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1 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) J Korean Med Ophthalmol Otolaryngol Dermatol 2019;32(2):68-93 pissn eissn Original Article / 원저식약처승인아토피피부염의약품국내임상시험의특성 - ClinicalTrials.gov 등록임상시험을중심으로 - 황미리 1 안재현 2 제하경 1 김수영 1 정현아 3 대전대학교대학원한의학과외관과학교실 ( 1 대학원생, 2 시간강사, 3 교수 ) Characteristics of Clinical Trials in Korea for Atopic Dermatitis - Focus on ClinicalTrials.gov Registered Clinical Trials - Mi-Lee Hwang Jae-Hyun Ahn Ha-Kyung Jea Soo-Young Kim Hyun-A Jung Department of Korean Medicine Ophthalmology & Otolaryngology & Dermatology, College of Korean Medicine, Daejeon University Abstract Objective : This study summarized the characteristics of clinical trials for atopic dermatitis medicines approved by the Ministry of Food Drug Safety(MFDS). This study may be a reference for the design of clinical trials of atopic dermatitis herbal medicine treatment which may be carried out later. Method : The characteristics of the clinical trial were analyzed for clinical trials registered with ClinicalTrials.gov, CRIS, the Korea Health Industry Development Institute among the clinical trial approval statuses posted on the website of the MFDS. Result : 1. Clinical trial drugs were developed in various formulations such as oral medicines, injections, dermatologic agents, similar proportions. Relatively little clinical trials were found for herbal medicine. 2. In the control evaluation test, most of the treatments for the control group were performed with placebo using Vehicle. 3. In most clinical trials, one intervention group was in the form of a parallel assignment with only one treatment. 4. The age of the subjects was 11 out of 28 studies including minors, clinical trials targeting minors were also found to be significant. 5. In the case of atopic dermatitis, the cases of subacute chronic or atopic dermatitis more than 6 months or more than 1 year were often used. 6. Most clinical trials were divided into mild to moderate atopic dermatitis or moderate to severe atopic dermatitis. The SCORAD index, EASI, IGA, BSA, NRS were used as the evaluation criteria. c 2019 the Society of Korean Medicine Ophthalmology & Otolaryngology & Dermatology This is an Open Access journal distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, reproduction in any medium, provided the original work is properly cited. 68

2 황미리외 4 인 : 식약처승인아토피피부염의약품국내임상시험의특성 7. Regulations for the drugs used prior to the trial period for the treatment of atopic dermatitis vary somewhat from one clinical trial to another. 8. IGA was used most often as a primary efficacy tool, SCORAD index, EASI, NRS were also used. Key words : Atopic Dermatitis, Clinical Trials, MFDS, Drug I. 서론 의임상시험설계에참고하고자한다. 아토피피부염은소양감, 태선화등을동반하는만성염증성피부질환의일종으로그원인은아직까지명확하게밝혀지지않았다 1). 그러나아토피피부염은전세계적으로점차증가하는추세로해외연구에서 10년간약 2~3배가량증가한것으로보고된바있다 2). 또한국내에서학동기소아를대상으로전국적으로시행한아토피피부염의유병률조사에서도 1995년 15.3%, 2000년 17.0%, 2006년 21.0%, 2010년 27.0% 로점차증가하는것으로나타났다 3). 아토피피부염환자에서증상치료를위해항히스타민제, 경구스테로이드제, 국소스테로이드제, 면역억제제등의다양한약물이사용되고있으나 4) 장기간사용시각종부작용및내성등으로새로운약물개발에관한필요성이지속적으로제기되고있다 6). 그러나실제로임상시험을통과하여시판허가를받는의약품은많지않은실정이며특히한약제로개발된아토피피부염치료제가시판허가를받은경우는전무한상태이다. 더욱이한약을이용한아토피치료제의경우의약품보다는보습크림등의화장품제형개발위주로연구가이뤄지고있는실정으로 2) 이는한방치료제의임상시험설계및진행에대한어려움, 제형개발의어려움, 처방의문제등의다양한원인이있을것으로생각된다. 이에저자는현재국내에서아토피피부염의치료제개발을위하여시행되고있는의약품임상시험의특징에대하여정리하여향후한약외용제, 경구약등 Corresponding author : Hyun-Ah Jung, 75, Daedeok-daero 176beon-gil, Seo-gu, Daejeon, Republic of Korea. (Tel : , acua3739@dju.kr) Received 2019/4/5 Revised 2019/4/17 Accepted 2019/4/24 II. 본론 1. 연구대상 식품의약품안전처의약품통합정보시스템에공고된임상시험승인현황의약품중대상질환이아토피피부염인임상시험을대상으로하였다. 검색결과총 43 개의임상시험이승인받은것으로나타났는데이중기존연구의연장승인을받은연구 2개를우선제외하였다. 이들임상시험들의구체적인임상시험정보를수집하기위하여아래의사이트에서연구계획서를검색하였다. 1) ClinicalTrials.gov 위의식약처의승인을받은임상시험들중미국국립의학도서관에서운영하고있으며, 약 200여개국가에서시행중인임상시험정보를공개하고있는 ClinicalTrials.gov에등록되어있는연구계획서를검색하였다. 검색결과총 24개의연구계획서가검색되었다. 2) CRIS(Clinical Research Information Service) 질병관리본부산하국내에서진행되는임상시험및임상연구온라인등록시스템인 CRIS(cris.nih.go.kr) 에서 아토피피부염 으로검색되는연구중의약품 (Drug) 에해당하는연구를검색하여확인한총 2개의연구계획서를찾을수있었다. 이중 1개의연구계획서는 ClinicalTrials.gov 와중복되는정보로대상에서 69

