Conditions: Atopic Dermatitis
Keywords: atopic dermatitis AD eczema atopic eczema itch, pruritus histamine 4 receptor antagonist H4R ZPL389 ZPL389A2203 dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 293
Healthy volunteers: no

Brief summary:
This was a randomized, double-blind, placebo-controlled, parallel-group study to assess safety and efficacy of ZPL389 in subjects with moderate to severe atopic dermatitis with a total study duration up to 24 weeks

Detailed description:
A screening period of up to 4 weeks was followed by a 16-week double blinded treatment period.

After the end of treatment visit, subjects were offered the possibility of ongoing treatment in the extension study (CZPL389A2203E1/ NCT03948334), or of entering the 4 week treatment-free follow-up period.

Arms:
arm 1: Placebo arm 2: ZPL389 3 mg oral powder arm 3: ZPL389 10 mg oral powder arm 4: ZPL389 30 mg oral powder arm 5: ZPL389 50 mg oral powder

Interventions: intervention 1: Placebo intervention 2: ZPL389 3mg intervention 3: ZPL389 10mg intervention 4: ZPL389 30mg intervention 5: ZPL389 50mg
Intervention descriptions: intervention 1: once daily from baseline until week 16 intervention 2: ZPL389 3 mg oral powder; once daily from baseline to week 16 intervention 3: ZPL389 10 mg oral powder; once daily from baseline to week 16 intervention 4: ZPL389 30 mg oral powder; once daily from baseline to week 16 intervention 5: ZPL389 50 mg oral powder; once daily from baseline to week 16

Protocol document:
SAP_002.pdf: 
Clinical Development 
ZPL389 
CZPL389A2203 and A2203E1 / NCT03517566 and NCT03948334 
A randomized, double-blind, placebo-controlled multicenter 
dose-ranging study and extension to assess the safety and 
efficacy of multiple oral ZPL389 doses and long-term safety 
and efficacy of oral ZPL389 with concomitant or 
intermittent use of TCS and/or TCI in patients with 
moderate to severe atopic dermatitis 
Statistical Analysis Plan (SAP) 
Author: 
Statistician, 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
29-Sep-2020
Number of pages: 
35 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
29-
Sep-
2020 
Prior 
to 
DB 
lock 
Creation 
of final 
version 
N/A - First version 
NA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 8 
2 
Statistical methods ............................................................................................................. 12 
2.1 
Data analysis general information ......................................................................... 12 
2.1.1 
General definitions ................................................................................ 13 
2.2 
Analysis sets .......................................................................................................... 15 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 16 
2.3.1 
Patient disposition ................................................................................. 16 
2.3.2 
Demographics and baseline characteristics ........................................... 16 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 17 
2.4.1 
Study treatment / compliance ................................................................ 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 18 
2.5 
Analysis of the primary objective .......................................................................... 19 
2.5.1 
Primary endpoint ................................................................................... 19 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 20 
2.5.4 
Supportive analyses ............................................................................... 20 
2.6 
Analysis of secondary objectives ........................................................................... 22 
2.6.1 
Dose-response for EASI50 response and EASI75 response at week 
16 ........................................................................................................... 22 
2.6.2 
Dose-response for percentage change from baseline in EASI at 
week 16 ................................................................................................. 22 
 
 23 
 
 
 23 
2.6.5 
Efficacy over time up to week 16 ......................................................... 24 
2.6.6 
Efficacy over time in the presence of TCS and/or TCI use after 
week 16 ................................................................................................. 25 
2.6.7 
Statistical hypothesis, model, and method of analysis .......................... 26 
2.6.8 
Handling of missing values/censoring/discontinuations ....................... 26 
2.7 
Safety analyses ....................................................................................................... 26 
2.7.1 
Adverse events (AEs) ............................................................................ 26 


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2.7.2 
Deaths .................................................................................................... 28 
2.7.3 
Laboratory data ..................................................................................... 28 
2.7.4 
Other safety data ................................................................................... 28 
 
