A Study for AR100DP1 in Mild to Moderate Atopic Dermatitis (AD)

Study Overview
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Brief Summary
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This is a Phase I/IIa Open-Label, Dose-Escalation Study to Determine the Safety, Tolerability, and Efficacy of AR100DP1 in Health Subjects, and Subjects with Mild to Moderate Atopic Dermatitis.

Detailed Description
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This phase I/IIa study will be composed of a Phase I study, which includes 14 days of treatment with AR100DP1 followed by 2 weeks of follow-up period to find the maximum tolerated dose (MTD) of AR100DP1 and a following single-arm Phase IIa study with 28 days of treatment followed by 2 weeks of follow-up period to evaluate the efficacy of AR100DP1 with the recommended Phase II dose (RP2D) in treating atopic dermatitis on target lesion. Target lesion area(s) is defined as one or multiple patches of lesion areas selected by the investigator for topical administration of AR100DP1. The size of target lesion area(s) is 0.5-5% body surface area (BSA) and the maximum is 750 cm2 (maximal treated area, inclusive) in this study. Eligible healthy subjects in Phase I will have the test skin area(s) of 750 cm2 from chest and abdomen. Eligible subjects with mild to moderate AD in Phase IIa will have target lesion area(s) selected by the investigator. The skin area treated with AR100DP1 will be recorded for AR100DP1 topical administration before dosing. AR100DP1 should be topically administered twice daily on the test skin area(s) of 750 cm2 of eligible healthy subjects for 14 days in Phase I study. The administration of AR100DP1 should be topically applied twice daily on target lesion area(s) (0.5-5% BSA, maximum as 750 cm2, inclusive) of eligible subjects with mild to moderate AD for 28 days in Phase IIa study.

Official Title
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A Phase I/IIa Open-Label, Dose-Escalation Study to Determine the Safety, Tolerability, and Efficacy of AR100DP1 in Healthy Subjects, and Subjects With Mild to Moderate Atopic Dermatitis

Conditions
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Dermatitis, Atopic

Intervention / Treatment
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* Drug: AR100DP1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase I: Dated and signed informed consent Either gender, ≥ 20 years old (the legal age of consent majority is 20 years old in Taiwan) Healthy subjects, who have no clinically relevant abnormalities, identified by medical history, physical examination, 12-lead electrocardiogram (ECG), and clinical laboratory tests Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures Healthy skin on which reddening can be easily recognized in the area of the test fields, evaluated by the investigator Subject of childbearing potential must agree to use abstinence to intercourse, or highly effective contraceptives from signing informed consent to 14 days after the last dose of study drug administration At least two forms of effective birth control must be adopted for contraception, and one of which must be a barrier method. Acceptable forms include: Established use of oral, injected or implanted hormonal methods of contraception Placement of an intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of contraception: condom (highly recommended with spermicide), or occlusive cap (diaphragm or cervical/vault caps) Phase IIa: Dated and signed informed consent Either gender, ≥ 20 years old (the legal age of consent majority is 20 years old in Taiwan) Confirmed clinical diagnosis of atopic dermatitis (based on the criteria of Hanifin and Rajka for AD) With at least 0.5% body surface area (BSA) as target lesion area(s) Clinical diagnosis of AD that has been clinically stable, which means the IGA score stays as 2 or 3 when evaluated for ≥ 4 weeks at the investigator's discretion prior to Screening Visit With Investigator's Global Assessment (IGA) score of 2 (mild) or 3 (moderate) at screening Subject of childbearing potential must agree to use abstinence to intercourse, or highly effective contraceptives from signing informed consent to 14 days after