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

Study Overview

• Status: Terminated
• Conditions: Chronic Spontaneous Urticaria
• Intervention / Treatment: Biological: Benralizumab; Biological: Placebo and Benralizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Haskovo, Bulgaria, 6300
    • Research Site
  • Pleven, Bulgaria, 5800
    • Research Site
  • Ruse, Bulgaria, 7013
    • Research Site
  • Sofia, Bulgaria, 1000
    • Research Site
  • Sofia, Bulgaria, 1606
    • Research Site
  • Sofia, Bulgaria, 1463
    • Research Site
  • Sofia, Bulgaria, 1680
    • Research Site
• Germany
  • Berlin, Germany, 10117
    • Research Site
  • Dresden, Germany, 01307
    • Research Site
  • Leipzig, Germany, 04103
    • Research Site
• Japan
  • Hiroshima-shi, Japan, 734-8551
    • Research Site
  • Kamimashikigun,, Japan, 861-3106
    • Research Site
  • Kawasaki-shi, Japan, 211-0063
    • Research Site
  • Kobe-shi, Japan, 650-0017
    • Research Site
  • Sakai-shi, Japan, 593-8324
    • Research Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 6591
    • Research Site
  • Seoul, Korea, Republic of, 06973
    • Research Site
• Poland
  • Gdańsk, Poland, 80-546
    • Research Site
  • Krakow, Poland, 30-033
    • Research Site
  • Poznań, Poland, 60-214
    • Research Site
  • Warszawa, Poland, 02-507
    • Research Site
  • Wrocław, Poland, 50-449
    • Research Site
• Spain
  • Alicante, Spain, 03010
    • Research Site
  • Barcelona, Spain, 8003
    • Research Site
  • Cordoba, Spain, 14004
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Manises, Spain, 46940
    • Research Site
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85260
      • Research Site
  • California
    • Los Angeles, California, United States, 90025
      • Research Site
    • Mission Viejo, California, United States, 92691
      • Research Site
    • Newport Beach, California, United States, 92663
      • Research Site
  • Florida
    • Miami, Florida, United States, 33173
      • Research Site
    • Tampa, Florida, United States, 33606
      • Research Site
  • Georgia
    • Columbus, Georgia, United States, 31904
      • Research Site
  • Michigan
    • Ypsilanti, Michigan, United States, 48197
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Research Site
    • Cincinnati, Ohio, United States, 45236
      • Research Site
  • Oklahoma
    • Norman, Oklahoma, United States, 73071
      • Research Site
  • Texas
    • Austin, Texas, United States, 78745
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Benralizumab Arm 1; 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; 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.; Other Names: Benralizumab, Benra, Fasenra
Experimental: Benralizumab Arm 2; 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; 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.; Other Names: Benralizumab, Benra, Fasenra
Experimental: Benralizumab Arm 3; 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; 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.; Other Names: Benralizumab, Benra, Fasenra
Experimental: Benralizumab Arm 4; 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; 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.; Other Names: Benralizumab, Benra, Fasenra
Experimental: Placebo and Benralizumab; 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; 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.; Other Names: Benralizumab, Benra, Fasenra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Least Square (LS) Mean Change From Baseline in Itch Severity Score Over 7 Days (ISS7) at Week 12	The urticaria participant daily diary (UPDD) was completed twice daily (morning and evening) to capture key measures of urticaria disease activity including the itch severity score (ISS). The ISS represents severity on a scale ranging from 0 to 3 (where 0= none, 1= mild, 2= moderate and 3= severe). The ISS7 is the sum of ISS for the previous 7 days. The ISS7 represents itch severity on a scale ranging from 0 (minimum) to 21 (maximum). Higher scores indicate greater intensity of itch. Baseline was defined as the sum of the daily scores for the 7 days prior to the day of randomization.	