 28 
2.9 
Patient-reported outcomes ..................................................................................... 28 
 
 28 
 
 28 
2.12 
Interim analysis ...................................................................................................... 28 
3 
Sample size calculation ..................................................................................................... 29 
4 
Change to protocol specified analyses .............................................................................. 29 
5 
Appendix ........................................................................................................................... 29 
5.1 
Imputation rules ..................................................................................................... 29 
5.1.1 
Study drug ............................................................................................. 29 
5.1.2 
Concomitant medication date imputation ............................................. 30 
5.1.3 
Prior therapies date imputation ............................................................. 30 
5.1.4 
Post therapies date imputation .............................................................. 31 
5.1.5 
First diagnosis date imputation ............................................................. 31 
5.2 
Statistical models ................................................................................................... 31 
5.2.1 
Analysis of continuous data .................................................................. 31 
5.2.2 
Analysis of binary data .......................................................................... 32 
5.2.3 
Multiple imputations for response variables ......................................... 33 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
 
 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
 
 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TCI 
Topical Calcineurin Inhibitors 
TCS 
Topical Corticosteroids 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
This Statisticial Analysis Plan (SAP) describes the statistical analysis planned for the Clinical 
Study Report (CSR) for studies ZPL389A2203 and ZPL389A2203E1 (henceforth called A2203 
and A2203E1, respectively). Both studies will be reported in the same CSR.  
Following an interim analysis with database lock in May 2020, the decision was made to stop 
both study A2203 (the core study) and A2203E1 (an extension study) and this SAP reflects 
changes to the analysis strategy described in the protocols (V3 for A2203 and V1 for A2203E1) 
that were made following this decison. 
1.1 
Study design 
The core study (A2203) was planned as a randomized, double blind, placebo controlled, parallel 
group, 5-arm study in at least 360 subjects with moderate to severe Atopic Dermatitis (AD). 
Unbalanced randomization ratio was used, intending to result in approximately 90 subjects 
randomized in each of the 30 mg/day and 50 mg/day dose arms as well as in the placebo arm, 
and 45 subjects in each of the 3 mg/day and 10 mg/day arms. The randomization was stratified 
by baseline severity of atopic dermatitis (IGA score moderate or severe) and by geographical 
region. 
The possibility to perform an interim analysis (IA) in order to support decision making 
concerning the current clinical study or project was addeded to the protocol in V3. This interim 
analysis was performed in May 2020 on 187 patients who had completed week 16 or 
discontinued before this timepoint. Based on the results from this IA, it was decided to stop 
both the core and extension studies for reasons of lack of efficacy and thus the final number of 
patients, and follow-up time per patient is less than planned in the protocol. 
The core study (A2203) consisted of a screening period of up to 4 weeks (depending on current 
medication use and associated washout period), and a 16-week double blinded treatment period. 
The primary endpoint was to be assessed at the end of the 16 week treatment period. 
After the end of treatment visit, subjects were offered the possibility of ongoing treatment in 
the extension study (A2203E1), or of entering the 4 week treatment-free follow up period. 


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Figure 1-1 
Core study design (A2203) 
 
The extension study (A2203E1) was intended to be a randomized, double blind, parallel group, 
2-arm study in up to approximately 202 to 230 subjects. This number assumed a  discontinuation 
rate of 15% to 25% in the core study (A2203)  
In the extension study, subjects who had received ZPL389 30 mg o.d. or 50 mg o.d. doses in 
the core study, would continue to receive the same doses in a double-blinded fashion. Subjects 
who had received ZPL389 3 mg, 10 mg or placebo in the core study, would be randomized to 
receive ZPL389 30 mg o.d. or 50 mg o.d. in a 1:1 ratio. All subjects would receive concomitant 
or intermittent topical corticosteroids (TCS) and/or topical calcineurin inhibitors  (TCI) along 
in a standardized regimen with ZPL389. 
After completing 100 weeks of study treatment during the extension study (i.e. up to Week 116 
including 16 weeks of the core study), subjects were to enter the 4 weeks treatment-free follow-
up period. 


