Bullous Pemphigoid
Conditions
Keywords
Bullous pemphigoid, rare disease, skin eruptions, itching autoimmune blistering disorder, eosinophilia, urticarial or eczematous or erythematous plaques, bullae, pruritus
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).
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).
Interventions
BIOLOGICALBenralizumab
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.
BIOLOGICALPlacebo
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.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Participants are eligible to be included in the study only if all of the following criteria apply: Informed Consent/Age 1. 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. 2. Adult participants ≥ 18 years of age at the time of signing the ICF. Type of Participant and Disease Characteristics 3. 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: 1. Histology. 2. Positive direct immunofluorescence (from skin biopsy) (IgG and/or C3 at the basement membrane zone). 3. 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). 4. BPDAI activity score ≥ 24 at the screening and randomization visits. 5. Candidate for systemic corticosteroid therapy. 6. 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 1. 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. 2. 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). 3. Current or history of malignancy within 5 years before the screening visit with the following exceptions: 1. 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 2. Participants with superficial basal cell or squamous skin cancer. 3. 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. History of anaphylaxis to any biologic therapy or vaccine. 5. 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. 6. 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. 7. Current active liver disease. 1. 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. 2. 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. 8. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test. Prior/Concomitant Therapy 9. 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 10. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained. 11. 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. 12. Known history of allergy or reaction to any component of the IP formulation. 13. Receipt of live attenuated vaccines 30 days prior to the date of randomization. 14. Previously received benralizumab (MEDI-563, FASENRA). 15. 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. 16. Planned elective major surgical procedures during the conduct of the study. 17. Previous randomization in the present study. 18. Concurrent enrollment in another interventional (eg, investigational drug or device) clinical trial. 19. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 20. 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. 21. Participant is unable to complete PRO assessments because of cognitive function (eg, dementia).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders at Week 36 | At Week 36 | A responder was defined as a participant who was in complete remission while off OCS for ≥2 months at Week 36. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Remained Relapse-Free up to Week 36 | Up to Week 36 | Relapse was defined as the appearance of 3 or more new lesions per month (blisters, eczematous lesions, or urticarial plaques); or at least 1 large (\>10 centimeter \[cm\] diameter) eczematous lesion or urticarial plaques that did not heal within 1 week; or the extension of established lesions or daily pruritus in participants who had achieved disease control. |
| Cumulative OCS Exposure From Baseline to Week 36 | Baseline (Day 1) and Week 36 | The cumulative OCS exposure was estimated as the sum over the relevant 4-week periods from the mixed-effect model for repeated measures (MMRM) model. Baseline was defined as the last recorded value on or prior to the date of randomization. Equivalents were prednisone equivalents (converted from mg). |
| Change From Baseline in Bullous Pemphigoid Disease Area Index (BPDAI) Activity Score at Week 36 | Baseline (Day 1) and Week 36 | BPDAI is a clinician completed tool that is used for independent disease severity assessment to measure disease extent in BP. The total BPDAI activity score is calculated as the arithmetic sum of the 3 subcomponents - cutaneous blisters/erosions, cutaneous urticaria/erythema, and mucosal blisters/erosions. The BPDAI total activity gives an indication of disease activity, with score range from 0 (no disease activity) to 360 (severe disease activity). Higher scores indicating greater disease activity. Baseline was defined as the last recorded value on or prior to the date of randomization. |
| Change From Baseline in BPDAI-Pruritus Score at Week 36 | Baseline (Day 1) and 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 a numeric rating scale (NRS) ranging from 0 for no itch to 10 for maximal itching. The BPDAI-Pruritus score was computed as the sum of 3 components ranging from 0 to 30. Higher scores indicated worse condition. Baseline was defined as the last recorded value on or prior to the date of randomization. |
| Cumulative OCS Exposure From Baseline to Week 16 | Baseline (Day 1) and Week 16 | The cumulative OCS exposure was estimated as the sum over the relevant 4-week periods from the MMRM model. Baseline was defined as the last recorded value on or prior to the date of randomization. Equivalents were prednisone equivalents (converted from mg). |
Countries
Australia, Bulgaria, China, France, Germany, Greece, Israel, Italy, Japan, Spain, United States
Participant flow
Recruitment details
This study was conducted in adult participants with symptomatic bullous pemphigoid (BP) at 32 sites in 11 countries. Study consisted of screening period, double-blind (DB) period in which 67 participants were randomized in 1:1 ratio to either receive benralizumab or placebo for 36 weeks followed by optional open-label extension (OLE) period (for participants who completed the DB period), in which all participants received benralizumab for at least 1 year.