3 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) 제외하였다. 3) 보건산업진흥원 ( 위의임상시험정보데이터베이스에서검색되지않는임상시험중보건산업진흥원의연구지원을받아진행된연구의연구보고서를검색하여 3개의연구계획정보를연구대상에추가하였다. 위의데이터베이스에서임상시험정보를정리한후중복되는경우를제외하고최종적으로 28개의임상시험정보를대상으로하였다. 2. 연구항목위의데이터베이스에서임상시험정보를알수있는경우에는위데이터베이스의정보를바탕으로하여임상시험정보를분석하였다. 공개되지않은항목이있는경우에는공개된항목만을분석하였다. 분석한항목은아래와같다. 1 중재약물의종류 - 약물투약방법 - 한약 / 양약 - 대조군에대한처리 - 임상시험기간 2 임상시험단계 3 피험자수 4 임상시험설계 - 임상시험형태 - 시험군배정 - 선정기준 - 제외기준 - 유효성평가도구 III. 결과 1. 중재약물의종류 사용한약물의종류를경구약, 외용제, 주사제로분류하였다. 28개임상시험중경구약을대상으로한임상시험은총 9개였으며외용제 8개, 주사제는 11개로서로비슷한비율로임상시험이이뤄지고있음을알수있었다 (Table 1). 2) 한약 / 양약 29개임상시험중자운고, 황련해독탕, 단미엑스제등한약을중재약물로시행한임상시험은외용제 1 개, 경구제 2개로총 3개였으며이를제외한 25개는모두양약에해당하였다. 3) 대조군에대한처리 28개임상시험중 3개의시험은단일군시험으로별도의대조군이존재하지않았다. 1개의연구는중재군 2군을저용량군과고용량군으로나누어임상시험을진행하였다. 이를제외한 24개의연구에서는주로약물의 Vehicle 을활용한위약 (Placebo) 을이용하여연구를진행하였다 (Table 1). 4) 임상시험기간피험자개인별임상시험기간의경우평균 16.8주로나타났다. 이같은임상시험기간의경우약물의종류별로다소차이가있었는데먼저가장짧게나타난것은외용제로최단 4주, 최장 12주로평균약 7 주간약물을투약하고방문을하는것으로나타났다. 다음으로주사제의경우최장 4주, 최장 164주간진행되는것으로나타났고평균 23.4주동안진행되는것으로나타났는데이는단회투약후에약물의지속효과를평가하기위에방문하는것까지모두포함된수치였다. 마지막으로경구약의경우최단 8주, 최장 20주로평균 14.8주동안임상시험이이루어지는것으로나타났다. 1) 약물투약방법 70

4 황미리외 4 인 : 식약처승인아토피피부염의약품국내임상시험의특성 2. 임상시험단계임상시험의단계의경우 1상임상시험이 2개, 1/2 상에해당하는임상시험이 3개, 2상이 6개, 2/3상 1 개, 3상 14개, 4상이 1개였으며연구자주도임상시험으로단계설정이명확하지않은시험이 1개있었다 (Table 1). 3. 피험자수피험자수의경우는최저 13명, 최대 2300명으로평균은 467.3명이었다. 이중다기관에서수행된연구는총 23개로이들연구의피험자수는평균 명이었다. 반면단일기관에서수행된연구는총 5개로이들연구의피험자수는 40.3 명으로나타났다 (Table 1). 4. 임상시험설계 1) 임상시험형태연구설계는전체임상시험중 3개의시험에서는단일군에대해서동일한약물이투약되는단일군시험 (Single Group ) 으로진행되었다. 나머지시험중 1개에서는교차시험 (Cross-over Study) 으로설계되었으며이를제외한나머지 24개의연구는모두평행설계 ( ) 로시험이진행되었다 (Table 1). 2) 시험군배정전체임상시험 28개중단일군시험을제외한 25개의시험에서는모두무작위배정으로설계되었으며임상시험눈가림은피험자와시험자모두에게맹검이진행되는이중맹검으로이루어졌다 (Table 1). 5. 선정기준각각임상시험의목적에따라나이, 체중등의기준을달리적용하고있었다 (Table 2). 이중성별, 나이, 아토피피부염병력및중증도에대한정보만을별도 로정리해보았다. 1) 성별 Phase I에해당하는 1개의임상시험에서는약물의안정성과약동학을보기위해서건강한성인남성만을대상자로하였으며이를제외한 27개의임상시험에서는모든성별을대상으로하였다. 2) 나이피험자의나이를크게 18세이상을성인, 12세이상 18세미만을청소년, 12세미만을아동으로구분하였을때성인만을대상으로한임상시험은총 17건이었으며청소년만을대상으로한임상시험이 1건, 아동만을대상으로한임상시험이 2건이었다. 청소년과성인모두를대상으로한임상시험은 6건이었으며아동과청소년만을대상으로한임상시험이 1건, 유아, 청소년, 성인모두를대상으로한임상시험도 1건이었다. 3) 아토피피부염에대한병력전체임상시험중 1개의임상시험은건강한성인남성을대상으로한시험으로아토피피부염을앓지않은사람을대상으로했으며나머지 27개의임상시험은건강한사람을제외하고아토피피부염을앓고있는환자들을대상으로하였다. 먼저아토피피부염에이환된기간을기준으로명시를한임상시험은 15개가있었다. 이중 4개의임상시험은아급성과만성 (Subacute, Chronic) 아토피피부염환자를대상으로하였으며 4개임상시험모두 6개월이상아토피에이환된경우를아급성과만성아토피피부염의기준으로보았다. 다음으로 11개의임상시험은모두만성 (Chronic) 아토피피부염환자를임상시험대상자로하였는데구체적인기간은임상시험마다다소차이가있었다. 6 개의임상시험에서는 1년이상이환된경우를만성아토피피부염의기준으로하였으며 1개의임상시험에서는 1년이상, 4개의임상시험에서는 3년이상이 71

