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A First-in-Human study to determine safety, tolerability and systemic exposure of topically applied CEE321 in adult subjects

A First-in-Human study of CEE321 in adult subjects

28

Part A (healthy subjects) Of the 17 subjects, majority (82.4%) were male, 52.9 % were Asians (Chinese (29.4%) and Japanese (23.5%)), and the mean age was 46.0 (range 25, 62) years. Part B (AD subjects) Of the 11 subjects, 81.8% were male and 81.8 % were Asians (all Japanese. The mean age was 37.5 (range 22, 65) years.

A total of 17 subjects completed screening and were enrolled in Part A. There were 9 subjects in cohort 1 and 8 subjects in cohort 2 as the subject in cohort 1, who discontinued the study treatment period, was replaced, but no replacement was considered in cohort 2. The majority of the subjects (88.2%) across the two cohorts completed the treatment period. The primary reasons for the 2 subjects (1 from each cohort) who discontinued from the study treatment period included AE (5.9%) or subject/guardian decision (5.9%). Overall, 15 subjects entered the post-treatment follow-up period and all these subjects completed the posttreatment follow-up period. All subjects in the study received open label CEE321 (0.2%) cream for topical application. To standardize and control the quantity of CEE321 0.2 % cream (3 mg/cm2) during the treatment period D1 until D15 (morning dose), in both Part A and Part B, treatment consisted of controlled topical application of CEE321 cream by a trained nurse or designated trained person. A total of 11 subjects completed screening and were enrolled in the AD cohort. All subjects completed the treatment period and the post-treatment follow-up period. In Part B, for the 'self-application' part of the treatment period (D15 evening dose until D28), the subject was required to apply CEE321 cream by themselves to the treatable skin area in an amount guided by an 'adapted fingertip unit' approach.

Part A (Healthy Subjects) Overall, across cohorts, the most reported AEs (> 20%) by primary SOC were skin and subcutaneous tissue disorders (35.3%) (11.1% in cohort 1, and 62.5% in cohort 2) Part B (AD subjects) The most reported AEs (> 20%) by primary SOC were skin and subcutaneous tissue disorders (63.6%)

- Overall, 7 out of 17 subjects (41.2%) had at least one AE during Part A and all events reported were of mild severity. The most frequent AEs (> 10%) by PT were skin exfoliation (17.6%) and skin irritation (11.8%). During Part B, 9 out of 11 subjects (81.8%) had at least one AE and all events were of mild (54.5%) or moderate severity (54.5%). The most frequent AEs (> 10%) by PT were dermatitis atopic (63.6%), dermatitis contact (18.2%), and post procedural erythema (18.2%). - During Part A, AEs suspected to be related to the study drug, were reported in 2 subjects in cohort 2. One subject had skin irritation, while the other subject had a burning sensation, rash, and skin exfoliation. The severity of all of these AEs was mild. During Part B, 3 subjects had AEs suspected to be related to the study drug, of which 2 subjects had dermatitis contact of moderate severity and 1 subject had application site dryness and application site pain of mild severity. - No deaths were reported during the study. - No SAEs were reported during the study. - In Part A, 1 subject (5.9%) in cohort 2 discontinued from the study due to a study drug related AE (skin irritation of mild severity). In Part B, there were no AEs leading to study discontinuation, however, 1 subject discontinued the study treatment due to study drug related AE (dermatitis contact of moderate severity). - One subject in AD cohort had an AE of increased blood creatine phosphokinase, however it was not suspected to be related to the study drug by the investigator. There were no other clinically significant abnormalities in hematology, clinical chemistry, urinalysis, coagulation parameters, and vital signs including BP and ECG observed during the study. - In part A, mean trough concentrations increased continuously with time achieving mean (+- SD) plasma Ctrough at Day 15 (0 hours pre-dose) of 0.0544 (+- 0.0564) ng/mL in cohort 1 and 0.103 (+- 0.0978) ng/mL in cohort 2. The intersubject variability (CV% mean) was high (103.8% in cohort 1 and 95.0% in cohort 2). - In part B, the mean (+- SD) plasma Ctrough at Day 15 (0 hours pre-dose) was 0.104 (+- 0.0722) ng/mL and 1.07 (+- 1.12) ng/mL for the two groups respectively. The mean (+- SD) plasma Ctrough at Day 15 (0 hours pre-dose) was 0.368 (+- 0.678) ng/mL. The intersubject variability (CV% mean) overall was 184.2%.

No deaths or SAEs were reported during this study. CEE321 0.2% cream was generally safe and well tolerated in healthy subjects as well as in AD subjects except for some skin-related AEs. Overall, a low systemic exposure of CEE321 was seen as expected, somewhat higher plasma exposure in AD subjects was measured as compared to healthy subjects.

No

https://jrct.niph.go.jp/latest-detail/jRCT2031200317

Yamada Hiroyuki

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

rinshoshiken.toroku@novartis.com

Yamada Hiroyuki

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

+81-120-003-293

rinshoshiken.toroku@novartis.com

Complete

Jan. 20, 2021

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

treatment purpose

Key Inclusion Criteria for Healthy Subjects (Part A)
- Written informed consent
- Able to communicate well with the investigator to understand and comply with the requirements of the study, including skin biopsies
- Healthy male and female subjects aged >= 18 and =< 65 years
- Able to comply with requirement of domiciliation at the investigational site

Key Inclusion Criteria for Atopic Dermatitis Subjects (Part B)
- Written informed consent
- Able to communicate well with the investigator to understand and comply with the requirements of the study, including skin biopsies
- Adult male and female subjects aged >= 18 and =< 65 years with confirmed clinical diagnosis of atopic dermatitis (AD)

Key Exclustion Criteria for Healthy Subjects (Part A)
- Subjects with a history of hypertrophic scars or keloids.
- Any infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals and/or hispitalization, isolation, quarantine within 4 weeks prior to first treatment
- Women of childbearig potential defined as all women physiologically capabel of becoming pregnant.
- History of drug or alcohol abuse within the 12 months prior to dosing
Key Exclusion Criteria for Atopic Dermatitis Subjects (Part B)
- Subjects with a history of hypertrophic scars or keloids.
- Any infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals and/or hispitalization, isolation, quarantine within 4 weeks prior to first treatment
- Women of childbearig potential defined as all women physiologically capabel of becoming pregnant, unless they are using highly effective methods of contraceptin
- History of drug or alcohol abuse within the 3 months prior to dosing.
- Any skin disease that, in the opinion of the investigator, would confound the diagnosis or evaluation of AD disease activity
- Clinical significant medical condition, including psychiaric condition, wihich in the Investigator's opinion may interfere with safety of subjects, study objectives or adherence to the protocol.

Both

Atopic Dermatitis

CEE321 (Topical use)

Number of subjects with adverse events

+81-42-625-5216

US