psoriasis omeract 2004 methods to assess disease activity in clinical trials

Psoriasis OMERACT 2004 Methods to assess disease activity in

clinical trials

Gerald G Krueger MD

Professor, Cumming Presidential Endowed Chair

Dept of Dermatology University of Utah

5/2004

The challenge

6p1 4 16 17

04/19/23

Qualities for Assessment of psoriasis Investigators want

– Quick and easy to perform

– Clear definitions, reproducible FDA seeks

– “Static” ratings — indicating severity at the time the patient is seen

– Results in steps (segmented).e.g. clear, mild, moderate, severe

– Results that have clinical relevance to patient

Tools to quantitate clinical improvement in psoriasis

Clinical Assessments - Subjective– PASI– PGA: Dynamic + / - assisted recall; Static– OLA– National Psoriasis Foundation Psoriasis Score (NPF-PS)– Lattice System-Global Psoriasis Score (LS-GPS)– Target lesions: + / - BSA– QOL (SF36, DLQI, others)

Clinical Assessments - Objective – Biopsy -- thickness, biomarkers (real time PCR, EGIR, etc)– Photographs

PASIE = ErythemaI = Infiltration (induration; thickness; elevation)D = Desquamation (scale; scaling)A = Score for % involvement in each body area

Fredriksson & Pettersson, Dermatologica 1978; 157:238

Gordon KB, et al. 9th IPS 2003; Poster 29.

*P=0.0001 vs placebo.

Improvement in PASI score vs time

Week

50

40

30

20

10

00 2 4 6 8 10 12

Placebo (n=479)

*

*

* *

Efalizumab 1 mg/kg/wk (n=763)

Mea

n P

erce

nta

ge

Imp

rove

men

t in

PA

SI S

core

Fro

m B

asel

ine

60

*

*

*P<0.001 vs placebo.

Gordon KB, et al. 9th IPS 2003; Poster 29.

Improvement in PASI 50 and 75

15%

4%

28%*

55%*

Placebo(n=479)

Efalizumab2 mg/kg/wk

(n=409)

28%*

57%*

Efalizumab1 mg/kg/wk

(n=763)

0

Per

cen

tag

e o

f P

atie

nts

70

60

40

30

10

50

20

PASI 75

PASI 50

PASI 75/PASI 50

Baseline 2 Weeks After Last Dose(PASI = 9.5)

33% PASI Reduction

3 Months After Last Dose(PASI = 4.8)

66% PASI Reduction

PASI < 75 is clinically meaningful

(PASI = 14.2)

Alefacept 7.5 mg/week x 12

PASI problems Plaque qualities (e.g., induration) not defined Area is non-linear, uses a 1-6 scale (1 = <10% BSA, 2 = 10-<30%

BSA, 3 = 30-<50% BSA, 4 = 50-<70% BSA, 5 = 70-<90% BSA, and 6 = 90-100% BSA)

Erythema, infiltration, scaling all weighted equally– Plaque elevation may be more important

(FDA and investigator consensus) Small amount of disease = less reduction than appreciated clinically Continuous, not in steps, PASI 50 and PASI 75 arbitrary endpoints

PASI problems, cont’d

Not intuitive to physicians or patients– PASI = 28 -- what does it mean? – 50% or 75% reduction in PASI -- what does this

mean when recognized that score is non-linear? Clear/almost clear not defined

– What scores = clear to almost clear?– FDA interested in percent of patients who achieve

clear or almost clear

The NPF Psoriasis Score:Development and Use of a New

Psoriasis Scoring System

The NPF Score

Primary End Points

Induration, Target Lesion A (0-5) 5

Induration, Target Lesion B (0-5) 5

BSA Current /Baseline (0-5) 5

Physician's Global Assessment (0-5) 5

Patient's Global Assessment (0-5) 5

Patient's Assessment of Itch (0-5) 5

Maximum Possible Score 30

Target Lesion Assessment Induration = most heavily weighted

score Felt to be most important of EIS system Possible to improve inter-observer

reliability via NPF Reference Card embossed with elevations that increase at 0.25 mm intervals