5 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) Table 1. Clinical Trials List Designs. No. Title Number of gruoups Drug Control Allocation Design Masking Duratio n(wks) Phase Sample size Multi-ce nter 1 The Effectiveness of Montelukast on Atopic Dermatitis in Koreans 2 Montelukast Placebo RCT Crossover Double 18 Not Applicable 54 X 2 A Study of Long-term Baricitinib (LY ) Therapy in Atopic Dermatitis (BREEZE-AD3) 8 Baricitinib Placebo RCT Double O 3 A Study of Baricitinib (LY ) in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis (BREEZE-AD7) 3 Baricitinib Placebo RCT Double O 4 Study of Baricitinib (LY ) in Adults With Moderate to Severe Atopic Dermatitis (BREEZE-AD2) 4 Baricitinib Placebo RCT Double O Internal medicine 5 6 A Study to Evaluate Upadacitinib in Adolescent Adult Subjects With Moderate to Severe Atopic Dermatitis Study Evaluating Efficacy Safety of PF in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-2) 4 Upadacitinib Placebo RCT 3 PF Placebo RCT Double X Double O 7 Study to Evaluate Efficacy Safety of PF With or Without Topical Medications in Subjects Aged 12 Years Older With Moderate to Severe Atopic Dermatitis (JADE EXTEND) 2 PF Placebo RCT Double O 8 Study Evaluating Efficacy Safety of PF Dupilumab in Adult Subjects With Moderate to Severe Atopic Dermatitis on Background Topical Therapy (JADE Compare) 5 PF Dupilumab Placebo RCT Double O 9 Clinical trials of HH01 for adult atopic dermatitis 2 Hwanglyeonha edok-tang Placebo RCT Double X 10 A Phase I Study of HY209 Gel in Healthy Male Volunteers for Atopic Dermatitis 7 HY209 gel Placebo RCT Double X 11 A Study to Evaluate the Safety Efficacy of PAC Cream in Adults With Atopic Dermatitis 4 PAC cream Placebo RCT Double X Dermatologi c agents CAPTAIN-AD: Clinical Study of AmorePacific's TRPV1 Antagonist in Atopic Dermatitis A Study to Evaluate the Safety Efficacy of PAC Cream in Pediatric Atopic Dermatitis 2 4 PAC cream PAC cream Placebo RCT Placebo RCT Double O Double 4 1/2 56 O 14 Efficacy, Safety Dose Finding Trial of Topical Jaungo Application in Atopic Dermatitis Patients 2 Jaungo Placebo RCT Double O 72

6 황미리외 4 인 : 식약처승인아토피피부염의약품국내임상시험의특성 Dermatologi c agents injections No. Title 15 Romized, double-blind, multicenter,, placebo-controlled therapeutic exploratory study for the validation safety of CP001 for patients with atopic dermatitis 16 Double-blind, romized, placebo-controlled,, multicenter, Phase II clinical trial to assess the dose-response of HL009 in pediatric patients with mild moderate atopic dermatitis. 17 A 6-week, double-blind, romized trial to evaluate the efficacy safety of Elidel 1% cream for patients aged 2 to 11 years with a mild to moderate facial atopic dermatitis intolerant or dependent on topical corticosteroids, Placebo-controlled, 12-week multicenter trial consisting of a 6-week open-label trial 18 Safety Efficacy of ADSTEM Inj. in Patients With Moderately Subacute Chronic Atopic Dermatitis 19 Safety Efficacy of FURESTEM-AD Inj. in Patients With Moderately Subacute Chronic Atopic Dermatitis (AD) 20 Study of Autologous Total Immunoglobulin G Therapy for Atopic Dermatitis 21 Safety Efficacy of FURESTEM-AD Inj. in Patients With Moderate to Severe Chronic Atopic Dermatitis(AD) 22 Tralokinumab Monotherapy for Moderate to Severe Atopic Dermatitis - ECZTRA 2 (ECZema TRAlokinumab Trial no. 2) (ECZTRA 2) 23 Open-label Study of Dupilumab (REGN668/ SAR231893) in Patients With Atopic Dermatitis 24 Study to Assess the Efficacy Long-term Safety of Dupilumab (REGN668/SAR231893) in Adult Participants With Moderate-to-Severe Atopic Dermatitis (CHRONOS) Number of gruoups Drug Control Allocation Design Masking Duratio n(wks) Phase Sample size Multi-ce nter 3 CP001 Placebo RCT Double O 4 HL-009 gel Placebo RCT Double O 2 Elidel cream 1% Placebo RCT Double O 1 ADSTEM Inj. None None RCT None O 1 FURESTEM-A D Inj. None None RCT None 4 1/2a 34 O 2 Autologous immunoglobul in Placebo RCT Double 8 2/3 51 X 2 FURESTEM-A D Inj. Placebo RCT Double O 6 Tralokinumab Placebo RCT Double O 1 Dupilumab None None RCT None O 3 Dupilumab Placebo RCT Double O 73

7 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) No. Title Number of gruoups Drug Control Allocation Design Masking Duratio n(wks) Phase Sample size Multi-ce nter 25 A Study of Lebrikizumab in Participants With Persistent Moderate to Severe Atopic Dermatitis 4 Lebrikizumab Placebo RCT Double O 26 Study of Dupilumab (REGN668/SAR231893) Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO 2) 3 Dupilumab Placebo RCT Double O injections 27 A Dose Ranging Placebo-Controlled Double-Blind Study to Evaluate the Safety Efficacy of Tezepelumab in Atopic Dermatitis 4 Tezepelumab Placebo RCT Double 16 2b 300 O 28 Ⅰ/Ⅱa clinical research to evaluate the safety effectiveness of EBI-H (Auto-derived activated lymphocyte) for subacute above medium severity chronic atopic dermatitis patients 2 EBI-H None RCT Double 12 1/2a 23 O Table 2. Inclusion Criteria of Clinical Trials No. Age gender Inclusion Criteria all The ages of 2 to 6 years old, 54 children with moderate to severe atopic dermatitis diagnosed by the criteria of Haniffin Rajka were included in the study. Volunteer children with moderate to severe atopic dermatitis were recruited from the Pediatric Allergy respiratory Center of the SoonChunHyang University Hospital (Seoul, Korea). At the time of recruitment, written consent was obtained. The ethical committee at the SoonChunHyang University Hospital approved the trial. Volunteers who agreed by their parents. The severity of their disease was assessed by modified SCORAD index. Internal medicines 2 18 all 3 18 all Have been diagnosed with moderate to severe Atopic Dermatitis for at least 12 months. Have had inadequate response or intolerance to existing topical (applied to the skin) medications within 6 months preceding screening. Are willing to discontinue certain treatments for eczema (such as systemic topical treatments during a washout period). Agree to use emollients daily. Have been diagnosed with moderate to severe atopic dermatitis for at least 12 months. Have had inadequate response to existing topical (applied to the skin) medications within 6 months preceding screening. Are willing to discontinue certain treatments for eczema (such as systemic topical treatments during a washout period). Agree to use emollients daily all Have been diagnosed with moderate to severe Atopic Dermatitis for at least 12 months. Have had inadequate response or intolerance to existing topical (applied to the skin) medications within 6 months preceding screening. Are willing to discontinue certain treatments for eczema (such as systemic topical treatments during a washout period). Agree to use emollients daily all Active moderate to severe atopic dermatitis defined by Eczema Area Severity Index (EASI), Investigator's Global Assessment (IGA), Body surface area (BSA), pruritus Cidate for systemic therapy or have recently required systemic therapy for atopic dermatitis 74

