Efficacy, Safety, and Pharmacokinetic Profiles of REGN3500 Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis

Study Overview
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Brief Summary
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The primary objective of the study is to assess the efficacy of REGN3500 monotherapy in Atopic dermatitis (AD), as well as understand the dose-response relationship, compared with placebo treatment, in adult patients with moderate-to-severe AD. Secondary objectives are to: Assess the safety and tolerability of subcutaneous (SC) doses of REGN3500 monotherapy in adult patients with moderate-to-severe AD Assess the Pharmacokinetics (PK) of REGN3500 in adult patients with moderate-to-severe AD Assess the immunogenicity of REGN3500 in adult patients with moderate-to-severe AD

Official Title
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A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Ranging Study Investigating the Efficacy, Safety, and Pharmacokinetic Profiles of REGN3500 Administered to Adult Patients With Moderate-to- Severe Atopic Dermatitis

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: REGN3500
* Drug: REGN3500-Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Chronic AD, according to American Academy of Dermatology Consensus Criteria (Eichenfield, 2014), that has been present for at least 3 years before the screening visit Eczema Area and Severity Index (EASI) score ≥16 at the screening and baseline visits IGA score ≥3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at screening and baseline visits ≥10% Body surface area (BSA) of AD involvement at the screening and baseline visits Documented recent history (within 6 months before the screening visit) of inadequate response to topical AD medication(s) or for whom topical treatments are medically inadvisable Key Exclusion Criteria: Participation in a prior anti-Interleukin (IL)-33 medication clinical study Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the baseline visit Having used any of the following treatments within 4 weeks before the baseline visit 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: Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, cyclosporine, mycophenolate-mofetil, Interferon-gamma (IFN-γ), Janus kinase inhibitors, azathioprine, methotrexate, etc) Phototherapy for AD Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the baseline visit Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline visit Known or suspected history of immunosuppression History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening Positive with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (HCV Ab) at the screening visit Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study Note: Other protocol defined Inclusion/Exclusion Criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment 1<br> | Drug: REGN3500<br>* Administered subcutaneous (SC)<br>Drug: REGN3500-Matching Placebo<br>* Administered subcutaneous (SC)<br>|
| Experimental: Treatment 2<br> | Drug: REGN3500<br>* Administered subcutaneous (SC)<br>Drug: REGN3500-Matching Placebo<br>* Administered subcutaneous (SC)<br>|
| Experimental: Treatment 3<br> | Drug: REGN3500<br>* Administered subcutaneous (SC)<br>Drug: REGN3500-Matching Placebo<br>* Administered subcutaneous (SC)<br>|
| Experimental: Treatment 4<br> | Drug: REGN3500<br>* Administered subcutaneous (SC)<br>Drug: REGN3500-Matching Placebo<br>* Administered subcutaneous (SC)<br>|
| Experimental: Treatment 5<br>Matching placebo | Drug: REGN3500-Matching Placebo<br>* Administered subcutaneous (SC)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, induration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Percent change from baseline in EASI score at Week 16 was reported. Values after first rescue treatment were set to missing. | Week 16 | 
| Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score Based on All Observed Values Regardless of Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, induration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Percent change from baseline in EASI score at Week 16 based on all observed values regardless of rescue treatment was reported. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Eczema Area and Severity Index-50 (EASI-50) (Greater Than or Equal to [≥] 50 Percent [%] Improvement From Baseline) Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Percentage of participants who achieved EASI-50 (≥50% Improvement from baseline) at Week 16 were reported. Values after first rescue treatment were set to missing and participants with missing EASI score at Week 16 were counted as non-responders. | Week 16 | 
| Percentage of Participants Who Achieved Eczema Area and Severity Index-50 (EASI-50) (Greater Than or Equal to [≥] 50% Improvement From Baseline) Based on All Observed Values Regardless of Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Percentage of participants who achieved EASI-50 (≥50% Improvement from baseline) at Week 16 were based on all observed values regardless of rescue treatment were reported. | Week 16 | 
| Percentage of Participants Who Achieved Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Percentage of participants who achieved EASI-75 (≥75% Improvement from baseline) at Week 16 based on observed values set to missing after rescue treatment were reported. Values after first rescue treatment were set to missing and participants with missing EASI score at Week 16 were counted as non-responders. | Week 16 | 
