Radiographic Analyses of Radiographic Analyses of Disease ProgressionDisease Progression

Radiographic Analyses of Radiographic Analyses of Disease ProgressionDisease Progression

Vibeke Strand, MD Vibeke Strand, MD

Biopharmaceutical ConsultantBiopharmaceutical Consultant Clinical Associate ProfessorClinical Associate Professor

Division of ImmunologyDivision of ImmunologyStanford University School of MedicineStanford University School of Medicine

Vibeke Strand, MD Vibeke Strand, MD

Biopharmaceutical ConsultantBiopharmaceutical Consultant Clinical Associate ProfessorClinical Associate Professor

Division of ImmunologyDivision of ImmunologyStanford University School of MedicineStanford University School of Medicine

X-ray Analyses of Disease ProgressionX-ray Analyses of Disease ProgressionX-ray Analyses of Disease ProgressionX-ray Analyses of Disease Progression

DMARDs– Leflunomide– Methotrexate– Sulfasalazine

Biologic Agents– Etanercept– Infliximab– Anakinra

Phase III Trials: Analysis of X-ray DataPhase III Trials: Analysis of X-ray Data

34 – 36 joints in the hands, 12 in feet34 – 36 joints in the hands, 12 in feet

44 for erosions: 0 - 5; 48 for joint space narrowing: 0 - 444 for erosions: 0 - 5; 48 for joint space narrowing: 0 - 4

Total score = sum of erosions + joint space narrowingTotal score = sum of erosions + joint space narrowing X-rays at baseline and endpoint in all studiesX-rays at baseline and endpoint in all studies All films read by Dr. John Sharp; blinded, random sequenceAll films read by Dr. John Sharp; blinded, random sequence All films read by Dr. Arvi Larsen; erosion scores correlatedAll films read by Dr. Arvi Larsen; erosion scores correlated 12 month ITT in 301US despite entry into alternate therapy or 12 month ITT in 301US despite entry into alternate therapy or

exit from protocol for active treatmentexit from protocol for active treatment Clinical data in patients with and without complete radiologic Clinical data in patients with and without complete radiologic

data were comparabledata were comparable Sensitivity analysis to account for early withdrawalsSensitivity analysis to account for early withdrawals

Sharp Scoring MethodSharp Scoring Method

N N 482 482 358 358 999 999

ControlControl Placebo Placebo Placebo Placebo – –

MTX MTX 7.5–15 mg/wk 7.5–15 mg/wk – – 7.5–15 mg/wk 7.5–15 mg/wk

[median dose] [median dose] 15.015.0 11.0 11.0

SSZ SSZ – – 0.5–2 gm/d 0.5–2 gm/d – –

Duration (mo) Duration (mo) 12 12 6 6 12 12 12 12

Disease duration (yr)Disease duration (yr) 6.7 6.7 7.0 7.0 3.7 3.7

2 Years 2 Years 33–40% 33–40% 38–42% 38–42% 43–44% 43–44%

DMARDs failedDMARDs failed 0.9 0.9 1.0 1.0 1.1 1.1

No Prior DMARD No Prior DMARD 40–45% 40–45% 40–53% 40–53% 33–34% 33–34%

Mean HAQ DIMean HAQ DI 1.31.3 1.7-1.9 1.7-1.9 1.5 1.5

301US 301MN 302MN

Phase III Trials: Design, DemographicsPhase III Trials: Design, DemographicsPhase III Trials: Design, DemographicsPhase III Trials: Design, Demographics

Phase III Trials – Total Sharp Scores at BaselinePhase III Trials – Total Sharp Scores at Baseline

Total SharpTotal Sharpscore 23.1 25.4 22.8 46.3 46.2 41.9 24.9 24.6score 23.1 25.4 22.8 46.3 46.2 41.9 24.9 24.6