8 황미리외 4 인 : 식약처승인아토피피부염의약품국내임상시험의특성 Internal medicines No. Age gender Inclusion Criteria 6 12 all 7 12 all Evidence of a personally signed dated informed consent document indicating that the subject or their parent(s)/legal guardian, if applicable, have been informed of all pertinent aspects of the study. Male or female subjects of 12 years of age or older, at the time of informed consent body weight greater than or equal to 40 kg. Adolescent subjects below the age of 18 years old will only be enrolled in this study if instructed by the sponsor approved by the country or regulatory/health authority. If these approvals have not been granted, only subjects aged 18 years older will be enrolled. Willing able to comply with scheduled visits, treatment plan, laboratory tests other study procedures. Must have completed the full treatment period of a qualifying Phase 3 study OR must have completed the full rescue treatment period of a qualifying Phase 3 study (if applicable). Female subjects who are of childbearing potential (which includes all female subjects aged 12 years older, regardless of whether they have experienced menarche) must not be intending to become pregnant, currently pregnant, or lactating. The following conditions apply: 1.Female subjects of childbearing potential must have a confirmed negative pregnancy test prior to romization. 2.Female subjects of childbearing potential must agree to use a highly effective method of contraception for the duration of the active treatment period for at least 28 days after the last dose of investigational product. Female subjects of non childbearing potential must meet at least 1 of the following criteria: 1.Have undergone a documented hysterectomy /or bilateral oophorectomy; 2.Have medically confirmed ovarian failure; or 3.Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause have a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential. Must agree to avoid prolonged exposure to the sun not to use tanning booths, sun lamps or other ultraviolet light sources during the study. Must agree to avoid use of prohibited medications throughout the duration of the study all Male or female subjects aged 18 years or older at the time of informed consent Diagnosis of atopic dermatitis (AD) for at least 1 year current status of moderate to severe disease (>= the following scores: BSA 10%, IGA 3, EASI 16, Pruritus NRS severity 4) Documented recent history (within 6 months before the screening visit) of inadequate response to treatment with medicated topical therapy for AD for at least 4 weeks, or who have required systemic therapies for control of their disease. Must be willing able to comply with stardized background topical therapy, as per protocol guidelines throughout the study Female subjects who are of childbearing potential must not be intending to become pregnant, currently pregnant, or lactating. The following conditions apply: 1.Female subjects of childbearing potential must have a confirmed negative pregnancy test prior to romization; 2.Female subjects of childbearing potential must agree to use a highly effective method of contraception for the duration of the active treatment period for at least 28 days after the last dose of investigational product. Female subjects of non-childbearing potential must meet at least 1 of the following criteria: Have undergone a documented hysterectomy /or bilateral oophorectomy; Have medically confirmed ovarian failure; or Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause have a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential. -If receiving concomitant medications for any reason other than AD, must be on a stable regimen prior to Day 1 through the duration of the study 75

9 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) Dermatologic Agents No. Age gender Inclusion Criteria 9 19 all Typical clinical manifestations of intermittent or persistent atopic dermatitis for more than 6 months, If the diagnostic criteria for Hanifin Rajka are met. Have been diagnosed with atopic dermatitis from two oriental medical doctors. Those who have agreed in writing to the clinical trial agreement male Healthy male aged from 20 to 50 at screening test Weight 45kg ~ 90kg with BMI 17kg/m2 ~ 27kg/m2 No skin diseases, no skin damages(scars, tattoo, etc), no hairy skin all Male female patients aged years. Who was diagnosed with Atopic Dermatitis according to Haniffin Rajka criteria. Whose affected BSA is over 5% IGA score is 2 (mild) to 3 (moderate). Who voluntarily agreed to participate in the study signed an informed consent form all Male female patients aged years. Who was diagnosed with Atopic Dermatitis according to Haniffin Rajka criteria. Whose affected TBSA is over 5% below 30%, IGA score is 2 (mild) to 3 (moderate). Who voluntarily agreed to participate in the study signed an informed consent form all Male female patients aged 24 months - 12 years Who was diagnosed with Atopic Dermatitis according to Haniffin Rajka criteria, whose affected BSA is over 5% IGA score is 2 (mild) to 3 (moderate). Who has applied stable amount of emollients daily before baseline visit Who voluntarily agreed to participate in the study signed an informed consent form all The diagnosis of AD will be made according to the criteria of Hanifin Rajka Age: 5 years to 65 years objective SCORAD 40, Diagnosis of Mild to Moderate Atopic Dermatitis (AD) Exoriation 1, Lichenification 1, Dryness 1 or Exoriation+Lichenification+Dryness 3 Participants who able to express intention Participants willing to provide written informed consent all (Hanifin Rajka diagnosis criteria) Those diagnosed with atopic dermatitis Severity of SCORAD atopic dermatitis Objective index below 40 A person who agrees to participate in the trial after hearing the details of the trial agrees to observe the notice all Patients suffering from mild to moderate atopic dermatitis all Mild to moderate facial atopic dermatitis Patients intolerant of, or dependent on, topical corticosteroids 76

