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A Quintet of Trials: Part 5 Meaning of LITHE

A Quintet of Trials: Part 5 Meaning of LITHE. A Kavanaugh University of California, San Diego, USA. SAMURAI: S tudy of A ctive controlled M onotherapy U sed for R heumatoid A rthritis, an I L-6 inhibitor. A multicentre, X-ray reader-blinded, randomised, controlled trial

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A Quintet of Trials: Part 5 Meaning of LITHE

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  1. A Quintet of Trials: Part 5 Meaning of LITHE A KavanaughUniversity of California, San Diego, USA

  2. SAMURAI: Study of Active controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 inhibitor A multicentre, X-ray reader-blinded, randomised, controlled trial Enrolled patients with active RA with a previous inadequate response to ≥1 DMARD or immunosuppressant Disease duration <5 years Evaluated the ability of tocilizumab (TCZ) monotherapy, vs. conventional DMARD monotherapy, to prevent progressive joint damage Primary endpoint Change from baseline to Week 52 in total Sharp score (TSS) Secondary endpoints ACR20, ACR50 and ACR70 DAS28 Safety DAS=disease activity score DMARD=disease-modifying anti-rheumatic drug Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  3. –10 –20 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 SAMURAI: Significant improvement in TSS with TCZ (ITT) DMARDs (n=145) TCZ 8 mg/kg (n=157) 70 60 50 40 30 Change from baseline in TSS 20 10 0 Cumulativeprobability TSS=total Sharp score Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  4. 6.1 3.2 2.9 SAMURAI: Significant improvement in radiographic outcomes with TCZ (ITT) DMARDs (n=145) TCZ 8 mg/kg (n=157) p<0.01 p<0.001 p<0.05 7 6 5 4 Mean change from baseline 3 2.3 2 1.5 0.9 1 0 Total Sharpscore Erosion score Joint space narrowing score Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  5. LITHE: Study design Optionalextension (Years 3–5) open label Screen Core (Year 1) double-blind Core (Year 2) double-blind or open label 0 16 28 52 Week Rescue 1 Eligible for Rescue 2 PBO + MTXn=393 Double-blindTCZ 8/TCZ 4/PBO + MTX N=1,196 Open label TCZ+ MTX TCZ 4 mg/kg + MTXn=399 R Open label TCZ 8 mg/kg + MTX TCZ 8 mg/kg + MTXn=398 Rescue 1: Patients who failed to respond to treatment at 16 weeks were offered blind rescue therapy with TCZ Rescue 2: Patients who failed to respond to Rescue 1 were offered a second step of TCZ rescue therapy at any time between Week 28 and Week 52 PBO=placebo Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  6. Patient disposition 1,196 patients enrolled TCZ 4 mg/kg + MTXn=401 Placebo + MTXn=394 TCZ 8 mg/kg + MTXn=401 2 did not receive treatment 1 did not receive treatment 3 did not receive treatment 392 treated 399 treated 399 treated 44 withdrew 36 withdrew 48 withdrew Rescue therapy n=95 (24%) Rescue therapy n=195 (50%) Rescue therapy n=59 (15%) 22 withdrew: R1: 21R2: 1 11 withdrew: R1: 10R2: 1 9 withdrew: R1: 6R2: 3 Completed 52 weeksn=334 (85%) Completed 52 weeksn=344 (86%) Completed 52 weeksn=342 (86%) Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14. Roche. Data on file. R1=Rescue 1; R2=Rescue 2