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Figure 1-2 
Extension study design (A2203E1) 
 
 
1.2 
Study objectives and endpoints 
Following the decision to stop the studies, not all 
 will be evaluated in 
the abbreviated CSR, as indicated in the table below. 
Table 1-1 
Objectives for the core study A2203  
Objective 
Endpoint 
Included in CSR? 
Primary objective 
 
 
To characterize the dose-
response relationship of 
ZPL389 in subjects with 
moderate to severe AD 
assessed by IGA response 
after 16 weeks of treatment 
IGA response at Week 16 
Yes 
Secondary objectives 
 
 
Into 2 treatment arms 
in a 1:1 ratio 
ZPL389  
50 mg/day 
ZPL389  
30 mg/day 
ZPL389  
10 mg/day 
ZPL389  
3 mg/day 
Placebo 
 
ZPL389 50 mg/day + 
TCS and/or TCI 
ZPL389 30 mg/day + 
TCS and/or TCI 
ZPL389 50 mg/day + 
TCS and/or TCI 
ZPL389 30 mg/day + 
TCS and/or TCI 
Baseline 
(Core Study) 
Week 16 
(Core Study) 
Baseline/Randomization 
for CZPL389A2203E1 
(Week 16 of core study) 
End of Treatment 
for 
CZPL389A2203E1 
(Week 116) 
Follow-up  
(Week 120) 
4 Weeks 
follow-up 
4 Weeks 
follow-up 
4 Weeks 
follow-up 
4 Weeks 
follow-up 
Subjects will be 
randomized
Subjects will continue 
Subjects will continue 
CZPL389A2203
CZPL389A2203E1 
Treatment Period 
100 Weeks


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Objective 
Endpoint 
Included in CSR? 
To characterize the dose-
response relationship of 
ZPL389 in subjects with 
moderate to severe AD 
assessed using the percent 
change from Baseline in 
Eczema Area and Severity 
Index (EASI) score after 16 
weeks of treatment 
Percent change from baseline 
EASI score at Week 16 
Yes 
To evaluate the efficacy across 
different dose levels as 
assessed by EASI and IGA 
compared to placebo over time 
At each visit:  
IGA score 
IGA response 
EASI score (absolute and 
percent change from Baseline)  
EASI50 response, EASI75 
response 
Yes (except IGA score and 
absolute change in EASI score 
from baseline) 
To assess the safety and 
tolerability of different doses of 
ZPL389 as compared to 
placebo 
Frequency of adverse events 
Yes 


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Objective 
Endpoint 
Included in CSR? 
 
Table 1-2 
Objectives for the extension study A2203E1 
Objectives 
Endpoints 
Included in 
CSR? 
Primary objective 
 
 


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Objectives 
Endpoints 
Included in 
CSR? 
To assess the short-term and long-
term safety of 30 mg o.d and 50 mg 
o.d ZPL389 with concomitant or 
intermittent use of TCS and/or TCI up 
to total of 32 weeks and 116 weeks of 
treatment. 
Frequency of AEs at Week 32 (short-
term) and Week 116 (long-term). 
Yes 
Secondary objectives 
 
 
To evaluate the efficacy of 30 mg o.d 
and 50 mg o.d ZPL389 with 
concomitant or intermittent use of 
TCS and/or TCI as assessed by IGA 
response over time. 
IGA score over time (absolute and 
relative frequencies from core study 
baseline). 
 
Yes 
To evaluate the efficacy of 30 mg o.d 
and 50 mg o.d ZPL389 with 
concomitant or intermittent use of 
TCS and/or TCI as assessed by EASI 
over time. 
EASI score over time (absolute and 
percent change from core study 
baseline). 
 
Yes 


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Objectives 
Endpoints 
Included in 
CSR? 
 