the last dose of study drug administration At least two forms of effective birth control must be adopted for contraception, and one of which must be a barrier method. Acceptable forms include: Established use of oral, injected or implanted hormonal methods of contraception Placement of an intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of contraception: condom (highly recommended with spermicide), or occlusive cap (diaphragm or cervical/vault caps) Exclusion Criteria: Phase I: Subjects who have any visible skin disease at the application site which, in the opinion of the investigator, will interfere with the evaluation of the test site reaction Subjects who have a history of AD, psoriasis and/or active AD/eczema Subjects who have damaged skin in or around the test sites, including sunburn, excessively deep tans, uneven skin tones, tattoos, scars, excessive hair, numerous freckles, or other disfigurations of the test site Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing) Phase IIa: Unstable or actively infected AD judged by the investigator. Active or potentially recurrent dermatologic condition other than atopic dermatitis that may confound evaluation (e.g. fungal infection), judged by the investigator. Received systemic medication including corticosteroid, immunosuppressant, anti-histamine, phototherapy, or other therapy, which could affect AD within 4 weeks before Screening. However, subjects are allowed to enter the study if subjects have been taking at least 2 weeks of fixed dose anti-histamine prior to Screening and this application does not affect the study judged by the investigator Received topical medication including corticosteroid, immunosuppressant, anti-histamine, phototherapy, calcineurin inhibitors, or other therapy for AD on the target lesion area(s) within 1 week before Screening The following exclusion criteria are applied for all subjects in Phase I/IIa study: Plan to receive immunosuppressive agents (including azathioprine, mycophenolate, cyclophosphamide, chlorambucil, methotrexate, cyclosporine), or systemic steroid with equivalent dosage higher than prednisolone 30 mg/day for more than 14 days at Screening Unwilling or unable to comply with the criteria in Life Style Guidelines during the study History of use of biologic therapy (including intravenous immunoglobulin) within 12 weeks or 5 half-lives (whichever is longer) prior to Screening Received any other investigational drug within 4 weeks prior to Screening Required or received systemic CYP3A4 inhibitors with strong potency within 1 week prior to screening, including but not limited to clarithromycin, itraconazole, nefazodone and atazanavir, evaluated by the investigator Treatment for any type of cancer (except squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the skin, curatively treated with cryosurgery or surgical excision only) within 5 years before screening Had surgery within 4 weeks prior to Screening Visit, or plan to have surgery during the study Allergies requiring acute or chronic treatment at the investigator's discretion Known hypersensitivity to any of the components of the study drug Active clinically serious infection or history of human immunodeficiency virus (HIV) infection Any of the following serum test abnormalities: Total bilirubin > 1.5 × ULN AST or ALT > 3.0 × ULN Serum albumin < 2.5 g/dL Creatinine > 1.5 × ULN Any other ≥ Grade 2 (grading of vaccine clinical trials for Phase I and NCI-CTCAE v5.0 for Phase IIa) laboratory abnormality at baseline (other than those listed above) With ongoing acute diseases or within the past 2 years serious medical conditions (e.g. concomitant illness) such as cardiovascular (e.g. New York Heart Association (NYHA) grade III or IV), hepatic (e.g. Child-Pugh Class C), psychiatric condition (e.g. alcoholism, drug abuse), medical history, physical findings, or laboratory abnormality that in the investigators' opinion could interfere with the results of the trial or adversely affect the safety of the subject Female subject who is lactating or has positive urine pregnancy test at screening Other conditions not suitable for participating in this study judged by the investigator

