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
Overview
- Phase
- Phase 1
- Intervention
- AR100DP1
- Conditions
- Dermatitis, Atopic
- Sponsor
- Arjil Pharmaceuticals LLC
- Enrollment
- 17
- Locations
- 1
- Primary Endpoint
- Number of Subjects With DLTs
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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)
Exclusion Criteria
- •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)
- •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
Arms & Interventions
AR100DP1 (1.25%)_Phase I
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).
Intervention: AR100DP1
AR100DP1 (2.5%)_Phase I
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).
Intervention: AR100DP1
AR100DP1 (5%)_Phase I
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).
Intervention: AR100DP1
AR100DP1 (5%)_Phase IIa
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).
Intervention: AR100DP1
Outcomes
Primary Outcomes
Number of Subjects With DLTs
Time Frame: up to Day 29 for each cohort in phase I
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).
Percentage of Subjects With the Investigator's Global Assessment (IGA) Score of 0 or 1 on Day 29 (Phase IIa)
Time Frame: 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).
Maximum Tolerated Dose (MTD) of AR100DP1
Time Frame: up to Day 29 for each cohort in phase I
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).
Secondary Outcomes
- Number of Subjects With Physical Examination Abnormalities(Day -14 to 29 (Phase I); Day -14 to 43 (Phase IIa))
- Number of Subjects With 12-lead ECG Abnormalities(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)(Day 8 to Day 29 (Phase I); Day 8 to Day 43 (Phase IIa))
- Change From Baseline in Vital Signs (Diastolic Blood Pressure)(Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa))
- Change From Baseline in Vital Signs (Pulse Rate)(Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa))
- Change From Baseline in Vital Signs (Respiration Rate)(Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa))
- Change From Baseline in Vital Signs (Body Temperature)(Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa))
- Number of Subjects With Clinically Significant Laboratory Abnormalities (Biochemistry)(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)(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))
- Change From Baseline in Pruritus Numerical Rating Scale (NRS) of Itch Level on Target Lesions(Day 8, Day 15, Day 22, Day 29, Day 36 and Day 43 (Phase IIa))
- Fold Change of IL-4 Compared to Baseline (Day 1 )(Day 15 and 29 (Phase IIa))
- Change From Baseline in the Total Score of Patient-Oriented Eczema Measure (POEM)(Day 8, Day 15, Day 22, Day 29, Day 36 and Day 43 (Phase IIa))
- Percentage of Subjects With the Investigator's Global Assessment (IGA) Score of 0 ~ 4 (Phase IIa)(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))
- Change From Baseline in Signs of Atopic Dermatitis (Erythema, Edema, Excoriation and Lichenification) on Target Lesions(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)(Day 1 to 29 (Phase I); Day 1 to 43 (Phase IIa))