A Study to Assess the Safety and Efficacy of ZPL389 With TCS/TCI in Atopic Dermatitis Patients

Study Overview
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Brief Summary
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This extension study (CZPL389A2203E1) was designed as a 2-year (100 weeks) extension to the core study (CZPL389A2203/ NCT03517566) which is disclosed separately. It aimed to assess the short-term and long-term safety of (blinded) 30 mg o.d and 50 mg o.d ZPL389 with concomitant or intermittent use of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI).

Detailed Description
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Subjects who had received ZPL389 30 mg or 50 mg doses in the core study (CZPL389A2203), continued to receive the same doses in double-blinded fashion. Subjects who had received ZPL389 3 mg, 10 mg or placebo in the core study were randomized to 30 mg or 50 mg ZPL389 in a 1:1 ratio. All subjects received concomitant or intermittent TCS and/or TCI along with ZPL389. Short-term safety was assessed up to week 16 of this extension study (week 16 to week 32 referring to the start of core study treatment) and long-term safety was assessed after week 16 of this extension study (after week 32 referring to the start of core study treatment). The entire planned time frame (100 weeks) was not assessed as originally planned due to early termination of the core and extension studies.

Official Title
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A Randomized, Double Blind, Multicenter Extension to CZPL389A2203 Dose-ranging Study to Assess the Short-term and Long-term Safety and Efficacy of Oral ZPL389 With Concomitant Use of TCS and/or TCI in Adult Patients With Atopic Dermatitis.

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: ZPL389 30mg
* Drug: ZPL389 50mg
* Drug: TCS and/or TCI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must give a written, signed and dated informed consent Subjects with atopic dermatitis who have participated in and completed 16 weeks of treatment in CZPL389A2203 study. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, diary completion and other study procedures. Exclusion Criteria: Inability to use TCS and/or TCI due to history of important side effects of topical medication (e.g., intolerance or hypersensitivity reactions). Treatment discontinued subject from CZPL389A2203 study. Any skin disease that would confound the diagnosis or evaluation of atopic dermatitis disease activity.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZPL389 30mg<br>30mg of ZPL389 + TCS and/or TCI for patients re-randomized from the core study (received placebo/ZPL389 3mg/ 10mg in the core study) and for patients continuing in the same arm from the core study | Drug: ZPL389 30mg<br>* 30mg of ZPL389; once daily<br>Drug: TCS and/or TCI<br>* Topical corticosteroids (TCS) and /or topical calcineurin inhibitors (TCI) were used concomitantly or intermittently based on disease severity.<br>|
| Experimental: ZPL389 50mg<br>50mg of ZPL389 + TCS and/or TCI for patients re-randomized from the core study (received placebo/ZPL389 3mg/ 10mg in the core study) and for patients continuing in the same arm from the core study | Drug: ZPL389 50mg<br>* 50mg of ZPL389; once daily<br>Drug: TCS and/or TCI<br>* Topical corticosteroids (TCS) and /or topical calcineurin inhibitors (TCI) were used concomitantly or intermittently based on disease severity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events in the First 16 Weeks of This Extension Study | An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study until the end of study visit. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis. | 16 weeks (week 16 to week 32 referring to core study) | 
| Number of Patients With Adverse Events After 16 Weeks of Treatment in This Extension Study | An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study until the end of study visit. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis. | From week 16 to week 67 of this extension study (week 32 to week 83 referring to core study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Investigator's Global Assessment (IGA) Responders Over Time | IGA score is used to determine the severity of atopic dermatitis symptoms and clinical response to treatment. The scale ranges from 0=clear to 4=severe. It is a static scale and doesn't refer to previous status of the subject. IGA response is an achievement of an IGA score of 0 or 1 with a 2-point reduction from baseline without use of confounding therapy up to the assessment time point. Treatment discontinuations for lack of efficacy or AE are considered non-responders.Presentation of the results is stratified by if patients were re-randomized from the core study or not. As all patients were rolling over from the core study, in addition to the timeframe referring to the start in this extension study, the timeframe corresponding to the start in the core study (+16 weeks) are provided in parenthesis. Percentage of responders was calculated based on a logistic regression model with response as outcome variable and treatment (dose as categorical variable) and baseline IGA as covariates. | Week 4, Week 8, Week 12, Week 16, Week 28, Week 40 (Week 20, Week 24, Week 28 ,Week 32, Week 44, Week 56 referring to core study) | 
| Percentage of EASI50 Responders Over Time | Eczema Area and Severity Index (EASI) is used to assess the extend and severity of atopic dermatitis on a scale from 0 to 72 where 72 is worst eczema. EASI50 response is defined as achieving ≥ 50% improvement (reduction) in EASI score compared to baseline. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders. Presentation of the results is stratified by if patients were re-randomized from the core study or not. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis. Percentage of responders was calculated based on a logistic regression model with response as outcome variable and treatment (dose as categorical variable) and baseline EASI as covariates. | Week 4, Week 8, Week 12, Week 16, Week 28, Week 40 (Week 20, Week 24, Week 28 ,Week 32, Week 44, Week 56 referring to core study) | 
| Percentage of EASI75 Responders Over Time | Eczema Area and Severity Index (EASI) is used to assess the extend and severity of atopic dermatitis on a scale from 0 to 72 where 72 is worst eczema. EASI75 response is defined as a reduction from baseline of ≥ 75% in EASI score. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders. Presentation of the results is stratified by if patients were re-randomized from the core study or not. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis. Percentage of responders was calculated based on a logistic regression model with response as outcome variable and treatment (dose as categorical variable) and baseline EASI as covariates. | Week 4, Week 8, Week 12, Week 16, Week 28, Week 40 (Week 20, Week 24, Week 28 ,Week 32, Week 44, Week 56 referring to core study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atopic dermatitis, AD, eczema, itch, pruritus, H4R, ZPL389