10 황미리외 4 인 : 식약처승인아토피피부염의약품국내임상시험의특성 Injections No. Age gender Inclusion Criteria all Of either gender, aged years Atopic dermatitis subjects who are coincident with Hanifin Rajka diagnosis criteria Subacute chronic atopic subjects who have atopic dermatitis symptoms continually at least 6 months Subjects with over moderate atopic dermatitis (SCORAD score > 20) Subjects who underst voluntarily sign an informed consent form all Of either gender, aged years Atopic Dermatitis subjects who are coincident with Hanifin Rajka diagnosis criteria subacute chronic Atopic subjects who have Atopic Dermatitis symptoms continually at least 6 months Subjects with over moderate atopic dermatitis( SCORAD score > 20 ) Subjects who underst voluntarily sign an informed consent form all Suitability of autologous blood donation criteria Current stard medical therapies more than 2 months moderate-to-severe atopic dermatitis 10% lesion body surface area (BSA) of atopic dermatitis involvement in area all Atopic Dermatitis subjects who are coincident with Hanifin Rajka diagnosis criteria Chronic Atopic Dermatitis that has been present for at least 3 years EASI>=12 at screening baseline visit IGA>=3, SCORAD index>=25, BSA >=10% of AD involvement at screegning baseline visit Subjects with documented record of inadequate response to the stable use of topical atopic dermatitis treatment within 24 weeks before participating in the study, or whom are inadvisable due to safety risks Subjects who underst voluntarily sign an informed consent form all Age 18 above. Diagnosis of AD as defined by the Hanifin Rajka (1980) criteria for AD. Diagnosis of AD for 1 year. Subjects who have a recent history of inadequate response to treatment with topical medications or for whom topical treatments are otherwise medically inadvisable. AD involvement of 10% body surface area at screening baseline. Subjects must have applied a stable dose of emollient twice daily (or more, as needed) for at least 14 days before romisation all Participation in a prior clinical trial of dupilumab for AD met one of the following: 1.Received study treatment adequately completed the assessments required for both the treatment follow-up periods of the parent studies (except studies listed in b) as defined in the parent protocols 2.Received study treatment in one the studies that have completed last patient last visit : R668-AD-0914, R668-AD-1026, R668-AD-1117, R668-AD-1021, R668-AD-1121, R668-AD-1307 irrespective of duration of participation. 3.Underwent screening in R668-AD-1334 (Liberty AD SOLO 1) or R668-AD-1416 (Liberty AD SOLO 2), but could not be romized due to romization closure. Willing able to comply with all clinic visits study-related procedures Able to underst complete study-related questionnaires Provide signed informed consent all Chronic AD that had been present for at least 3 years before the screening visit; Documented recent history (within 6 months before the screening visit) of inadequate response to a sufficient course of out-patient treatment with topical AD medication(s). 77

11 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) Injections No. Age gender Inclusion Criteria all 12 years of age or older with a minimum body weight of 40 kg Diagnosis of atopic dermatitis (AD) for at least 1 year current status of moderate to severe disease (>= the following scores: BSA 10%, IGA 3, EASI 16, Pruritus NRS severity 4) Recent history of inadequate response or inability to tolerate topical AD treatments or require systemic treatments for AD control all Chronic AD that has been present for at least 3 years before the screening visit; 10% body surface area (BSA) of AD involvement at the screening baseline visits; Documented recent history (within 6 months before the screening visit) of inadequate response to treatment with topical medications or for whom topical treatments are otherwise medically inadvisable (eg, because of important side effects or safety risks) all Subject has provided informed consent prior to initiation of any study specific activities/procedures. Age greater than or equal to 18 to less than or equal to 75 years at screening. Clinical diagnosis of chronic AD (also known as atopic eczema) for at least 2 years prior to screening has confirmed AD (Hanifin Rajka criteria for AD (Hanifin Rajka, 1980). AD that affects greater than or equal to' 10% body surface area as assessed by EASI at screening on day 1. An IGA score of greater than or equal to 3 at screening on day 1. An EASI score of greater than or equal to 16 at screening on day 1. Subject discontinued treatment with TCS, topical calcineurin inhibitors (TCI), prescription moisturizers, or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin for at least the 7 days immediately prior to the first dose of investigational product. Documented recent history (within 12 months before the screening visit) of inadequate response totreatment with topical TCS or subjects for whom topical treatments are otherwise medically inadvisable (ie, because of important side effects or safety risks). Inadequate response is defined as failure to achieve maintain remission or a low disease activity state (comparable to IGA 0 = clear to IGA 2 = mild) despite treatment with a daily regimen of TCS of medium or higher potency (with or without TCI as appropriate) all Patients with atopic dermatitis meeting the Hanifin Rajka diagnostic criteria Subacute chronic patients with symptoms of atopic dermatitis lasting at least 6 months Patients with moderate to severe atopic dermatitis (EASI score> 7) Patients who are unable to use conventional therapy due to lack of improvement with conventional treatment methods or concerns about potential side effects For those who are pregnant, those who are negative during the screening pregnancy test who consent to contraception during the period of clinical trials Patients who have voluntarily agreed in writing to participate in the trial 78

12 황미리외 4 인 : 식약처승인아토피피부염의약품국내임상시험의특성 Table 3. Inclusion Criteria of Severity of Atopic dermatitis Internal medicine Dermatologic agents Injections No. Severity Scoring Systems SCORAD BSA (%) IGA EASI NRS 1 Moderate to Severe SCORAD Unknown 2 Moderate to Severe 3 Moderate to Severe 4 Moderate to Severe 5 Moderate to Severe BSA, IGA, EASI, NRS Unknown Unknown Unknown Unknown 6 Moderate to Severe 7 Moderate to Severe 8 Moderate to Severe BSA, IGA, EASI, NRS Unknown 10 Healthy person 11 Mild to Moderate BSA, IGA, EASI >5 2 or 3 12 Mild to Moderate BSA, IGA, EASI >5 <30 2 or 3 13 Mild to Moderate BSA, IGA, EASI >5 2 or 3 14 Mild to Moderate SCORAD Mild to Moderate SCORAD Mild to Moderate EASI unknown 17 Mild to Moderate 18 Moderate to Severe SCORAD >20 19 Moderate to Severe SCORAD >20 20 Moderate to Severe BAS Moderate to Severe SCORAD, BAS, IGA, EASI Moderate to Severe BSA Moderate to Severe 24 Moderate to Severe 25 Moderate to Severe BSA, IGA, EASI, NRS Moderate to Severe BSA Moderate to Severe BSA, IGA, EASI Moderate to Severe EASI >7 79

