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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. 1. 4. 6p. 16. 17. Qualities for Assessment of psoriasis. Investigators want - PowerPoint PPT Presentation
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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
2 = 21-40% BSA remaining
3 = 41-60% BSA remaining
4 = 61-80% BSA remaining
5 = 81-100% 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
3 = majority of lesions have individual scores for I, E, S that average 3
4 = majority of lesions have individual scores for I, E, S that average 4
5 = majority of lesions have individual scores for I, E, S that average 5
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
2 = 40% as bad as my psoriasis has ever been
3 = 60% as bad as my psoriasis has ever been
4 = 80% 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
s
Cance
r
Depre
ssio
n
Hyper
tensi
on
Arthrit
is
Myo
card
ial i
nfarc
tion
Chronic
lung d
isea
se
Type
2 dia
betes
Psoria
sis
Congestiv
e hea
rt fa
ilure
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
y ad
ults
Hyper
tensi
on
Type
2 dia
betes
Myo
card
ial i
nfarc
tion
Congestiv
e hea
rt fa
ilure
Cance
r
Arthrit
is
Derm
atiti
s
Psoria
sis
Chronic
lung d
isea
se
Depre
ssio
n
Men
tal
Co
mp
on
ent
Su
mm
ary
Sco
re o
f th
e S
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