Mean diseaseMean diseasedurationduration 7.0 7.0 6.9 6.9 6.5 6.5 7.6 7.6 5.7 5.7 7.4 7.4 3.7 3.8 3.7 3.8

PredictedPredictedyearlyyearlyprogressionprogression 3.3 3.3 3.7 3.7 3.5 6.1 3.5 6.1 8.1 5.7 6.7 6.5 8.1 5.7 6.7 6.5

LEF PL MTX LEF PL SSZ LEF MTX(131) (83) (138) (89) (62) (85) (304) (331)

301US 301MN (6 mos) 302MN

3.33.7 3.5

3.1

4.1

2.9

6.7 6.5

0.5

2.2

0.9 1.2

5.9

2.3 2.5

1.6

0.0

5.0

10.0 301US 301MN 302MN

LEF PL MTX LEF PL SSZ LEF MTX

Phase III Trials – Change in Total Sharp ScoresPhase 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 0.0 0.0 0.0 0.0 3.0 0.5 0.0 0.0

3.1

4.1

2.8

6.15.7

1.2

5.9

2.3

1.01.6

0

5

10301MN 301/3MN

( 6 mos ) ( 12 mos )

LEF PL SSZ LEF SSZ

Phase III Trials – Change in Total Sharp ScoresPhase 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

ULTRA Trial: US 301ULTRA Trial: US 301Mean Changes in Erosion + JSN Scores:1 yearMean Changes in Erosion + JSN Scores:1 year

ULTRA Trial: US 301ULTRA Trial: US 301Mean Changes in Erosion + JSN Scores:1 yearMean Changes in Erosion + JSN Scores:1 year

Me

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0.30.2

1.2

0.8

0.30.4

0

1

2

Erosions JSN

LEF

PL

MTX

0.0 0.0 0.0 0.0 0.0 0.0 Medians

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

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

0.6 0.6

3.82.1

1.4

0.9

0

1

2

Erosions JSN

LEFPL

SSZ

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0.0 0.0 0.0 0.0 3.0 0.5 Medians

MN302MN302Mean Changes in Erosion + JSN Scores: 1 yearMean Changes in Erosion + JSN Scores: 1 year

MN302MN302Mean Changes in Erosion + JSN Scores: 1 yearMean Changes in Erosion + JSN Scores: 1 year

1.5

1.0

0.5

1.1

0.0

1.0

2.0

Erosions JSN

LEF

MTX

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0.0 0.0 0.0 0.0 Medians

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301US 301MN 302MN

LEF PL MTX LEF PL SSZ LEF MTX

Total Sharp Scores for ACR Responders vs Total Sharp Scores for ACR Responders vs Non-RespondersNon-Responders

RespondersResponders N N 71 71 27 27 66 50 66 50 18 18 50 50 181 232 181 232

Baseline:Baseline: 25.525.5 22.6 27.4 22.6 27.4 44.2 49.3 40.9 44.2 49.3 40.9 21.8 21.8 24.7 24.7

at endpoint: at endpoint: 0.20.2 1.0 1.0 0.4 1.3 4.7 2.7 0.4 1.3 4.7 2.7 1.7 0.1 1.7 0.1

Non-respondersNon-responders N N 58 58 56 56 72 39 72 39 44 44 35 123 35 123 99 99

Baseline:Baseline: 20.220.2 26.726.7 18.5 48.9 44.9 43.3 18.5 48.9 44.9 43.3 29.6 29.6 24.4 24.4

at Endpoint: at Endpoint: 1.01.0 2.7 2.7 1.4 -1.7 6.0 -0.4 1.4 -1.7 6.0 -0.4 3.0 3.0 3.8 3.8

Phase III TrialsPhase III Trials% of Patients with No Newly Eroded Joints% of Patients with No Newly Eroded Joints

Phase III TrialsPhase III Trials% of Patients with No Newly Eroded Joints% of Patients with No Newly Eroded Joints

