A Study to Evaluate the Safety and Efficacy of Bermekimab in Patients With Moderate to Severe Atopic Dermatitis

Study Overview
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Brief Summary
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A Study to Evaluate the Safety and Efficacy of Bermekimab in Patients With Moderate to Severe Atopic Dermatitis

Detailed Description
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This is a phase II, randomized, double-blind, placebo-controlled study of bermekimab in patients with moderate to severe atopic dermatitis. The primary objective of the study is to analyze the safety and efficacy of different dose regimens of bermekimab compared to placebo treatment in adult patients with moderate-to-severe AD. The study is multicenter and will consist of three groups: Treatment Arm 1: Bermekimab every week (qw) Treatment Arm 2: Bermekimab every other week (q2w) Arm 3 (Placebo): Placebo every week (qw)

Official Title
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A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Bermekimab in Patients With Moderate to Severe Atopic Dermatitis

Conditions
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Atopic Dermatitis, Eczema

Intervention / Treatment
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* Drug: Bermekimab Monoclonal Antibody
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, at least 18 years Willing and able to attend all clinic visits and comply with study-related procedures Participant can understand and complete study-related questionnaires Written informed consent provided by the participant Chronic atopic dermatitis present for at least 3 years Eczema Area and Severity Index Score (EASI) score greater than or equal to (>=) 16 at screening and baseline visits Investigators Global Assessment (IGA) >= 3 at screening and baseline visits Baseline pruritis numerical rating scale average score for maximum intensity of at least 3, based on the average of daily pruritis numerical rating scale scores for maximum itch intensity reported during the 7 days prior to randomization Has applied a stable dose of topical moisturizer twice daily for at least 7 consecutive days immediately prior to the baseline visit and is willing to continue this regimen on a daily basis for the duration of the study >= 10 percent (%) body surface area (BSA) of Atopic Dermatitis (AD) involvement at screening and baseline visits Documented recent history (within 6 months prior to screening) of inadequate response to treatment with topical medications, or participants for whom topical treatments are medically inadvisable (because of important side effects or safety risks): (a) Inadequate response is defined as failure to achieve and maintain remission or a low disease activity state (comparable to an IGA score of 0-2), despite treatment with a daily regimen of topical corticosteroids of medium to higher potency (with or without topical calcineurin inhibitors as appropriate), applied for at least 28 days or for the maximum duration recommended by the product prescribing information, whichever is shorter; (b) Participants with documented systemic treatment for atopic dermatitis in the preceding 6 months are also considered to be inadequate responders to topical treatments and are potentially eligible for treatment with MABp1, after appropriate washout; (c) Important side effects or risks are those that outweigh the potential treatment benefits, and include: intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and adverse systemic effects; and (d) Acceptable documentation includes contemporaneous chart notes that record topical medication prescription and treatment outcome, or investigator documentation based on communication with the participant's treating physician. Exclusion Criteria: Participants has been treated for AD with any investigational drug of chemical or biologic nature within a minimum of 30 days or 5 half-lives (whichever is longer) of the drug prior to baseline Treatment with bermekimab at any time in the past Treatment with immunosuppressive/immunomodulatory drugs or phototherapy for atopic dermatitis within 4 weeks of baseline, or any condition that, in the opinion of the investigator, is likely to require such treatment(s) during the first 4 weeks of study treatment Treatment with topical corticosteroids or topical calcineurin inhibitors for the treatment of AD within 14 days prior to baseline Treatment with biologics as follows: (a) Any cell-depleting agents including, but not limited to, rituximab, within 5 half-lives (if known) or 30 days prior to baseline visit, or until lymphocyte count returns to normal, whichever is longer; (b) Other biologics: within 5 half-lives (if known) or 30 days prior to baseline visit, whichever is longer Initiation of treatment of atopic dermatitis with prescription moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during the screening period (participants may continue to use stable doses of such moisturizers if initiated before the screening visit) Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the screening visit Planned or anticipated use of any prohibited medications and procedures during study treatment Treatment with a live (attenuated) vaccine within 30 days prior to the screening visit Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks prior to the baseline visit, or superficial skin infections within 1 week