A Study to Investigate the Use of Benralizumab in Patients With Bullous Pemphigoid.

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 patients symptomatic Bullous Pemphigoid (BP).

Detailed Description
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Bullous pemphigoid (BP) is a rare disease mainly affecting the elderly. BP is associated with significant morbidity and increased mortality secondary to increased risk of secondary infections, comorbid conditions, and serious side effects from high-dose steroids and immunosuppressants. The aim of this study is to investigate the use of benralizumab as a treatment for patients symptomatic with Bullous Pemphigoid (BP).

Official Title
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A Multinational, Randomized, Double-blind, Parallel-group, Placebo-controlled Study to Investigate the Use of Benralizumab as a Treatment Option for Patients With Bullous Pemphigoid (FJORD)

Conditions
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Bullous Pemphigoid

Intervention / Treatment
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* Biological: Benralizumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Informed Consent/Age Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Adult participants ≥ 18 years of age at the time of signing the ICF. Type of Participant and Disease Characteristics Participants must have clinical features of BP (eg, urticarial or eczematous or erythematous plaques, bullae, pruritus) at the screening visit and confirmed diagnosis with histology, direct immunofluorescence, and serology at randomization. Required for inclusion: Histology. Positive direct immunofluorescence (from skin biopsy) (IgG and/or C3 at the basement membrane zone). AND at least one of the following serologic assessments positive (all assessed from participant's blood sample): (i) indirect immunofluorescence (IgG on the roof of salt- split skin). (ii) positive serology on ELISA for BPAG1 (230-kd). (iii) positive serology on ELISA for BPAG2 (180-kd). BPDAI activity score ≥ 24 at the screening and randomization visits. Candidate for systemic corticosteroid therapy. Able to complete PRO assessments on a tablet and on a handheld device. Some participants may be exempted from completing home PROs on the handheld device upon agreement with the AstraZeneca physician (eg, if the patient has a medical condition such as BP lesions of the fingers/hand, a neurologic condition affecting fingers/hand, or severe visual impairment). Sex 7 Male or female. Reproduction 8 Female participants capable of having children must meet both of the following conditions ([a] and [b]): (a) Have a negative urine pregnancy test at screening and (b) Must agree to use a highly effective method of birth control (confirmed by the investigator) from randomization throughout the study duration and within 12 weeks after last dose of IP. Highly effective forms (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) of birth control include: (i) Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation - oral, intravaginal, or transdermal. (ii) Progestogen-only hormonal contraception associated with inhibition of ovulation - oral, injectable, or implantable. (iii) Intrauterine device. (iv) Intrauterine hormone-releasing system. (v) Bilateral tubal occlusion. (vi) 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). (vii) Vasectomized sexual partner provided that partner is the sole sexual partner of the female of childbearing potential (FOCBP) study participant and that the vasectomized partner has received medical assessment of the surgical success. (c) 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 amenorrhoeic for ≥ 12 months prior to the planned date of randomization without an alternative medical cause. The following age-specific requirements apply: (i) 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, treat the participant as a female of childbearing potential. (ii) Females ≥ 50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions Forms of BP other than classic, predominantly cutaneous BP: eg, mucous membrane BP, epidermolysis bullosa acquisita, Brunsting-Perry BP, p200 BP, p105 BP, BP with concomitant pemphigus vulgaris, and drug-induced BP. Comorbid disease that in the Investigator's judgement might interfere with the evaluation of the IP or safety of the participant. This includes any disorder that in the opinion of the Investigator is not stable (eg, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical impairment). Current or history of malignancy within 5 years before the screening visit with the following exceptions: Participants treated for in situ carcinoma of the cervix who have completed curative therapy and are in remission for at least 12 months prior to signing the informed consent and Participants with superficial basal cell or squamous skin cancer. 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. 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, electrocardiogram (ECG), hematology, or clinical chemistry during screening, 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. Current active liver disease. Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen 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. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 times the upper limit of normal, confirmed by repeated testing during screening 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. 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, within 4 weeks or 5 half-lives prior to the date informed consent is obtained, whichever is longer. Other Exclusions Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained. 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. Participants on stable therapy for at least 3 months before randomization who intend to stay on treatment throughout the study with marketed biologics that are not likely to interfere with the assessment of safety and/or efficacy of benralizumab (eg, for the treatment of osteoporosis, migraine, pain, diabetes, obesity, ocular, cardiovascular, or metabolic diseases) can participate in the study. Known history of allergy or reaction to any component of the IP formulation. Receipt of live attenuated vaccines 30 days prior to the date of randomization. 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 interventional (eg, investigational drug or device) clinical trial. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). For females only: Currently pregnant, breastfeeding, or lactating females. (a) A urine pregnancy test must be performed for FOCBP at Visit 1. A positive urine test result must be confirmed with a serum pregnancy test. If serum test is positive, the participant should be excluded. Participant is unable to complete PRO assessments because of cognitive function (eg, dementia).

