A Phase III Study of Efficacy and Safety of Ligelizumab in the Treatment of CSU in Adolescents and Adults Inadequately Controlled With H1-antihistamines.

Study Overview
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Brief Summary
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The purpose of this study was to establish efficacy and safety of ligelizumab in adolescent and adult subjects with CSU who remained symptomatic despite standard of care treatment by demonstrating better efficacy over omalizumab and over placebo. The study population consisted of 1,079 male and female subjects aged ≥ 12 years who were diagnosed with CSU and who remained symptomatic despite the use of H1-antihistamines. This was a multi-center, randomized, double-blind, active- and placebo-controlled, parallel-group study. There was a screening period of up to 28 days, a 52 week double-blind treatment period, and a 12 week post-treatment follow-up period.

Official Title
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A Multi-center, Randomized, Double-blind, Active and Placebo-controlled Study to Investigate the Efficacy and Safety of Ligelizumab (QGE031) in the Treatment of Chronic Spontaneous Urticaria (CSU) in Adolescents and Adults Inadequately Controlled With H1-antihistamines

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Biological: Ligelizumab
* Biological: Omalizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. The subject's', parent'ssubject's, parent's or legal guardian's signed written informed consent and child's assent, if appropriate, must be obtained before any assessment is performed. Of note, if the subject reaches age of consent (age as per local law) during the study, they will also need to sign the corresponding study Informed Consent Form (ICF) at the next study visit. Male and female subjects ≥ 12 years of age at the time of screening. CSU diagnosis for ≥ 6 months. Diagnosis of CSU refractory to H1-AH at approved doses at the time of randomization, as defined by all of the following: The presence of itch and hives for ≥ 6 consecutive weeks at any time prior to Visit 1 (Day - 28 to Day -14) despite current use of non-sedating H1-AH UAS7 score (range 0-42) ≥ 16 and HSS7 (range 0-21) ≥ 8 during the 7 days prior to randomization (Visit 110, Day 1) Subjects must be on H1-AH at only approved doses for treatment of CSU starting at Visit 1 (Day -28 to Day -14) Willing and able to complete a daily symptom eDiary for the duration of the study and adhere to the study visit schedules. Key Exclusion Criteria: History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar chemical classes (i.e. to murine, chimeric or human antibodies). Subjects having a clearly defined cause of their chronic urticaria, other than CSU. This includes, but is not limited to, the following: symptomatic dermographism (urticaria factitia), cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, cholinergic- or contact-urticaria. Diseases, other than chronic urticaria, with urticarial or angioedema symptoms such as urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) and hereditary or acquired angioedema (eg, due to C1 inhibitor deficiency). Subjects with evidence of helminthic parasitic infection as evidenced by stools being positive for a pathogenic organism according to local guidelines. All subjects will be screened at Visit 1. If stool testing is positive for pathogenic organism, the subject will not be randomized and will not be allowed to rescreen. Any other skin disease associated with chronic itching that might influence in the investigators opinion the study evaluations and results (e.g. atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, etc.). Prior exposure to ligelizumab or omalizumab. Any H2 antihistamine, LTRA (montelukast or zafirlukast) or H1 antihistamines use at greater than approved doses after Visit 1.

Ages Eligible for Study
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Minimum Age: 12 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
Interventional Model Description: This is a Phase III multi-center, randomized, double-blind, active- and placebo-controlled, parallel-group study. There is a screening period of up to 28 days, a 52 week double-blind treatment period, and a 12 week post-treatment follow-up period.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ligelizumab Dose A<br>Ligelizumab Dose A q4w | Biological: Ligelizumab<br>* Liquid in vial<br>|
| Experimental: Ligelizumab Dose B<br>Ligelizumab Dose B q4w | Biological: Ligelizumab<br>* Liquid in vial<br>|
| Active Comparator: Omalizumab 300 mg<br>Omalizumab 300 mg q4w | Biological: Omalizumab<br>* Lyophilized powder for solution in vial<br>|
| Placebo Comparator: Placebo<br>Placebo q4w from randomization to week 20. Ligelizumab Dose B from week 24 to week 48. | Other: Placebo<br>* Liquid in vial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change from baseline in UAS7 at Week 12 | The Urticaria Activity Score (UAS) is the sum of the Hive Severity Score (HSS) and the Itch Severity Score (ISS). The HSS has a scale of 0 (none) to 3 (intense/severe). A weekly score (HSS7) is derived by adding up the average daily scores of the preceding 7 days. The ISS also has a scale of 0 (none) to 3 (severe/difficult to tolerate). A weekly score (ISS7) is derived by adding up the average daily scores of the preceding 7 days. The UAS7 is the sum of the HSS7 score and the ISS7 score, and has a possible range in score of 0-42. Complete hives response is defined as HSS7 (average daily HSS over the preceding 7 days) = 0. Complete itch response is defined as ISS7 (average daily ISS over the preceding 7 days) = 0. Complete UAS7 response is defined as UAS7=0. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete absence of hives and itch at Week 12 | Assessed as percentage of subjects achieving UAS7 = 0 | Week 12 | 
| Improvement of severity of itch | Assessed as absolute change from baseline in ISS7 score at Week 12 | Week 12 | 
| No impact on subject's quality of life at Week 12 | Assessed as percentage of subjects achieving DLQI = 0-1 | Week 12 | 
| Cumulative number of weeks that subjects achieve AAS7 = 0 responses between baseline and Week 12 | To assess the cumulative period of time that treated subjects are angioedema occurrence-free | Weekly to Week 12 | 
| Occurrence of treatment emergent adverse events and serious adverse events during the study | Treatment emergent adverse events and serious adverse events are those which occur at any time only after treatment has started | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-IgE, CSU (Chronic Spontaneous Urticaria), hives severity score, itch severity score, urticaria activity score