70%70%MTXMTX

68%68%LEFLEFMN 302:MN 302:

73%73%SSZSSZ

66%66%PLPL69%69%LEFLEFMN 301:MN 301:

77%77%MTXMTX

72%72%PLPL

79%79%LEFLEFULTRA:ULTRA:

ERA Trial: Analysis of X-ray DataERA Trial: Analysis of X-ray DataModified Sharp Scoring MethodModified Sharp Scoring Method

ERA Trial: Analysis of X-ray DataERA Trial: Analysis of X-ray DataModified Sharp Scoring MethodModified Sharp Scoring Method 36 joints for erosions (grades 0-5); 36 joints for erosions (grades 0-5);

42 for joint space narrowing (grades 0-4);42 for joint space narrowing (grades 0-4);summed for total score summed for total score

X-rays at baseline, 6 months and 1 yearX-rays at baseline, 6 months and 1 year

Modifications:Modifications:

– Included feet (van der Heijde)Included feet (van der Heijde)

– Added percentage joints eroded or narrowed to grading Added percentage joints eroded or narrowed to grading method (Rau)method (Rau)

Each case read by 2 of 6 physicians trained in the same Each case read by 2 of 6 physicians trained in the same method (inter-reader variability: r = 0.85) method (inter-reader variability: r = 0.85)

Sequence of films blinded to readersSequence of films blinded to readers

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

Methotrexate(n = 217)

25 mg(n = 207)

Etanercept

10 mg(n = 208)

ERA Trial: DemographicsERA Trial: Demographics

8.3

1.4

PredictedPredicted /Actual/Actual

Etanercept 10 mgEtanercept 10 mgEtanercept 25 mgEtanercept 25 mg

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9.5

1.3

8.7

0.8

0

2

4

6

8

10

PredictedPredicted /Actual/Actual PredictedPredicted /Actua/Actuall

MethotrexateMethotrexate

ERA TrialERA Trial

1 Year change1 Year change in Total Sharp Scores in Total Sharp Scores

ERA TrialERA Trial

1 Year change1 Year change in Total Sharp Scores in Total Sharp Scores

* * PP < 0.05 vs methotrexate < 0.05 vs methotrexate

00

22

JSNJSNErosionsErosions

11

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0.90.9

0.40.4** 0.40.4 0.40.4

1.01.0

Etanercept 25 mgEtanercept 25 mg

Etanercept 10 mgEtanercept 10 mg

MethotrexateMethotrexate

0.40.4

ERA TrialERA TrialMean changes in Erosion + JSN Scores: 1 YearMean changes in Erosion + JSN Scores: 1 Year

ERA TrialERA TrialMean changes in Erosion + JSN Scores: 1 YearMean changes in Erosion + JSN Scores: 1 Year

ERA Trial: Patients With No Newly ErodedERA Trial: Patients With No Newly Eroded

Joints at 1 YearJoints 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

ATTRACT: Analysis of X-ray DataATTRACT: Analysis of X-ray Datavan der Heijde Modification of Sharp Scoring Methodvan der Heijde Modification of Sharp Scoring Method

44 joints for erosions: scored 0–5 in hands; 0–10 in feet;44 joints for erosions: scored 0–5 in hands; 0–10 in feet;

40 joints for joint space narrowing; summed for total score40 joints for joint space narrowing; summed for total score

Two experienced readers scored every filmTwo experienced readers scored every film

– blinded to patient identity, treatment, sequence of filmblinded to patient identity, treatment, sequence of film

– Baseline, 30 and 54week films presented in random orderBaseline, 30 and 54week films presented in random order

348 of 428 (81%) patients included in primary analysis348 of 428 (81%) patients included in primary analysis

Clinical data in patients with and without complete radiologic Clinical data in patients with and without complete radiologic data were comparabledata were comparable

Sensitivity analyses to account for missing dataSensitivity analyses to account for missing data

