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

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.

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

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  1. 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 • 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: 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

  14. Loratadine Study C87-056

  15. 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

  16. Loratadine Study C86-044

  17. 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

  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

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