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A Quintet of Trials: Part 4, The Solo Superiority over Methotrexate – An AMBITIOus Goal in RA

A Quintet of Trials: Part 4, The Solo Superiority over Methotrexate – An AMBITIOus Goal in RA. J Gómez-Reino Universidad de Santiago de Compostela, Santiago, Spain. Background. Three trials to date in monotherapy ERA (etanercept, N=632) 1 TEMPO (etanercept, N=682) 2

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A Quintet of Trials: Part 4, The Solo Superiority over Methotrexate – An AMBITIOus Goal in RA

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  1. A Quintet of Trials: Part 4, The SoloSuperiority over Methotrexate – An AMBITIOus Goal in RA J Gómez-Reino Universidad de Santiago de Compostela, Santiago, Spain

  2. Background • Three trials to date in monotherapy • ERA(etanercept, N=632)1 • TEMPO (etanercept, N=682)2 • PREMIER (adalimumab, N=686)3 • None of these trials were able to show superiority over MTX 1. Bathon JM, et al. N Eng J Med 2000; 343:1586–1593. 2. Klareskog L, et al. Lancet 2004; 363:675–681. 3. Breedveld F, et al.Arthritis Rheum 2006; 54:26–37.

  3. The AMBITION study

  4. The AMBITION study objective • AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy) study • To assess the efficacy and safety of tocilizumab (TCZ) monotherapy vs. methotrexate (MTX) monotherapy Jones G, et al. Ann Rheum Dis 2009 [epub].

  5. Study population • Moderateto severe active RA 3 months duration • Swollen joint count (SJC) 6 (of 66) and tender joint count (TJC) 8 (of 68) at screening/baseline • CRP 1.0 mg/dl or ESR 28 mm/h Patients were excluded if: • Treated with MTX in the 6 months prior to the study • 66% were MTX-naïve • 34% discontinued MTX for reasons other than lack of efficacy or toxicity • Unsuccessfully treated with TNF antagonists CRP=C-reactive proteinESR=erythrocyte sedimentation rate Jones G, et al. Ann Rheum Dis 2009 [epub].

  6. AMBITION: Study design Randomised, double-blind, double-dummy, multicentre study Double-blind Open label TCZ 8 mg/kg (n=288) TCZ 8 mg/kg Treated (N=673) MTX 7.5–20 mg/wk (n=284) TCZ8 mg/kg Substudy*Placebo (n=101) Day 1 8 weeks 24 weeks Screening Randomisation Jones G, et al. Ann Rheum Dis 2009 [epub].Roche. Data on file. * For regulatory purposes

  7. Statistical analysis • Primary endpoint: Proportion of ACR20 responders at Week 24 in the per-protocol (PP) population using a non-inferiority approach • PP included all patients in the ITT population who received morethan two-thirds of the study treatments and did not change concomitant corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) • If non-inferiority was met, superiority was tested using the intention-to-treat (ITT†) population † ITT included all randomised patients who received at least one infusion of study treatment Jones G, et al. Ann Rheum Dis 2009 [epub].

  8. Patient disposition EnrolledN=673 Methotrexate(7.5–20 mg/week) n=284 TCZ 8 mg/kgn=288 Placebo for 8 weeks then TCZ 8 mg/kg for 16 weeks n=101 Withdrew from initial treatmentn=22 Withdrew from initial treatmentn=18 Withdrew from initial/post-Week 8 treatment n=18 Rescue therapyn=11* Rescue therapyn=7* Rescue therapyn=14 Withdrawn from rescue therapyn=0 Withdrawn fromrescue therapyn=1 Withdrawn from rescue therapyn=2 Completed 24 weeksn=262 (92%) Completed 24 weeksn=82 (81%) Completed 24 weeksn=268 (93%) Jones G, et al. Ann Rheum Dis 2009 [epub]. * Substudy only

  9. Baseline characteristics were balanced between arms • Baseline characteristics were similar between the ITT and PP populations Data shown as mean except where indicated * Safety population (TCZ 8 mg/kg, n=288; MTX, n=284) † Patients with prior MTX use had discontinued MTX because of intolerance or desire to become pregnant Jones G, et al. Ann Rheum Dis 2009 [epub].Roche. Data on file.