Score 0 to 5 Pso

rias

is S

core

0.0 mm

0.25 mm

0.50 mm

0.75 mm

1.00 mm

1.25 mm

Body Surface Area

Percent relative to baseline, therefore able to make cross-study comparison

Uses 1%=palm to PIP joint system

Does not account for worsening of disease

% Current

% Baseline

0 = 0% BSA remaining with psoriasis (complete clearing except residual discoloration)

1 = 1-20% BSA remaining





BSA = X 100

Physician’s Global Assessment

Felt to be most important score, but not very dynamic alone

EIS scores are used by physician to assist in making a single PGA score

0 = cleared except residual discoloration

1=majority of lesions have individual scores for I, E, S that average 1

2 = majority of lesions have individual scores for I, E, S that average 2




Patient’s Global Assessment

Dynamic assessment that relies on “set point” of individual rather than baseline

Rank severity of psoriasis, 0 = no psoriasis, 5 = worst psoriasis has been:

0 = no psoriasis

1 = 20% as bad as my psoriasis has ever been




5 = the worst my psoriasis has ever been

Patient’s Assessment of Itch

Static Assessment

Averaged over past 24 hours

Felt to be significant indicator of improvement

0 = No itching

1=Mild; only aware of itching at times, only present when relaxing, not present when focused on other activities

2 = Intermediate between 1 and 3

3 = Moderate; often aware of itching, annoying; sometimes disturbs sleep and daytime activities

4 = Intermediate between 3 and 5.

5 = Severe; constant itching, distressing, frequent sleep disturbance, interferes with activities

0

5

10

15

20

25

30

1 2 3 4 5 6 7

Vis it #

P AS I NP F

Average score -- all patients

Example (Patient #6)

NPF vs. PASI

Prospective Trial of Acitretin and Commercial Tanning

Scor

e

0.0

5.0

10.0

15.0

20.0

25.0

30.0

1 2 3 4Vis it #

P AS I NP F

Scor

e

National Psoriasis Foundation Psoriasis Score as a tool to assess efficacy of

efalizumab (anti-CD11a) in treatment of moderate to severe plaque psoriasis

G G Krueger, Alan Menter, Stephen Tyring,

David Harvey, Wolfgang Dummer,

Dan Henderson, Alice B Gottlieb

Responders @ 12 Weeks Partial responders @ 12 Weeks

NPF PS Induration score during extended treatment in subjects who were responders @ 12 weeks

Target lesion assessment +/- BSA Chose two or more target lesions

– Representative of all lesions– Representative of therapeutic target, e.g. lichenified,

intertriginous, knees, scalp, palms, soles, etc– Assess chosen physical parameters, (E, I, S and area)

using definitions of eachNo standard definitionsNo standard scale, 0 to 3, 0 to 4, 0 to 5, 0 to 6

BSA baseline, 1 palm = 1%

Conclusions re: Assessment of response to therapeutic intervention

Many ways to assess response to Rx None have met the non-existent definition of what is “clinically

meaningful” PASI strengths: Widespread use, will distinguish active from

placebo PASI weaknesses: “Steps” (PASI 75, PASI 50) are artificial and

do not correspond with 75% and 50% improvement, correlate poorly with QOL, unless trained - scores are disparate, not effective for topical studies, not effective for systemic studies if PASI is low, FDA dislikes it and clinicians do not use it nor understand it

Conclusions re: Assessment of response to therapeutic intervention, cont’d

NPF-PS strengths: – Correlates well to PASI, better than PASI to QOL – Works with low BSA (topical agents, PsA) – Has patient input

Dynamic patient global (recall to worst ever been) Quantification of pruritus (most troublesome symptom),

– Has defined physician global (static), – The major element -- induration of 2 target lesions -- early change

= strong predictor of response useful to assess subtle change, easy and consistent assessment with validated induration tool