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<br>Benralizumab subcutaneously (SC) loading dose followed by repeat dosing of SC benralizumab plus Oral Corticosteroids per SoC tapering. Open-Label (OLE): after completion of the double-blind treatment period, all participants will have the option of entering an OLE period, starting at week 36 benralizumab SC until study closure. | Biological: Benralizumab<br>* Benralizumab subcutaneously (SC) loading dose followed by repeat dosing of SC benralizumab plus Oral Corticosteroids per SoC tapering. Open-Label (OLE): after completion of the double-blind treatment period, all participants will have the option of entering an OLE period, starting at week 36 benralizumab SC until study closure.<br>* Other names: Benralizumab, Benra, Fasenra;|
| Experimental: Placebo<br>Placebo plus Oral Corticosteroids per SoC tapering. Open-Label (OLE): after completion of the double-blind treatment period, all participants will have the option of entering an OLE period, starting at week 36 benralizumab SC until study closure. | Biological: Placebo<br>* Placebo plus Oral Corticosteroids per SoC tapering. Open-Label (OLE): after completion of the double-blind treatment period, all participants will have the option of entering an OLE period, starting at week 36 benralizumab SC until study closure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who are in complete remission while off OCS for ≥ 2 months at Week 36 (FAS) | A binary response, whereby a responder is defined as a participant who is in complete remission while off OCS for ≥ 2 months at Week 36. Otherwise, a participant is a non-responder. | Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who remain relapse-free up to Week 36. | Relapse is defined as participants experiencing: 3 or more new lesions a per month (blisters, eczematous lesions, or urticarial plaques); or at least one large (> 10 cm diameter) eczematous lesion or urticarial plaques that do not heal within 1 week; or the extension of established lesions or daily pruritus in participants who have achieved disease control. | Week 36 | 
| Cumulative OCS exposure (mg/kg) from baseline to Week 36. | For each 4 weekly interval and for the sum of the 4-weekly intervals over the whole of the 36-week treatment period, and for the sum of the 4-weekly intervals over the initial 16-week treatment period, the model will be used to estimate the mean cumulative OCS exposure (mg/kg) for each treatment group and the difference versus placebo, with corresponding 95% confidence limits. | Week 36 | 
| Change from baseline in BPDAI activity score at Week 36. | Bullous Pemphigoid Disease Area Index is a clinician completed tool that is used for independent disease severity assessment to measure disease extent in BP. The BPDAI total activity and BPDAI damage give an indication of disease activity, with higher scores indicating greater disease activity or damage. | Week 36 | 
| Change from baseline in BPDAI-Pruritus score at Week 36. | The BPDAI-Pruritus is a separate component of the BPDAI that asks the participant to grade the severity of pruritus over the past 24 hours, the past week, and the past month. For each recall period, severity of pruritus is rated on an NRS ranging from 0 for no itch to 10 for maximal itching. The three scores are then summed for a total score ranging from 0 to 30. | Week 36 | 
| Proportion of participants in sustained complete/ partial remission on minimal OCS/ off OCS for at least 2 months at week 36 | Sustained complete remission on minimal steroid therapy/off steroid therapy. The absence of new or established lesions or pruritus while the participant is on minimal steroid therapy/ off steroid therapy for at least 2 months: Sustained partial remission: the presence of transient new lesions that heal within 1 week while the participant is on minimal steroid therapy or off steroid therapy for at least 2 months. | Week 36 | 
| Cumulative time (weeks) in complete remission off OCS from baseline to Week 36 | Complete remission off steroid therapy is defined as the absence of new or established lesions or pruritus while the participant is off steroid therapy for at least 2 months. | Week 36 | 
