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Radiographic Analyses of Disease Progression

Radiographic Analyses of Disease Progression. Vibeke Strand, MD Biopharmaceutical Consultant Clinical Associate Professor Division of Immunology Stanford University School of Medicine. X-ray Analyses of Disease Progression. DMARDs – Leflunomide – Methotrexate – Sulfasalazine

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Radiographic Analyses of Disease Progression

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  1. Radiographic Analyses of Disease Progression Vibeke Strand, MD Biopharmaceutical ConsultantClinical Associate ProfessorDivision of ImmunologyStanford University School of Medicine

  2. X-ray Analyses of Disease Progression • DMARDs – Leflunomide – Methotrexate – Sulfasalazine • Biologic Agents – Etanercept – Infliximab – Anakinra

  3. Phase III Trials: Analysis of X-ray Data Sharp Scoring Method • 34 – 36 joints in the hands, 12 in feet 44 for erosions: 0 - 5; 48 for joint space narrowing: 0 - 4 Total score = sum of erosions + joint space narrowing • X-rays at baseline and endpoint in all studies • All films read by Dr. John Sharp; blinded, random sequence • All films read by Dr. Arvi Larsen; erosion scores correlated • 12 month ITT in 301US despite entry into alternate therapy or exit from protocol for active treatment • Clinical data in patients with and without complete radiologic data were comparable • Sensitivity analysis to account for early withdrawals

  4. Phase III Trials: Design, Demographics 301US 301MN 302MN N 482 358 999 Control Placebo Placebo – MTX 7.5–15 mg/wk – 7.5–15 mg/wk [median dose] 15.0 11.0 SSZ – 0.5–2 gm/d – Duration (mo) 12 6  12 12 Disease duration (yr) 6.7 7.0 3.7  2 Years 33–40% 38–42% 43–44% DMARDs failed 0.9 1.0 1.1 No Prior DMARD 40–45% 40–53% 33–34% Mean HAQ DI 1.3 1.7-1.9 1.5

  5. Phase III Trials – Total Sharp Scores at Baseline 301US 301MN (6 mos) 302MN Total Sharpscore 23.1 25.4 22.8 46.3 46.2 41.9 24.9 24.6 Mean diseaseduration 7.0 6.9 6.5 7.6 5.7 7.4 3.7 3.8 Predictedyearlyprogression 3.3 3.7 3.5 6.1 8.1 5.7 6.7 6.5 LEF PL MTX LEF PL SSZ LEF MTX(131) (83) (138) (89) (62) (85) (304) (331)

  6. Phase III Trials – Change in Total Sharp Scores 301US 301MN 302MN Medians 0.0 0.0 0.0 0.0 3.0 0.5 0.0 0.0 * ‡ * ‡ LEF PL MTX LEF PL SSZ LEF MTX Estimated Yearly Progression in back;Change at Endpoint in front * Active v PL p ≤ 0.05 ‡ LEF v PL p ≤ 0.01

  7. Phase III Trials – Change in Total Sharp Scores 301MN 301/3MN ( 6 mos ) ( 12 mos )  * LEF PL SSZ LEF SSZ Estimated Yearly Progression in back; Change at Endpoint in front * LEF v PL p ≤ 0.01  SSZ v PL p≤ 0.05

  8. ULTRA Trial: US 301Mean Changes in Erosion + JSN Scores:1 year 0.0 0.0 0.0 0.0 0.0 0.0 Medians Mean Change

  9. MN 301Mean Changes in Erosion + JSN Scores: 6 mos. 0.0 0.0 0.0 0.0 3.0 0.5 Medians Mean Change

  10. MN302Mean Changes in Erosion + JSN Scores: 1 year 0.0 0.0 0.0 0.0 Medians Mean Change

  11. Total Sharp Scores for ACR Responders vs Non-Responders 301US 301MN 302MN LEF PL MTX LEF PL SSZ LEF MTX Responders N 71 27 66 50 18 50 181 232 Baseline: 25.5 22.6 27.4 44.2 49.3 40.9 21.8 24.7 at endpoint: 0.2 1.0 0.4 1.3 4.7 2.7 1.7 0.1 Non-responders N 58 56 72 39 44 35 123 99 Baseline: 20.2 26.7 18.5 48.9 44.9 43.3 29.6 24.4 at Endpoint: 1.0 2.7 1.4 -1.7 6.0 -0.4 3.0 3.8 038 11/02/98

  12. ULTRA: LEF 79% PL 72% MTX 77% MN 301: LEF 69% PL 66% SSZ 73% MN 302: LEF 68% MTX 70% Phase III Trials% of Patients with No Newly Eroded Joints