Baseline (Day -1) and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LS Mean Change From Baseline in Urticaria Activity Score Over 7 Days (UAS7) at Weeks 12 and 24	The UPDD was completed twice daily (morning and evening) to capture key measures of urticaria disease activity including the UAS7. Participants were asked to document the number of hives they experienced on a scale ranging from 0 to 3 (where 0= none, 1= mild [1 - 6 hives/12 hour], 2= moderate [7 - 12 hives/12 hour] and 3= intense [(> 12 hives/12 hour]). The UAS7 is the sum of UAS for the previous 7 days, that is, the sum of ISS7 and HSS7. The UAS7 represents urticaria severity on a scale from 0 (minimum) to 42 (maximum). Higher scores indicate greater severity of urticaria symptoms. Baseline was defined as the sum of the daily scores for the 7 days prior to the day of randomization.	Baseline (Day -1) and Weeks 12 and 24
LS Mean Change From Baseline in ISS7 at Week 24	The UPDD was completed twice daily (morning and evening) to capture key measures of urticaria disease activity including the ISS. The ISS represents severity on a scale ranging from 0 to 3 (where 0= none, 1= mild, 2= moderate and 3= severe). The ISS7 is the sum of ISS for the previous 7 days. The ISS7 represents itch severity on a scale ranging from 0 (minimum) to 21 (maximum). Higher scores indicate greater intensity of itch. Baseline was defined as the sum of the daily scores for the 7 days prior to the day of randomization.	Baseline (Day -1) and Week 24
Percentage of Responders at Weeks 12 and 24	Responder was defined as a participant whose condition was considered clinically well controlled with UAS7 <=6 at specific time points. The UAS7 is the sum of UAS for the previous 7 days, that is, the sum of ISS7 and HSS7. The UAS7 represents urticaria severity on a scale from 0 (minimum) to 42 (maximum). Higher scores indicate greater severity of urticaria symptoms.	Weeks 12 and 24
LS Mean Change From Baseline in Hives Severity Score Over 7 Days (HSS7) at Weeks 12 and 24	The UPDD was completed twice daily (morning and evening) to capture key measures of urticaria disease activity including the HSS7. Participants were asked to document the number of hives they experienced on a scale ranging from 0 to 3 (where 0= none, 1= mild [1 - 6 hives/12 hour], 2= moderate [7 - 12 hives/12 hour] and 3= intense [(> 12 hives/12 hour]). The HSS7 is the sum of hives severity score for the previous 7 days. The HSS7 represents hives severity on a scale from 0 (minimum) to 21 (maximum). Higher scores indicate greater intensity of hives. Baseline was defined as the sum of the daily scores for the 7 days prior to the day of randomization.	Baseline (Day -1) and Weeks 12 and 24
Time to >=5-Point Decrease in ISS7	The time to >=5-point decrease (clinically relevant decrease) in ISS7 was reported. The ISS7 is the sum of ISS for the previous 7 days. The ISS7 represents itch severity on a scale ranging from 0 (minimum) to 21 (maximum). Higher scores indicate greater intensity of itch.	From Baseline (Day -1) up to Week 24
Percentage of Participants With Complete UAS7 Response at Weeks 12 and 24	Complete response was defined as participants with UAS7= 0 at specific time points. The UAS7 is the sum of UAS for the previous 7 days, that is, the sum of ISS7 and HSS7. The UAS7 represents urticaria severity on a scale from 0 (minimum) to 42 (maximum). Higher scores indicate greater severity of urticaria symptoms.	Weeks 12 and 24
Mean Percentage of Angioedema-Free Days Over the Past 7 Days at Weeks 12 and 24	The UPDD included a daily yes/no question asking whether the participant experienced angioedema during the past 24 hours. If yes, the participant was asked a follow-up question about how they treated the swelling. The percentage of angioedema-free days was calculated over the past 7 days by (number of angioedema-free days/number of non-missing responses) x 100.	Weeks 12 and 24