ATTRACT: Infliximab (ch ATTRACT: Infliximab (ch TNFTNFmAb)+ MTXmAb)+ MTX

Trial design; DemographicsTrial design; Demographics

ATTRACT: Infliximab (ch ATTRACT: Infliximab (ch TNFTNFmAb)+ MTXmAb)+ MTX

Trial design; DemographicsTrial design; Demographics 428 patients; 34 centers in EU and US428 patients; 34 centers in EU and US

Active RA despite MTXActive RA despite MTX 12.5mg/week for mean 3 yrs 12.5mg/week for mean 3 yrsMedian dose: 15 mg/weekMedian dose: 15 mg/weekConcomitant steroids: 61%; NSAIDs: 76%Concomitant steroids: 61%; NSAIDs: 76%

Mean disease duration: Mean disease duration: 10.4 years10.4 yearsMedian number DMARDs failed: 3Median number DMARDs failed: 381% RF+; 37% with previous joint surgery81% RF+; 37% with previous joint surgeryBaseline mean HAQ DI scores: 1.7-1.8Baseline mean HAQ DI scores: 1.7-1.8

Placebo vsPlacebo vs 3.0 mg mAb 3.0 mg mAb IV IV q 4 weeksq 4 weeks3.0 mg 3.0 mg q 8 weeksq 8 weeks

10.0 mg 10.0 mg q 4 weeksq 4 weeks10.0 mg 10.0 mg q 8 weeksq 8 weeks

ATTRACT: Mean Changes in Total Sharp Scores at ATTRACT: Mean Changes in Total Sharp Scores at

Week 54Week 54

-2

-1

0

1

2

3

4

5

6

7

8

PL +MTX

(n = 63)

3mg/kgq8w

(n = 71)

3mg/kgq4w

(n = 71)

10mg/kgq8w

(n = 77)

10mg/kgq4w

(n = 66)

All infliximal(n = 285)

p-value vs. PL < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

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7.0

1.2 1.1

0.4 0.55-0.5

Mean age (yr)Mean age (yr) 5252 5353 5353 5454

Mean ds duration (yr) Mean ds duration (yr) 3.73.7 4.34.3 4.24.2 3.93.9

% RF+% RF+ 6969 7171 6969 6969

% with erosions% with erosions 7474 7777 7474 6969

% No Prior DMARD % No Prior DMARD 1919 2121 2525 3434

% Conc steroids% Conc steroids 4141 4949 4141 4141

% Conc NSAIDs % Conc NSAIDs 8989 8282 8888 8585

Baseline Sharp scoresBaseline Sharp scores 27.3927.39 29.5529.55 29.0629.06 24.6624.66

IL-1raIL-1ra IL-1raIL-1ra IL-1raIL-1raTotal patients Total patients Placebo Placebo 30 mg30 mg 75 mg75 mg 150 mg150 mg (n = 472) (n = 472) (n = 121)(n = 121) (n = 119)(n = 119) (n = 116)(n = 116) (n = 116)(n = 116)

IL-1ra EU Monotherapy Trial:IL-1ra EU Monotherapy Trial: DemographicsDemographics

IL-1ra EU Monotherapy Trial:IL-1ra EU Monotherapy Trial: DemographicsDemographics

European Monotherapy StudyEuropean Monotherapy StudyEuropean Monotherapy StudyEuropean Monotherapy Study

IL-1ra EU Monotherapy: Analysis of X-ray DataIL-1ra EU Monotherapy: Analysis of X-ray DataGenant Modification of Sharp Scoring MethodGenant Modification of Sharp Scoring Method

IL-1ra EU Monotherapy: Analysis of X-ray DataIL-1ra EU Monotherapy: Analysis of X-ray DataGenant Modification of Sharp Scoring MethodGenant Modification of Sharp Scoring Method