Pre-assignment details
Study was terminated following a pre-planned futility analysis as efficacy results did not pass pre-defined futility hurdle. Prior to futility analysis,AstraZeneca created protocol#5 and Statistical analysis plan(SAP)#3. Updated protocol was never submitted to health authorities as study was terminating. Results align with protocol#5 and SAP#3.
Participants by arm
| Arm | Count |
|---|---|
| DB Period: Benralizumab Participants received benralizumab with an initial loading dose of 60 mg followed by a maintenance dose of 30 mg Q4W as a SC injection for 36 weeks. | 34 |
| DB Period: Placebo Participants received volume-matched placebo as a SC injection on the same dosing schedule as benralizumab Q4W for 36 weeks. | 33 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| DB Period (Up to 36 Weeks) | Adverse Event | 2 | 0 | 0 | 0 |
| DB Period (Up to 36 Weeks) | Death | 1 | 1 | 0 | 0 |
| DB Period (Up to 36 Weeks) | Other | 1 | 0 | 0 | 0 |
| DB Period (Up to 36 Weeks) | Physician Decision | 4 | 3 | 0 | 0 |
| DB Period (Up to 36 Weeks) | Study terminated by sponsor | 8 | 6 | 0 | 0 |
| DB Period (Up to 36 Weeks) | Withdrawal by Subject | 2 | 4 | 0 | 0 |
| OLE Period (Up to 1 Year) | Investigator decision | 0 | 0 | 2 | 1 |
| OLE Period (Up to 1 Year) | Other | 0 | 0 | 0 | 1 |
| OLE Period (Up to 1 Year) | Study terminated by sponsor | 0 | 0 | 14 | 15 |
| OLE Period (Up to 1 Year) | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | DB Period: Placebo | Total | DB Period: Benralizumab |
|---|---|---|---|
| Age, Continuous | 72.5 Years STANDARD_DEVIATION 11.4 | 70.2 Years STANDARD_DEVIATION 11.1 | 68.0 Years STANDARD_DEVIATION 10.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 66 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 27 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 20 Participants | 36 Participants | 16 Participants |
| Sex: Female, Male Female | 22 Participants | 42 Participants | 20 Participants |
| Sex: Female, Male Male | 11 Participants | 25 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 34 | 1 / 33 | 0 / 16 | 0 / 18 |
| other Total, other adverse events | 22 / 34 | 23 / 33 | 8 / 16 | 8 / 18 |
| serious Total, serious adverse events | 9 / 34 | 8 / 33 | 4 / 16 | 2 / 18 |
Outcome results
Primary
Percentage of Responders at Week 36
A responder was defined as a participant who was in complete remission while off OCS for ≥2 months at Week 36.
Time frame: At Week 36
Population: FAS included all randomized participants who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only participants who had the opportunity to reach Week 36 are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB Period: Benralizumab | Percentage of Responders at Week 36 | 11.1 Percentage of participants |
| DB Period: Placebo | Percentage of Responders at Week 36 | 5.26 Percentage of participants |
Comparison: Estimates were from a logistic regression model using the Firth adjustment (adj) that included treatment group, baseline disease severity (moderate, severe) and time of BP diagnosis (participants with newly diagnosed BP, participants with a previous diagnosis of BP who have relapsed) as categorical covariates.p-value: 0.50995% CI: [-10.9, 24.29]Logistic regression model with Firth adj
Secondary
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 a numeric rating scale (NRS) ranging from 0 for no itch to 10 for maximal itching. The BPDAI-Pruritus score was computed as the sum of 3 components ranging from 0 to 30. Higher scores indicated worse condition. Baseline was defined as the last recorded value on or prior to the date of randomization.
