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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
Radiographic Analyses of Disease Progression

Vibeke Strand, MD Biopharmaceutical ConsultantClinical Associate ProfessorDivision of ImmunologyStanford University School of Medicine

x ray analyses of disease progression
X-ray Analyses of Disease Progression
  • DMARDs – Leflunomide – Methotrexate – Sulfasalazine
  • Biologic Agents – Etanercept – Infliximab – Anakinra
phase iii trials analysis of x ray data
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
phase iii trials design demographics
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

phase iii trials total sharp scores at baseline
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)

phase iii trials change in total sharp scores
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

phase iii trials change in total sharp scores7
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

ultra trial us 301 mean changes in erosion jsn scores 1 year
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

mn 301 mean changes in erosion jsn scores 6 mos
MN 301Mean Changes in Erosion + JSN Scores: 6 mos.

0.0 0.0 0.0 0.0 3.0 0.5 Medians

Mean Change

mn302 mean changes in erosion jsn scores 1 year
MN302Mean Changes in Erosion + JSN Scores: 1 year

0.0 0.0 0.0 0.0 Medians

Mean Change

total sharp scores for acr responders vs non responders
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

phase iii trials of patients with no newly eroded joints

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
era trial analysis of x ray data modified sharp scoring method
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
slide14

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

era trial 1 year change in total sharp scores
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

era trial mean changes in erosion jsn scores 1 year
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

era trial patients with no newly eroded joints at 1 year
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)

slide18

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
attract infliximab ch a tnf a mab mtx trial design demographics
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
slide20

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

il 1ra eu monotherapy trial demographics
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

il 1ra eu monotherapy analysis of x ray data genant modification of sharp scoring method
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

il 1ra eu monotherapy trial mean changes total sharp genant scores 24 wks
IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp/Genant Scores: 24 wks

Mean Change

*

*

*

p <.01

European Monotherapy Study

il 1ra eu monotherapy trial mean changes total sharp scores 0 24 24 48 wks
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

il 1ra eu monotherapy trial change in genant sharp scores at 24 48 wks

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

il 1ra eu monotherapy trial all active doses mean changes in erosion jsn scores 24 48 wks
IL-1ra EU Monotherapy Trial: All active dosesMean Changes in Erosion + JSN Scores: 24; 48 wks

Mean Change

European Monotherapy Study

il 1ra eu monotherapy trial patients without radiographic progression at 24 wks
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

modified sharp analyses blinded sequence randomized
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

modified sharp analyses estimated v observed yearly progression
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

decreasing radiographic progression conclusions
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
decreasing radiographic progression methodologic questions
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
delaying radiographic progression methodologic questions
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
x ray results inter reader variability
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

repeated scoring of x rays
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

ultra us 301 repeated scoring of x rays
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

changes in total sharp scores us 301 year 2 cohort
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%

slide38

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

slide39

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

slide40

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

slide41

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.

il 1ra eu monotherapy trial change in larsen scores at 24 weeks
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

us301 and mn302 mtx populations medication differences
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%