28 joints for erosions (grades 0-3.5);28 joints for erosions (grades 0-3.5);26 for joint space (JSN) narrowing (grades 0-4); 26 for joint space (JSN) narrowing (grades 0-4); summed for total scoresummed for total score

X-rays at baseline, 24 weeks and 48 weeks continuing RxX-rays at baseline, 24 weeks and 48 weeks continuing Rx

Genant modification of Sharp methodGenant modification of Sharp method

– Did not include feetDid not include feet

– Maximum score 202Maximum score 202

Scored in pairs or triplicates by GenantScored in pairs or triplicates by Genant

Sequence of films blindedSequence of films blinded

European Monotherapy StudyEuropean Monotherapy StudyEuropean Monotherapy StudyEuropean Monotherapy Study

IL-1ra EU Monotherapy Trial: IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp/Genant Scores: 24 wksMean Changes Total Sharp/Genant Scores: 24 wks

IL-1ra EU Monotherapy Trial: IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp/Genant Scores: 24 wksMean Changes Total Sharp/Genant Scores: 24 wks

3.63.4 3.5

3.2

1.91.8

3.5

1.8

0.0

1.0

2.0

3.0

4.0

5.0

Placebo 30 mg 75 mg 150 mg

Predicted

0 - 24

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European Monotherapy StudyEuropean Monotherapy Study

** *

p <.01

IL-1ra EU Monotherapy Trial: IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp Scores: 0-24; 24-48 wksMean Changes Total Sharp Scores: 0-24; 24-48 wksIL-1ra EU Monotherapy Trial: IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp Scores: 0-24; 24-48 wksMean Changes Total Sharp Scores: 0-24; 24-48 wks

1.91.8

1.0 0.9

3.5

1.8 1.61.3

0.0

1.0

2.0

3.0

4.0

5.0

Placebo 30 mg 75 mg 150 mg

0-24 24-48

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IL-1ra European Monotherapy StudyEuropean Monotherapy Study

*p < .01*p <.01

*p<.01

European Monotherapy StudyEuropean Monotherapy Study

IL-1ra EU Monotherapy Trial: IL-1ra EU Monotherapy Trial:

Change inChange in Genant/Sharp Scores at 24; 48 WksGenant/Sharp Scores at 24; 48 Wks

IL-1ra EU Monotherapy Trial: IL-1ra EU Monotherapy Trial:

Change inChange in Genant/Sharp Scores at 24; 48 WksGenant/Sharp Scores at 24; 48 Wks

Placebo 30 mg 75 mg 150 mg

Weeks 0-24

Weeks 24-48C

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Baselin

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Erosion

Joint Space Narrowing

1

2

0

1

2

0

Treatment GroupEuropean Monotherapy StudyEuropean Monotherapy Study

1.5

0.8 0.

5

0.6

1.01.4 1.1

2.0

0.7

0.9 0.5

0.5

0.5

0.4

***** **

* p< .05

** p< .01

*** p= .001

**

IL-1ra EU Monotherapy Trial: All active dosesIL-1ra EU Monotherapy Trial: All active dosesMean Changes in Erosion + JSN Scores: 24; 48 wksMean Changes in Erosion + JSN Scores: 24; 48 wks

IL-1ra EU Monotherapy Trial: All active dosesIL-1ra EU Monotherapy Trial: All active dosesMean Changes in Erosion + JSN Scores: 24; 48 wksMean Changes in Erosion + JSN Scores: 24; 48 wks

1.2

0.6 0.60.6

0.0

1.0

2.0

Erosions JSN

0-24

24-48

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European Monotherapy StudyEuropean Monotherapy Study

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 StudyEuropean Monotherapy Study

Modified Sharp AnalysesModified Sharp AnalysesBlinded, Sequence RandomizedBlinded, Sequence RandomizedModified Sharp AnalysesModified Sharp AnalysesBlinded, Sequence RandomizedBlinded, Sequence Randomized