Conclusions re: Assessment of response to therapeutic intervention, cont’d

NPF-PS weaknesses:

– Not in widespread use– “Not validated” – “Steps” remain to be defined – Approval agencies, e.g., FDA has not “blessed” it – Clinicians have not been exposed to it – Unknown = more or less acceptable than a simple

PGA

Quality of Life (QOL)

Doesn’t directly measure the impact of drug on the disease

Does measure the impact on the patient’s life The overall goal of therpeutic intervention is to

improve patient’s lives However direct measure of disease activity is the

usual primary endpoint

QOL vs Disease Severity

Some patients have lots of lesions but aren’t bothered by them

Some have very few lesions and are very bothered by them

QOL correlates to a degree with skin lesions, but certainly not 100%

QOL Measures

Non-specific– SF-36– Euro QOL– Utility

Skin specific– DLQI– Skindex

Psoriasis specific– PDI

Short Form-36

General health, health change, physical functioning, limitations due to physical health/emotional health, social functioning, pain, energy, emotional well-being

Walking, climbing stairs, working Physical and mental dimensions

Psoriasis: Impact on Physical Health–Comparison With Other Diseases

55

4745 45 44 43 43 42 42 41

35

30

35

40

45

50

55

60

Health

y ad

ults

Derm

atiti

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Cance

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Depre

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Hyper

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on

Arthrit

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Myo

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Chronic

lung d

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Type

2 dia

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Psoria

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Congestiv

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Rapp SR et al. J Am Acad Dermatol. 1999;41:401.

Ph

ysic

al C

om

po

nen

t S

um

mar

y S

core

of

SF

-36

Psoriasis: Impact on Mental Health–Comparison With Other Diseases

53 52 52 5250 49 49

46 46 45

35

30

35

40

45

50

55

Health

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ults

Hyper

tensi

on

Type

2 dia

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Myo

card

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nfarc

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Congestiv

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Cance

r

Arthrit

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Derm

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Psoria

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Depre

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Men

tal

Co

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ent

Su

mm

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Sco

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f th

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F-3

6

Rapp SR et al. J Am Acad Dermatol. 1999;41:401.

Dermatology Life Quality Index

Consists of 10 questions covering 6 domains– Symptoms and feelings– Daily activities– Leisure– Work and school– Personal relationships– Bother with psoriasis

treatment

Response options– Very much: scored 3– A lot: scored 2– A little: scored 1– Not at all: scored 0

Range 0-30 Lower scores = Better

QOL

Finlay AY et al. Clin Exp Dermatol. 1994;19:210.

Correlation of Change in DLQI and Change in PASI and PGA

PASI PGA

Correlation of absolute changes

0.49 0.46

Correlation of percent changes

0.61 0.58

Spearman rank correlations Data on file, Centocor, Inc.

0 = Minimum effect on QOL; 30 = Maximum effect on QOL.

*P<0.001 vs placebo.Feldman SR, et al. AAD Annual Meeting 2002; Poster.

*

11.7 11.5 12.0

9.9

6.1 6.3

0

2

4

6

8

10

12

14

Placebo(n=170)

Efalizumab 1.0 mg/kg/wk

(n=162)

Efalizumab 2.0 mg/kg/wk

(n=166)

Mea

n D

LQ

I Sco

re

Baseline

Week 12

*6.1 6.3

34

Efalizumab Phase III Results: DLQI Scores at Weeks 0 & 12

Improvement From Baseline in DLQI at Week 10

10.3*

0

8*

10*8.8*

2.6

0

2

4

6

8

10

12

Placebo Infliximab 3mg/kg Infliximab 5mg/kg

Mean changeMedian change

Data on file, Centocor, Inc.

Imp

rove

men

t F

rom

Bas

elin

e In

DL

QI

*p<0.001 vs placebo

Summary

QOL measures supplement lesion measures

psoriasis omeract 2004 methods to assess disease activity in clinical trials

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