2 
Statistical methods 
2.1 
Data analysis general information 
Novartis will perform the analyses for this study. Statistical software SAS verion 9.4 or later 
will be used. 
All available data from the core and extension studies will be presented together. 
Where summary statistics are presented these will include, for continuous variables N, mean, 
standard deviation, minimum, and maximum, and for discrete variables, counts and appropriate 
percentages. 
If not otherwise specified, p-values will be presented for two-sided hypothesis testing, two- 
sided confidence intervals will be displayed and the level of significance will be set to 5% two-
sided. 
In general listings will be presented by treatment sequence showing the sequence of treatments 
in the core and extension study, i.e as follows and in this order 
• Placebo – did not participate in extension 
• Placebo – ZPL389 50mg 
• Placebo – ZPL389 30mg 


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• ZPL389 3mg – did not participate in extension 
• ZPL389 3mg – ZPL389 30mg 
• ZPL389 3mg – ZPL389 50mg 
• ZPL389 10mg – did not participate in extension 
• ZPL389 10mg – ZPL389 30mg 
• ZPL389 10 mg – ZPL389 50mg 
• ZPL389 30mg – did not participate in extension 
• ZPL389 30mg – ZPL389 30mg 
• ZPL389 50mg – did not participate in extension 
• ZPL389 50mg – ZPL389 50mg 
2.1.1 
General definitions 
Study treatment is either placebo or 3, 10, 30 or 50mg ZPL389. 
Day 1 is defined to be the first day of administration of any study treatment. 
All other study days will be labeled relative to Day 1. For event dates on or after Day 1, studyday 
for a particular event date is calculated as [Date of event] – [Date of first dose]+1, i.e., Day 2, 
Day 3, etc., will be one day, two days, etc., after Day 1, respectively. For the dates beforeDay 
1, study day for an event date is calculated as [Date of event] – [Date of first dose], i.e., Day -
1, Day -2, etc., will be one day, two days, etc., before Day 1, respectively. Duration of an event 
will be calculated as (Event end date – Event start date + 1). 
The descriptor “Day 0” will not be used. 
Screening refers to any procedure (e.g., checking inclusion and exclusion criteria) performed 
prior to the date of first dose of study treatment. Per protocol, subject informed consent must 
be obtained prior to performing any study related activity. The date of signing informed consent 
is the start date of screening period.  
Baseline is considered to be the last assessment (including those from unscheduled visits) 
obtained before the first dose of study treatment. All assessments obtained after first dose of 
study treatment are considered as post-baseline unless otherwise specified. 
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. However, if no pre-treatment value exists, values obtained after 
first dose of treatment but on that same day of dosing will be considered as the baseline. 
The date of last dose will be collected via the CRF. The end of the treatment period will be 
defined as the last dose date or last visit in treatment period whichever occurs earlier. i.e., for 
subjects who discontinued or have their last visit earlier than last dose date, the end of study 
treatment will be the date of the last study visit in the corresponding treatment period. 
The core study treatment period is defined to be the time up until the date of the first visit in the 
extension study whilst the patient is receiving study treatment. 
The extension study treatment period is defined to be the time up from the first visit in the 
extension study until the end of study treatment 


