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

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)

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.

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.

Inclusion Criteria:

Informed Consent/Age/Gender

1. Provision of the signed and dated written informed consent of the participant prior to any mandatory study-specific procedures, sampling, and analyses.

2. Adult participants≥18 years of age at the time of signing the Informed Consent Form (ICF).

   Type of Participants and Disease

3. Physician-confirmed diagnosis of CSU (also known as chronic idiopathic urticaria) for at least 6 months prior to screening (Visit 1).

4. 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.

5. Symptomatic during run-in, defined by the following:

   1. UAS7 total score of ≥ 16 with an ISS7 of ≥ 8, during the 7 days prior to randomisation (Visit 2)
   2. In-clinic UAS total score of ≥ 4 on at least one of the screening days.

6. 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.

7. Participants must complete daily PRO assessments and meet the following compliance criteria:

   1. Complete at least 80% of daily PRO assessments between Visit 1 and Visit 2 and
   2. Complete at least 6 of 7 daily PRO assessments in the 7 days prior to Visit 2.

8. Compliance with the locally-approved dose of antihistamine, maintained at randomisation.

   Reproduction

9. 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:

   1. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal.
   2. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable.
   3. Intrauterine device.
   4. Intrauterine hormone-releasing system.
   5. Bilateral tubal occlusion or ligation.
   6. 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).
   7. 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).

10. 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:

    1. 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.
    2. 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

1. 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]).

2. 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.).

3. 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.

4. 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.

5. History of anaphylaxis to any biologic therapy or vaccine.

6. 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.

7. 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.

8. Current active liver disease:

   1. 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.
   2. 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.

9. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test. Prior/concomitant Therapy

10. 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.

11. Known history of allergy or reaction to any component of the IP formulation Other

12. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained

13. 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.

14. Receipt of live attenuated vaccines 30 days prior to the date of randomisation

15. Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior to the date informed consent is obtained, whichever is longer

16. Previously received benralizumab (MEDI-563, FASENRA)

17. 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

18. Planned elective major surgical procedures during the conduct of the study

19. Previous randomization in the present study

20. Concurrent enrollment in another clinical trial

21. AstraZeneca staff involved in the planning and/or conduct of the study

22. 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.