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase I: conventional 3+3 design of dose escalation Phase IIa: single-arm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AR100DP1 (1.25%)_Phase I<br>Subjects topically apply AR100DP1 twice per day with at least 4 hour interval. The daily dosage of 1.25% AR100DP1 topical administration is 31.25 mg/day (1.25% × 1,250 × 2 = 31.25). | Drug: AR100DP1<br>* topical ointment<br>|
| Experimental: AR100DP1 (2.5%)_Phase I<br>Subjects topically apply AR100DP1 twice per day with at least 4 hour interval. The daily dosage of 2.5% AR100DP1 topical administration is 62.5 mg/day (2.5% × 1,250 × 2 = 62.5). | Drug: AR100DP1<br>* topical ointment<br>|
| Experimental: AR100DP1 (5%)_Phase I<br>Subjects topically apply AR100DP1 twice per day with at least 4 hour interval. The daily dosage of 5% AR100DP1 topical administration is 125 mg/day (5% × 1,250 × 2 = 125). | Drug: AR100DP1<br>* topical ointment<br>|
| Experimental: AR100DP1 (5%)_Phase IIa<br>Subjects topically apply AR100DP1 twice per day with at least 4 hour interval. The daily dosage of 5% AR100DP1 topical administration is 125 mg/day (5% × 1,250 × 2 = 125). | Drug: AR100DP1<br>* topical ointment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With DLTs | Phase I study included 14 days of treatment with AR100DP1, followed by 2 weeks of follow-up period to find the maximum tolerated dose (MTD) of AR100DP1. DLTs were defined as any adverse event (AE) ≥ Grade 2 (Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued by United States Food and Drug Administration in September 2007), that was considered to be causally related (possibly, probably, or definitely related) to AR100DP1 as judged by the investigator up to Day 29. The definition of Grade 5 (death related to AE) was added to this grading system as it was not defined in the guidance. (reported in the subsequent Primary Outcome Measure). MTD is defined as the highest dose level at which < 2 of 6 subjects experienced a dose-limiting toxicity (DLT). | up to Day 29 for each cohort in phase I | 
| Maximum Tolerated Dose (MTD) of AR100DP1 | Per protocol, MTD is defined as the highest dose level at which < 2 of 6 subjects experienced a dose-limiting toxicity (DLT). MTD was determined by testing increasing doses up to 125 mg/day via topical administration on AR100DP1_1.25%, 2.5%, and 5% groups with 3 to 6 subjects each. DLTs were defined as any adverse event (AE) ≥ Grade 2 (Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued by United States Food and Drug Administration in September 2007), that was considered to be causally related (possibly, probably, or definitely related) to AR100DP1 as judged by the investigator up to Day 29. The definition of Grade 5 (death related to AE) was added to this grading system as it was not defined in the guidance. (reported in the previous Primary Outcome Measure). | up to Day 29 for each cohort in phase I | 
| Percentage of Subjects With the Investigator's Global Assessment (IGA) Score of 0 or 1 on Day 29 (Phase IIa) | The IGA is a 5-point scale that provides a global clinical assessment of AD severity based on an ordinal scale, scored by the investigator. The scores of IGA are 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate) and 4 (Severe). | Day 29 (Phase IIa) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With the Investigator's Global Assessment (IGA) Score of 0   4 (Phase IIa) | The IGA is a 5-point scale that provides a global clinical assessment of AD severity based on an ordinal scale, scored by the investigator. The scores of IGA are 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate) and 4 (Severe). | Day 8, Day 15, Day 22, Day 29, Day 36 and Day 43 (Phase IIa) | 
| Change From Baseline in Pruritus Numerical Rating Scale (NRS) of Itch Level on Target Lesions | The pruritus NRS is comprised itch level grading from the numbers 0 (no itch) to 10 (worst imaginable itch). Subjects are asked to rate the intensity of their itch by visits. | Day 8, Day 15, Day 22, Day 29, Day 36 and Day 43 (Phase IIa) | 
| Change of IgE Compared to Baseline (Day 1) |  | Day 15 and 29 (Phase IIa) | 
| Fold Change of IL-4 Compared to Baseline (Day 1 ) |  | Day 15 and 29 (Phase IIa) | 
