2006 Comparison: 03 Etanercept s.c. licensed dose only (25 mg twice weekly) vs other active treatment Outcome: 09 Malignancy Study or subcategory 01 Partial responders to comparator DMARD (SSZ) Codreanu, 2003 103 [24 weeks] Subtotal (95% CI) Total events: 2 (etanercept), 0 (control) Test for heterogeneity: NA Test for overall effect: z = 0.95 (p = 0.34) Etanercept n/N Etanercept plus methotrexate versus methotrexate Only TEMPO 110,127 included this comparison and the results are summarised in Table 11 and are also shown in the lower parts of Figures 24–34. Efficacy The combination of etanercept plus methotrexate was significantly more effective than methotrexate monotherapy for all the efficacy outcomes considered. Tolerability The combination was better tolerated than methotrexate monotherapy. Significantly fewer patients withdrew owing to lack of efficacy and for any reason in the combination group. Safety No significant differences were found in any of the outcomes being meta-analysed. Nevertheless, SAEs and malignancy occurred more frequently in the combination group. Infliximab Description of included infliximab trials Nine trials comprising a total of 2835 patients (2823 actually treated) were included in the metaanalyses. A prepublication manuscript of BeSt was Control n/N 2/103 0/50 103 50 02 Responders or naive to comparator DMARD (MTX) TEMPO110 [104 weeks] ERA124 [104 weeks] Subtotal (95% CI) Total events: 10 (etanercept), 7 (control) Test for heterogeneity: 2 = 0.46, df = 1 (p = 0.50), I2 5/223 2/228 5/207 5/217 430 445 = 0% Test for overall effect: z = 0.81 (p = 0.42) Total (95% CI) Total events: 12 (etanercept), 7 (control) Test for heterogeneity: 2 = 0.70, df = 2 (p = 0.71), I2 533 495 = 0% Test for overall effect: z = 1.07 (p = 0.28) FIGURE 23 Malignancy RD: etanercept licensed dose versus other active treatment RD (fixed) 95% CI –0.5 –0.25 0 0.25 0.5 Favours etanercept Favours control Weight % 13.34 13.34 44.68 41.98 86.66 100.00 RD (fixed) 95% CI 0.02 [–0.02, 0.06] 0.02 [–0.02, 0.06] 0.01 [–0.01, 0.04] 0.00 [–0.03, 0.03] 0.01 [–0.01, 0.03] 0.01 [–0.01, 0.03] made available by the investigators, but did not meet the inclusion criteria. However, because of its importance it is described in detail, but the data are not used in the meta-analyses. Clinical study reports were provided by Schering-Plough for three of the studies: ATTRACT, 132–134 Active-controlled Study of Patient Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset, (ASPIRE) 135 and START. 105,111 Additional data from these reports were included in this systematic review. Data were available only from published papers for the remaining six studies: Elliott, 136 Maini, 137 Kavanaugh, 138 Durez, 139 Taylor, 140 and Quinn. 141 Treatment comparators and baseline patient characteristics are shown in Table 12. Quality assessments of trials are summarised in Table 13. In most trials active RA was defined by six or more swollen joints (ten for ASPIRE), with additional criteria related to tender joints, ESR, CRP and morning stiffness. Taylor 140 and Quinn 141 focused on ultrasonographic and MRI outcomes, respectively. Low-dose oral steroids (
were not allowed, except in START. 105,111 Three trials (ASPIRE, 135 Taylor 140 and Quinn 141 ) recruited exclusively early RA patients. Key features for studies that included the licensed dose of infliximab are described below. Maini and colleagues, 1998 137 This 26-week, multicentre, double-blind RCT compared three doses of infliximab (1, 3 or 10 mg kg –1 , with or without ongoing methotrexate 7.5 per mg week) with placebo plus ongoing methotrexate. Patients who had taken methotrexate at a dose of 7.5–15 mg per week for at least 6 months, with at least six swollen joints were recruited. Other DMARDs were not permitted. The primary efficacy measurement was the total time (in weeks) for which a patient exhibited a Paulus 20% response. © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 42 TABLE 10 Meta-analyses: etanercept s.c. licensed dose only (25 mg twice weekly or equivalent) versus placebo (with or without ongoing conventional DMARDs), end of trial Comparison or outcome Studies N included Statistical Effect size (95% CI) in analysis method ACR20 responder 7103,121,122,125,126,129,130 1172 RR (fixed) 3.59 (2.89 to 4.46)* ACR50 responder 7 103,121,122,125,126,129,130 1172 RR (fixed) 5.72 (3.92 to 8.34)* ACR70 responder 6 103,122,125,126,129,130 1084 RR (fixed) 9.44 (3.98 to 22.38)* RD ACR20 responder 7 103,121,122,125,126,129,130 1172 RD (fixed) 0.48 (0.42 to 0.53)* RD ACR50 responder 7 103,121,122,125,126,129,130 1172 RD (fixed) 0.32 (0.28 to 0.37)* RD ACR70 responder 6 103,122,125,126,129,130 1084 RD (fixed) 0.13 (0.10 to 0.16)* SJC, end of study result 7 103,121,122,125,126,129,130 1178 WMD (random) –6.75 (–8.95 to –4.56)* Patient’s global assessment, end of 7 103,121,122,125,126,129,130 study result 1178 WMD (fixed) –2.49 (–2.74 to –2.24)* HAQ, end of study result 6 103,122,125,126,129,130 1055 WMD (fixed) –0.50 (–0.59 to, –0.42)* DAS, end of study result 1 103 150 WMD (fixed) –1.50 (–1.89 to –1.11)* Modified van de Heijde–Sharp score 0 0 Not estimable No data available Withdrawal for any reasons 7 103,104,121,122,125,126,129 1657 RR (fixed) 0.37 (0.29 to 0.46)* Withdrawal due to lack of efficacy 6 103,104,121,122,125,126 1237 RR (fixed) 0.19 (0.13 to, 0.28)* Withdrawal due to adverse events 7 103,104,121,122,125,126,129 1657 RR (fixed) 0.80 (0.49 to 1.30) Death 7 103,104,121,122,125,126,129 1657 RR (fixed) 2.22 (0.50 to 9.80) SAEs 5 103,104,122,125,129 1353 RR (fixed 1.25 (0.75 to 2.08) Malignancy: all 6 103,104,122,125,126,129 1569 RR (fixed) 0.44 (0.11 to 1.68) Malignancy: skin cancer excluding 6 103,104,122,125,126,129 melanoma 1569 RR (fixed) 0.98 (0.17 to 5.59) Malignancy: all cancer excluding 6 103,104,122,125,126,129 non-melanoma skin cancer 1569 RR (fixed) 0.19 (0.02 to 1.71) Serious infection 7 103,104,122,125,126,129,130 1627 RR (fixed) 0.78 (0.37 to 1.62) Any infection 6 103,104,122,125,126,129 1569 RR (fixed) 1.00 (0.87 to 1.14) * Statistically significant result (p < 0.05). ATTRACT: Maini and colleagues, 1999; 132 Lipsky and colleagues, 2000 133 This double-blind, multicentre RCT compared four dosing regimens of infliximab (3 or 10 mg kg –1 , i.v. at 0, 2 and 6 weeks and then every 4 or 8 weeks) with placebo, with concomitant methotrexate therapy. Patients who had been receiving methotrexate for at least 3 months and had been stable at 12.5 mg per week or more before screening were recruited. At least six swollen joints and six tender joints were required. The primary end-point was ACR20 response at week 30. The study was planned to run for 54 weeks, but it was extended by a protocol amendment to 102 weeks based on FDA guidance. 134 A clinical study report for the 2-year results was provided by the 47
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A systematic review of the effectiv
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A systematic review of the effectiv
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Objectives: This report reviews the
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Glossary and list of abbreviations
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viii Glossary and list of abbreviat
Page 13 and 14: Background Rheumatoid arthritis (RA
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Page 19 and 20: Summary RA is a common, chronic, in
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Page 34 and 35: 18 Effectiveness Monoclonal Antibod
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Page 89 and 90: Summary of review of existing econo
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Page 109 and 110: TABLE 39 Strategy set: adalimumab a
Page 111 and 112: 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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TABLE 102 Variation 3: TNF inhibito
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