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The follow-up period is defined to be the time from last dose of study treatment until the end of 
the study (latest of core and extension for that patient). 
The concept of assessment windows will be used for the data that is summarized by visit. Each 
assessment window is based on the study evaluation schedule and comprises a set of days 
around the nominal visit day. For any assessment, there are the protocol defined scheduled visits 
around which windows were created to cover the complete range of days within the study. The 
visit windows are shown in Table 2-1. 
These assessment windows apply to measurements taken at every visit. For assessments which 
are not collected at every visit, the assessment windows defined in Table 2-1 will be combined. 
For example, if an assessment is measured at Week 4 and Week 8 only, the Week 4 assessment 
window for this parameter will extend from Day 2 to Day 43 (combining Week 2 to Week 4), 
Week 8 will extend from Day 44 to Day 71 (combining Week 6 to Week 8). 
When assessment windows are used, all visits will be re-aligned, i.e., they will be mapped into 
one of the assessment windows. For example, if the Week 4 visit of a subject is delayed and 
occurs on Day 60 instead of on Day 29, the data will be considered to relate to Week 8. In the 
case of major deviations from the visit schedule, or due to unscheduled visits, several 
assessments of a subject may fall in a particular assessment window (either scheduled or 
unscheduled). The approaches  to handle multiple assessments in a given window are specified 
below. 
Assignment of data to the assessment windows will be done before deriving further parameters 
(e.g. change from baseline, responder status) from the assessments. The assessment windows 
will be used for summary tables and figures but listings will show the original visit at which the 
data were recorded, along with the study day of the assessment. 
Table 2-1 
Visit windows 
Visit as used for 
reporting 
Week 
Scheduled study day 
Assessment window 
Screening 
SCN 
-35 to -1 
Day -35 to -1 
Baseline 
0 
1 
Day 1 
Week 2 
2 
15 
Day 2 – 22 
Week 4 
4 
29 
Day 23 – 26 
Week 6 
6 
43 
Day 37 – 50 
Week 8 
8 
57 
Day 51 – 71 
Week 12 
12 
85 
Day 72 – 99 
Week 16 
16 
113 
Day 100 – 127 
Week 20 
20 
141 
Day 128 – 155 
Week 28 
28 
197 
Day 184-211 
Week 32 
32 
225 
Day 212-267 
Week 44 
44 
309 
Day 268-351 
Week 56 
56 
393 
Day 352-435 
Week 68 
68 
477 
Day 436-519 
Week 80 
80 
561 
Day 520-603 
Week 92 
92 
645 
Day 604-687 


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Visit as used for 
reporting 
Week 
Scheduled study day 
Assessment window 
Week 104 
104 
729 
Day 688-771 
Week 116 
116 
8130 
Day 772-827 
Week 120 
120 
841 
Day >= 828 
If more than one assessment falls into the interval, the rules defined below will be applied unless 
otherwise specified.  
• for quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen); 
• for qualitative variables, the worst record is selected.  
Confounding medications 
Any use of rescue medication or prohibited medication will be considerd as confounding 
therapy, where rescue medications are collected from the rescue therapy CRF and 
concomitant medications listed below will be considered as prohibited medications. 
1. All cases of conmeds in the following ATC classes 
• D07 CORTICOSTEROIDS, DERMATOLOGICAL PREPARATIONS 
• R06A ANTIHISTAMINES for systemic use               
2. Conmeds in the class L04 IMMUNOSUPPRESSANTS that are also PDs with PD 
identifier COMD3. 
2.2 
Analysis sets  
Randomized Set (RAN): All subjects randomized. Subjects will be analyzed according to the 
treatment assigned to at randomization. 
Full Analysis Set (FAS): All subjects to whom study treatment has been assigned. Subjects will 
be analyzed according to the treatment assigned to at randomization. Mis-randomized subjects 
(mis-randomized in IRT) will be excluded from FAS. Mis-randomized subjects are defined as 
cases where IRT contacts were made by the site either prematurely or inappropriately prior to 
confirmation of the subject’s final randomization eligibility and no study medication was 
administered to the subject. 
Safety Set: All subjects who received at least one dose of study treatment. Subjects will be 
analyzed according to treatment received. 
Extension study set: All subjects in the full analysis set who have at least one visit in the 
extension study. 
The protocol deviation codes leading to exclusion from the analysis sets defined above are 
presented in below. 
Table 2-2 
Subject classification rules 
Analysis set 
PD codes that cause a subject 
to be excluded 
Non-PD criteria that cause a 
subject to be excluded 
Randomization set 
None 
Not-randomized. 