13 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) Table 4. Exclusion Criteria of Clinical Trials No. Exclusion Criteria 1 Too severe atopic dermatitis defined as the sum of scores is 80 above by SCORAD index. A history of liver disease; allergy to montelukast or cross-reacting medication; use of phenobarbital, phenytoin or rifampicin. Patients on systemic steroids, immune-suppression or Korean herbal medicine during the previous 6 weeks. 2 Had investigational product permanently discontinued at any time during a previous baricitinib study. Had temporary investigational product interruption continue at the final study visit of a previous baricitinib study, in the opinion of the investigator, this poses an unacceptable risk for the participant's participation in the study Are currently experiencing or have a history of other concomitant skin conditions (e.g., psoriasis or lupus erythematosus), or a history of erythrodermic, refractory, or unstable skin disease that requires frequent hospitalizations /or intravenous treatment for skin infections. A history of eczema herpeticum within 12 months, /or a history of 2 or more episodes of eczema herpeticum in the past. Participants who are currently experiencing a skin infection that requires treatment, or is currently being treated, with topical or systemic antibiotics. Have any serious illness that is anticipated to require the use of systemic corticosteroids or otherwise interfere with study participation or require active frequent monitoring (e.g., unstable chronic asthma). 3 Have been treated with the following therapies: Monoclonal antibody for less than 5 half-lives prior to romization. Received prior treatment with any oral Janus kinase (JAK) inhibitor less than 4 weeks prior to romization. Received any parenteral corticosteroids administered by intramuscular or intravenous (IV) injection within 6 weeks prior to planned romization or are anticipated to require parenteral injection of corticosteroids during the study. Have had an intra-articular corticosteroid injection within 6 weeks prior to planned romization. Internal medicine Have high blood pressure characterized by a repeated systolic blood pressure >160 millimeters of mercury (mm Hg) or diastolic blood pressure >100 mm Hg. Have had major surgery within the past eight weeks or are planning major surgery during the study. Have experienced any of the following within 12 weeks of screening: venous thromboembolic event (VTE), myocardial infarction (MI), unstable ischemic heart disease, stroke, or New York Heart Association Stage III/IV heart failure. Have a history of recurrent ( 2) VTE or are considered at high risk of VTE as deemed by the investigator. Have a history or presence of cardiovascular, respiratory, hepatic, chronic liver disease gastrointestinal, endocrine, hematological, neurological, lymphoproliferative disease or neuropsychiatric disorders or any other serious /or unstable illness. Have a current or recent clinically serious viral, bacterial, fungal, or parasitic infection including herpes zoster, tuberculosis. Have specific laboratory abnormalities. Have received certain treatments that are contraindicated. Pregnant or breastfeeding. Are currently experiencing or have a history of other concomitant skin conditions (e.g., psoriasis or lupus erythematosus), or a history of erythrodermic, refractory, or unstable skin disease that requires frequent hospitalizations /or intravenous treatment for skin infections. A history of eczema herpeticum within 12 months, /or a history of 2 or more episode of eczema herpeticum in the past. Participants who are currently experiencing a skin infection that requires treatment, or is currently being treated, with topical or systemic antibiotics. Have any serious illness that is anticipated to require the use of systemic corticosteroids or otherwise interfere with study participation or require active frequent monitoring (e.g., unstable chronic asthma). 4 Have been treated with the following therapies: Monoclonal antibody for less than 5 half-lives prior to romization. Received prior treatment with any oral Janus kinase (JAK) inhibitor. Received any parenteral corticosteroids administered by intramuscular or intravenous (IV) injection within 2 weeks prior to study entry or within 6 weeks prior to planned romization or are anticipated to require parenteral injection of corticosteroids during the study. Have had an intra-articular corticosteroid injection within 2 weeks prior to study entry or within 6 weeks prior to planned romization. Have high blood pressure characterized by a repeated systolic blood pressure >160 millimeters of mercury (mm Hg) or diastolic blood pressure >100 mm Hg. Have had major surgery within the past eight weeks or are planning major surgery during the study. Have experienced any of the following within 12 weeks of screening: venous thromboembolic event (VTE), myocardial infarction (MI), unstable ischemic heart disease, stroke, or New York Heart Association Stage III/IV heart failure. 80

14 황미리외 4 인 : 식약처승인아토피피부염의약품국내임상시험의특성 Internal medicine Dermatolo gic agents No. Exclusion Criteria 4 Have a history of recurrent ( 2) VTE or are considered at high risk of VTE as deemed by the investigator. Have a history or presence of cardiovascular, respiratory, hepatic, chronic liver disease gastrointestinal, endocrine, hematological, neurological, lymphoproliferative disease or neuropsychiatric disorders or any other serious /or unstable illness. Have a current or recent clinically serious viral, bacterial, fungal, or parasitic infection including herpes zoster, tuberculosis. Have specific laboratory abnormalities. Have received certain treatments that are contraindicated. Pregnant or breastfeeding. 5 Prior exposure to any Janus kinase (JAK) inhibitor Unable or unwilling to discontinue current AD treatments prior to the study Requirement of prohibited medications during the study Other active skin diseases or skin infections requiring systemic treatment or would interfere with appropriate assessment of atopic dermatitis lesions Female subject who is pregnant, breastfeeding, or considering pregnancy during the study 6 7 Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, in the judgment of the investigator, would make the subject inappropriate for entry into this study. Currently have active forms of other inflammatory skin diseases, ie, not atopic dermatitis. Have evidence of skin conditions (eg, psoriasis, seborrheic dermatitis, Lupus) at the time of Day 0 that would interfere with evaluation of atopic dermatitis or response to treatment. Discontinued from treatment (or rescue treatment period, if applicable) early in a qualifying Phase 3 study OR triggered discontinuation criteria at any point during the qualifying Phase 3 study OR meets exclusion criteria of the qualifying Phase 3 study. Ongoing adverse event in the qualifying Phase 3 study which in the opinion of the investigator, or sponsor, is an ongoing safety concern OR the subject is currently triggering safety monitoring criteria in the qualifying Phase 3 study. Investigator site staff members directly involved in the conduct of the study their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study. 8 Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, in the judgment of the investigator, would make the subject inappropriate for entry into this study Medical history including thrombocytopenia, coagulopathy or platelet dysfunction, Q wave interval abnormalities, current or history of certain infections, cancer, lymphoproliferative disorders other medical conditions at the discretion of the investigator Unwilling to discontinue current AD medications prior to the study or require treatment with prohibited medications during the study Other active nonad inflammatory skin diseases or conditions affecting skin Prior treatment with JAK inhibitors Previous treatment with dupilumab Unwilling to discontinue current AD medications prior to the study or require treatment with prohibited medications during the study 9 If you have other skin diseases or systemic diseases other than atopic dermatitis, they are excluded from the study. Exclude patients who have been orally administered steroids immunosuppressive agents up to one week before the subject interview (dermatologic agents are irrelevant). Pregnant women who are breastfeeding or who do not have adequate contraception are excluded. Excludes those who have clinically significant liver disease or LFT elevated more than twice the reference value. Those who have participated in other clinical trials within one month before the start of the study are excluded. Exclude individuals with irritable allergies to study-related drugs. Exclude those who have digestive disorders after having a disease that may affect the absorption of the drug or surgery associated therewith. Mentally retarded Excludes those who do not underst the agreement or are unable to follow the study due to emotional intellectual problems. Exclude those who are deemed inappropriate by other clinical trial personnel. 10 Those who have a history of hypersensitivity or clinically significant hypersensitivity reactions to generic drugs (aspirin, antibiotics, etc.) Those who have clinically significant liver, kidney, respiratory, endocrine, neurologic diseases or hematologic diseases, mental diseases, especially hemorrhagic diseases (hemophilia, von Willebr disease, etc.), cardiovascular diseases (coronary artery disease, Congestive heart failure, arrhythmia, cerebrovascular disease, etc.) or who have a history of those diseases 81