prior to the baseline visit Known or suspected history of immunosuppression, including history of invasive opportunistic infections (for example, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis) despite infection resolution; or unusually frequent, recurrent, or prolonged infections, per investigator judgment History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening Positive for hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody at the screening visit At baseline, presence of any conditions listed as criteria for study drug discontinuation Presence of skin comorbidities that may interfere with study assessments History of malignancy within 5 years before the screening visit, except completely treated in situ carcinoma of the cervix, and completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin diagnosed active endoparasitic infections; suspected or high risk of endoparasitic, unless clinical and (if necessary) laboratory assessments have ruled out active infection before randomization Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect the Participant's participation in the study. Examples include, but are not limited to, participants with short life expectancy, participants with uncontrolled diabetes (HbA1c >= 9%), participants with cardiovascular conditions (for example, stage III or IV cardiac failure according to the New York Heart Association classification), severe renal conditions (for example, participants on dialysis), hepato-biliary conditions (for example, Child-Pugh class B or C), neurological conditions (for example, demyelinating diseases), active major autoimmune diseases (for example, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinological, gastrointestinal, metabolic, pulmonary or lymphatic diseases. The specific justification for participants excluded under this criterion will be noted in study documents (chart notes, case report forms [CRFs], etc.) Planned or anticipated major surgical procedure during the participant's participation in this study Membership of the investigational team or his/her immediate family Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study Women unwilling to use adequate birth control, if of reproductive potential and sexually active. Adequate birth control is defined as consistent practice of an effective and accepted method of contraception throughout the duration of the study and for 120 days after the last dose of study drug. These methods include hormonal contraceptives, intrauterine device, double barrier contraception (that is, condom + diaphragm), or male partner with a documented vasectomy History of severe allergic or anaphylactic reactions to monoclonal antibodies Any other medical or psychological condition (including relevant laboratory abnormalities at screening) that, in the opinion the investigator, may suggest a new and/or insufficiently understood disease, may present an unreasonable risk to the study participant as a result of his/her participation in the study, may make participant's participation unreliable, or may interfere with study assessments. The specific justification for participant excluded under this criterion will be noted in study documents (chart notes, case report forms, etc.)

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm 1 (bermekimab every week)<br>Loading Dose: 400 mg subcutaneous (SC) injection of bermekimab and a SC injection of matching placebo at week 0 (Baseline). Treatment Dose: 400 mg subcutaneous injection of bermekimab administered weekly (qw) from week 1 through Week 31. | Drug: Bermekimab Monoclonal Antibody<br>* Bermekimab 400 mg or 800 mg will be administered subcutaneously.<br>Drug: Placebo<br>* Placebo will be administered subcutaneously.<br>|
| Experimental: Treatment Arm 2 (bermekimab every other week)<br>Loading Dose: 800 mg SC injection of bermekimab at week 0 (Baseline). Treatment Dose: 400 mg SC injection of bermekimab administered every other week (q2w) alternating with matching placebo q2w through Week 31. | Drug: Bermekimab Monoclonal Antibody<br>* Bermekimab 400 mg or 800 mg will be administered subcutaneously.<br>Drug: Placebo<br>* Placebo will be administered subcutaneously.<br>|
| Placebo Comparator: Placebo<br>Loading Dose: Placebo matching to bermekimab (4 milliliters [mL]) SC injection at Week 0, (Baseline). Treatment Dose: SC injection of matching placebo administered once weekly (qw) from week 1 to week 15 during placebo-controlled period. After completion of placebo-controlled period, participants will cross-over and receive bermekimab 400 mg SC injection qw at Week 16 through Week 31. | Drug: Placebo<br>* Placebo will be administered subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Eczema Area and Severity Index-75 (EASI-75) Response at Week 16 | Percentage of participants achieving EASI-75 at Week 16 were reported. EASI-75 response was defined as at least 75% improvement from baseline in EASI total score. The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, infiltration/papulation, excoriation and lichenification on 4 anatomic regions of the body: head/neck, trunk, upper and lower extremities. The severity of the clinical signs of AD for each of 4 body regions was scored on a 4-point scale: 0=absent, 1=mild, 2=moderate and 3=severe. The total EASI score is the sum of four body-region scores ranged from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. This outcome measure was planned to be analyzed for specified arms only. