Clinical Development Programs

for Chronic Idiopathic Urticaria

Indication for H1-antihistamines

Badrul A. Chowdhury, MD, PhD

Medical Team Leader, Division of Pulmonary and
Allergy Drug Products, CDER, US FDA
 Outline

• General overview on urticaria and clinical

program for chronic idiopathic urticaria (CIU)
• CIU clinical programs
• Summary remarks

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 Types of Urticaria

• Acute Urticaria
– Lasts for less than 6 weeks
– Can occur with anaphylaxis
• Chronic urticaria
– Daily or almost daily urticaria for at least 6 weeks
– Very unusual to find a cause : CIU
• Intermittent urticaria
– Bouts of urticaria lasting days or weeks with intervals of days,
weeks, or months
• Urticaria of known cause
– Physical urticaria; delayed pressure urticaria; cold urticaria;
cholinergic urticaria
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 Clinical Features of CIU

• Repeated occurrence of short-lived cutaneous

wheals or hives
– Can occur anywhere on the skin
– Few mm to several cm in diameter
– Wheals are paler than the surrounding red skin
– Individual wheals lasts less than 24 hours
• Itching at and around the wheals
• Redness or erythema of the skin

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 Clinical Program for CIU Indication

• The FDA requires evidence of efficacy from at least

two clinical studies, including exploration of the
appropriate dose, and demonstration of safety of the
proposed dose
– Pivotal efficacy studies are randomized, multi-center, double-
blind, parallel group, placebo-controlled, and are often
active-controlled
– Safety of the proposed dose must be demonstrated
• Wheal-and-flare suppression studies are not
considered as substantial evidence of efficacy

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 Patients Enrolled in CIU Studies

• Males and females 12 or 18 years and older

and free of clinically significant diseases
• Clinical diagnosis of CIU
– Excluded: patients with physical urticaria; cholinergic
urticaria; urticaria due to known cause; urticaria associated
with underlying diseases; hereditary angioedema or C1
esterase deficiency
– Important differentials: urticarial vasculitis; erythema
multiforme; urticaria pigmentosa (cutaneous or systemic
mastocytosis); non-specific maculopapular exanthems;
cutaneous blistering disease, e.g., bullous pemphigoid,
dermatitis herpetiformis
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 Patients Enrolled in CIU Studies

• Active urticaria on study entry

– Symptomatic for 3 or 6 consecutive weeks with hives
present for 50% of the days or 2 days/week or 3 days/week
• Enriched patient population
– Some response to antihistamines in the past
– High baseline score, specifically for pruritus, e.g., at least 2
on a 0-3 scale
• Medication restriction
– Corticosteroids, antihistamines, NSAIDS, leukotriene
blockers, etc.

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 Primary Efficacy Variables

• Patient or physician scoring of symptoms,

once or twice daily, reflective over 12 hours
and instantaneous at the time of assessment
– Pruritus severity on a 0-3 scale
• 0=none; 1=mild, clearly present but minimal awareness;
2=moderate, definite awareness that is bothersome but
tolerable; 3=severe, hard to tolerate
– Number of hives on a 0-3 scale
• 0=none; 1=one to six; 2=seven to twelve; 3=more than twelve
– Size of largest hive on a 0-3 scale
• 0=none; 1=<1.5cm; 2=>1.5cm; 3=>2.5cm
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 Secondary Efficacy Variables

• Patient or physician (or jointly) scoring of

symptoms, recorded once or twice daily
– Erythema severity on a 0-3 scale
– Overall condition on a 0-3 scale
– Overall therapeutic response on a 0-5 scale
– Percentage of pruritus relief on a 0-3 scale
– Interference with sleep on a 0-3 scale
– Interference with daily activities on a 0-3 scale

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 Safety Assessment

• Safety of the antihistamine typically well

established in the allergic rhinitis studies
• In CIU studies safety assessment includes
– Spontaneous reporting of adverse events
– Physical examination, including vital signs, body
weight, etc.,
– Clinical laboratory tests
– Electrocardiogram

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 Outline

• General overview on urticaria and clinical

program for chronic idiopathic urticaria (CIU)
• CIU clinical programs
– Loratadine
– Desloratadine
– Cetirizine
– Fexofenadine
• Summary remarks

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 Loratadine Clinical Program

• Pivotal studies
– C88-067: multi-center (7 US, n=172), placebo and active
(hydroxyzine) controlled study
– C86-044: multi-center (7 US, n=153), placebo controlled study
• Supporting studies
– C87-056: single-center (n=37) pilot dose-ranging study
– I86-214: single-center (Spain, n=45), placebo and active
(terfenadine) controlled study
– I85-216/219: multi-center (Spain, France, n=172), placebo
and active (terfenadine) controlled study
– I85-310: multi-center (Canada, Australia, n=78), placebo and
active (terfenadine) controlled study
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 Loratadine Study C87-056

• Single center pilot dose-ranging study

• Subjects: 18-65 year old CIU patients
• Design: placebo and active controlled, with 1-day
baseline followed by 7-day double-blind treatment
• Baseline scores: pruritus 2.0-2.5, erythema 2.0-2.5,
number of hives 2.14-2.5, size of largest hive 1.8-2.5
(all on 0-3 scale)
• Treatment: loratadine 10mg, 20mg or 40mg QD,
hydroxyzine 25mg TID, and placebo
• Symptoms scored by investigators
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 Loratadine Study C87-056
Pruritus Score Number of Hives Score
% Change from Baseline