15 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) Dermatolo gic agents No. Exclusion Criteria 10 Those who had clinical symptoms suspected of acute infectious disease within 2 weeks before the scheduled date of the first administration, or whose temperature measured by the screening test (eardrum) was 38.0 C or higher Those who have taken any prescription drugs, herbal medicines, crude drugs within 2 weeks before the scheduled date of administration of the medicines for clinical trials, or over-the-counter medicines or vitamin preparations within 1 week. Those who have a history of substance abuse, or positive urine screening tests (cannabinoid, opiates, amphetamine, cocaine, barbiturate, benzodiazepine) Those who have a history of smoking within 3 months (However, if they quit smoking three months before the first scheduled medication, they are eligible for selection) Those who have been found to be positive in serological tests (HBs antigen, hepatitis C virus antibody HIV antibody) Those who drink continuously (above 21 units / week, 1 unit = 10 g of pure alcohol) Those who have been taking medicines by participating in other clinical trials or bioequivalence studies within 3 months prior to the date of first dosing Those who have been bleeding, blood drawings or blood donation of 400mL or more within 8 weeks before the scheduled date of administration of the drug for clinical trials Those who have vital signs measured at sitting position after the break for more than 3 minutes, Low blood pressure (systolic blood pressure <90 mmhg, diastolic blood pressure <50 mmhg) High blood pressure (systolic blood pressure greater than 150 mmhg, diastolic blood pressure greater than 100 mmhg) Test subjects who are deemed unsuitable for participating in clinical trials due to clinical laboratory tests, ECG results, or other reasons 11 Who has skin diseases other than atopic dermatitis or scar in the affected area which can affect the study, determined by the study investigators. Who has clinically significant medical history or diseases involving liver, kidney, neurological system, psychical disorder that can affect study results. Who has used systemic steroids, antibiotics, immunosuppressants, or received photochemical therapy within 28 days before study drug administration. Who has used topical steroids, immunosuppressants or antibiotics to treat atopic dermatitis within 14 days before study drug administration. Who has used or is expected to inevitably use prohibited concomitant medications during the study. Women who is pregnant /breast-feeding, or who has childbearing potential does not use available contraceptives. Who has dosed other study medications within 30 days before screening. Who is determined ineligible for study participation by investigators for any other reasons. 12 Who has skin diseases other than atopic dermatitis or scar in the affected area which can affect the study, determined by the study investigators. Who has clinically significant medical history or diseases involving liver, kidney, neurological system, psychical disorder that can affect study results. Who has used systemic steroids, antibiotics, immunosuppressants, or received phototherapy within 28 days before study drug administration. Who has used topical steroids, topical calcineurin inhibitors or antibiotics to treat atopic dermatitis within 14 days before study drug administration. Who has used or is expected to inevitably use prohibited concomitant medications during the study. Women who is pregnant /breast-feeding, or who has childbearing potential does not use available contraceptives. Who has dosed other study medications within 30 days before screening. Who is determined ineligible for study participation by investigators for any other reasons. 13 Who has skin diseases other than atopic dermatitis or scar in the affected area which can affect the study, determined by the study investigators. Who has clinically significant medical history or diseases involving liver, kidney, neurological system, psychial disorder that can affect study results. Who has used systemic steroids, antibiotics, immunosuppressants, or received photochemical therapy within 28 days before study drug administration. Who has used topical steroids, immunosuppressants or antibiotics to treat atopic dermatitis within 14 days before study drug administration. Who has used or is expected to inevitably use prohibited concomitant medications during the study. Women who is pregnant /breast-feeding, or who has childbearing potential does not use available contraceptives. Who has dosed other study medications within 30 days before screening. Who is determined ineligible for study participation by investigators for any other reasons. 14 Participants have oozing in the lesion Users of following medications prior to trial periods 1 Oral steroids, immunosuppressants antibiotics within 4 weeks prior to this trial 2 Topical steroids, immunosuppressants antibiotics within 2 weeks prior to this trial 3 Light therapy within 2 weeks prior to this trial 4 Other medications thought to be inappropriate by researchers Participants have severe burn or wide wound Participants have oozing or ulcer in the lesion Allergic reactions to Angelica gigas, Siebold et Zuccarini, sesame oil lard Participants have skin disease except atopic dermatitis Participants have severe renal function disease (scr > 2.0 mg/dl) Participants have severe liver function disease (ALT, AST, ALP 2.5 normal limits) 82

