A Study to Investigate the Use of Benralizumab in Patients With Chronic Spontaneous Urticaria Who Are Symptomatic Despite the Use of Antihistamines (ARROYO)

Study Overview
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Brief Summary
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The purpose of this study is to investigate the use of benralizumab is effective in the treatment of chronic spontaneous urticaria (CSU) who are symptomatic despite the use of antihistamines.

Detailed Description
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The aim of this study is to investigate the use of benralizumab as treatment for patients with chronic spontaneous urticaria (CSU) who are symptomatic despite the use of antihistamines. It is proposed that benralizumab will deplete eosinophils and basophils from affected skin, improve symptoms of CSU, and improve CSU-related quality of life. This Phase 2b study is designed to evaluate induction and maintenance dosing regimens.

Official Title
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A Phase 2b Multinational, Randomised, Double-blind, Parallel- Group, 24-week Placebo-controlled Study With 28-week Extension to Investigate the Use of Benralizumab in Patients With Chronic Spontaneous Urticaria Who Are Symptomatic Despite the Use of Antihistamines (ARROYO)

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Biological: Benralizumab
* Biological: Placebo and Benralizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent/Age/Gender Provision of the signed and dated written informed consent of the participant prior to any mandatory study-specific procedures, sampling, and analyses. Adult participants≥18 years of age at the time of signing the Informed Consent Form (ICF). Type of Participants and Disease Physician-confirmed diagnosis of CSU (also known as chronic idiopathic urticaria) for at least 6 months prior to screening (Visit 1). Presence of pruritus and wheals for at least 6 consecutive weeks prior to screening (Visit 1), despite receiving standard of care, which may include second generation H1 antihistamines (at approved or up to 4-times approved doses) as monotherapy or in combination with LTRAs and/or H2 blockers. Symptomatic during run-in, defined by the following: UAS7 total score of ≥ 16 with an ISS7 of ≥ 8, during the 7 days prior to randomisation (Visit 2) In-clinic UAS total score of ≥ 4 on at least one of the screening days. Willing to use a second-generation H1 antihistamine at the approved dose and as monotherapy from the screening visit (Visit 1) until the end of the study. Participants must complete daily PRO assessments and meet the following compliance criteria: Complete at least 80% of daily PRO assessments between Visit 1 and Visit 2 and Complete at least 6 of 7 daily PRO assessments in the 7 days prior to Visit 2. Compliance with the locally-approved dose of antihistamine, maintained at randomisation. Reproduction Females of childbearing potential (FOCBP) must agree to use a highly effective method of birth control (confirmed by the Investigator) from randomisation, throughout the study duration, and within12 weeks after last dose of IP and have a negative serum pregnancy test result on Visit 1. Highly effective methods of birth control include: Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable. Intrauterine device. Intrauterine hormone-releasing system. Bilateral tubal occlusion or ligation. Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant). Vasectomised sexual partner (provided that partner is the sole sexual partner of the FOCBP study participant and that the vasectomised partner has received medical assessment of the surgical success). Females not of childbearing potential are defined as Females who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Females will be considered postmenopausal if they have been amenorrhoeic for≥12 months prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply: Females<50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone (FSH) levels in the postmenopausal range. Until FSH is documented to be within menopausal range, the participant should be treated as a FOCBP. Females≥50 years old will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment. Exclusion Criteria: Medical Conditions Participants with predominant inducible urticaria, ie, urticaria that is predominantly due to a clearly defined stimulus (eg, pressure [dermographism], delayed pressure, cold, heat, sunlight, vibration, water, physical exercise, or increased body temperature [cholinergic]). Participants with diseases, other than chronic urticaria, with urticaria or angioedema symptoms such as urticaria vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) and hereditary or acquired angioedema (eg, due to C1-inhibitor deficiency). Additionally, any other skin disease associated with chronic itching and/or skin lesions that, in the investigators opinion, might influence the study evaluations and results (eg, atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, etc.). Current malignancy, or history of malignancy, with the exception of: (a) Participants who have had basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided that the participant is in remission and curative therapy was completed at least 12 months prior to the date informed consent, was obtained. (b) Participants who have had other malignancies are eligible provided that the participant is in remission and curative therapy was completed at least 5 years prior to the date informed consent, was obtained. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could: (a) Affect the safety of the participant throughout the study (b) Influence the findings of the studies or their interpretations (c) Impede the participant's ability to complete the entire duration of study. History of anaphylaxis to any biologic therapy or vaccine. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with,or has failed to respond to standard of care therapy. Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening/run-in period which, in the opinion of the Investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete entire duration of the study. Current active liver disease: Chronic stable hepatitis B andC (including positive testing for hepatitis B surface antigen [HBsAg] or hepatitis C antibody), or other stable chronic liver disease are acceptable if participant otherwise meets eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level≥3 times the upper limit of normal (ULN), confirmed by repeated testing during the run-in period. Transient increase of AST/ALT level that resolves by the time of randomisationis acceptable if in the Investigator's opinion the participant does not have an active liver disease and meets other eligibility criteria. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test. Prior/concomitant Therapy Use of immunosuppressive medication, including, but not limited to: methotrexate, cyclosporine, azathioprine, topical and systemic corticosteroids within 4 weeks or 5 half-lives prior to the date informed consent is obtained, whichever is longer. Known history of allergy or reaction to any component of the IP formulation Other Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained Receipt of any marketed (eg, omalizumab) or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer. Receipt of live attenuated vaccines 30 days prior to the date of randomisation Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior to the date informed consent is obtained, whichever is longer Previously received benralizumab (MEDI-563, FASENRA) Change to allergen immunotherapy or new allergen immunotherapy within 30 days prior to the date of informed consent and anticipated changes in immunotherapy throughout the study Planned elective major surgical procedures during the conduct of the study Previous randomization in the present study Concurrent enrollment in another clinical trial AstraZeneca staff involved in the planning and/or conduct of the study For Females only: Currently pregnant, breastfeeding, or lactating Females (a) A serum pregnancy test will be done for FOCBP at Visit 1 and a urine pregnancy test must be performed for FOCBP at each treatment visit prior to IP administration. A positive urine test result must be confirmed with a serum pregnancy test. If serum test is positive, the participant should be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab Arm 1<br>Benralizumab Dose A regimen A until Week 12, Dose B regimen A until Week 24, and Dose B regimen B during the extension period until Week 52 (n=30) | Biological: Benralizumab<br>* 2 induction doses of benralizumab (dose A and B) compared to placebo, and a comparison of maintenance dosing regimens (B vs A) in the 28-week extension period.<br>* Other names: Benralizumab, Benra, Fasenra;|
| Experimental: Benralizumab Arm 2<br>Benralizumab Dose A regimen A until Week 12, Dose B regimen A until Week 24,and Dose B regimen A during the extension period until Week 52 (n=30) | Biological: Benralizumab<br>* 2 induction doses of benralizumab (dose A and B) compared to placebo, and a comparison of maintenance dosing regimens (B vs A) in the 28-week extension period.<br>* Other names: Benralizumab, Benra, Fasenra;|
| Experimental: Benralizumab Arm 3<br>Benralizumab Dose B regimen A until Week 12, Dose B regimen A until Week 24, and Dose B regimen B during the extension period until Week 52 (n=30) | Biological: Benralizumab<br>* 2 induction doses of benralizumab (dose A and B) compared to placebo, and a comparison of maintenance dosing regimens (B vs A) in the 28-week extension period.<br>* Other names: Benralizumab, Benra, Fasenra;|
| Experimental: Benralizumab Arm 4<br>Benralizumab Dose B regimen A until Week 12, Dose B regimen A until Week 24, and Dose B regimen A during the extension period until Week 52 (n=30) | Biological: Benralizumab<br>* 2 induction doses of benralizumab (dose A and B) compared to placebo, and a comparison of maintenance dosing regimens (B vs A) in the 28-week extension period.<br>* Other names: Benralizumab, Benra, Fasenra;|
| Experimental: Placebo and Benralizumab<br>Placebo regimen A until Week 24, benralizumab Dose B regiment A until Week 36, and Dose B regimen B until Week 52 (n=40). | Biological: Placebo and Benralizumab<br>* 2 induction doses of benralizumab (dose A and B) compared to placebo, and a comparison of maintenance dosing regimens (B vs A) in the 28-week extension period.<br>* Other names: Benralizumab, Benra, Fasenra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in weekly Itch Severity Score (ISS7) at Week 12 | Change from baseline in weekly Itch Severity Score (ISS7) at Week 12 between benralizumab and placebo. The minimum ISS7 is 0 and the maximum is 21, being 21 the most severe score. The baseline ISS7 will be the sum of the ISS during the 7 days prior to day of randomisation. The ISS7 at Week 12 will be the sum of the daily ISS during the previous 7 days. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Urticaria Activity Score (UAS7) at Week 12 |  | Week 12 for all patients | 