| Percentage of Participants Who Achieved Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) Based on All Observed Values Regardless of Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Percentage of participants who achieved EASI-75 (≥75% Improvement from baseline) at Week 16 based on all observed values regardless of rescue treatment were reported. | Week 16 | 
| Percentage of Participants Who Achieved Eczema Area and Severity Index-90 (EASI-90) (≥90% Improvement From Baseline) Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Percentage of participants who achieved EASI-90 (≥90% Improvement from baseline) at Week 16 based on observed values set to missing after rescue treatment were reported. Values after first rescue treatment were set to missing and participants with missing EASI score at Week 16 were counted as non-responders. | Week 16 | 
| Percentage of Participants Who Achieved Eczema Area and Severity Index-90 (EASI-90) (≥90% Improvement From Baseline) Based on All Observed Values Regardless of Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Percentage of participants who achieved EASI-90 (≥90% Improvement from baseline) at Week 16 based on all observed values regardless of rescue treatment were reported. | Week 16 | 
| Absolute Change From Baseline in Eczema Area and Severity Index (EASI) Score Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, induration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Absolute change from baseline in EASI score at Week 16 based on observed values set to missing after rescue treatment was reported. | Week 16 | 
| Absolute Change From Baseline in Eczema Area and Severity Index (EASI) Score Based on All Observed Values Regardless of Rescue Treatment at Week 16 | The EASI score was used to measure the severity and extent of AD and measures erythema, induration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Absolute change from baseline in EASI score at Week 16 based on all observed values regardless of rescue treatment was reported. | Week 16 | 
| Percentage of Participants With Both Investigator Global Assessment (IGA) Score 0 or 1 (on 0 to 5 IGA Scale) and a Reduction From Baseline of ≥2 Points Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5 point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear). Participants with both IGA score of 0 or 1 and a reduction from baseline of ≥2 points at Week 16 based on observed values set to missing after rescue treatment were reported. Values after first rescue treatment were set to missing and participants with missing IGA score at Week 16 were counted as non-responders. | Week 16 | 
| Percentage of Participants With Both IGA Score 0 or 1 (on the 0 to 5 IGA Scale) and a Reduction From Baseline of ≥2 Points Based on All Observed Values Regardless of Rescue Treatment at Week 16 | IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5 point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear). Participants with both IGA score of 0 or 1 and a reduction from baseline of ≥2 points at Week 16 based on all observed values regardless of rescue treatment were reported. | Week 16 | 
| Absolute Change From Baseline in Weekly Average of Daily Peak Pruritus Numerical Rating Scale (NRS) Score Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | Pruritus NRS was an assessment tool used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, using an electronic questionnaire (e-diary). Participants were asked the following question: how would you rate your itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Absolute change from baseline in weekly average of daily Peak Pruritus NRS score at Week 16 based on observed values set to missing after rescue treatment was reported. | Week 16 | 
| Absolute Change From Baseline in Weekly Average of Daily Peak Pruritus NRS Score Based on All Observed Values Regardless of Rescue Treatment at Week 16 | Pruritus NRS was an assessment tool used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, using an electronic questionnaire (e-diary). Participants were asked the following question: how would you rate your itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Absolute Change From Baseline in Weekly Average of Daily Peak Pruritus NRS Score Based on All Observed Values Regardless of Rescue Treatment at Week 16 | Week 16 | 
| Percent Change From Baseline in Weekly Average of Daily Peak Pruritus NRS Score Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | Pruritus NRS was an assessment tool used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, using an electronic questionnaire (e-diary). Participants were asked the following question: how would you rate your itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Percent change from baseline in weekly average of daily peak pruritus NRS score at Week 16 based on observed values set to missing after rescue treatment was reported. Values after first rescue treatment were set to missing and participants with missing NRS score at Week 16 were counted as non-responders. | Week 16 | 
| Percent Change From Baseline in Weekly Average of Daily Peak Pruritus NRS Score Based on All Observed Values Regardless of Rescue Treatment at Week 16 | Pruritus NRS was an assessment tool used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, using an electronic questionnaire (e-diary). Participants were asked the following question: how would you rate your itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Percent change from baseline in weekly average of daily peak pruritus NRS score at Week 16 based on all observed values regardless of rescue treatment was reported. | Week 16 | 
