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Radiographic Analyses of Disease Progression Vibeke Strand, MD Biopharmaceutical Consultant Clinical Associate Professor Division of Immunology Stanford.

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Presentation on theme: "Radiographic Analyses of Disease Progression Vibeke Strand, MD Biopharmaceutical Consultant Clinical Associate Professor Division of Immunology Stanford."— Presentation transcript:

1 Radiographic Analyses of Disease Progression Vibeke Strand, MD Biopharmaceutical Consultant Clinical Associate Professor Division of Immunology Stanford 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  34 – 36 joints in the hands, 12 in feet 44 for erosions: 0 - 5; 48 for joint space narrowing: 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 Sharp Scoring Method

4 N Control Placebo Placebo – MTX 7.5–15 mg/wk – 7.5–15 mg/wk [median dose] SSZ – 0.5–2 gm/d – Duration (mo) 12 6  Disease duration (yr)  2 Years 33–40% 38–42% 43–44% DMARDs failed No Prior DMARD 40–45% 40–53% 33–34% Mean HAQ DI US 301MN 302MN Phase III Trials: Design, Demographics

5 Phase III Trials – Total Sharp Scores at Baseline Total Sharp score Mean disease duration Predicted yearly progression LEFPLMTX LEF PL SSZ LEF MTX (131)(83)(138) (89) (62) (85) (304) (331) 301US301MN (6 mos)302MN

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

7 301MN301/3MN ( 6 mos )( 12 mos ) LEF PL SSZ LEF SSZ Phase III Trials – Change in Total Sharp Scores 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 301 Mean Changes in Erosion + JSN Scores:1 year Mean Change Medians

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

10 MN302 Mean Changes in Erosion + JSN Scores: 1 year Mean Change Medians

11 11/02/ US 301MN 302MN LEF PL MTX LEF PL SSZ LEF MTX Total Sharp Scores for ACR Responders vs Non-Responders Responders N Baseline:  at endpoint: Responders N Baseline:  at endpoint: Non-responders N Baseline: at Endpoint: Non-responders N Baseline: at Endpoint:

12 Phase III Trials % of Patients with No Newly Eroded Joints 70%MTX 68%LEF MN 302: 73%SSZ 66%PL 69%LEF MN 301: 77%MTX 72%PL79%LEFULTRA:

13 ERA Trial: Analysis of X-ray Data Modified 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 Mean age Female (%) RA duration (mean months) RF positive (%) Baseline HAQ DI Mean prior DMARDs Conc NSAIDs (%) Steroids (%) Methotrexate (n = 217) 25 mg (n = 207) Etanercept 10 mg (n = 208) ERA Trial: Demographics

15 Predicted/Actual Etanercept 10 mg Etanercept 25 mg Mean Change Predicted/ActualPredicted /Actual Methotrexate ERA Trial 1 Year change in Total Sharp Scores

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

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

18 ATTRACT: Analysis of X-ray Data van 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  TNF  mAb)+ MTX Trial design; Demographics  428 patients; 34 centers in EU and US  Active RA despite MTX  12.5mg/week for mean 3 yrs Median dose: 15 mg/week Concomitant steroids: 61%; NSAIDs: 76%  Mean disease duration: 10.4 years Median number DMARDs failed: 3 81% RF+; 37% with previous joint surgery Baseline mean HAQ DI scores:  Placebo vs3.0 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 ATTRACT: Mean Changes in Total Sharp Scores at Week PL +MTX (n = 63) 3mg/kg q8w (n = 71) 3mg/kg q4w (n = 71) 10mg/kg q8w (n = 77) 10mg/kg q4w (n = 66) All infliximal (n = 285) p-value vs. PL < Mean Change from Baseline

21 Mean age (yr) Mean ds duration (yr) % RF % with erosions % No Prior DMARD % Conc steroids % Conc NSAIDs Baseline Sharp scores IL-1raIL-1raIL-1ra Total patients Placebo 30 mg75 mg150 mg (n = 472) (n = 121)(n = 119)(n = 116)(n = 116) (n = 472) (n = 121)(n = 119)(n = 116)(n = 116) IL-1ra EU Monotherapy Trial: Demographics European Monotherapy Study

