12 Markus Margel ; nouvelles strat gies anti H1allergo.lyon.inserm.fr/urticaire/12_Margel.pdf · nouvelles stratégies URTICAIRE CHRONIQUE – Actualités et controverses Lyon, jeudi

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Markus Magerl

Anti-histaminiques dans l’UC:nouvelles stratégies

URTICAIRE CHRONIQUE – Actualités et controverses Lyon, jeudi 21 janvier 2010

Allergie-Centrum-CharitéKlinik für Dermatologie, Venerologie und Allergologie

Charité - Universitätsmedizin Berlin

Allergie-Centrum-CharitéDepartment of Dermatology and Allergy


Anti-histaminiques dans l’UC:nouvelles stratégies

Anti-histamines in chronic urticaria:new strategies

URTICAIRE CHRONIQUE – Actualités et controverses Lyon, jeudi 21 janvier 2010

Allergie-Centrum-CharitéKlinik für Dermatologie, Venerologie und Allergologie


Allergie-Centrum-CharitéDepartment of Dermatology and Allergy


EAACI/WAO/GA 2LEN/EDF Guidelines

Urticaria 20083333rdrdrdrd International Consensus Meeting on UrticariaInternational Consensus Meeting on UrticariaInternational Consensus Meeting on UrticariaInternational Consensus Meeting on Urticaria

Non sedating H 1-Antihistamine (nsAH)

Antihistamines are the basis of CU treatment

+

If symptoms persistafter 2 weeks

If symptoms persistafter 1-4 weeks


+Leukotrieneantagonist, change nsAH

nsAH updosing (up to 4x)

+H2-Antihistamine, Ciclosporine A, Dapsone, anti-IgE

EAACI/GA 2LEN/EDF guideline: management of urticaria

Non sedating H 1-Antihistamine ( nsAH )


+







EAACI/GA2LEN/EDF guideline: management of urticaria

Step 1: Non sedating H1-Antihistamines (nsAH)

level of evidence: 1++

grade of recommendation: A

most pts. are treated this way

sounds good, but:

> 40% affecting partnership

> 50% impairment of sleep

> 50% influence on cognitive functioning/concentration

> 55% interferes with execution of daily work load

> 60% short tempered and bad mood

> 75% impairment of leisure time/activities

n = 362

Implications of urticaria

www.urtikaria.net

CU patients

healthy control

Staubach et al., Br J Dermatol 2006; 154: 294-8

0

20

40

60

SK

IND

EX

Sco

re

80

***

n = 196

Chronic urticaria = bad quality of life

Chronic urticaria = bad quality of life

Basra MK et al. Br J Dermatol. 2008 Nov;159(5):997-1035

DLQ

I

number of nights per week

Impairment of sleep

n = 321

0%

10%

20%

30%

0 <1 1 2 3 4 5 6 7

patie

nts

Maurer, Ortonne and Zuberbier. Br J Dermatol. 2008

0%

20%

40%

60%

80%

100%

prescrmed lotions

doc

OTC

bath ice

others

nothing

cover

Impatient patients: Wait and see is no option

patie

nts

n = 321 Maurer, Ortonne and Zuberbier. Br J Dermatol. 2008

0

20

40

60

80

100

very satisfied

satisfiedmodest

not satisfiedvery unsatisfied

Are you satisfied with the treatment?P

atie

nten

(%

)

total

n = 321

WHY?

Patients are not enthusiastic

16 of 37 CU studies report responder rates.

Only 42.5% (range: 4% to 68%) of patients show complete symptom control.

Complete symptom control

WHY?

What can be improved?