| Percentage of Participants With Improvement (Reduction From Baseline) in Weekly Average of Peak Daily Pruritus NRS Score ≥4 Based on Observed Values Set to Missing After Rescue Treatment at Week 16 | Pruritus NRS was an assessment tool used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, using an electronic questionnaire (e-diary). Participants were asked the following question: how would you rate your itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Percentage of participants with improvement of weekly average of daily peak pruritus NRS score ≥4 from baseline to Week 16 based on observed values set to missing after rescue treatment were reported. Values after first rescue treatment were set to missing and participants with missing NRS score at Week 16 were counted as non-responders. | Week 16 | 
| Percentage of Participants With Improvement (Reduction From Baseline) in Weekly Average of Daily Peak Pruritus NRS Score ≥4 Based on All Observed Values Regardless of Rescue Treatment at Week 16 | Pruritus NRS was an assessment tool used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, using an electronic questionnaire (e-diary). Participants were asked the following question: how would you rate your itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Percentage of participants with improvement of weekly average of daily peak pruritus NRS score ≥4 from baseline to Week 16 based on all observed values regardless of rescue treatment were reported. | Week 16 | 
| Time to Onset of Effect on Pruritus (≥4-point Reduction of Weekly Average of Daily Peak Pruritus NRS From Baseline) | Peak Pruritus NRS is an assessment tool used by participants to report intensity of pruritus (itch) during a 24-hour recall period. Participants were asked the following question: For maximum itch intensity: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable,' how would you rate your itch at the worst moment during the previous 24 hours? | Week 16 | 
| Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16 | The SCORAD index is a clinical tool for assessing the severity of atopic dermatitis (AD). Extent and intensity of eczema as well as subjective signs (insomnia, etc.) are assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). | Week 16 | 
| Absolute Change From Baseline in Percent Body Surface Area (BSA) of Atopic Dermatitis (AD) Involvement at Week 16 | BSA affected by AD will be assessed for each section of the body using the rule of nines (the possible highest score for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]) and will be reported as a percentage of all major body sections combined. The proportion assigned to different body regions is different in younger children as compared to older children (head and neck area is assigned a higher proportion in younger children as compared to older children). | Week 16 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs) up to Week 16 | Adverse Event (AE): any untoward medical occurrence in a participant administered a study drug which may/may not have a causal relationship with study drug. Serious AE (SAE): any untoward medical occurrence that resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. TEAE: AEs starting/worsening after first intake of study drug. TEAEs included: serious TEAEs and Non-serious TEAEs. AESI included: Anaphylactic or acute allergic reactions; Severe injection site reactions; Mycosis fungoides/other forms of cutaneous T-cell lymphoma; severe infections; any clinical endoparasitosis; Conjunctivitis, keratitis, or blepharitis; significant Alanine aminotransferase (ALT) elevation. Number of participants with TEAEs, Serious TEAES and AESIs from baseline up to Week 16 were reported. | Up to week 16 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs) up to Week 36 | AE: any untoward medical occurrence in a participant administered a study drug which may/may not have a causal relationship with study drug. SAE: any untoward medical occurrence that resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. TEAE: AEs starting/worsening after first intake of study drug. TEAEs included both Serious TEAEs and Non-serious TEAEs. AESI included: Anaphylactic or acute allergic reactions; Severe injection site reactions; Mycosis fungoides/other forms of cutaneous T-cell lymphoma; severe infections; any clinical endoparasitosis; Conjunctivitis, keratitis, or blepharitis; significant Alanine aminotransferase (ALT) elevation. Number of participants with TEAEs, Serious TEAES and AESIs from baseline up to Week 36 were reported. | Up to week 36 | 
| Serum Concentration of Functional REGN3500 | Serum Concentration of Functional REGN3500 was reported. | Baseline (Week 0), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32 and 36 | 
| Number of Participants With Positive Treatment-Emergent Anti-REGN3500 Antibodies (ADA) | Treatment-Emergent (TE) ADA was defined as any positive post baseline assay response when baseline results were negative or missing. Treatment-Emergent ADA responses were further classified as: - persistent (treatment-emergent positive ADA response detected in at least 2 consecutive post baseline samples separated by at least a 16-week post baseline period [based on nominal sampling time], with no ADA-negative samples in-between, regardless of any missing samples or a positive response at the last ADA sampling time point),- indeterminate (a positive assay response at the last collection time point only, regardless of any missing samples), - transient (not persistent/indeterminate, regardless of any missing samples). Number of participants with positive treatment-emergent anti-REGN3500 antibodies (ADA) were reported. Here, Number of Participants Analyzed signifies those participants who were evaluable for this endpoint. | Up to week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate, Severe