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Analysis set 
PD codes that cause a subject 
to be excluded 
Non-PD criteria that cause a 
subject to be excluded 
Full analysis set 
None 
Not-randomized, mis-
randomized. 
Safety set 
None 
No treatment taken 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
Patient dispostion will be summarized based on the randomization set and will focus on showing 
the number of patients enrolled and the times at which they discontinued the study, including 
how many progressed to the extension study and how many did not. Data will be summarised 
by treatment group to determine whether discontinuation rates and reasons were similar across 
groups.  
The key focus is on enrolment and discontinuation during the core study. Subject disposition in 
the extension is unlikely to be as intended due to the early stopping of the trial. 
Since part of the study was conducted during the COVID-19 pandemic summary tables will 
also indicate how many patients were enrolled and completed the trial during the pandemic time 
period.  
2.3.2 
Demographics and baseline characteristics 
The demography and baseline characteristics summaries are intended to answer the questions: 
• Is the trial population the one we intended to recruit? 
• Are the characteristics of the trial population similar across treatment groups? 
Contrary to the protocol, demographics and baseline characteristics will be summarized for the 
full analysis set instead of the randomized set. This will enable a comparison of the population 
for whom efficacy data is presented, with other studies.  
Only key demographic and baseline characteristics that would be important to understand the 
patient population and put efficacy results into context of other trials will be presented.  
Specifically these are: 
• Age and age category (<65 years, 65 years and older) 
• Weight  
• Body mass index 
• Gender 
• Race  
• Smoking status 
• Baseline IGA  score categories (moderate, severe) 
• Baseline EASI 
 
  


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• Baseline total body surface area (BSA) affected by AD 
 
 
• Time since diagnosis of AD 
• Age at the time of diagnosis of AD 
• Previous exposure to systemic corticosteroids(yes, no)  
• Previous exposure to topical corticosteroids (TCS) therapy (yes, no) 
• Previous exposure to topical calcineurin inhibitors (TCI) therapy (yes, no) 
• Previous exposure immunosuppressant therapy for atopic dermatitis (yes, no) 
• Previous exposure biologic systemic therapy for atopic dermatitis (yes, no) 
• Previous exposure to other therapy for atopic dermatitis (including phototherapy and 
tanning booths) (yes, no) 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The summaries of study treatment intake are intended to answer the question: 
• Was there a difference in study treatment intake across the dose groups? 
Other questions related to the intake of study treatment, such as whether this affected the 
efficacy outcomes are considered in later sections.  
This summary will be based on the safety set to include all patients who received study 
treatment according to the treatment they received. 
Although not expected based on the interim results, in case there are large differences between 
study analysis sets, further summaries may be produced based on other analysis sets. 
Duration of exposure is defined as the time from first dose of study medication to the last dose, 
i.e.  
• duration of exposure (days) = last dose date – first dose date +1 
• duration of exposure (years) = duration of exposure (days) / 365.25 
In addition to summaries of the total duration of exposure, the number of subjects with exposure 
of particular durations will be summarized, i.e. the number and percentage of patients with 
exposure of 
• ≥2 weeks 
• ≥4 weeks 
• ≥8 weeks 
• ≥12 weeks 
• ≥16 weeks 
• ≥20 weeks 
• ≥24 weeks 
• ≥28 weeks 


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• ≥32 weeks 
• ≥40 weeks 
• ≥44 weeks 
• ≥1 year 
• ≥56 weeks 
• ≥1.5y  
• ≥2y 
2.4.2 
Prior, concomitant and post therapies 
The summaries of study treatment intake are intended to answer the question: 
• What medications were used by patients before start of this trial? 
• What medications were used by patients whilst on treatment in this trial? 
• What medications were used by patients after study treatment in this trial 
Other questions related to the intake of confounding treatment (treatment that may be 
considered to affect the efficacy outcomes) are considered in later sections.  
This summary will be based on the safety set to include all patients who received study 
treatment according to the treatment they received. 
Medications will be presented by ATC code and preferred term. ATC codes will be displayed 
in alphabetical order, and grouped by anatomical main group (the first level of the ATC code). 
Medical procedures and significant non-drug therapies as coded in MedDRA will be 
summarized along with medications.  
Prior medications 
Prior medications are defined as drugs taken and stopped prior to the first dose of study 
treatment in the core study. 
These will be displayed for the baseline period by core study treatment group 
Concomitant medication 
Concomitant medications are defined as drugs taken at least once between start and end of study 
treatment (inclusive)  
Concomitant treatments will be displayed for:  
• the core study treatment period by the relevant treatment group for that period,  
• the extension study treatment period by the relevant treatment group for that period 
Follow-up medications 
Follow-up medications are defined as drugs started after the last dose of study treatment. 
These will be displayed for the follow-up period by the last treatment received prior to entering 
the follow-up period. 


