FJORD: A Study to Investigate the Use of Benralizumab in Patients With Bullous Pemphigoid.
Study Details
Study Description
Brief Summary
The purpose of this study is to investigate the use of benralizumab is effective in the treatment of patients symptomatic Bullous Pemphigoid (BP).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Benralizumab 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
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.
Other Names:
|
| Experimental: Placebo 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
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.
|
Outcome Measures
Primary Outcome Measures
- Proportion of participants who are in complete remission while off OCS for ≥ 2 months at Week 36 (FAS) [Week 36]
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.
Secondary Outcome Measures
- Proportion of participants who remain relapse-free up to Week 36. [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.
- Cumulative OCS exposure (mg/kg) from baseline to Week 36. [Week 36]
The cumulative OCS exposure over the 36 weeks will be estimated as the sum over the relevant 4-week periods.
- Change from baseline in BPDAI activity score at Week 36. [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.
- Change from baseline in BPDAI-Pruritus score at Week 36. [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.
- Proportion of participants in sustained complete/ partial remission on minimal OCS/ off OCS for at least 2 months at week 36 [Week 36]
Sustained complete remission on minimal steroid a /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.
- Cumulative time (weeks) in complete remission off OCS from baseline to Week 36 [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.
- Proportion of participants off OCS by Week 36. [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).
- IGA Score at Week 36. [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.
- Change from baseline in IGA score at Week 36. [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 catgorical 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
- Cumulative OCS exposure (mg/kg) from baseline to Week 16. [Week 16]
The cumulative OCS exposure over the 16 weeks will be estimated as the sum over the relevant 4-week periods.
- Proportion of participants who remain relapse-free up to Week 16. [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.
- 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. [Week 16]
To assess partial and complete remission during taper, with no steroid use, or with minimal steroid use at week 16)
- Time to disease control, OCS dose (mg/kg) at disease control and time to the end of the consolidation phase. [Week 16]
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.
- Change from baseline in BPDAI activity score at Week 16. [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
- Change from baseline in BPDAI-Pruritus score at Week 16. [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.
- Serum benralizumab concentration. [Weeks 0,2,4,6,8,16,24,36, 60 and 12 weeks after last IP dose]
To estimate the PK of benralizumab in participants with BP.
- Determination of Anti-drug antibodies (ADA) in serum [Weeks 0,4,6,8,16,24,36, 60 and 12 weeks after last IP dose]
Blood samples for determination of ADA in serum will be assayed to assess immunogenicity of benralizumab.
Eligibility Criteria
Criteria
Inclusion Criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent/Age
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Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and protocol.
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Adult participants ≥ 18 years of age at the time of signing the ICF.
Type of Participant and Disease Characteristics
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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:
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Histology.
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Positive direct immunofluorescence (from skin biopsy) (IgG and/or C3 at the basement membrane zone).
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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).
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BPDAI activity score ≥ 24 at the screening and randomization visits.
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Candidate for systemic corticosteroid therapy.
Sex 6 Male or female.
Reproduction 7 Female participants capable of having children must meet both of the following conditions ([a] and [b]):
(a) Have a negative urine pregnancy test prior to administration of the IP 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 woman of childbearing potential study participant and that the vasectomized partner has received medical assessment of the surgical success.
(c) Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women 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) 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, treat the participant as a woman of childbearing potential.
(ii) Women ≥ 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
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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, drug-induced BP (eg, new onset or current exacerbation from angiotensin-converting enzyme inhibitors, penicillamine, furosemide, phenacetin, dipeptidyl peptidase-4 inhibitors or some immuno-Oncology therapies).
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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:
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Affect the safety of the participant throughout the study.
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Influence the findings of the studies or their interpretations.
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Prevent the participant's ability to complete the entire duration of study.
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Impact the participant's ability to complete the required PRO assessments.
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Current malignancy, or history of malignancy, except for:
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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, and assent when applicable was obtained.
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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, and assent when applicable, was obtained.
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History of anaphylaxis to any biologic therapy or vaccine.
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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.
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Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis 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, or the participant's ability to complete entire duration of the study.
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Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality obtained during the screening/run-in period, which in the opinion of the Investigator may put the participant at risk or interfere with study assessments.
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Current active liver disease.
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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.
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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.
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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, intramuscular (IM) long-acting depot corticosteroid, or any experimental anti-inflammatory therapy) within 3 months prior to the date informed consent is obtained.
Other Exclusions
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Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
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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.
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Known history of allergy or reaction to any component of the IP formulation.
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Receipt of live attenuated vaccines 30 days prior to the date of randomization.
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Previously received benralizumab (MEDI-563, FASENRA).
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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.
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Planned major surgical procedures during the conduct of the study.
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Previous randomization in the present study.
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Concurrent enrollment in another clinical trial.
