Clinical Development Programs for Chronic Idiopathic Urticaria Indication for H1-antihistamines

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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

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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
• 0none 1mild, clearly present but minimal
  awareness 2moderate, definite awareness that is
  bothersome but tolerable 3severe, hard to
  tolerate
• Number of hives on a 0-3 scale
• 0none 1one to six 2seven to twelve 3more
  than twelve
• Size of largest hive on a 0-3 scale
• 0none 1lt1.5cm 2gt1.5cm 3gt2.5cm

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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, n172), placebo and
  active (hydroxyzine) controlled study
• C86-044 multi-center (7 US, n153), placebo
  controlled study
• Supporting studies
• C87-056 single-center (n37) pilot dose-ranging
  study
• I86-214 single-center (Spain, n45), placebo and
  active (terfenadine) controlled study
• I85-216/219 multi-center (Spain, France, n172),
  placebo and active (terfenadine) controlled study
• I85-310 multi-center (Canada, Australia, n78),
  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
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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
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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

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Desloratadine Clinical Program

• Pivotal studies
• P00220 multi-center (25 US and international,
  n225), placebo controlled 6-week study in CIU
  patients ages 12 years and older
• P00221 multi-center (27 US and international,
  n189), placebo controlled 6-week study in CIU
  patients ages 12 years and older
• Supporting study
• P01196 single-center (n38) wheal-and-flare
  suppression study in normal volunteers

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Cetirizine Clinical Program

• Pivotal studies
• URT-1 multi-center (6 center, n153) placebo
  controlled fixed-dose dose-ranging 4-week study
• URT-2 multi-center (14 center, n219) placebo
  and active (hydroxyzine) controlled
  dose-titration 4-week study
• Supporting studies
• PRU-1 multi-center (6 center, n129) placebo
  controlled, two arms (cetirizine 10mg QD,
  placebo) 3-week study in patients with idiopathic
  dry skin pruritus
• PRU-2 multi-center (6 center, n142) 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,
  n439), placebo controlled dose-ranging
  (fexofenadine 20mg, 60mg, 120mg, or 240mg, and
  placebo) 4-week study
• RJPR0067 multi-center (35 US and Canadian,
  n418), placebo controlled dose ranging
  (fexofenadine 20mg, 60mg, 120mg, or 240mg, and
  placebo) 4-week study
• Supporting study
• RJPR0019 multi-center (52 European, n224),
  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