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving >=4 Point Improvement (Reduction From Baseline) in Weekly Average Peak (Worst) Daily Pruritus (Itch) Numeric Rating Scale (NRS) Score From Baseline at Week 4, 8, 12, 16 and 32 Among Participants With Baseline Score >=4 | Percentage of participants achieving greater than or equal to (>=4) point improvement (reduction from baseline) in weekly average peak (worst) daily pruritus NRS score from baseline at Weeks 4, 8, 12, 16 and 32 among participants with a baseline score >=4 were reported. The eczema skin pain and itch NRS is a 2-item patient-reported outcome that participants used to rate the severity of their eczema-related skin pain and eczema related itch daily. To rate the severity of eczema-related itch participants were asked the following question: please rate the severity of your eczema-related itch at its worst in the past 24 hours. The response was rated on a 0 to 10 NRS ranging from 0 none to 10 worst possible. Higher score indicated more severity. Seven daily average NRS scores are into a weekly score. | Weeks 4, 8, 12, 16 and 32 | 
| Percentage of Participants Achieving >= 4 Point Improvement (Reduction From Baseline) in Weekly Average of Average Daily Pruritis (Itch) NRS Score From Baseline at Weeks 4, 8, 12, 16 and 32 Among Participants With a Baseline Score >=4 | Percentage of participants achieving >= 4 improvement (reduction from baseline) in weekly average of average daily pruritis NRS score from baseline at Weeks 4, 8, 12, 16 and 32 among participants with a baseline score >=4 were reported. The eczema skin pain and itch NRS is a 2-item patient-reported outcome that participants used to rate the severity of their eczema-related skin pain and eczema related itch daily. To rate the severity of eczema-related itch participants were asked the following question: please rate the severity of your eczema-related average itch in the past 24 hours. The response was rated on a 0 to 10 NRS. Higher score indicated more severity. Seven daily averaged NRS scores were averaged into a weekly score. | Weeks 4, 8, 12, 16 and 32 | 
| Percentage of Participants Achieving >=4 Improvement (Reduction From Baseline) in Weekly Average Peak (Worst) Daily Skin Pain NRS Score From Baseline at Weeks 4, 8, 12, 16 and 32 Among Participants With a Baseline Score >=4 | Percentage of participants achieving >=4 improvement (reduction from baseline) in weekly average peak (worst) daily skin pain NRS score from baseline at Weeks 4, 8, 12, 16 and 32 among participants with a baseline score >=4 were reported. The eczema skin pain and Itch NRS is a 2-item patient-reported outcome that participants used to rate the severity of their eczema-related skin pain and eczema related itch daily. To rate the severity of eczema-related skin pain participants were asked the following question: Please rate the severity of your eczema-related skin pain at its worst in the past 24 hours. The response was rated on a 0 to 10 NRS ranging from 0 none to 10 worst possible. Seven daily NRS scores were averaged into a weekly score. Higher score indicated more severity. | Weeks 4, 8, 12, 16 and 32 | 
| Percentage of Participants Achieving >=4 Improvement (Reduction From Baseline) in Weekly Average of Average Daily Skin Pain NRS Score From Baseline at Weeks 4, 8, 12, 16 and 32 Among Participants With a Baseline Score >=4 | Percentage of participants achieving >=4 improvement (reduction from baseline) in weekly average of average daily skin pain NRS score from baseline to Weeks 4, 8, 12, 16 and 32 among participants with a baseline score >=4 were reported. The eczema skin pain and Itch NRS is a 2-item patient-reported outcome that participants used to rate the severity of their eczema-related skin pain and eczema related itch daily. To rate the severity of eczema-related skin pain participants were asked the following question: Please rate the severity of your eczema-related average skin pain in the past 24 hours; The response was rated on a 0 to 10 NRS. Higher score indicated more severity. Seven daily averaged NRS scores were averaged into a weekly score. | Weeks 4, 8, 12, 16 and 32 | 
| Percentage of Participants Achieving EASI-75 Response at Weeks 4, 8, 12, and 32 | Percentage of participants achieving EASI-75 response at Weeks 4, 8, 12, and 32 were reported. EASI-75 response was defined as at least 75% improvement from baseline in EASI total score. The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration/papulation, excoriation and lichenification on 4 anatomic regions of the body: head/neck, trunk, upper and lower extremities. The severity of the clinical signs of AD for each of 4 body regions was scored on a 4-point scale: 0=absent, 1=mild, 2=moderate and 3=severe. The total EASI score is the sum of four body-region scores ranged from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. | Weeks 4, 8, 12, and 32 | 
| Percentage of Participants With an Investigators Global Assessment (IGA) Score of 0 or 1 and a Reduction From Baseline of >=2 Points at Week 16 | Percentage of participants with both IGA score of 0 or 1 and a reduction from baseline of >=2 points was reported. IGA assesses AD severity and clinical response using a 5-point scale: 0 = clear, 1= almost clear, 2 = mild, 3 = moderate, 4 = severe. A higher score indicated more severity of AD. The score was determined by ranking the extent of erythema and population/infiltration. A clinical response to therapy was an IGA score of 0 (clear) or 1 (almost clear). This outcome measure was planned to be analyzed for specified arms only. | Week 16 | 