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Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
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For women only: Currently pregnant, breastfeeding, or lactating women. (a) A urine pregnancy test must be performed for women of childbearing potential (WOCBP) at Visit 1 and 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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Phoenix | Arizona | United States | 85006 |
| 2 | Research Site | Scottsdale | Arizona | United States | 85260 |
| 3 | Research Site | San Diego | California | United States | 92103 |
| 4 | Research Site | Centennial | Colorado | United States | 80112 |
| 5 | Research Site | Margate | Florida | United States | 33063 |
| 6 | Research Site | Atlanta | Georgia | United States | 30322 |
| 7 | Research Site | Iowa City | Iowa | United States | 52242 |
| 8 | Research Site | Beverly | Massachusetts | United States | 01915 |
| 9 | Research Site | New York | New York | United States | 11415 |
| 10 | Research Site | Norfolk | Virginia | United States | 23502 |
| 11 | Research Site | Kogarah | Australia | 2217 | |
| 12 | Research Site | Parkville | Australia | 3050 | |
| 13 | Research Site | Westmead | Australia | 2145 | |
| 14 | Research Site | Woodville South | Australia | 5011 | |
| 15 | Research Site | Haskovo | Bulgaria | 6300 | |
| 16 | Research Site | Pleven | Bulgaria | 5800 | |
| 17 | Research Site | Sofia | Bulgaria | 1431 | |
| 18 | Research Site | Beijing | China | 100730 | |
| 19 | Research Site | Guangzhou | China | 510515 | |
| 20 | Research Site | Hohhot | China | 10050 | |
| 21 | Research Site | Nanjing | China | 210042 | |
| 22 | Research Site | Shanghai | China | 200025 | |
| 23 | Research Site | Shenyang | China | 110001 | |
| 24 | Research Site | Bobigny cedex | France | 93009 | |
| 25 | Research Site | Brest | France | 29609 | |
| 26 | Research Site | Clermont Ferrand | France | 63003 | |
| 27 | Research Site | Lille Cedex | France | 59037 | |
| 28 | Research Site | Limoges | France | 87042 | |
| 29 | Research Site | Marseille | France | 13008 | |
| 30 | Research Site | Nice | France | 06200 | |
| 31 | Research Site | ParisParis | France | 75006 | |
| 32 | Research Site | Poitiers | France | 86000 | |
| 33 | Research Site | Rouen Cedex | France | 76031 | |
| 34 | Research Site | Toulouse | France | 31059 | |
| 35 | Research Site | Bad Bentheim | Germany | 48455 | |
| 36 | Research Site | Bielefeld | Germany | 33647 | |
| 37 | Research Site | Dresden | Germany | 01307 | |
| 38 | Research Site | Frankfurt am Main | Germany | 60590 | |
| 39 | Research Site | Gera | Germany | 07548 | |
| 40 | Research Site | Leipzig | Germany | 04103 | |
| 41 | Research Site | Luebeck | Germany | 23538 | |
| 42 | Research Site | Athens | Greece | 12462 | |
| 43 | Research Site | Athens | Greece | 16121 | |
| 44 | Research Site | Thessaloniki | Greece | 54643 | |
| 45 | Research Site | Thessaloniki | Greece | 56249 | |
| 46 | Research Site | Ramat Gan | Israel | 5262000 | |
| 47 | Research Site | Tel-Aviv | Israel | 64239 | |
| 48 | Research Site | Bologna | Italy | 40138 | |
| 49 | Research Site | Catania | Italy | 95123 | |
| 50 | Research Site | Florence | Italy | 50121 | |
| 51 | Research Site | Rome | Italy | 168 | |
| 52 | Research Site | Iruma-Gun | Japan | 350-0495 | |
| 53 | Research Site | Kitakyusyu-shi | Japan | 806-8501 | |
| 54 | Research Site | Kobe-shi | Japan | 650-0017 | |
| 55 | Research Site | Kurume-shi | Japan | 830-0011 | |
| 56 | Research Site | Okayama | Japan | 700-8558 | |
| 57 | Research Site | Osaka-shi | Japan | 545-8586 | |
| 58 | Research Site | Ota-ku | Japan | 143-8541 | |
| 59 | Research Site | Sapporo-shi | Japan | 060-8648 | |
| 60 | Research Site | Shimotsuga-gun | Japan | 321-0293 | |
| 61 | Research Site | Shimotsuke-shi | Japan | 329-0498 | |
| 62 | Research Site | Urayasu-shi | Japan | 279-0021 | |
| 63 | Research Site | Alicante | Spain | 03010 | |
| 64 | Research Site | Barcelona | Spain | 08036 | |
| 65 | Research Site | Barcelona | Spain | 08041 | |
| 66 | Research Site | Barcelona | Spain | 08907 | |
| 67 | Research Site | Madrid | Spain | 28041 |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Principal Investigator: Janet A. Fairley, MD, University of Iowa
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- D325AC00002