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2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary objective for the extension study is to assess safety of ZPL389. This is described 
in section 2.8. This section focuses on the primary objective of the core study which is to 
characterize the dose-response relationship of ZPL389 in subjects with moderate to severe AD 
assessed by IGA response after 16 weeks of treatment. 
The primary clinical question of interest is: What is the effect of ZPL389 versus placebo on 
IGA response after the full 16 weeks of treatment in patients with moderate or severe atopic 
dermatitis, who do not use confounding therapy that may affect their AD or the assessment of 
it, regardless of their use of protocol-allowed concomitant medicatons? 
This estimand will enable assessment of the effect of ZPL389 in the absence of confounding 
medication (such as rescue medication) and after the intended 16 weeks of treatment.  
The primary estimand is described by the following attributes: 
Population: Adult moderate to severe atopic dermatitis patients as defined by the study 
inclusion and exclusion criteria who were randomized to treatment, and not mis-randomized 
in the IRT. This implies that analyses will be based on the full analysis set.  
Endpoint: IGA response at week 16, where IGA response is defined as an IGA score of 0 or 1 
with at least a 2 point improvement compared to baseline and no use of confounding therapy 
before the assessment time point. 
Treatment of interest: the randomized treatment (ZPL389 or placebo) plus medications as 
allowed by the protocol but with no further treatment for patients who discontinue study 
treatment due an AE or lack of efficacy. 
Handling of remaining intercurrent events: 
• Treatment discontinuations for lack of efficacy or adverse event: consider as non-
responder 
• Treatment discontinuations for any other reason: set data after discontinuation to be 
missing 
The summary measure: difference in response rates between ZPL389 and placebo. 
This estimand differs from that intended by the protocol in that the definition of the endpoint of 
IGA response has changed to include any use of confounding medication as a non-response, 
rather than only confounding medication that was adjudicated as having an effect on the IGA 
response, as specified in the protocol. This change was made following the interim analysis 
where it was established that handling use of confounding medication did not affect the overall 
conclusions and so it was decided not to perform the adjudication. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The key questions to address this objective are 
• Is there a dose-response relationship for IGA response after 16 weeks of treatment? 
• What is the form of this dose-response? 