LS Mean Change From Baseline in Urticaria Control Test (UCT) at Weeks 12 and 24	Urticaria disease control was assessed by the UCT using the electronic participant-reported outcome device. The UCT has a retrospective approach using a recall period of 4 weeks and responses on 5-point Likert scales with score ranging from 0 to 4 for each question. Subsequently, the scores for all 4 questions were summed up. The UCT scale range from 0 (minimum) to 16 (maximum). Higher scores indicate better disease control.	Baseline (Day -1) and Weeks 12 and 24
LS Mean Change From Baseline in Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) at Weeks 12 and 24	The CU-Q2oL is a 23-item assessment of CSU-specific health-related quality of life. Participants were asked to rate their CSU symptoms and the impact of their symptoms over the last 2 weeks on several domains: pruritus, swelling, impact on life activities, sleep problems, limits, and looks. The questions were scored as 1= not at all, 2= a little, 3= moderately, 4= very much, 5= extremely. The scores were transformed into percentages of the maximum possible score. The CU-Q2oL scale range from 0 (minimum) to 100 (maximum). Higher scores indicate greater impact of urticaria on health-related quality of life.	Baseline (Day -1) and Weeks 12 and 24
LS Mean Change From Baseline in Dermatology Life Quality Index (DLQI) at Weeks 12 and 24	The DLQI is a 10-item assessment of dermatology-specific health-related quality of life. Participants were asked to rate their symptoms and the impact of their symptoms over the last week on several domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. The questions (except question 7) were scored on a 4-point Likert scale: 0= not at all, 1= a little, 2= a lot, 3= very much. Scoring question 7, the first part asked: 'Over the last week, has your skin prevented you from working or studying?' Scoring was for response of 0= not relevant and 3= yes. If response was 'no', a further question was asked: 'How much has your skin been a problem at work or studying', and scored as: 0= not at all, 1= a little, 2= a lot. The DLQI was calculated by summing the score of each question. The DLQI scale range from 0 (minimum) to 30 (maximum). Higher scores indicate greater impact on participant's life.	Baseline (Day -1) and Weeks 12 and 24
Serum Concentration of Benralizumab	Blood samples were collected to determine the serum concentration of benralizumab.	Pre-dose on Weeks 4, 12 and 24
Number of Participants With Anti-Drug Antibody (ADA) Response to Benralizumab	Blood samples were measured for the presence of ADAs for benralizumab using validated assays. The ADA incidence (treatment-emergent ADA positive) was defined as ADA negative at baseline and post-baseline ADA positive, or ADA positive at baseline and boosted the pre-existing titre by > 4-fold during the study period. Persistently positive was defined as ADA negative at baseline and positive at >= 2 post-baseline assessments (with >= 16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as ADA negative at baseline, having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. The median of maximum titres was calculated based on the maximum titre for each ADA positive participant within each treatment group (including both baseline and post-baseline measurements).	Pre-dose on Weeks 12 and 24

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Iqvia Pty Ltd
• Investigators: Principal Investigator: Sabine Altrichter, MD, Charite Universitaetsmedizin Berlin - Campus Charite Mitte

Publications and helpful links

Helpful Links

• ARROYO Patient Brochure
• ARROYO Patient Flyer
• Redacted CSR synopsis

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2020
• Primary Completion (Actual): October 13, 2022
• Study Completion (Actual): March 28, 2023

Study Registration Dates

• First Submitted: September 18, 2020
• First Submitted That Met QC Criteria: October 27, 2020
• First Posted (Actual): November 3, 2020

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: chronic spontaneous urticaria,; skin lesion,; pruritus and wheals
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Disease Attributes; Skin Diseases, Vascular; Hypersensitivity; Chronic Disease; Urticaria; Chronic Urticaria; Anti-Asthmatic Agents; Respiratory System Agents; Benralizumab
• Other Study ID Numbers: D3259C00001; 2020-000169-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No