| Change from baseline in Urticaria Activity Score (UAS7) at Week 24 |  | Week 24 relative to baseline for all patients | 
| Proportion of responders Urticaria Activity Score (UAS7≤6) at Week 12 |  | Week 12 for all patients | 
| Change from baseline in weekly hives severity score (HSS7) at Week 12 | The minimum HSS7 is 0 and the maximum is 21. The baseline HSS7 will be the sum of the HSS during the 7 days prior to day of randomisation. The HSS7 at Week 12 will be the sum of the daily HSS during the previous 7 days. | Week 12 for all patients | 
| Time to ≥ 5 point decrease (clinically relevant decrease) in Itch Severity Score (ISS7) |  | Week 12 for all patients | 
| Proportion of participants with complete Urticaria Activity Score (UAS7) response (Urticaria Activity Score =0) at Week 12 |  | Week 12 for all patients | 
| Measures of angioedema activity at Week 12 in patients with angioedema at baseline | The Urticaria Patient Daily Diary includes a daily yes/no question asking whether the participant experienced angioedema during the past 24 hours. If yes, the participant is asked a follow-up question about how they treated the swelling: 0 = Did nothing = Took some prescription or non-prescription medication, = Called my doctor, nurse or nurse practitioner, = Went to see my doctor, nurse or nurse practitioner, = Went to the emergency room at the hospital, = Was hospitalized. The percentage of angioedema free days will be calculated over the past 7 days. | Week 12 for all patients | 
| Change from baseline in Urticaria Control Test (UCT) at Week 12 | The minimum and maximum UCT scores are 0 and 16, with 16 points indicating complete disease control. The UCT score will be calculated when all four questions are answered, otherwise the UCT will be missing. A UCT score of <12 shows poorly controlled urticaria, a UCT score of ≥12 presents well controlled urticaria. | Week 12 for all patients | 
| Change from baseline in Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) at Weeks 12 and 24 | The minimum possible score is defined as 0 and the maximum possible score is defined as 100. Higher scores indicate worse Quality of Life. | Week baseline, weeks 12 & 24 for all patients | 
| Change from baseline in Dermatology Life Quality Index (DLQI) at Weeks 12 and 24 | The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. | Week baseline, weeks 12 & 24 for all patients | 
| Serum benralizumab concentration and anti-drug antibodies (ADA). |  | Week 60 for all patients | 
| Change from baseline in weekly Itch Severity Score (ISS7) at Week 24 | Change from baseline in weekly Itch Severity Score (ISS7) at Week 24 between benralizumab and placebo. The minimum ISS7 is 0 and the maximum is 21, being 21 the most severe score. The baseline ISS7 will be the sum of the ISS during the 7 days prior to day of randomisation. The ISS7 at Week 24 will be the sum of the daily ISS during the previous 7 days. | Week 24 relative to baseline for all patients | 
| Proportion of responders (Urticaria Activity Score UAS7≤6) at Week 24 |  | Week 24 relative to baseline for all patients | 
| Change from baseline in weekly hives severity score (HSS7) at Week 24 | The minimum HSS7 is 0 and the maximum is 21. The baseline HSS7 will be the sum of the HSS during the 7 days prior to day of randomisation. The HSS7 at Week 24 will be the sum of the daily HSS during the previous 7 days. | Week 24 relative to baseline for all patients | 
| Proportion of participants with complete Urticaria Activity Score (UAS7) response (UAS7 =0) at Week 24 |  | Week 24 relative to baseline for all patients | 
| Measures of angioedema activity at Week 24 in patients with angioedema at baseline | The Urticaria Patient Daily Diary includes a daily yes/no question asking whether the participant experienced angioedema during the past 24 hours. If yes, the participant is asked a follow-up question about how they treated the swelling: 0 = Did nothing = Took some prescription or non-prescription medication, = Called my doctor, nurse or nurse practitioner, = Went to see my doctor, nurse or nurse practitioner, = Went to the emergency room at the hospital, = Was hospitalized. The percentage of angioedema free days will be calculated over the past 7 days. | Week 24 relative to baseline for all patients | 
| Change from baseline in Urticaria Control Test (UCT) at Week 24 | The minimum and maximum UCT scores are 0 and 16, with 16 points indicating complete disease control. The UCT score will be calculated when all four questions are answered, otherwise the UCT will be missing. A UCT score of <12 shows poorly controlled urticaria, a UCT score of ≥12 presents well controlled urticaria. | Week 24 relative to baseline for all patients | 
| Change from baseline in Itch Severity Score (ISS7) at Week 52 | Change from baseline in ISS7 at Week 52Itch Severity Score (ISS7) at Week 52 between benralizumab and placebo. The minimum ISS7 is 0 and the maximum is 21, being 21 the most severe score. The baseline ISS7 will be the sum of the ISS during the 7 days prior to day of randomisation. The ISS7 at Week 52 will be the sum of the daily ISS during the previous 7 days. | Week 52 relative to baseline for all patients | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic spontaneous urticaria,, skin lesion,, pruritus and wheals