16 황미리외 4 인 : 식약처승인아토피피부염의약품국내임상시험의특성 Dermatolo gic agents injections No. Exclusion Criteria 14 Participants have uncontrolled chronic diseases Pregnancy, lactation Participation in another clinical trial within one month of enrolment Underlying disease or history of severe disease, abnormal state (paralysis; mental retardation other emotional or mental problems; diseases that can affect the absorption of drugs; no enough time to participate in this trial; visual disturbance hearing impairment; inability to underst written consent or engage in this study) Judgment by experts that the potential subject's participation is inappropriate. 15 Those who have serious skin diseases other than atopic dermatitis The subjects were clinically diagnosed with bacterial viruses or fungi, If you have salty atopic dermatitis Persons with intractable chronic diseases such as hypertension, chronic active hepatitis, diabetes mellitus Pregnant or lactating women or those who are pregnant during the clinical trial Those who received oral steroids or oral antibiotics, systemic photochemotherapy other immunosuppressive agents within 4 weeks of the start of the study Persons with liver function or renal impairment Those with a history of substance abuse The person who showed hypersensitivity to the raw material preparation of CP001 Those who participated as subjects in other clinical studies within 60 days of the start of the test 16 Unknown 17 Concurrent skin diseases (infections) Immunocompromised Recently received phototherapy or systemic therapy 18 Unknown 19 Subjects who have systemic infection at the baseline visit Subjects who have asthma at the baseline visit Treatment with oral corticosteroids, oral antibiotics, whole body photochemotherapy, immunosuppressive drug within 4 weeks before the baseline visit Treatment with topical steroids, antibiotics within 2 weeks before the baseline visit Subjects who already took or need to take the medicine which is prohibited to take during the clinical study. Pregnant, breast-feeding women or women who plan to become pregnant during this study. (Females of Childbearing Potential must have a negative urine pregnancy test at Screening Baseline) Subjects who currently participate in other clinical trial or participated in other clinical trial within 30 days Creatinine value 2 Upper limit of the normal range at screening test AST/ALT value 2 Upper limit of the normal range at screening test Any other condition which the investigator judges would make patient unsuitable for study participation 20 Patients under the age of 13 year. Patients who are unable to agree on their own (emergency patients, patients with mental disability, patients with limited capacity to consent due to stroke or delirium caused by diabetes). Patients with severe disease whose expected survival duration is less than 3 months. Pregnancy or planned pregnancy within 1 year Skin condition not appropriate for blood sampling transfusion The stardized clinical severity scoring system for atopic dermatitis (SCORAD) values <25 (Mild atopic dermatitis) 21 Subjects with medical history or surgery/procedure history Subjects with diseases at the time of participation in this study (systemic infection, other serious skin disorders, pigmentation or extensive scarring in atopic dermatitis symptom region) Subjects who need prohibited medication during clinical period Pregnant, breast-feeding women or women who plan to become pregnant during this study Subjects who currently participate in other clinical trial or participated in other clinical trial within 4 weeks Any other condition which the investigator judges would make patient unsuitable for study participation 83

17 한방안이비인후피부과학회지제 32 권제 2 호 (2019 년 5 월 ) injections No. Exclusion Criteria 22 Active dermatologic conditions that may confound the diagnosis of AD. Use of tanning beds or phototherapy within 6 weeks prior to romisation. Treatment with systemic immunosuppressive/immunomodulating drugs /or systemic corticosteroid within 4 weeks prior to romisation. Treatment with TCS /or TCI within 2 weeks prior to romisation. Active skin infection within 1 week prior to romisation. Clinically significant infection within 4 weeks prior to romisation. A helminth parasitic infection within 6 months prior to the date informed consent is obtained. Tuberculosis requiring treatment within the 12 months prior to screening. Known primary immunodeficiency disorder. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 2.0 times the ULN (upper limit of normal) at screening. Positive hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody or hepatitis C virus antibody serology at screening. History of anaphylaxis following any biologic therapy. 23 Patients who, during their participation in a previous dupilumab clinical trial, developed a serious adverse event (SAE) deemed related to dupilumab*, which in the opinion of the investigator or of the medical monitor could indicate that continued treatment with dupilumab may present an unreasonable risk for the patient. Patients who, during their participation in a previous dupilumab clinical trial, developed an AE that was deemed related to dupilumab* led to study treatment discontinuation, which in the opinion of the investigator or of the medical monitor could indicate that continued treatment with dupilumab may present an unreasonable risk for the patient. Conditions in the previous dupilumab study consistent with protocol-defined criteria for permanent study drug discontinuation, if deemed related to dupilumab* or led to investigator - or sponsor-initiated withdrawal of patient from the study (eg, non-compliance, inability to complete study assessments, etc.). *Note for exclusion criteria # 1, 2, 3: In studies that are still blinded, conditions deemed related to the study treatment will be considered related to dupilumab. Treatment with an investigational drug, other than dupilumab, within 8 weeks or within 5 half-lives (if known), whichever is longer, before the baseline visit Pregnant or breastfeeding women, or planning to become pregnant or breastfeed during the patient's participation in this study 24 Participation in a prior Dupilumab clinical trial; Important side effects of topical medication (e.g. intolerance to treatment, hypersensitivity reactions, significant skin atrophy, systemic effects), as assessed by the investigator or treating physician; Having used any of the following treatments within 4 weeks before the baseline visit, or any condition that, in the opinion of the investigator, was likely to require such treatment(s) during the first 2 weeks of study treatment: 1.Immunosuppressive/immunomodulating drugs (e.g, systemic steroids, cyclosporine, mycophenolate-mofetil, Janus kinase inhibitors, interferon-gamma [IFN-γ], azathioprine, methotrexate, etc.); 2.Phototherapy for AD; Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit; History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening; Positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody at the screening visit; Active or acute infection requiring systemic treatment within 2 weeks before baseline visit; Known or suspected history of immunosuppression; Pregnant or breastfeeding women, or planning to become pregnant or breastfeed during the participant's participation in this study. 25 Unwilling to discontinue current AD medications prior to the study or require treatment with prohibited medications during the study Prior treatment with JAK inhibitors Other active nonad inflammatory skin diseases or conditions affecting skin Medical history including thrombocytopenia, coagulopathy or platelet dysfunction, Q wave interval abnormalities, current or history of certain infections, cancer, lymphoproliferative disorders other medical conditions at the discretion of the investigator Pregnant or breastfeeding women, or women of childbearing potential who are unwilling to use contraception 26 Participation in a prior Dupilumab 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, IFN-γ, Janus kinase inhibitors, azathioprine, methotrexate, etc.) 84