Patients are not enthusiastic

Daily vs As-Needed Desloratadine in Chronic Spontaneous Urticaria

• Randomized, double-blind, parallel-group study at 35 centers in France

• Patients initially received desloratadine 5 mg for 28 days

• Responders received 2-month therapy with either:– Desloratadine 5 mg continuous treatment, or– Desloratadine 5 mg as needed, i.e. when patients had wheals

• Assessments– Primary: Change in quality of life– Secondary: Change in pruritus symptoms and in overall condition

Grob et al., Allergy 2009

Improvement of Quality of Life


Improvement of Quality of Life

50

40

30

20

10

0

QoL

Impa

irmen

t

ContinuousPRN

P = 0.091

P = 0.007

P = 0.005

P = 0.044

P = NS

P = NS

P = 0.077

P = 0.016

Self-perception

Daily lifeactivities

Mood Social life Leisureactivities

Limitationdue to

treatment

Physicalpains

Global VQ-Dermato

index


VQ

-Der

mat

o D

imen

sion

Sco

re

Days with Moderate/Severe Pruritus

P=0.012

Day

s w

ith M

oder

ate

/ Sev

ere

Pru

ritus

Daily As needed

6.3 days

12.7 days

0

5

10

15

6.3 days

12.7 days


Complete Relief

P=0.097

Pat

ient

s w

ith C

ompl

ete

Rel

ief (

%)

Daily As needed

52.5%

30.8%

0

20

40

60

52.5%

30.8%


Conclusions

Continuous / daily use of antihistamineis superior to treatment as needed



+








Testing the effects of desloratadine updosing:

Aerius updosing in acquired cold urticaria

(AUDACU)

The AUDACU trial

Phase IV

RandomisedDouble-blind

Placebo controlledCrossover study5mg vs. 20mg Desloratadine

Acquired cold urticaria (ACU)n = 30

Acquired Cold Urticaria: Symptoms after cold shower

Parameters assessed

Wheal volume (Volumetry)

Hyperthermic skin area (Thermography)

Critical Temperature Threshold (TempTest 2.0)

The AUDACU trial

Study design

▼▼▼▼ ▼▼▼▼ ▼▼▼▼ ▼▼▼▼

▼▼▼▼ Cold provocation

ScreeningDay0

Visit 1Week 2

Visit 2Week 5

Visit 3Week 8

Treatment7 days

Washout14 days

+Treatment

7 days

Washout14 days

+Treatment

7 days

Cold provocation with TempTest 2.0 at 4°C for 5 minutes

The AUDACU trial

TempTest 2.1 TempTest 2.0

Volumetry

• 3D in vivo skin measurement

• readings of wheal volume, area, and height

Volumetry

Volumetry

Volumetry

Volumetry

Volumetry

Volumetry

Volumetry

Thermography

•Visualization of thermal energy (heat)at site of inflammation• Assessment of hyperthermic skin area after cold provocation

Thermography in a cold urticaria patient

Thermography in a healthy control person

Critical temperature thresholds (CTT) at baseline

Critical Temperature Threshold (CTT)

Num

ber

of P

atie

nts

12

10

8

6

4

2

028-31°°°°C23-27°°°°C18-22°°°°C13-17°°°°C4-7°°°°C 8-12°°°°C

28°C: Swimming in indoor pool

4°C: snowball fight, cold drink

20°C: Using normal toilet seat

16°C: Swimming in Atlantic Ocean, France

10°C: Preparing food, skiing

30

25

20

15

10

5

0

Critical Temperature Threshold (CTT)

Crit

ical

Tem

pera

ture

Thr

esho

ld (

°C)

******

***

20mg5mgPlaceboBaselineDesloratadine

Critical Stimulation Time Threshold (CSTT)

DL 20mgDL 5mgPlaceboBaseline

6

5

4

3

2

1

0

Crit

ical

Stim

ulat

ion

Tim

e T

hres

hold

(m

in)

**

***

***

AUDACU-Patient #24: Knut, S. 62y


Patient #24: Volumetric changes under treatment

Desloratadine 5mg

Desloratadine 20mg

0 min 5 min 10 min 20min

Placebo

Patient #24: Volumetric changes under treatment

Desloratadine 5mg

Desloratadine 20mg


Placebo

Updosing of Desloratadine Improves Urticaria Skin Symptoms


Whe

al v

olum

e (m

m³)

1200

1000

800

600

400

200

0

***

*** ***

Patient #18: Thermographic changes under treatment

Desloratadine 5mg

Desloratadine 20mg


Placebo


Hyp

erth

erm

ic s

kin

area

(m

m²)

4000

3000

2000

1000

0

Updosing of desloratadine improves urticaria skin symptoms

*

*

*


Whe

al v

olum

e (m

m³)

1200

1000

800

600

400

200

0

***

*** ***


No

of c

ompl

ete

resp

onde

rs


What about updosing of antihistamines in chronic spontaneous urticaria?

