1. Badrul A. Chowdhury, MD, PhD
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

2. Outline
General overview on urticaria and clinical program for chronic idiopathic urticaria (CIU)
CIU clinical programs
Summary remarks

3. Types of Urticaria Acute Urticaria Chronic 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

4. 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

5. 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

6. 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

7. 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.

8. 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

9. 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

10. 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

11. Outline
General overview on urticaria and clinical program for chronic idiopathic urticaria (CIU)
CIU clinical programs
Loratadine
Desloratadine
Cetirizine
Fexofenadine
Summary remarks

12. 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

13. Loratadine Study C87-056 Single center pilot dose-ranging study
Subjects: year old CIU patients
Design: placebo and active controlled, with 1-day baseline followed by 7-day double-blind treatment
Baseline scores: pruritus , erythema , number of hives , size of largest hive (all on 0-3 scale)
Treatment: loratadine 10mg, 20mg or 40mg QD, hydroxyzine 25mg TID, and placebo
Symptoms scored by investigators

14. Loratadine Study C87-056

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

16. Loratadine Study C86-044

17. Loratadine Study C88-067
Seven-center US study on year old CIU patients
Baseline scores: pruritus , number of hives 2.2 (0-3 scale)
Design: 1-day baseline followed by 28-day double-blind treatment with placebo, loratadine 10mg QD, and hydroxyzine 25mg TID
Primary efficacy endpoint: patient assessed pruritus score at day 7 as change from baseline

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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