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 Moderate to Severe Chronic Spontaneous Urticaria (ARROYO)

JRCT ID: jRCT2031200322

Registered date:25/01/2021

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Chronic Spontaneous Urticaria
• Date of first enrollment: 28/10/2020
• Target sample size: 16
• Countries of recruitment: Bulgaria,Japan,Germany,Japan,Poland,Japan,Spain,Japan,US,Japan,Korea,Japan
• Study type: Interventional

Intervention(s)

The study is designed to evaluate 2 induction doses of benralizumab (60 mg and 30 mg) compared to placebo, and a comparison of maintenance dosing regimens (Q8W versus Q4W) in the 28-week extension period.
Following the 10 days to 4-week run-in period, approximately 160 participants will be randomised at Visit 2 stratified by region, in a ratio of 3:3:3:3:4 (n=30:30:30:30:40), respectively, to one of the following 5 treatment sequences:
- Benralizumab 60 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg Q8W during the extension period until Week 52 (n = 30)
- Benralizumab 60 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg Q4W during the extension period until Week 52 (n = 30)
- Benralizumab 30 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg Q8W during the extension period until Week 52 (n = 30)
- Benralizumab 30 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg Q4W during the extension period until Week 52 (n = 30)
- Placebo Q4W until Week 24, benralizumab 30 mg Q4W until Week 36, and 30 mg Q8W until Week 52 (n = 40).

Outcome(s)

Primary Outcome

Change from baseline in weekly Itch Severity Score (ISS7) at Week 12 [ Time Frame: 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.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

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 participants18 years of age or more 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: a. UAS7 total score of 16 or more with an ISS7 of 8 or more, during the 7 days prior to randomisation (Visit 2) b. In-clinic UAS total score of 4 or more 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: a. Complete at least 80% of daily PRO assessments between Visit 1 and Visit 2 and b. 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. Women of childbearing potential (WOCBP) 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:
a. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal.
b. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable. c. Intrauterine device.
d. Intrauterine hormone-releasing system.
e. Bilateral tubal occlusion or ligation.
f. 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).
g. Vasectomised sexual partner (provided that partner is the sole sexual partner of the WOCBP study participant and that the vasectomised partner has received medical assessment of the surgical success).
10. Women not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months or more prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply:
a. Women<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 WOCBP. b. Women 50 years old or more will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment.

Exclude criteria

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: a. 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.
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 3 times or more 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. Doses administered daily or every other day for 5 or more consecutive days of systemic or topical corticosteroids, hydroxychloroquine, methotrexate, cyclosporine, cyclophosphamide, or (IV) immunoglobulin within 30 days before day -14.
11. Use of immunosuppressive medication (including but not limited to: methotrexate, troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, oral corticosteroid, or any experimental anti-inflammatory therapy) within 3 months prior to the date informed consent is obtained.Short-term treatmentsincluding systemicsteroids for CSU related angioedema may be an exceptionand cases should be discussed with sponsor/study physician.
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 major surgical procedures during the conduct of the study
19. Previous randomisationin 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 women only: Currently pregnant, breastfeeding, or lactating women (a) A serum pregnancy test will be done for WOCBP at Visit 1 and a urine pregnancy test must be performed for WOCBP 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.

Related Information

• Primary Sponsor: Yamaji Shigeyuki
• Secondary ID(s): NCT04612725