22 IL-1ra EU Monotherapy: Analysis of X-ray Data Genant 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

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

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

25 IL-1ra EU Monotherapy Trial: Change in Genant/Sharp Scores at 24; 48 Wks Placebo30 mg75 mg150 mg Weeks 0-24 Weeks Change from Baseline Erosion Joint Space Narrowing Treatment Group European Monotherapy Study ** *** ** * p<.05 ** p<.01 *** p=.001 * *

26 IL-1ra EU Monotherapy Trial: All active doses Mean 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 No change in erosion score No change in JSN score No change in TOTAL score 42% 44% 33% 53% 59% 43% Placebo (n = 78) All doses (n = 248) IL-1ra European Monotherapy Study

28 Modified Sharp Analyses Blinded, Sequence Randomized ULTRA, MN301 MN302 ATTRACTERA EU IL-1ra 46 jts for erosions: jts for JSN: reader; Sensitivity analysis 44 jts for erosions: 0 - 5, jts for JSN: readers; Sensitivity analysis 36 jts for erosions: jts for JSN: of 6 readers 28 jts for erosions: jts for JSN: reader; Sensitivity analysis TOTAL SCORE

29 Modified Sharp Analyses Estimated v Observed Yearly Progression ULTRAMN301ATTRACT EU IL-1ra Disease Duration: 6.9 yrs Baseline score:25 Est. yearly progression: 3.7 Disease Duration: 5.7 yrs Baseline score:46.2 Est. 6 mos progression: 4.1 Disease Duration: 10.7 yrs Baseline score:79-82 Est. yearly progression: 7.6 Disease Duration: 3.7 yrs Baseline score:27 Est. 6 mos progression: 3.6 Placebo progression 2.2 [formal ITT]

30 Decreasing Radiographic Progression Conclusions  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 Progression Methodologic 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 Progression Methodologic 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 11/02/98038 X-ray Results Inter-Reader Variability* ReaderCorrelation (# subjects) Coefficient 1,3 (122) ,2 (230) ,4 (72) ,5 (71)0.993 *Sharp, Wolfe, Corbett, et al. Radiological Progression in Rheumatoid Arthritis: How Many Patients Are Required in a Treatment Trial to Rest Disease Modification? Ann Rheum Dis, 1993;52:

35 11/02/98038 Repeated Scoring of X-Rays Correlation Reader# FilmsInterval Coefficient Correlation Reader# FilmsInterval Coefficient 1409 mos mos mos mos mos mo.966 Sharp JT, Bluhm GB, Gofton JP, Mitchell DM, Weinstein AS (unpublished)

36 11/02/98038 ULTRA US 301: Repeated Scoring of X-rays Correlation Reader (JS) Coefficient 159 subjectsBaseline0.972 Week

37 Changes in Total Sharp Scores US 301 : Year 2 Cohort LEFMTX (n=71)(n=66) Baseline Total Sharp Score Change at 24 months Change during year Change during year Change year 2 v year 1 NS NS % Pts w/ no newly eroded jts 89% 80%

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

39 ATTRACT: Clinical Responders vs. Nonresponders at Week 54 MTX+PL3q83q410q810q4 p-value vs. PL < ACR20 responders Median Changes from Baseline MTX+PL3q83q410q810q4 p-value vs. PL< ACR20 nonresponders

40 ATTRACT: Comparison of Readers 1 and 2 at Week PL 3q83q4 10q8 10q4 PL 3q83q4 10q8 10q4 Reader 1 Reader 2 Median Change from Baseline p-value vs. PL<

41 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) Larsen Scoring Method * 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 Change in Score at Week 24 (±SEM) Placebo30 mg 75 mg 150 mg (n = 83)(n = 89)(n = 89)(n = 86) Larsen Score Erosive Joint Count IL-1ra EU Monotherapy Trial Change in Larsen Scores at 24 weeks Treatment Group European Monotherapy Study

43 US301 MN302 (182) (498) US301 and MN302 MTX Populations Medication Differences Folate Administration98%11% Mean MTX dose year Range( )( ) Mean MTX dose year Range( )( ) Median MTX dose year Median MTX dose year Conc steroids 53%45% Conc NSAIDs70%87% Conc NSAIDs70%87%


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