Efficacy of Levocetirizine Fourfold Dosage in Chronic Spontaneous Urticaria

Study Overview
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Brief Summary
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Chronic Spontaneous Urticaria (CSU), defined by the persistence of daily or almost daily urticaria over 6 weeks, affects 0.5% to 1% of the general population. In more than half of the cases, it lasts more than 2 years. It can dramatically alter the quality of life, in particular sleep, and generates numerous consultations and hospitalizations, with an average annual cost per patient close to 2000 euros in Europe. The treatment is based on the validated 2nd generation anti-H1 antihistamines dosage of one tablet per day whose effectiveness is satisfactory, however about half the time. In cases of severe CSU refractory to treatment with anti-H1 licensed dosage, few therapeutic alternatives exist, still off-label: the monketulast, an anti-leukotriene, ciclosporine or methotrexate, as immunosuppressants. Various studies have shown the important benefit of an expensive anti-IgE biological: the omaluzimab. Several open studies have also suggested superior efficacy and good tolerability of anti-H1 in higher dosage (double, triple or quadruple) including levocetirizine. The off-label use of these high dosages of anti-H1 is growing very rapidly in France, tending to replace the use of anti-H1 first generation or substitution to another 2nd generation anti-H1 recommended by the French Society of Dermatology. This study, under the aegis of the Urticaria Group of the French Society of Dermatology, intends to compare the efficacy of levocetirizine 4 tablets/day versus 1 tablet/day in the treatment of CSU resistant to anti-H1 licensed dosage.

Official Title
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Efficacy of Levocetirizine Fourfold Dosage in Chronic Spontaneous Urticaria Resistant to the Licensed Dosage

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Drug: Levocetirizine (as levocetirizine dihydrochloride), 5mg ( then 20 mg) per day . Oral administration.
* Drug: Levocetirizine, (as levocetirizine dihydrochloride) 20 mg ( then 5 mg) per day. Oral administration.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be ≥18 years of age at screening. Chronic spontaneous urticaria already treated with anti-H1 for at least two months without sufficient efficacy. Urticaria Activity Score (UAS7) >12 at the randomization visit (visit 2). For female : Of childbearing potential: female must use an acceptable method of contraception during the period of 1 month before the inclusion to 1 month after the last study visit; Of non-childbearing potential: e.g. postmenopausal (absence of menstrual bleeding for 1 years), or having had a hysterectomy or bilateral ovariectomy or tubal ligation. Patient agrees not to take other treatments than those provided in the study. Willingness and ability to comply with the protocol requirements. Written informed consent given prior to any study-related procedure. Subject affiliated to the National Social Security System. Exclusion Criteria: Pregnancy, breastfeeding or planned pregnancy during the study. Inducible urticaria (except immediate dermographism associated with CSU) Differential diagnosis of CSU (urticarial vasculitis). Known hypersensitivity to antihistamine. Known hypersensitivity to one of the product components, to hydroxyzine or to piperazine derivative. Sleepiness disorders or with Epworth sleepiness scale >15. Treatment with systemic corticosteroids within the month before the screening visit. Treatment with montelukast within the week before the screening visit. Treatment with H2-antihistamine within the week before the screening visit. Treatment with immunosuppressive drugs (e.g. methotrexate, cyclosporine, azathioprine, mycophenolate mofetil …) within the month before the screening visit. Known congenital galactosemia, glucose and galactose malabsorption, lactase deficiency, or lactose and fructose intolerance. Swallowing disorders. Liver dysfunction with transaminase greater than twice the normal value. Renal failure with creatinine clearance <50mL/min (calculated by MDRD formula). Regular or excessive alcohol consumption. Unstabilized chronic disease under treatment. Subject protected by the law (adult under guardianship, or hospitalized in a public or private institution for a reason other than the study, or incarcerated). Subject with any additional condition that, in the opinion of the investigator, may interfere with the study assessment or put the subject at risk. Linguistic or mentally incapacity to sign the consent form. Subject in an exclusion period from a previous study or who is participating in another clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group1 : Regulatory dosage<br>In a first time, every day, one tablet of 5 mg of levocetirizine is taken the morning and a second tablet of placebo is taken the evening, during 5 weeks (between visit 2 and 3). In a second time,and after primary endpoint assessment, every day, one tablet of 10 mg of levocetirizine is taken the morning and a second tablet of 10 mg of levocetirizine is taken the evening, during 5 weeks (between visit 3 and 4). | Drug: Levocetirizine (as levocetirizine dihydrochloride), 5mg ( then 20 mg) per day . Oral administration.<br>* Week 1 to week 5, every day : - the morning : 5 mg of levocetirizine (capsule) the evening : placebo capsule Week 6 to week 10, every day : - the morning : 10 mg of levocetirizine (capsule) the evening : 10 mg of levocetirizine (capsule))<br>|
| Experimental: Group 2 : fourfold dosage<br>In a first time, every day, one tablet of 10 mg of levocetirizine is taken the morning and a second tablet of 10 mg of levocetirizine is taken the evening, during 5 weeks (between visit 2 and 3). In a second time, every day, one tablet of 5 mg of levocetirizine is taken the morning and a second tablet of placebo is taken the evening, during 5 weeks (between visit 3 and 4). | Drug: Levocetirizine, (as levocetirizine dihydrochloride) 20 mg ( then 5 mg) per day. Oral administration.<br>* Week 1 to week 5, every day : - the morning : 10 mg of levocetirizine (tablet) the evening : 10 mg of levocetirizine(tablet) Week 6 to week 10, every day : - the morning : 5 mg of levocetirizine (tablet) the evening : placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| UAS7≤6 (Proportion of patients with a UAS7≤6). | The UAS7 (Urticaria activity score) is calculated as the sum of UAS over 1 week. | After 5 weeks of treatment (plus or minus 2 days; week 5- visit 3). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score of pruritus -> Assessment of the weekly score of pruritus |  | 5 weeks -> After 5 weeks of treatment (visit 3). | 
| Complete remission of urticaria at week 5 | Proportion of patients in complete remission of urticaria after 5 weeks of treatment (UAS7 = 0). | 5 weeks -> After 5 weeks of treatment (visit 3). | 
| Complete remission of urticaria | Proportion of patients in complete remission of urticaria after 10 weeks of treatment (UAS7 =0). | 10 weeks -> After 10 weeks of treatment (visit 4). | 
| Quality of life -> Evolution of the quality of life (between week 0, week 5 and week 10). | The quality of the life is evaluated by two questionnaires, the DLQI (DERMATOLOGY LIFE QUALITY INDEX) and the CU-Q2oL (Chronic Urticaria Quality of Life Questionnaire). The DLQI and CU-Q2oL scores are calculated by summing the score of each question. | week 0, week 5 and week 10 -> At the study beginning (week 0), at the week 5 of the study and finally at the end of the study (week 10). | 
| Tolerance of the treatment -> assessment of the tolerance of the H1-antihistamine in up 4 times conventional doses compared to the regulatory dosage of H1-antihistamine. | The tolerance is evaluated by one questionnaire, the Epworth sleepiness scale (ESS). The ESS is an effective instrument used to measure average daytime vigilance and sleepiness. It is calculated by summing the score of each question. | week 0, week 5 and week 10 -> At the study beginning (week 0), at the week 5 of the study and finally at the end of the study (week 10). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic spontaneous urticaria, Levocetirizine, H1-antihistamine, Fourfold dosage, Efficacy, Tolerance, UAS7 (Urticaria activity score), resistant