  13. ERA Trial: Analysis of X-ray DataModified Sharp Scoring Method • 36 joints for erosions (grades 0-5); 42 for joint space narrowing (grades 0-4);summed for total score • X-rays at baseline, 6 months and 1 year • Modifications: • Included feet (van der Heijde) • Added percentage joints eroded or narrowed to grading method (Rau) • Each case read by 2 of 6 physicians trained in the same method (inter-reader variability: r = 0.85) • Sequence of films blinded to readers

  14. ERA Trial: Demographics Etanercept Methotrexate (n = 217) 10 mg (n = 208) 25 mg (n = 207) Mean age 49 51 51 Female (%) 74 74 74 RA duration (mean months) 11.9 10.9 11.9 RF positive (%) 89 87 87 Baseline HAQ DI 1.4 1.5 1.5 Mean prior DMARDs 0.6 0.5 0.5 Conc NSAIDs (%) 80 76 86 Steroids (%) 41 42 39

  15. ERA Trial1 Year change in Total Sharp Scores Etanercept 25 mg Etanercept 10 mg Methotrexate 9.5 10 8.7 8.3 8 6 Mean Change 4 2 1.4 1.3 0.8 0 Predicted /Actual Predicted /Actual Predicted /Actual

  16. ERA TrialMean changes in Erosion + JSN Scores: 1 Year 2 Etanercept 25 mg Etanercept 10 mg Methotrexate 1.0 0.9 Mean Change 1 0.4 0.4 0.4* 0.4 0 JSN Erosions * P < 0.05 vs methotrexate

  17. ERA Trial: Patients With No Newly ErodedJoints at 1 Year Etanercept Methotrexate (n = 217) 25 mg (n = 206) All patients With erosions at BL With NO erosions at BL 75% 72% (n=181) 96% (n=25) 57% 52% (n=188) 86% (n=29)

  18. ATTRACT: Analysis of X-ray Datavan der Heijde Modification of Sharp Scoring Method • 44 joints for erosions: scored 0–5 in hands; 0–10 in feet;40 joints for joint space narrowing; summed for total score • Two experienced readers scored every film • blinded to patient identity, treatment, sequence of film • Baseline, 30 and 54week films presented in random order • 348 of 428 (81%) patients included in primary analysis • Clinical data in patients with and without complete radiologic data were comparable • Sensitivity analyses to account for missing data

  19. ATTRACT: Infliximab (ch aTNFamAb)+ MTXTrial design; Demographics • 428 patients; 34 centers in EU and US • Active RA despite MTX 12.5mg/week for mean 3 yrsMedian dose: 15 mg/weekConcomitant steroids: 61%; NSAIDs: 76% • Mean disease duration: 10.4 yearsMedian number DMARDs failed: 381% RF+; 37% with previous joint surgeryBaseline mean HAQ DI scores: 1.7-1.8 • Placebo vs 3.0 mg mAb IV q 4 weeks 3.0 mg q 8 weeks 10.0 mg q 4 weeks 10.0 mg q 8 weeks

  20. 8 7 6 5 4 3 2 1 0 -1 -2 ATTRACT: Mean Changes in Total Sharp Scores at Week 54 7.0 Mean Change from Baseline 1.2 1.1 0.55 0.4 -0.5 3mg/kg q8w (n = 71) 10mg/kg q8w (n = 77) All infliximal (n = 285) PL +MTX (n = 63) 3mg/kg q4w (n = 71) 10mg/kg q4w (n = 66) < 0.001 < 0.001 < 0.001 p-value vs. PL < 0.001 < 0.001

  21. Mean age (yr) 52 53 53 54 Mean ds duration (yr) 3.7 4.3 4.2 3.9 % RF+ 69 71 69 69 % with erosions 74 77 74 69 % No Prior DMARD 19 21 25 34 % Conc steroids 41 49 41 41 % Conc NSAIDs 89 82 88 85 Baseline Sharp scores 27.39 29.55 29.06 24.66 IL-1ra EU Monotherapy Trial:Demographics IL-1ra IL-1ra IL-1ra Total patients Placebo 30 mg 75 mg 150 mg (n = 472) (n = 121) (n = 119) (n = 116) (n = 116) European Monotherapy Study European Monotherapy Study

  22. IL-1ra EU Monotherapy: Analysis of X-ray DataGenant Modification of Sharp Scoring Method • 28 joints for erosions (grades 0-3.5);26 for joint space (JSN) narrowing (grades 0-4); summed for total score • X-rays at baseline, 24 weeks and 48 weeks continuing Rx • Genant modification of Sharp method • Did not include feet • Maximum score 202 • Scored in pairs or triplicates by Genant • Sequence of films blinded European Monotherapy Study European Monotherapy Study

