Efficacy and Safety Study of the Use of Benralizumab for Patients With Moderate to Severe Atopic Dermatitis

A Phase 2 Multinational, Randomized, Double-blind, Parallel-group, 16-week Placebo-controlled Study With a 36-Week Extension to Investigate the Use of Benralizumab for Patients With Moderate to Severe Atopic Dermatitis Despite Treatment With Topical Medications (The HILLIER Study)

The purpose of the study is to compare the efficacy and safety of benralizumab versus placebo and to compare benralizumab dosing regimens during extension period.

Study Overview

• Status: Terminated
• Conditions: Atopic Dermatitis
• Intervention / Treatment: Biological: Benralizumab; Biological: Placebo / Benralizumab

Detailed Description

The aim of this study is to investigate the use of benralizumab as treatment for patients with moderate to severe atopic dermatitis (AD) who remain symptomatic despite treatment with topical medications. It is proposed that benralizumab will deplete eosinophils from affected skin, improve symptoms of AD, and improve AD-related quality of life. This Phase 2 study is designed to compare the efficacy of treatment with benralizumab versus placebo and compare benralizumab maintenance dosing regimens in the extension period.

• Study Type: Interventional
• Enrollment (Actual): 194
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Kogarah, Australia, 2217
    • Research Site
  • Parkville, Australia, 3050
    • Research Site
  • Sippy Downs, Australia, 4556
    • Research Site
  • Woolloongabba, Australia, 04102
    • Research Site
• Bulgaria
  • Haskovo, Bulgaria, 6300
    • Research Site
  • Pleven, Bulgaria, 5800
    • Research Site
  • Sofia, Bulgaria, 1000
    • Research Site
  • Sofia, Bulgaria, 1431
    • Research Site
• Czechia
  • Brno, Czechia, 602 00
    • Research Site
  • Ostrava, Czechia, 702 00
    • Research Site
  • Ostrava-Poruba, Czechia, 708 52
    • Research Site
  • Pardubice, Czechia, 530 02
    • Research Site
  • Praha, Czechia, 110 00
    • Research Site
  • Praha 10, Czechia, 100 00
    • Research Site
• France
  • Brest Cedex 2, France, 29609
    • Research Site
  • Lille Cedex, France, 59037
    • Research Site
• Korea, Republic of
  • Ansan-si, Korea, Republic of, 15355
    • Research Site
  • Daegu, Korea, Republic of, 41944
    • Research Site
  • Gwangju, Korea, Republic of, 61453
    • Research Site
  • Seongnam-si, Korea, Republic of, 13620
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 06591
    • Research Site
  • Seoul, Korea, Republic of, 04763
    • Research Site
  • Seoul, Korea, Republic of, 05278
    • Research Site
  • Seoul, Korea, Republic of, 06973
    • Research Site
  • Seoul, Korea, Republic of, 07441
    • Research Site
  • Seoul, Korea, Republic of, 5030
    • Research Site
  • Yangsan-si, Korea, Republic of, 50612
    • Research Site
• Poland
  • Krakow, Poland, 30-033
    • Research Site
  • Lodz, Poland, 90-302
    • Research Site
  • Osielsko, Poland, 86031
    • Research Site
  • Poznań, Poland, 60-214
    • Research Site
  • Warszawa, Poland, 01-262
    • Research Site
• Spain
  • Alicante, Spain, 03010
    • Research Site
  • Barcelona, Spain, 08041
    • Research Site
  • Cordoba, Spain, 14004
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Manises, Spain, 46940
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90025
      • Research Site
    • Newport Beach, California, United States, 92663
      • Research Site
  • Connecticut
    • Bridgeport, Connecticut, United States, 06606
      • Research Site
  • Florida
    • Fort Myers, Florida, United States, 33912
      • Research Site
    • Tampa, Florida, United States, 33606
      • Research Site
    • Tampa, Florida, United States, 33607
      • Research Site
  • Michigan
    • Ypsilanti, Michigan, United States, 48197
      • Research Site
  • New Hampshire
    • Portsmouth, New Hampshire, United States, 03801
      • Research Site
  • New York
    • New York, New York, United States, 10029
      • Research Site
    • Rochester, New York, United States, 14620
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Research Site
  • Oklahoma
    • Norman, Oklahoma, United States, 73071
      • Research Site
  • Pennsylvania
    • Sugarloaf, Pennsylvania, United States, 18249
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 130 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Physician-confirmed diagnosis of AD (according to American Academy of Dermatology Consensus Criteria) that is not adequately controlled with topical medications.
2. EASI score of ≥ 12 at screening and ≥ 16 at randomization.
3. IGA score of ≥ 3 (on a scale of 0 to 4, in which 3 is moderate and 4 is severe) at screening and at randomization.
4. Atopic dermatitis involvement of ≥ 8% body- surface area at screening and ≥ 10% body-surface area at randomization.
5. A pruritus numerical rating scale average score for maximum itch intensity of ≥ 4, based on the average of daily pruritus numerical rating scale scores for maximum itch intensity reported during the 7 days prior to randomization.
6. Documented recent history (within 6 months prior to screening) of inadequate response to treatment with topical medications, or patients for whom topical treatments are otherwise medically inadvisable (eg, because of important side effects or safety risks).
7. Participants that have applied a stable dose of topical emollient (moisturizer) twice daily for ≥ 7 consecutive days immediately before the randomization visit. (NOTE: See exclusion criterion 11 for limitations regarding emollients)

