# Presentation: 044081

## 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

## 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

## 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

## 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

## 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

## 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.

## 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

## 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

## 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

## Outline

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

## 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

## 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

## Loratadine Study C87-056

## 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

## Loratadine Study C86-044

## Loratadine Study C88-067

- Seven-center US study on 18-65 year old CIU patients
- Baseline scores: pruritus 2.3-2.4, 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

## 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

## 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

## 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

## 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

## 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

## 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