  23. IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp/Genant Scores: 24 wks Mean Change * * * p <.01 European Monotherapy Study

  24. IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp Scores: 0-24; 24-48 wks *p <.01 *p < .01 *p<.01 Mean Change European Monotherapy Study  IL-1ra European Monotherapy Study

  25. 2 2 1 1 0 0 IL-1ra EU Monotherapy Trial: Change inGenant/Sharp Scores at 24; 48 Wks Weeks 0-24 Joint Space Narrowing 1.5 Weeks 24-48 ** ** 0.9 *** 0.8 0.6 0.5 0.5 0.5 * p< .05 ** p< .01 *** p= .001 Change from Baseline Erosion 2.0 * 1.4 1.1 * 1.0 0.7 0.5 0.4 Placebo 30 mg 75 mg 150 mg Treatment Group European Monotherapy Study

  26. IL-1ra EU Monotherapy Trial: All active dosesMean Changes in Erosion + JSN Scores: 24; 48 wks Mean Change European Monotherapy Study

  27. IL-1ra EU Monotherapy Trial Patients without Radiographic Progression at 24 Wks IL-1ra Placebo (n = 78) All doses (n = 248) No change in erosion score No change in JSN score No change in TOTAL score 42% 44% 33% 53% 59% 43% European Monotherapy Study

  28. ULTRA,MN301MN302 ATTRACT ERA EU IL-1ra 46 jts for erosions: 0 - 548 jts for JSN: 0 - 41 reader; Sensitivity analysis 44 jts for erosions: 0 - 5, 0 -1040 jts for JSN: 0 - 42 readers; Sensitivity analysis 36 jts for erosions: 0 - 542 jts for JSN: 0 - 42 of 6 readers 28 jts for erosions: 0 - 3.526 jts for JSN: 0 - 41 reader; Sensitivity analysis Modified Sharp AnalysesBlinded, Sequence Randomized TOTAL SCORE 422 440 348 202

  29. ULTRA MN301 ATTRACT EU IL-1ra Disease Duration: 6.9 yrsBaseline score: 25Est. yearly progression: 3.7 Disease Duration: 5.7 yrsBaseline score: 46.2Est. 6 mos progression: 4.1 Disease Duration: 10.7 yrsBaseline score: 79-82Est. yearly progression: 7.6 Disease Duration: 3.7 yrsBaseline score: 27Est. 6 mos progression: 3.6 Modified Sharp AnalysesEstimated v Observed Yearly Progression Placebo progression 2.2 [formal ITT] 5.9 7.0 3.5

  30. Decreasing Radiographic ProgressionConclusions • Leflunomide effective: • 2 placebo controlled RCTs positive • Statistically equivalent to MTX; SSZ • Methotrexate effective: • Previous active controlled trials positive • Placebo controlled RCT positive • Active controlled trial: statistically equivalent to LEF • Infliximab effective: • All doses / dose schedules • v placebo in patients failing MTX • Etanercept effective: • Statistically equivalent to MTX in early RA • Anikinra effective: • v placebo at 24 wks; continued effect over 48 wks

  31. Decreasing Radiographic ProgressionMethodologic Questions • Each protocol population unique: • BL demographics, Sharp scores, rates of progression • Estimated yearly progression reasonable benchmark • Modified Sharp Analyses: • How many joints? Total scores: 422; 380; 348; 202 • Include feet? Score 0-5 or 0-10? • In view of heterogeneity; increased or decreased sensitivity with less number of joint assessed? • Analyses of change: • Marked variability; majority of patients, even with placebo treatment, do NOT progress; • Expressed as mean or median changes? • Expressed as Total score v erosion and/or JSN subscores

  32. Delaying Radiographic ProgressionMethodologic Questions • Can we define “healing”? • v “No progression” or “No newly eroded joints” • Some erosions healed, others enlarged…... • Measured when sequence of films blinded? • “Disconnect” between clinical responses and x ray benefit • Correlations between ACR responses, AUC weak • What is clinically meaningful v statistically significant? • Value of “sensitivity analyses” for missing data • Importance of “formal 12 month intent to treat analyses” • Applicability of group changes to individual definitions of improvement / lack of progression • Effect of variability assessment due to multiple readers