ULTRA,ULTRA,MN301MN301MN302MN302

ATTRACTATTRACT

ERAERA

EU IL-1raEU IL-1ra

46 jts for erosions: 0 - 546 jts for erosions: 0 - 548 jts for JSN: 0 - 448 jts for JSN: 0 - 41 reader; Sensitivity analysis1 reader; Sensitivity analysis

44 jts for erosions: 0 - 5, 0 -1044 jts for erosions: 0 - 5, 0 -1040 jts for JSN: 0 - 440 jts for JSN: 0 - 42 readers; Sensitivity analysis2 readers; Sensitivity analysis

36 jts for erosions: 0 - 536 jts for erosions: 0 - 542 jts for JSN: 0 - 442 jts for JSN: 0 - 42 of 6 readers2 of 6 readers

28 jts for erosions: 0 - 3.528 jts for erosions: 0 - 3.526 jts for JSN: 0 - 426 jts for JSN: 0 - 41 reader; Sensitivity analysis1 reader; Sensitivity analysis

TOTAL SCORE

422

440

348

202

Modified Sharp AnalysesModified Sharp AnalysesEstimated v Observed Yearly ProgressionEstimated v Observed Yearly ProgressionModified Sharp AnalysesModified Sharp AnalysesEstimated v Observed Yearly ProgressionEstimated v Observed Yearly Progression

ULTRAULTRA

MN301MN301

ATTRACTATTRACT

EU IL-1raEU IL-1ra

Disease Duration: 6.9 yrsDisease Duration: 6.9 yrsBaseline score:Baseline score: 2525Est. yearly progression: Est. yearly progression: 3.73.7

Disease Duration: 5.7 yrsDisease Duration: 5.7 yrsBaseline score:Baseline score: 46.246.2Est. 6 mos progression: Est. 6 mos progression: 4.14.1

Disease Duration: 10.7 yrsDisease Duration: 10.7 yrsBaseline score:Baseline score: 79-8279-82Est. yearly progression: Est. yearly progression: 7.67.6

Disease Duration: 3.7 yrsDisease Duration: 3.7 yrsBaseline score:Baseline score: 2727Est. 6 mos progression: Est. 6 mos progression: 3.63.6

Placebo progression

2.2 [formal ITT]

5.9

7.0

3.5

Decreasing Radiographic ProgressionDecreasing Radiographic ProgressionConclusionsConclusionsDecreasing Radiographic ProgressionDecreasing Radiographic ProgressionConclusionsConclusions Leflunomide effectiveLeflunomide effective: :

– 2 placebo controlled RCTs positive2 placebo controlled RCTs positive– Statistically equivalent to MTX; SSZStatistically equivalent to MTX; SSZ

Methotrexate effectiveMethotrexate effective:: – Previous active controlled trials positivePrevious active controlled trials positive– Placebo controlled RCT positivePlacebo controlled RCT positive– Active controlled trial: statistically equivalent to LEFActive controlled trial: statistically equivalent to LEF

Infliximab effectiveInfliximab effective:: – All doses / dose schedulesAll doses / dose schedules– v placebo in patients failing MTXv placebo in patients failing MTX

Etanercept effective:Etanercept effective:– Statistically equivalent to MTX in early RAStatistically equivalent to MTX in early RA

Anikinra effective:Anikinra effective:– v placebo at 24 wks; continued effect over 48 wksv placebo at 24 wks; continued effect over 48 wks

Decreasing Radiographic ProgressionDecreasing Radiographic ProgressionMethodologic QuestionsMethodologic QuestionsDecreasing Radiographic ProgressionDecreasing Radiographic ProgressionMethodologic QuestionsMethodologic Questions Each protocol population unique:Each protocol population unique:

– BL demographics, Sharp scores, rates of progression BL demographics, Sharp scores, rates of progression – Estimated yearly progression reasonable benchmarkEstimated yearly progression reasonable benchmark