| Percentage of Participants Achieving EASI-90 Response at Weeks 12, 16, and 32 | Percentage of participants achieving EASI-90 response at Weeks 12, 16 and 32 were reported. EASI-90 response was defined as at least 90% improvement from baseline in EASI total score. The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, infiltration/papulation, excoriation and lichenification on 4 anatomic regions of the body: head/neck, trunk, upper and lower extremities. The severity of the clinical signs of AD for each of 4 body regions was scored on a 4-point scale: 0=absent, 1=mild, 2=moderate and 3=severe. The total EASI score is the sum of four body-region scores ranged from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. | Weeks 12, 16, and 32 | 
| Change From Baseline in Dermatology Life Quality Index (DLQI) at Weeks 8, 12, 16, and 32 | The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The format is a simple response (0 to 3 where 0 is not at all and 3 is very much) to 10 questions, which assess QOL over the past week, with an overall scoring system of 0 to 30. The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. A higher score indicates more severe disease and poor QoL. | Baseline, Weeks 8, 12, 16 and 32 | 
| Change From Baseline in Hospital Anxiety and Depression Scale (HADS) (Anxiety) Score at Weeks 8, 12, 16, and 32 | In this outcome measure, change from baseline in HADS-Anxiety score at weeks 8, 12, 16 and 32 were reported. The HADS is an instrument for screening anxiety and depression in non-psychiatric populations; repeated administration also provides information about changes to a participant's emotional state. The HADS is a 14-item self-administered questionnaire, 7 each for anxiety and depression symptoms. Each item is scored from 0-3, resulting in total anxiety score ranging from 0 (less severity of anxiety) to 21 (greater severity of anxiety). Higher score indicated more anxiety symptoms. The following cut-off scores are recommended: 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety. | Baseline, Weeks 8,12,16 and 32 | 
| Change From Baseline in HADS (Depression) Score at Weeks 8, 12, 16, and 32 | In this outcome measure, change from baseline in HADS-depression score at weeks 8, 12, 16 and 32 were reported. The HADS is an instrument for screening anxiety and depression in non-psychiatric populations; repeated administration also provides information about changes to a participant's emotional state. The HADS is a 14-item self-administered questionnaire, and consists of 7 items each for anxiety and depression symptoms. Each item is scored from 0-3, resulting in total depression score ranging from 0 (less severity of depression) to 21 (greater severity of depression). Higher score indicated more depression symptoms. The following cut-off scores are recommended: 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe depression. | Baseline, Weeks 8,12,16 and 32 | 
| Change From Baseline in Patient Oriented Eczema Measure (POEM) Scores at Weeks 8, 12, 16, and 32 | The POEM is a 7-item, validated questionnaire used to assess disease symptoms in both children and adults. Participants respond to 7 questions, including dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping, each scored on a 5-point scale based on frequency of occurrence during the previous week: 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days. Item scores are added to provide a total score ranging from 0 (clear) to 28 (very severe atopic eczema). Higher scores indicated more severe disease and poor quality of life. | Baseline, Weeks 8, 12, 16, and 32 | 
| Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Total Score at Weeks 8, 12, 16, and 32. | SCORAD is a validated scoring index for AD, which consists of 3 components that is A =extent or affected body surface area assessed as percentage of each defined body area and reported as the sum of all areas, with a maximum score of 100%. B=severity of 6 specific symptoms of AD (redness, swelling, oozing/crusting, excoriation, skin thickening/lichenification, dryness) assessed using the following scale: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points) and C=subjective symptoms scored by participants on visual analogue scale, where 0 is no itch (or no sleeplessness) and 10 is worst imaginable itch (or sleeplessness) with a maximum score of 20. SCORAD total score was calculated using these 3 aspects: extent (A: 0-100), severity (B: 0-18), and subjective symptoms (C: 0-20) using the formula: A/5 + 7*B/2+ C to give the SCORAD total score range of 0 to 103, where 0 = no disease to 103 = severe disease. Higher values of SCORAD represent worse outcome. | Baseline to Weeks 8, 12, 16 and 32 | 
| Change From Baseline in Global Individual Signs Score (GISS) at Weeks 8, 12, 16, and 32. | GISS assesses AD lesions for erythema, excoriations, lichenification and edema/papulation. Each component was rated on a global basis (over the entire body surface rather than region) using a 4-point scale (0=none, 1=mild, 2=moderate and 3=severe) according to the EASI grading severity. The cumulative score, which ranges from 0 to 12, is the sum of the four components. A higher score indicates more severe disease. | Baseline, Weeks 8,12,16 and 32 |