The AUD2OCU trial

Chronic spontaneous urticaria

RandomisedDouble-blind

Parallel group5mg vs. 20mg Desloratadinen = 29

week 1 week 2 week 3screening

V1 V2 V3

Group A

Group B

desloratadine 20 mg

desloratadine 5 mg

Planimetric Morphometry , Volumetric and Thermographic Assessment

no antihistamines

no antihistamines

*

***

Desloratadine

20 mg5 mg

*

Red

uctio

n of

whe

al n

umbe

rat

5 h

ours

(in

%)

*

***

Desloratadine

20 mg5 mg

*

Red

uctio

n of

whe

al n

umbe

rat

5 h

ours

(in

%)

p = 0.008

0 1 2 3 4 5h

5 mgDL

spontaneousresolution

20 mgDL

Time to significant reduction of number of wheals

5h0h

Nothing

5h0h

0h 5h

Nothing

5mg Desloratadine

5h0h

Nothing

5h0h

0h 5h

Nothing

20 mg Desloratadine

Standard dose of DL works in chronic spontaneous urticaria

and cold urticaria.

UPDOSING (using 4x the standard dose) results in even

better total symptom control .

UPDOSING is safe.

Updosing of antihistamines



+










+










+








Study Aim and Design

Is anti-IgE (Omalizumab) effective and safe in patients with moderate to severe chronic urticaria?

Study Aim and Design

Is anti-IgE (Omalizumab) effective and safe in patients with moderate to severe chronic urticaria?

27-week, randomized, double-blind, placebo-controll ed, multicenter parallel-group study

Prescreening-Visit

Placebo

Omalizumab

24 weeksTreatment

3 weeksScreening

w -3 w 0 w 24

• Moderate to severe chronic spontaneous urticaria• „Antihistamine-resistant“ (UAS7 ≥ 10)• 18-70 years

• ≥ 20 kg and ≤ 150 kg KG• Total-IgE ≥ 30 and ≤700 I.E./ml

• IgE-anti-TPO-level > 8 IU/mL

Study population

Outcome parameters

Disease activity (urticaria activity score, UAS7)

Symptom loadWhealsPruritusErythemasAngioedemasSystemic symptoms

Quality of lifeDLQISkindexCU-Q2oL

Rescue medication

Combined score:pruritus intensity and number of wheals

UAS per day is between 0 and 6 points

UAS (Urticaria Activity Score)

+

• UAS7 = UAS of 7 days

• UAS7: between 0 and 42 points

• Time of UAS7 determination:– baseline (Screening-Phase � day -14 to -1 before

randomization)– End of treatment (week 22 to 24 after randomization)

UAS7

Xolair Dosing

>20-25

>25-30

>30-40

>40-50

>50-60

>60-70

>70-80

>80-90

>90-125

>125-150

>=30–100 75 75 75 150 150 150 150 150 300 300

>100–200 150 150 150 300 300 300 300 300 450 600

>200–300 150 150 225 300 300 450 450 450 600 750

>300–400 225 225 300 450 450 450 600 600

>400–500 225 300 450 450 600 600 750 750

>500–600 300 300 450 600 600 750

>600–700 300 450 450 600 750

Body Weight (kg)

Dosage ≤ 300 mg will be administered every 4 weeks

Dosage >300 mg will be split in two doses and admin isterd every 2 weeks

Body Weight (kg) T

otal

IgE

(IU

/ml)

Demographic Data

Omalizumab (n=27)

Placebo (n=22)

Age (years) mean ± SD 39.1 ± 9.0 42.3 ± 15.0

Gender female n (%) 19 (70.4) 19 (86.4)

Race caucasian n (%) 27 (100) 22 (100)