  7. Demographics were well balanced across all treatment groups at baseline Data shown as mean except where indicated* Not counting MTX to which patients showed inadequate response at screening Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  8. Disease activity was similar for all three groups at baseline Data shown as mean SJC=swollen joint count; TJC=tender joint count HAQ–DI=Health Assessment Questionnaire – Disability IndexCRP=C-reactive protein; ESR=erythrocyte sedimentation rate Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  9. Significantly higher ACR20, ACR50 and ACR70 response rates at Weeks 24 and 52 (ITT) Placebo + MTX (n=393) TCZ 4 mg/kg + MTX (n=399) TCZ 8 mg/kg + MTX (n=398) ACR50 ACR70 * * 36% 32% 29% * 25% 20% * 16% 13% 11% 10% 10% 4% 2% 24 52 24 52 ACR20 70 * * 60 * 56% 56% 51% 50 47% 40 Patients (%) 28% 30 25% 20 10 0 Week: 24 52 * p<0.0001 vs. placebo + MTX Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  10. Rapid and continuing increase in ACR50 response rate over time (ITT) Placebo + MTX (n=393) TCZ 4 mg/kg + MTX (n=399) TCZ 8 mg/kg + MTX (n=398) 50 40 Patients (% SE) 30 20 10 0 8 12 16 20 24 28 32 36 40 44 48 52 0 2 4 Time (weeks) Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  11. Significantly increased DAS28 remission rate (DAS28 <2.6) at Week 52 (ITT) p<0.0001 47% 50 40 p<0.0001 30% 30 Patients (%) 20 8% 10 0 Placebo + MTX(n=393) TCZ 4 mg/kg + MTX(n=399) TCZ 8 mg/kg + MTX(n=398) Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  12. Significant inhibition of radiographic progression at Week 52 (linear extrapolation method; ITT) Placebo + MTX (n=393) TCZ 4 mg/kg + MTX (n=399) TCZ 8 mg/kg + MTX (n=398) 1.13 0.71 0.42 0.34 0.29 0.21 0.17 0.13 0.12 Total Sharp–Genant score Erosion score Joint space narrowing score p<0.0001 p<0.0001 p<0.01 p<0.0001 p<0.0001 p<0.01 1.2 1.0 0.8 Mean change from baseline 0.6 0.4 0.2 0 n= 290 339 348 290 339 348 290 339 348 Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  13. Significantly greater proportion of patients without progression at Week 52 (linear extrapolation method; ITT) Placebo + MTX (n=393) TCZ 4 mg/kg + MTX (n=399) TCZ 8 mg/kg + MTX (n=398) Total Sharp–Genant score Erosion score Joint space narrowing score p<0.001 p<0.001 p<0.05 p<0.001 p<0.001 p<0.05 100 90.6 90.5 86.8 84.5 84.5 82.6 80.5 80 70.0 67.2 60 Patients without progression (%) 40 20 0 n= 290 339 348 290 339 348 290 339 348 Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  14. Cumulative probability: Greater inhibition of structural joint damage at Week 52 (linear extrapolation; ITT) Placebo + MTX (n=393) TCZ 4 mg/kg + MTX (n=399) TCZ 8 mg/kg + MTX (n=398) 25 20 15 10 Change from baseline in total Sharp–Genant scores 5 0 –5 –10 0 10 20 30 40 50 60 70 80 90 100 Cumulative percent (%) Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  15. Decrease in HAQ-DI from baseline to Week 52 (LOCF; ITT) Placebo + MTX (n=366) TCZ 4 mg/kg + MTX (n=376) TCZ 8 mg/kg + MTX (n=374) 1.75 1.65 1.55 1.45 1.35 MCID Mean HAQ–DI score 1.25 1.15 1.05 0.95 0.85 0 2 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) Kremer JM, et al. ACR, 24–29 October 2008.Oral Presentation L14. Roche. Data on file. MCID=minimal clinically important differenceLOCF=last observation carried forward

  16. Improved haemoglobin levels at Week 52 (ITT) p<0.0001 1.4 p<0.0001 1.24 1.2 1.0 Mean change from baseline in haemoglobin (g/dl) 0.8 0.71 0.6 0.4 0.2 0.13 0 Placebo + MTX(n=153) TCZ 4 mg/kg + MTX(n=239) TCZ 8 mg/kg + MTX(n=280) Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

  17. Meaning of LITHE: Summary and conclusion • At Week 52, ACTEMRA 8 mg/kg + MTX demonstrated: • Substantial (74%) inhibition of radiographic progression • Consistently high ACR responses and DAS28 remission rates • Patient-reported outcomes with ACTEMRA + MTX were significantly better than with MTX alone • The safety profile of ACTEMRA through 52 weeks was consistent with that seen in earlier studies; no new safety signals were identified • ACTEMRA inhibits structural joint damage in RA patients with an inadequate response to MTX Kremer JM, et al. ACR, 24–29 October 2008. Oral Presentation L14.

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