Time frame: Baseline (Day 1) and Week 36
Population: FAS included all randomized participants who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Benralizumab | Change From Baseline in BPDAI-Pruritus Score at Week 36 | -5.57 Score on a scale | Standard Deviation 7.23 |
| DB Period: Placebo | Change From Baseline in BPDAI-Pruritus Score at Week 36 | -16.58 Score on a scale | Standard Deviation 9.21 |
Secondary
Change From Baseline in Bullous Pemphigoid Disease Area Index (BPDAI) Activity Score at Week 36
BPDAI is a clinician completed tool that is used for independent disease severity assessment to measure disease extent in BP. The total BPDAI activity score is calculated as the arithmetic sum of the 3 subcomponents - cutaneous blisters/erosions, cutaneous urticaria/erythema, and mucosal blisters/erosions. The BPDAI total activity gives an indication of disease activity, with score range from 0 (no disease activity) to 360 (severe disease activity). Higher scores indicating greater disease activity. Baseline was defined as the last recorded value on or prior to the date of randomization.
Time frame: Baseline (Day 1) and Week 36
Population: FAS included all randomized participants who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Benralizumab | Change From Baseline in Bullous Pemphigoid Disease Area Index (BPDAI) Activity Score at Week 36 | -53.29 Score on a scale | Standard Deviation 46.33 |
| DB Period: Placebo | Change From Baseline in Bullous Pemphigoid Disease Area Index (BPDAI) Activity Score at Week 36 | -52.75 Score on a scale | Standard Deviation 17.36 |
Secondary
Cumulative OCS Exposure From Baseline to Week 16
The cumulative OCS exposure was estimated as the sum over the relevant 4-week periods from the MMRM model. Baseline was defined as the last recorded value on or prior to the date of randomization. Equivalents were prednisone equivalents (converted from mg).
Time frame: Baseline (Day 1) and Week 16
Population: FAS included all randomized participants who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only participants who had the opportunity to reach Week 16 are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Benralizumab | Cumulative OCS Exposure From Baseline to Week 16 | 46.90 mg/kg | Standard Deviation 27.19 |
| DB Period: Placebo | Cumulative OCS Exposure From Baseline to Week 16 | 42.15 mg/kg | Standard Deviation 33.33 |
Secondary
Cumulative OCS Exposure From Baseline to Week 36
The cumulative OCS exposure was estimated as the sum over the relevant 4-week periods from the mixed-effect model for repeated measures (MMRM) model. Baseline was defined as the last recorded value on or prior to the date of randomization. Equivalents were prednisone equivalents (converted from mg).
Time frame: Baseline (Day 1) and Week 36
Population: FAS included all randomized participants who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only participants who had the opportunity to reach Week 36 are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Benralizumab | Cumulative OCS Exposure From Baseline to Week 36 | 71.37 mg per kilogram (mg/kg) | Standard Deviation 63.19 |
| DB Period: Placebo | Cumulative OCS Exposure From Baseline to Week 36 | 62.71 mg per kilogram (mg/kg) | Standard Deviation 46.9 |
Secondary
Percentage of Participants Who Remained Relapse-Free up to Week 36
Relapse was defined as the appearance of 3 or more new lesions per month (blisters, eczematous lesions, or urticarial plaques); or at least 1 large (\>10 centimeter \[cm\] diameter) eczematous lesion or urticarial plaques that did not heal within 1 week; or the extension of established lesions or daily pruritus in participants who had achieved disease control.
Time frame: Up to Week 36
Population: FAS included all randomized participants who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only participants who had the opportunity to reach Week 36 are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB Period: Benralizumab | Percentage of Participants Who Remained Relapse-Free up to Week 36 | 23.78 Percentage of participants |
| DB Period: Placebo | Percentage of Participants Who Remained Relapse-Free up to Week 36 | 19.79 Percentage of participants |