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

Phase 2

Terminated

Conditions: Atopic Dermatitis

Interventions: Drug: REGN3500
Drug: REGN3500-Matching Placebo

Registration Number: NCT03738423

Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary: 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

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 129

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:
1. Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, cyclosporine, mycophenolate-mofetil, Interferon-gamma (IFN-γ), Janus kinase inhibitors, azathioprine, methotrexate, etc)
2. 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment 3	REGN3500-Matching Placebo	-
Treatment 5	REGN3500-Matching Placebo	Matching placebo
Treatment 4	REGN3500-Matching Placebo	-
Treatment 1	REGN3500-Matching Placebo	-
Treatment 2	REGN3500-Matching Placebo	-
Treatment 4	REGN3500	-
Treatment 1	REGN3500	-
Treatment 2	REGN3500	-
Treatment 3	REGN3500	-

Primary Outcome Measures

Name	Time	Method
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	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.
Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score Based on All Observed Values Regardless of Rescue Treatment at Week 16	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.

Secondary Outcome Measures

Name	Time	Method
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	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.
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	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.
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	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.
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	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.
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	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.
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	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.
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	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.
Absolute Change From Baseline in Eczema Area and Severity Index (EASI) Score Based on All Observed Values Regardless of Rescue Treatment at Week 16	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.
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	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.
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	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.
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	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.
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	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
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	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.
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	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.
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	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.
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	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.
Time to Onset of Effect on Pruritus (≥4-point Reduction of Weekly Average of Daily Peak Pruritus NRS From Baseline)	Week 16	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?"
Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16	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).
Absolute Change From Baseline in Percent Body Surface Area (BSA) of Atopic Dermatitis (AD) Involvement at Week 16	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).
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs) up to Week 16	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.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs) up to Week 36	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.
Serum Concentration of Functional REGN3500	Baseline (Week 0), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32 and 36	Serum Concentration of Functional REGN3500 was reported.
Number of Participants With Positive Treatment-Emergent Anti-REGN3500 Antibodies (ADA)	Up to week 36	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.