  33. BACK UP SLIDES; WILL NOT SHOW

  34. X-ray Results Inter-Reader Variability* Reader Correlation(# subjects) Coefficient 1,3 (122) 0.953 1,2 (230) 0.948 1,4 (72) 0.961 1,5 (71) 0.993 * Sharp, Wolfe, Corbett, et al. Radiological Progression in Rheumatoid Arthritis: How ManyPatients Are Required in a Treatment Trial to Rest Disease Modification? Ann Rheum Dis,1993;52:332-337. 038 11/02/98

  35. Repeated Scoring of X-Rays Correlation Reader # Films Interval Coefficient 1 40 9 mos .975 1 41 15 mos .975 2 39 11 mos .951 3 41 12 mos .968 4 41 12 mos .945 5 112 1 mo .966 Sharp JT, Bluhm GB, Gofton JP, Mitchell DM, Weinstein AS (unpublished) 038 11/02/98

  36. ULTRA US 301:Repeated Scoring of X-rays Correlation Reader (JS) Coefficient 159 subjects Baseline 0.972 Week 52 0.971 038 11/02/98

  37. Changes in Total Sharp ScoresUS 301 : Year 2 Cohort LEF MTX(n=71) (n=66) Baseline Total Sharp Score 23.8 25.1 Change at 24 months 1.6 1.2 Change during year 1 0.4 0.6 Change during year 2 1.1 0.7 Change year 2 v year 1 NS NS % Pts w/ no newly eroded jts 89% 80%

  38. ATTRACT: Median Changes in Total Sharp Scores at Week 54 5 4.0 4 3 2 Mean Change from Baseline 1 0.5 0.5 0.0 0.0 -0.5 0 -1 3mg/kg q8w (n = 71) 10mg/kg q8w (n = 77) All infliximal (n = 285) PL +MTX (n = 63) 3mg/kg q4w (n = 71) 10mg/kg q4w (n = 66) -2 < 0.001 < 0.001 < 0.001 p-value vs. PL < 0.001 < 0.001

  39. ATTRACT: Clinical Responders vs. Nonresponders at Week 54 ACR20 responders ACR20 nonresponders 5 5 4.04 4 4 3 3 2.0 2 2 Median Changes from Baseline 1 1 0.65 0.54 0.5 0.31 0.0 0 0 -0.05 -0.5 -1 -1 -1.0 -2 -2 MTX+PL 3q8 3q4 10q8 10q4 MTX+PL 3q8 3q4 10q8 10q4 p-value vs. PL < 0.001 < 0.001 < 0.001 0.003 p-value vs. PL 0.013 0.005 0.006 < 0.001

  40. ATTRACT:Comparison of Readers 1 and 2 at Week 54 6 6 Reader 2 Reader 1 5 5 5 4 4 3 3 2.5 Median Change from Baseline 2 2 1 .85 1 1 0 0 0 -1 0 0 0 0 -1 -1 3q8 3q4 10q8 10q4 PL PL 10q8 3q8 3q4 10q4 -2 -2 <0.0001 <0.0001 <0.0001 <0.0001 p-value vs. PL <0.0001 <0.0001 <0.0001 <0.0001

  41. Larsen Scoring Method 0 = normal 1 = slight abnormality, including 1 or more: periarticular soft tissue swelling, periarticular osteoporosis, and slight joint space narrowing 2 = definite early abnormality, including definite erosion, with or without joint space narrowing 3 = medium destructive abnormality 4 = severe destructive abnormality 5 = mutilating abnormality (the original articular surfaces have disappeared) * Fifteen areas are examined: interphalangeal of digit 1, distal and proximal interphalangeal of digits 2–5, metacarpophalangeal of digits 1–5, and the wrist. Dislocation and bony ankylosis are considered; if they are present, the scoring is based on the concomitant bone destruction. Maximum score (total for both hands) is 150.

  42. IL-1ra EU Monotherapy TrialChange in Larsen Scores at 24 weeks 8 7 Larsen Score 6.3 Erosive Joint Count 6 5 3.9 Change in Score at Week 24 (±SEM) 3.8 3.6 4 2.6 3 1.7 2 1.5 1.0 1 0 Placebo 30 mg 75 mg 150 mg (n = 83) (n = 89) (n = 89) (n = 86) Treatment Group European Monotherapy Study

  43. US301 and MN302 MTX PopulationsMedication Differences US301MN302(182)(498) Folate Administration 98% 11%Mean MTX dose year 1 12.3 10.9 Range (7.5 - 15) (7.5 - 15)Mean MTX dose year 2 12.8 12.2 Range (7.5 - 20) (7.5 - 15) Median MTX dose year 1 15.0 11.0 Median MTX dose year 2 15.0 11.0 Conc steroids 53% 45% Conc NSAIDs 70% 87%

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