  10. Baseline disease characteristics were balanced between arms • Baseline characteristics were similar between the ITT and PP populations Data shown as meanHAQ–DI=health assessment questionnaire–disabilityindexVAS=visual analogue scale Jones G, et al. Ann Rheum Dis 2009 [epub].

  11. p<0.0001 p=0.0023 p=0.0002 Treatment with TCZ met the non-inferiority criterion (PP) and was superior to treatment with MTX (ITT) TCZ 8 mg/kg (n=286) TCZ 8 mg/kg (n=265) MTX (n=259) MTX (n=284) 80 70.6%† 69.9% 70 60 52.5% 52.1% 50 44.1% 43.4%† Patients (%) 40 33.5% 32.8% 30 28.0% 27.5%† 20 15.1% 15.1% 10 0 ACR70 ACR20 ACR20 ACR50 ACR70 ACR50 PP population (non-inferiority) ITT population (superiority) Jones G, et al. Ann Rheum Dis 2009 [epub].Roche. Data on file. Data shown for ACR responses at Week 24† Lower limit of 95% CI for the difference vs. MTX was >0

  12. ACR responses in the TCZ arm were rapid and improved over time (ITT) MTX (n=284) TCZ 8 mg/kg (n=286) ACR20 ACR20 80 70 60 50 Patients (%) 40 30 20 10 0 0 4 8 12 16 20 24 Time (weeks) Jones G, et al. Ann Rheum Dis 2009 [epub].

  13. ACR responses in the TCZ arm were rapid and improved over time (ITT) MTX (n=284) TCZ 8 mg/kg (n=286) ACR20 ACR20 ACR50 ACR50 80 70 60 50 Patients (%) 40 30 20 10 0 0 4 8 12 16 20 24 Time (weeks) Jones G, et al. Ann Rheum Dis 2009 [epub].

  14. ACR responses in the TCZ arm were rapid and improved over time (ITT) ACR70 ACR70 MTX (n=284) TCZ 8 mg/kg (n=286) ACR20 ACR20 ACR50 ACR50 80 70 60 50 Patients (%) 40 30 20 10 0 0 4 8 12 16 20 24 Time (weeks) Jones G, et al. Ann Rheum Dis 2009 [epub].

  15. TCZ was superior to MTX in achieving ACR20 regardless of disease duration (ITT) RA <2 years RA ≥2 years TCZ 8 mg/kg (n=116) MTX (n=125) TCZ 8 mg/kg (n=159) MTX (n=170) 80 60 Patients (%) 40 Weighted treatment difference (95% CI) at Week 24: <2 years, 16% (4–28) ≥2 years, 22% (12–32) 20 0 0 4 8 12 16 20 24 Time (weeks) Genovese M, et al. ACR 2429 October, 2008; Poster:988.

  16. Treatment with TCZ led to rapid and continuing improvements in DAS28 (ITT) MTX (n=284) TCZ 8 mg/kg (n=286) 7.0 6.0 Mean DAS28 5.0 4.0 3.0 0 2 4 8 12 16 20 24 Time (weeks) Roche. Data on file.

  17. Superior DAS28 remission rate (DAS28 <2.6) at Week 24 with TCZ compared with MTX (ITT) 50 40 33.6% 30 Patients (%) 20 12.1% 10 0 MTX (n=284) TCZ 8 mg/kg (n=286) Jones G, et al. Ann Rheum Dis 2009 [epub].Roche. Data on file. Odds ratio (95% CI) = 5.8 (3.3, 10.4)

  18. TCZ was consistently superior to MTX in achieving remission (DAS28 <2.6) at Week 24 regardless of disease duration (ITT) RA <2 years RA ≥2 years TCZ 8 mg/kg (n=125) TCZ 8 mg/kg (n=170) MTX (n=116) MTX (n=159) 50 41.7%* 40 28.0%† 30 Patients (%) 20 18.0% 10 7.3% 0 * Mean difference vs. MTX (95% CI) = 24% (11–37)† Mean difference vs. MTX (95% CI) = 24% (14–34) Genovese M, et al. ACR 2429 October, 2008; Poster:988.