| Change From Baseline in Signs of Atopic Dermatitis (Erythema, Edema, Excoriation and Lichenification) on Target Lesions | 4 symptoms of atopic dermatitis (erythema, edema, excoriation and lichenification) will be evaluated on all target lesions and graded from 0 to 3 (none, mild, moderate and severe, respectively), with half points allowed | Day 8, Day 15, Day 22, Day 29, Day 36 and Day 43 (Phase IIa) | 
| Change From Baseline in the Total Score of Patient-Oriented Eczema Measure (POEM) | POEM is a validated, patient-derived assessment measure for monitoring atopic eczema severity , available at the HOME (Harmonising Outcome Measures for Eczema) group. It contains seven symptoms of AD on 5-point (0 to 4) scale with total score 0 to 28 during the study. A higher score means a worse outcome, whereas a lower score is a better outcome. | Day 8, Day 15, Day 22, Day 29, Day 36 and Day 43 (Phase IIa) | 
| Number of Subjects With AE and SAE |  | Day -14 to 29 (Phase I); Day -14 to 43 (Phase IIa) | 
| Change From Baseline in Vital Signs (Systolic Blood Pressure) | Vital signs measurement will consist of systolic/diastolic blood pressure, respiratory rate, pulse rate or heart rate, and body temperature. | Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa) | 
| Number of Subjects With Physical Examination Abnormalities | Physical examination will include the following items: general appearance, skin, eyes, ears, nose, throat, head and neck, heart, chest and lungs, abdomen, extremities, lymph nodes, musculoskeletal, neurological and others. | Day -14 to 29 (Phase I); Day -14 to 43 (Phase IIa) | 
| Number of Subjects With 12-lead ECG Abnormalities | ECG will be evaluated by the investigators and noted as Normal, Abnormal, non-clinical significant (NCS) or Abnormal, clinical significant (CS) | Day 1, Day 8, Day 15, Day 22, Day 29 (Phase I); Day 1, Day 8, Day 15, Day 22, Day 29, Day 43 (Phase IIa) | 
| Number of Subjects With Clinically Significant Laboratory Abnormalities (Hematology) | Laboratory tests include hematology (hemoglobin, hematocrit, RBC, platelet, WBC with different counts), biochemistry (total bilirubin, AST, ALT, serum creatinine and albumin) | Day 8 to Day 29 (Phase I); Day 8 to Day 43 (Phase IIa) | 
| Change From Baseline in Vital Signs (Diastolic Blood Pressure) | Vital signs measurement will consist of systolic/diastolic blood pressure, respiratory rate, pulse rate or heart rate, and body temperature. | Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa) | 
| Change From Baseline in Vital Signs (Pulse Rate) | Vital signs measurement will consist of systolic/diastolic blood pressure, respiratory rate, pulse rate or heart rate, and body temperature. | Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa) | 
| Change From Baseline in Vital Signs (Respiration Rate) | Vital signs measurement will consist of systolic/diastolic blood pressure, respiratory rate, pulse rate or heart rate, and body temperature. | Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa) | 
| Change From Baseline in Vital Signs (Body Temperature) | Vital signs measurement will consist of systolic/diastolic blood pressure, respiratory rate, pulse rate or heart rate, and body temperature. | Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa) | 
| Number of Subjects With Clinically Significant Laboratory Abnormalities (Biochemistry) | Laboratory tests include hematology (hemoglobin, hematocrit, RBC, platelet, WBC with different counts), biochemistry (total bilirubin, AST, ALT, serum creatinine and albumin) | Day 8 to Day 29 (Phase I); Day 8 to Day 43 (Phase IIa) | 
| Percentage of Subjects Achieving the Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) on Day 8, Day 15, Day 22, Day 36 and Day 43 (Phase IIa) | The IGA is a 5-point scale that provides a global clinical assessment of AD severity based on an ordinal scale, scored by the investigator. The scores of IGA are 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate) and 4 (Severe). | Day 8, Day 15, Day 22, Day 36 and Day 43 (Phase IIa) | 
| Change From Baseline of Target Lesion Area(s) on Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 (Phase IIa) |  | Day 8, Day 15, Day 22, Day 29, Day 36 and Day 43 (Phase IIa) |