Modified Sharp Analyses:Modified Sharp Analyses:– How many joints?How many joints? Total scores: 422; 380; 348; 202 Total scores: 422; 380; 348; 202– Include feet?Include feet? Score 0-5 or 0-10? Score 0-5 or 0-10? – In view of heterogeneity; increased or decreased In view of heterogeneity; increased or decreased

sensitivity with less number of joint assessed? sensitivity with less number of joint assessed? Analyses of change:Analyses of change:

– Marked variabilityMarked variability; majority of patients, even with placebo ; majority of patients, even with placebo treatment, do NOT progress; treatment, do NOT progress;

– Expressed as mean or median changes?Expressed as mean or median changes?

– Expressed as Total scoreExpressed as Total score v erosion and/or JSN subscores v erosion and/or JSN subscores

Delaying Radiographic ProgressionDelaying Radiographic ProgressionMethodologic QuestionsMethodologic QuestionsDelaying Radiographic ProgressionDelaying Radiographic ProgressionMethodologic QuestionsMethodologic Questions Can we define “healing”?Can we define “healing”?

– v “No progression” or “No newly eroded joints”v “No progression” or “No newly eroded joints”

– Some erosions healed, others enlarged…...Some erosions healed, others enlarged…...

– Measured when sequence of films blinded?Measured when sequence of films blinded?

““Disconnect” between clinical responses and x ray benefitDisconnect” between clinical responses and x ray benefit

– Correlations between ACR responses, AUC weakCorrelations between ACR responses, AUC weak

What is What is clinically meaningful v statistically significantclinically meaningful v statistically significant??

– Value of “sensitivity analyses” for missing dataValue of “sensitivity analyses” for missing data

– Importance of “formal 12 month intent to treat analyses”Importance of “formal 12 month intent to treat analyses”

– Applicability of group changes to individual definitions Applicability of group changes to individual definitions of improvement / lack of progressionof improvement / lack of progression

– Effect of variability assessment due to multiple readersEffect of variability assessment due to multiple readers

BACK UP SLIDES; BACK UP SLIDES; WILL NOT SHOW WILL NOT SHOW BACK UP SLIDES; BACK UP SLIDES; WILL NOT SHOW WILL NOT SHOW

11/02/98038

X-ray Results Inter-Reader Variability*X-ray Results Inter-Reader Variability*

ReaderReader CorrelationCorrelation(# subjects) (# subjects) CoefficientCoefficient

1,3 (122)1,3 (122) 0.9530.953

1,2 (230)1,2 (230) 0.9480.948

1,4 (72)1,4 (72) 0.9610.961

1,5 (71)1,5 (71) 0.9930.993

* 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.

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Repeated Scoring of X-RaysRepeated Scoring of X-Rays

CorrelationCorrelation Reader Reader # Films# Films Interval Interval Coefficient 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)

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ULTRA US 301:ULTRA US 301: Repeated Scoring of X-raysRepeated Scoring of X-rays

CorrelationCorrelation Reader (JS) Reader (JS) CoefficientCoefficient

159 subjects159 subjects BaselineBaseline 0.9720.972

Week 52Week 52 0.9710.971

Changes in Total Sharp ScoresChanges in Total Sharp ScoresUS 301 : Year 2 CohortUS 301 : Year 2 Cohort

LEFLEFMTXMTX

(n=71)(n=71)(n=66)(n=66)

Baseline Total Sharp ScoreBaseline Total Sharp Score 23.823.8 25.125.1

Change at 24 monthsChange at 24 months 1.6 1.6 1.2 1.2

Change during year 1Change during year 1 0.4 0.4 0.6 0.6

Change during year 2Change during year 2 1.1 1.1 0.7 0.7

Change year 2 v year 1Change year 2 v year 1 NS NS NS NS

% Pts w/ no newly eroded jts 89%% Pts w/ no newly eroded jts 89% 80% 80%

PL +MTX

(n = 63)