8. Participants must be willing and able to complete daily PRO assessments:

   • Complete at least 70% of daily PRO assessments between Visit 1 and Visit 2 and
   • Complete at least 5 of 7 daily PRO assessments in the 7 days prior to Visit 2.
9. Females of childbearing potential (FOCBP) must agree to use a highly effective method of birth control (confirmed by the Investigator) from randomization, throughout the study duration, and within 16 weeks after last dose of IP and have a negative serum pregnancy test result on Visit 1.

10. Females not of childbearing potential are defined as females who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Females will be considered postmenopausal if they have been amenorrheic for ≥ 12 months prior to the planned date of randomization without an alternative medical cause. The following age-specific requirements apply:

    1. Females < 50 years old will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and with 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:

1. Participants with active dermatological conditions (eg, psoriasis, seborrheic dermatitis, cutaneous lymphoma) other than atopic dermatitis that, in the investigator's opinion, may interfere with the study assessments
2. Known active allergic or irritant contact dermatitis that, in the investigator's opinion, may interfere with the study assessments

3. Current malignancy, or history of malignancy, with the exception of:

   1. Participants who have had basal cell carcinoma, localized 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.
   2. 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, hematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:

   1. Affect the safety of the participant throughout the study
   2. Influence the findings of the studies or their interpretations
   3. 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, hematology, 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 and C (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, hypoalbuminemia, esophageal 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 randomization is 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. Participants who have received treatment for AD with TCS, topical calcineurin inhibitors (TCI), or topical phosphodiesterase-4 (PDE4) inhibitors within the 7 days prior to the randomization visit
11. Initiation of treatment of AD with prescription moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during the screening period (patients may continue using stable doses of such moisturizers if initiated before the screening visit)
12. Regular use (2 visits per week) of a tanning booth/parlor or phototherapy for AD within 4 weeks prior to the randomization visit

13. Use of immunosuppressive medication including, but not limited to: methotrexate, cyclosporine, azathioprine, systemic corticosteroids within 4 weeks or 5 half-lives prior to the date informed consent is obtained, whichever is longer.