% Change from Baseline

80 70
70 60
60 50
50
40
40
30 30
20 20
10 10
0 0
Lor 10mg Lor 20mg Lor 40mg Hydr 25mg Placebo Lor 10mg Lor 20mg Lor 40mg Hydr 25mg Placebo
(n=6) (n=7) (n=6) (n=6) (n=6) (n=6) (n=7) (n=6) (n=6) (n=6)

Erythema Score Hive Size Score

% Change from Baseline

% Change from Baseline

70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
Lor 10mg Lor 20mg Lor 40mg Hydr 25mg Placebo Lor 10mg Lor 20mg Lor 40mg Hydr 25mg Placebo
(n=6) (n=7) (n=6) (n=6) (n=6) (n=6) (n=7) (n=6) (n=6) (n=6)

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 Loratadine Study C86-044

• Seven-center US study
• Subjects: 18-65 year old CIU patients
• Design: placebo controlled, with 1-day baseline
followed by 28-day double-blind treatment
• Baseline scores: pruritus 2.2; erythema 1.8-2.0,
number of hives 2.1, and size of largest hive 2.1-2.3
(all on 0-3 scale)
• Treatment: loratadine 10mg QD, placebo
• Symptoms scored by investigators
• Primary efficacy endpoint was not defined
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 Loratadine Study C86-044
Pruritus Score Number of Hives Score
% Change from Baseline

% Change from Baseline

100 80
*
* *
80 * *
60
60 *
Lor (n=77) Lor (n=77)
40
40 Pbo (n=76) Pbo (n=76)
20 20
*P<0.05 vs Pbo * P<0.05 vs Pbo
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Weeks Weeks

Erythema Score Hive Size Score

% Change from Baseline

% Change from Baseline

100 100
*
80 80 *
*
* *
60 Lor (n=77) 60 Lor (n=77)
40 Pbo (n=76) 40 Pbo (n=76)
20 20
* P<0.05 vs Pbo * P<0.05 vs Pbo
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Weeks Weeks

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 Loratadine Study C88-067
• Seven-center US study on Pruritis Score

18-65 year old CIU patients

% Change from Baseline

80
* *

• Baseline scores: pruritus 60 *

*
*

*
* Hydrox (n=56)
40 Lor (n=61)
2.3-2.4, number of hives 2.2 20
Pbo (n=55)

(0-3 scale) 0
* P<0.05 vs Pbo

• Design: 1-day baseline

0 1 2 3 4 5
Weeks

followed by 28-day double-

blind treatment with placebo, Change in Number of Hives Score
loratadine 10mg QD, and
60
hydroxyzine 25mg TID % Change from
50
Hydrox (n=56)
Baseline
40
• Primary efficacy endpoint: 30
20
Lor (n=61)
Pbo (n=55)
patient assessed pruritus 10
0
score at day 7 as change 0 1 2 3 4 5

from baseline Weeks

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 Desloratadine Clinical Program

• Pivotal studies
– P00220: multi-center (25 US and international, n=225),
placebo controlled 6-week study in CIU patients ages 12
years and older
– P00221: multi-center (27 US and international, n=189),
placebo controlled 6-week study in CIU patients ages 12
years and older
• Supporting study
– P01196: single-center (n=38) wheal-and-flare suppression
study in normal volunteers

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 Cetirizine Clinical Program

• Pivotal studies
– URT-1: multi-center (6 center, n=153) placebo controlled
fixed-dose dose-ranging 4-week study
– URT-2: multi-center (14 center, n=219) placebo and active
(hydroxyzine) controlled dose-titration 4-week study
• Supporting studies
– PRU-1: multi-center (6 center, n=129) placebo controlled, two
arms (cetirizine 10mg QD, placebo) 3-week study in patients
with idiopathic “dry skin” pruritus
– PRU-2: multi-center (6 center, n=142) placebo controlled,
three arm (cetirizine 10mg or 20mg QD, placebo) 2-week
study in patients with idiopathic “dry skin” pruritus
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 Fexofenadine Clinical Program

• Pivotal studies
– RJPR0039: multi-center (37 US and Canadian, n=439),
placebo controlled dose-ranging (fexofenadine 20mg, 60mg,
120mg, or 240mg, and placebo) 4-week study
– RJPR0067: multi-center (35 US and Canadian, n=418),
placebo controlled dose ranging (fexofenadine 20mg, 60mg,
120mg, or 240mg, and placebo) 4-week study
• Supporting study
– RJPR0019: multi-center (52 European, n=224), placebo
controlled dose-ranging study

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 Prescription Drugs Marketed in the
US for the Treatment of Urticaria
• Second or third generation H1-antihistamines
– cetirizine, desloratadine, fexofenadine, and loratadine are
approved for the treatment of CIU symptoms
• First generation H1-antihistamines
– a combination product containing chlorpheniramine plus
phenylephrine plus methscopolamine (Extendryl),
hydroxyzine, cyproheptadine, and promethazine are
approved for mild, uncomplicated allergic skin manifestations
of urticaria, or angioedema, or both

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 OTC Drugs for Urticaria

• No OTC drug products are approved in the

US for the treatment of CIU, urticaria of other
forms, or itching due to hives

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 Concluding Remarks

• Second or third generation H1-antihistamines

currently approved and available in the US
under prescription are safe and effective for
the treatment of CIU symptoms
– Of the various types of urticaria, CIU is amenable
to be studied in controlled clinical studies
– Demonstration of efficacy in CIU is possibly
reflective of efficacy in urticaria of other types
– If H1-antihistamines are marketed OTC, they are
likely to be used for all types of urticaria
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