3mg/kgq8w

(n = 71)

3mg/kgq4w

(n = 71)

10mg/kgq8w

(n = 77)

10mg/kgq4w

(n = 66)

All infliximal(n = 285)

p-value vs. PL < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

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ATTRACT: Median Changes in Total Sharp ATTRACT: Median Changes in Total Sharp Scores at Week 54Scores at Week 54

-2

-1

0

1

2

3

4

5

0.50.0

0.5-0.5 0.0

ATTRACT: Clinical Responders vs. ATTRACT: Clinical Responders vs. Nonresponders at Week 54Nonresponders at Week 54

MTX+PL 3q8 3q4 10q8 10q4

p-value vs. PL 0.013 0.005 0.006 < 0.001

ACR20 responders

Med

ian

Ch

ang

es f

rom

Bas

elin

e

-2

-1

0

1

2

3

4

5

2.0

-0.5-0.05

0.65

-1.0

-2

-1

0

1

2

3

4

5

MTX+PL 3q8 3q4 10q8 10q4

p-value vs. PL < 0.001 < 0.001 < 0.001 0.003

4.04

0.54 0.50.0

0.31

ACR20 nonresponders

-2

-1

0

1

2

3

4

5

6

ATTRACT:ATTRACT: Comparison of Readers 1 and 2 Comparison of Readers 1 and 2 at Week 54at Week 54

-2

-1

0

1

2

3

4

5

6

PL 3q8 3q4 10q8 10q4PL 3q8 3q4 10q8 10q4

Reader 1 Reader 2

Med

ian

Ch

ang

e fr

om

Bas

elin

e

p-value vs. PL <0.0001<0.0001<0.0001<0.0001 <0.0001<0.0001<0.0001<0.0001

5

.85

-10 0

2.5

1

0 0 0

0 = normal1 = slight abnormality, including 1 or more: periarticular soft

tissue swelling, periarticular osteoporosis, and slight joint space narrowing2 = definite early abnormality, including definite erosion, with or without joint space narrowing3 = medium destructive abnormality4 = severe destructive abnormality5 = mutilating abnormality (the original articular surfaces have disappeared)

Larsen Scoring MethodLarsen 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.

Ch

an

ge in

Score

at

Week 2

4 (

±S

EM

)

Placebo 30 mg 75 mg 150 mg(n = 83) (n = 89) (n = 89) (n = 86)

Larsen Score

Erosive Joint Count

0

1

2

3

4

5

6

7

8

IL-1ra EU Monotherapy TrialIL-1ra EU Monotherapy Trial Change in Larsen Scores at 24 weeksChange in Larsen Scores at 24 weeksIL-1ra EU Monotherapy TrialIL-1ra EU Monotherapy Trial Change in Larsen Scores at 24 weeksChange in Larsen Scores at 24 weeks

Treatment Group

3.6 3.8 3.9

6.3

1.51.0

1.7

2.6

European Monotherapy StudyEuropean Monotherapy Study

US301 MN302 (182) (498)

US301 and MN302 MTX PopulationsUS301 and MN302 MTX PopulationsMedication DifferencesMedication Differences

Folate AdministrationFolate Administration 98%98% 11%11%

Mean MTX dose year 1Mean MTX dose year 1 12.3 12.3 10.910.9 Range Range (7.5 - 15)(7.5 - 15) (7.5 - 15)(7.5 - 15)

Mean MTX dose year 2Mean MTX dose year 2 12.812.8 12.212.2 Range Range (7.5 - 20)(7.5 - 20) (7.5 - 15)(7.5 - 15)

Median MTX dose year 1Median MTX dose year 1 15.015.0 11.011.0

Median MTX dose year 2Median MTX dose year 2 15.015.0 11.011.0

Conc steroids Conc steroids 53%53% 45%45%

Conc NSAIDsConc NSAIDs 70%70% 87%87%