| Proportion of participants off OCS by Week 36. | The consolidation phase begins when disease control is achieved and continues until the time at which no new lesions or pruritic symptoms have developed for a minimum of 2 weeks and the majority of established lesions have healed (end of consolidation phase). At this point, participants will begin protocolled OCS tapering, with the aim to taper off OCS completely within 3 to 4 months (ie, 4 to 5 months from randomization). | Week 36 | 
| IGA Score at Week 36. | An IGA scale uses clinical characteristics to assess overall disease severity at any given time point. This scoring system allows clinicians to rate skin disease activity by general overall impressions. This IGA scale uses key signs of BP with ordinal levels of severity. The IGA is a 5-point categorical scale ranging from 0 (clear) to 4 (severe) with higher scores indicating greater disease activity or damage. The IGA uses clinical characteristics based on the number of lesions, blisters, erosions, erythema and number of anatomical locations. | Week 36 | 
| Change from baseline in IGA score at Week 36. | An IGA scale uses clinical characteristics to assess overall disease severity at any given time point. This scoring system allows clinicians to rate skin disease activity by general overall impressions. This IGA scale uses key signs of BP with ordinal levels of severity. The IGA is a 5-point categorical scale ranging from 0 (clear) to 4 (severe) with higher scores indicating greater disease activity or damage .The IGA uses clinical characteristics based on the number of lesions, blisters, erosions, erythema and number of anatomical locations | Week 36 | 
| Cumulative OCS exposure (mg/kg) from baseline to Week 16. | For each 4 weekly interval and for the sum of the 4-weekly intervals over the whole of the 36-week treatment period, and for the sum of the 4-weekly intervals over the initial 16-week treatment period, the model will be used to estimate the mean cumulative OCS exposure (mg/kg) for each treatment group and the difference versus placebo, with corresponding 95% confidence limits. | Week 16 | 
| Proportion of participants who remain relapse-free up to Week 16. | Relapse is defined as participants experiencing: 3 or more new lesions a per month (blisters, eczematous lesions, or urticarial plaques); or at least one large (> 10 cm diameter) eczematous lesion or urticarial plaques that do not heal within 1 week; or the extension of established lesions or daily pruritus in participants who have achieved disease control. | Week 16 | 
| Proportion of participants with any clinical benefit (eg, partial and complete remission during taper, with no steroid use, or with minimal steroid use [ie, < 0.1 mg/kg/day]) at Week 16. | To assess partial and complete remission during taper, with no steroid use, or with minimal steroid use at week 16) | Week 16 | 
| Time to disease control, OCS dose (mg/kg) at disease control and time to the end of the consolidation phase. | The time at which new lesions cease to form and established lesions begin to heal or pruritic symptoms start to abate. During the first 8 weeks of the study, participants will be assessed every 2 weeks for disease Control. When disease control is achieved, this marks the beginning of the consolidation phase. The end of the consolidation phase is the point that corticosteroid tapering will be initiated. | Week 16 | 
| Change from baseline in BPDAI activity score at Week 16. | The total BPDAI activity score (0 to 360) is the arithmetic sum of the 3 subcomponents - cutaneous blisters/ erosions, cutaneous urticarial/ erythema, and mucosal blisters/ erosions | Week 16 | 
| Change from baseline in BPDAI-Pruritus score at Week 16. | The BPDAI-Pruritus is a separate component of the BPDAI that asks the participant to grade the severity of pruritus is rated on an NRS ranging from 0 to no itch to 10 for maximal itching. | Week 16 | 
| Serum benralizumab concentration. | To estimate the PK of benralizumab in participants with BP. | Weeks 0,2,4,6,8,16,24,36, 60 and 12 weeks after last IP dose | 
| Determination of Anti-drug antibodies (ADA) in serum | Blood samples for determination of ADA in serum will be assayed to assess immunogenicity of benralizumab. | Weeks 0,4,6,8,16,24,36, 60 and 12 weeks after last IP dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bullous pemphigoid, rare disease, skin eruptions, itching autoimmune blistering disorder, eosinophilia, urticarial or eczematous or erythematous plaques, bullae, pruritus