    Other

14. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained
15. Receipt of any marketed or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer
16. Receipt of live attenuated vaccines 30 days prior to first dose of IP
17. Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior to the date informed consent is obtained, whichever is longer
18. Previously received benralizumab (MEDI-563, FASENRA)
19. 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
20. Planned elective major surgical procedures during the conduct of the study
21. Previous randomization in the present study
22. Concurrent enrollment in another clinical trial
23. AstraZeneca staff involved in the planning and/or conduct of the study
24. For females only: Currently pregnant, breastfeeding, or lactating females A serum pregnancy test will be done for FOCBP at Visit 1 and a urine pregnancy test must be performed for FOCBP at each subsequent 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: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Benralizumab	Biological: Benralizumab; Benralizumab by subcutaneous injection until Week 16, and then benralizumab by subcutaneous injection during the extension period.; Other Names: Benralizumab, Benra, Fasenra
Experimental: Placebo / Benralizumab	Biological: Placebo / Benralizumab; Placebo by subcutaneous injection until Week 16, then benralizumab by subcutaneous injection until Week 52.; Other Names: Benralizumab, Benra, Fasenra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With an Investigator Global Assessment (IGA) 0/1 and a Decrease in IGA of ≥2 Points at Week 16 Relative to Baseline	The IGA is an instrument used in clinical studies to rate the severity of AD globally, based on a 5-point scale ranging from 0 = clear; 1 = almost clear; 2 = mild disease; 3 = moderate disease; 4 = severe disease. The IGA used clinical characteristics of erythema, infiltration, papulation, oozing, and crusting as guidelines for the overall severity assessment. A higher score indicated greater severity. A responder at Week 16 was defined as having IGA 0/1 and a decrease in IGA of ≥2 points at Week 16 relative to baseline. Participants who withdrew from the study/required rescue therapy after Day 28 were considered as non-responders from the time these events occurred. Baseline was defined as the last recorded value on or prior to the date of randomization.	Baseline (Week 0) and at Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experienced 75% Reduction From Baseline in Eczema Area and Severity Index (EASI-75) at Week 16	The EASI assessed the severity and extent of AD. Severity of 4 AD disease characteristics (erythema, induration/papulation, excoriation [scratching], lichenification) each were assessed on a scale of 0 (absent) to 3 (severe) in each of 4 body regions (head/neck, trunk, upper limbs, and lower limbs). Total body total score=sum of the region total scores; ranged from 0 to 72. Participants were classified as responders if they achieved at least 75% reduction from baseline in their EASI total score at Week 16. Participants who withdrew from study/required rescue therapy after Day 28 were non-responders from the time these events occurred. Higher scores indicated a more severe or more extensive condition. Baseline was defined as the last recorded value on or prior to the date of randomization.	Baseline (Week 0) and at Week 16
Percentage of Participants Who Experienced 90% Reduction From Baseline in Eczema Area and Severity Index (EASI-90) at Week 16	The EASI assessed the severity and extent of AD. Severity of 4 AD disease characteristics (erythema, induration/papulation, excoriation [scratching], lichenification) each were assessed on a scale of 0 (absent) to 3 (severe) in each of 4 body regions (head/neck, trunk, upper limbs, and lower limbs). Total body total score=sum of the region total scores; ranged from 0 to 72. Participants were classified as responders if they achieved at least 90% reduction from baseline in their EASI total score at Week 16. Participants who withdrew from study/required rescue therapy after Day 28 were non-responders from the time these events occurred. Higher scores indicated a more severe or more extensive condition. Baseline was defined as the last recorded value on or prior to the date of randomization.	Baseline (Week 0) and at Week 16
Percentage of Participants With an Improvement of ≥4 or More Points in Peak Pruritus Weekly Score	The peak pruritus numeric rating scale (NRS) was a 1-item daily assessment of the worst itch the participant experienced over the past 24 hours. The score ranged from 0 to 10, with 0 being "no itch" and 10 being "worst itch imaginable" and so a reduction in score was considered an improvement. A responder was defined as having an improvement of 4 or more points relative to baseline. Participants who withdrew from the study/required rescue therapy after Day 28 were considered as non-responders from the time these events occurred. The Week 16 weekly scores were defined as the average of the daily scores for the 7 days prior to the weekly score.	At Week 16

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: IQVIA Pty Ltd
• Investigators: Principal Investigator: Emma Guttman, MD, PhD, Mount Sinai Hospital

Publications and helpful links

Helpful Links

• HILLIER Brochure
• HILLIER Flyer
• HILLIER Patient Brochure
• HILLIER Patient Flyer
• CSR Synopsis
• Statistical Analysis Plan (SAP)
• Protocol

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2020
• Primary Completion (Actual): April 25, 2022
• Study Completion (Actual): September 13, 2022

Study Registration Dates

• First Submitted: September 1, 2020
• First Submitted That Met QC Criteria: October 21, 2020
• First Posted (Actual): October 27, 2020

Study Record Updates

• Last Update Posted (Actual): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: pruritus; skin lesion; Moderate to severe atopic dermatitis
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Genetic; Hypersensitivity; Skin Diseases, Eczematous; Dermatitis; Eczema; Dermatitis, Atopic; Anti-Asthmatic Agents; Respiratory System Agents; Benralizumab
• Other Study ID Numbers: D3256C00001

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.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• 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 deidentified 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