Height (cm) mean ± SD 171.0 ± 7.2 164.1 ± 6.6

Weight (kg) mean ± SD 81.9 ± 20.2 71.2 ± 12.4

IgE-anti-TPO mean ± SD 7.3 ± 4.6 6.2 ± 3.7

Omalizumab Placebo

n (%) n (%)

Study completion treated 27 (100.0) 22 (100.0)

discontinued 2 (7.4) 5 (22.7)

completed 25 (92.6) 17 (77.3)

Reason for discontinuation

Adverse event(s) 0 (0.0) 1 (4.5)

Unsatisfactory therapeutic effect

1 (3.7) 4 (18.2)

Administrative problem 1 (3.7) 0 (0.0)

Drop outs

0

5

10

15

20

25

30

0 24 0 24

Change in disease activity

UA

S7

P=0.009

Week XolairPlacebo

Omalizumab Placebo

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Day0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190

UA

S p=0.0002

Change in disease activity

Responder analysis (UAS7)

Res

pond

er r

ates

(in

%)

100 % ≥ 90% ≥ 75%XolairPlacebo

48

56

71

0

10

20

30

40

50

60

70

80

90

Patients with Complete Disease Control (no more wheals …)

Pat

ient

s w

ithou

t whe

als

(in %

)

Xolair Placebo

70.4

4.5

0

10

20

30

40

50

60

70

80

XolairPlacebo

Quality of Life (QoL)

Impr

ovem

ent i

n Q

oL (

in %

)

CU-Q2oL DLQI SKINDEX

55

45

50

6

11

6

0

10

20

30

40

50

60

70

XolairPlacebo

Use of rescue medication

Lora

tadi

ne (

tabl

ets

/ wee

k)

WeekXolairPlacebo

2.9

0.3

3.53.3

0

1

2

3

4

5

0 24

Adverse Events

n % of patients n % of patients

Cardiovascular Disorder 0 0.0 1 4.5

Injection Site Irritation 0 0.0 1 4.5

Injection Site Pain 0 0.0 1 4.5

Anaphylactic Reaction 1 3.7 0 0.0

Nasopharyngitis 1 3.7 0 0.0

Vulvitis 1 3.7 0 0.0

Headache 2 7.4 2 9.1

Hypoaesthesia 0 0.0 1 4.5

Alopecia 0 0.0 1 4.5

Skin Burning Sensation 1 3.7 0 0.0

Haematoma 1 3.7 0 0.0

Omalizumab Placebo

First Results of the X-CUISITE Study

• Effective and safe in autoallergic CU patients

• High rate of “complete responders”

• Significant impact on QoL

• Fast onset of action

Pending Questions

• Efficacy in different types of urticaria?

• Mode of action?

• Dosing?

www.allergie-centrum-charite.de

b2

Diapositive 144

b2 bschinze; 13/02/2008

Woche 1

Randomisierung / Versand der

Prüfmedikation

Screening

DL 20mgGruppe A

Visit 1

DL 5mg

Visit 2

PlaceboWash out Wash out

Woche 2 Woche 5 Woche 8

DL 5mgGruppe B Placebo DL 20mgWash out Wash out

PlaceboGruppe C DL 20mg DL 5mgWash out Wash out

Visit 3

PlaceboGruppe D DL 5mg DL 20mgWash out Wash out

DL 20mgGruppe E Placebo DL 5mgWash out Wash out

DL 5mgGruppe F DL 20mg PlaceboWash out Wash out

Details of study design

week 1 week 2 week 5 week 8

Group B

Group C

Group D

Group E

Group F

Group A

Placebo daily + DL 5mg PRN (n=60)

DL 5mg daily + placebo PRN (n=46)

DL 5mg daily(N=126)

Month 1 2 3 4 5

DL 5 mg PRN (n=93)

Randomisation

V2 V3 V4 V5

TreatmentStart

Daily vs As-Needed Desloratadine in Chronic Spontaneous Urticaria


Documents

12 Markus Margel ; nouvelles strat gies anti H1allergo.lyon.inserm.fr/urticaire/12_Margel.pdf · nouvelles stratégies URTICAIRE CHRONIQUE – Actualités et controverses Lyon, jeudi