  19. HAQ–DI changes over time (ITT) 1.75 MTX (n=284) TCZ 8 mg/kg (n=286) 1.65 1.55 1.45 1.35 1.25 Mean HAQ–DI score 1.15 1.05 0.95 0.85 0.75 0.65 0 2 4 8 12 16 20 24 Time (weeks) Minimal clinically important difference (MCID) of –0.22 achieved at Week 2 with TCZ 8 mg/kg; 2.5 x MCID achieved at Week 81 Roche. Data on file. 1. Wells G, et al. J Rheumatol 1993; 20:557–560.

  20. TCZ induced rapid and sustained normalisation of CRP levels (ITT) 3.5 MTX (n=284) TCZ 8 mg/kg (n=286) 3.0 2.5 2.0 Mean CRP level (mg/dl) 1.5 1.0 0.5 * Upper limit of normal 0 0 2 4 8 12 16 20 24 Time (weeks) Jones G, et al. Ann Rheum Dis 2009 [epub]. *Adjusted mean difference (95% CI) = –0.9 (–1.5, –0.3)

  21. Haemoglobin levels improved with TCZ treatment (ITT) 19 MTX (n=284) TCZ 8 mg/kg (n=286) 18 Upper limit of normal 15 * Mean haemoglobin level (g/dl) 14 13 Lower limit of normal 12 0 2 4 8 12 16 20 24 Time (weeks) * Adjusted mean haemoglobin level increased by 1.19 g/dl from baseline in the TCZ group Jones G, et al. Ann Rheum Dis 2009 [epub]. Reference range is for healthy males

  22. TCZ improved FACIT–Fatigue scores at Week 24 (ITT) 9.3 10 9 8 6.9 7 Mean change from baseline in FACIT–Fatigue score 6 MCID=5.0 5 4 3 2 1 0 MTX(n=284) TCZ 8 mg/kg(n=286) Roche. Data on file.

  23. Consistent improvements in QoL across all SF-36 domains at Week 24 (ITT) 12 MTX (n=284) TCZ 8 mg/kg (n=286) 11 9.8* 10 9 7.8 6.8† 8 7 Mean change from baseline in SF-36 scores 6 4.8 5 4 MCID=2.5–5.01,2 3 2 1 0 Physical component score Mental component score Roche. Data on file. * Mean difference vs. MTX (95% CI)=2.01 (0.37–3.65)† Mean difference vs. MTX (95% CI)=1.96 (–0.31–4.23) 1. Lubeck DP, Pharmacoeconomics 2004; 22:27–38. 2. Kosinski M, et al. Arthritis Rheum 2000; 7:1478–1477.

  24. Incidence of adverse events at Week 24 was similar between MTX- and TCZ-treated patients (safety population) Pooled Phase III safety data were presented in previous sessions PY=patient-years Jones G, et al. Ann Rheum Dis 2009 [epub].

  25. Superiority over Methotrexate – An AMBITIOus Goal in RA: Summary • ACTEMRA monotherapy is superior to MTX alone in the treatment of patients with relatively early RA • ACTEMRA demonstrated superiority over MTX in ACR20, ACR50 and ACR70 responses, DAS28 remission and quality of life measurements • ACTEMRA was superior to MTX in improving the signs and symptoms of RA, regardless of disease duration and prior MTX treatment • ACTEMRA is the only biologic to date to show superiority over MTX • ACTEMRA therapy was generally well tolerated with a low rate of serious infections

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