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• What doses deliver sufficient efficacy in terms of IGA response after 16 weeks of 
treatment? 
Results from the interim analysis indicate that there is no dose-response relationship and 
therefore the second and third questions are no longer relevant. Thus the analysis of the primary 
variable will focus only on the logistic regression analysis described in the protocol, establishing 
the presence or absence of a dose-response relationship. The MCP-Mod procedure as outlined 
in the protocol will not be carried out. 
The primary objective will be achieved if the null hypothesis of no difference between treatment 
groups is rejected at 5% one-sided level. 
A logistic regression model will be fitted with IGA response as the outcome variable and 
treatment (dose as categorical variable) and baseline IGA as covariates. 
The response Yij for subject j in dose group i receiving dose di is modelled as Yij ~ Bin(1, pij) 
with pij = logit-1(δi+xij’β), i=1,…, 5, j=1, …, ni 
where Bin(1,p) denotes the binomial distribution with parameter 1 and p, δi is the effect of dose 
di, β refers to the vector of regression coefficients corresponding to additional covariates xij  
which represent the baseline IGA category. Finally, ni is the number of subjects allocated to 
each treatment group. If the covariate baseline IGA prevents fitting of a model, it will be 
dropped. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Where data for IGA response are missing, either because the IGA was not recorded or because 
the IGA response was set to missing as part of the handling of intercurrent events, the IGA score 
will be imputed using multiple impuation methods and the IGA response derived from this 
imputed IGA score. 
The multiple imputation model will include IGA categories from all visits from randomization 
up to Week 16. 
For the estimation of the IGA response rates at Week 16 for each treatment group, each imputed 
dataset for subjects with missing data above will be combined with the non-missing responses 
for subjects without missing data. For each imputed dataset the logistic regression will be 
performed and results combined for estimation.  
2.5.4 
Supportive analyses 
Supportive analyses for the primary estimand will focus on different methods of handling data 
in the cases of intercurrent events. 
The following supportive estimands will be considered: 
Supportive estimand 1: 
Population: Same as for the primary estimand 
Endpoint: IGA response at week 16, where IGA response is defined as an IGA score of 0 or 1 
with at least a 2 point improvement compared to baseline and no use of confounding therapy 
before the assessment time point. 


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Treatment of interest: the randomized treatment (ZPL389 or placebo) plus medications as 
allowed by the protocol but with no further treatment for patients who discontinue study 
treatment due an AE or lack of efficacy. 
Handling of remaining intercurrent events: 
• Treatment discontinuations for any reason: set data after discontinuation to be missing  
The summary measure: difference in response rates between ZPL389 and placebo. 
This estimand is considered since the classification of all patients who discontinue due to lack 
of efficacy or AE as non-responders in terms of IGA response may be too extreme. It is possible 
that patients experience improvement in their skin symptoms, but no improvement in another 
symptoms of their disease (such as itching) and for that reason discontinue study treatment. In 
this case, setting IGA response to non-response may not reflect what was happening to the 
patient. This supportive estimand will therefore help to assess whether the assumption that 
discontinuing the study due to lack of efficacy or AE implies lack of response on IGA is  a 
reasonable assumption. 
Supportive estimand 2: 
Population: Same as for the primary estimand 
Endpoint: IGA response at week 16, where IGA response is defined as an IGA score of 0 or 1 
with at least a 2 point improvement compared to baseline. Any use of confounding treatment is 
ignored. 
Treatment of interest: the randomized treatment (ZPL389 or placebo) plus medications as 
allowed by the protocol and further treatment taken to treat atopic dermatitis. 
Handling of remaining intercurrent events: 
• Treatment discontinuations for any reason: set data after discontinuation to be missing  
The summary measure: difference in response rates between ZPL389 and placebo. 
This estimand is considered to address the question of whether ZPL389 plus other medication 
as needed is more effective that placebo plus other medication as needed.  
Supportive estimand 3: 
Population: Adult moderate to severe atopic dermatitis patients as defined by the study 
inclusion and exclusion criteria who were randomized to treatment, and not mis-randomized 
in the IRT. This implies that analyses will be based on the full analysis set.  
Endpoint: IGA response at week 16, where IGA response is defined as an IGA score of 0 or 1 
with at least a 2 point improvement compared to baseline and no use of confounding therapy 
before the assessment time point. 
Treatment of interest: the randomized treatment (ZPL389 or placebo) plus medications as 
allowed by the protocol but with no further treatment for patients who discontinue study 
treatment due an AE or lack of efficacy. 
Handling of remaining intercurrent events: 
• Treatment discontinuations for any reason: consider as non-responder at week 16 


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The summary measure: difference in response rates between ZPL389 and placebo. 
This estimand is intended to assess the “worst case” situation where any discontinuation of 
study treatment is considered to represent lack of efficacy regardless of the reason entered on 
the CRF for the discontinuation. Given that a larger than expected proportion of patients gave 
“subject decision” as the reason for discontinuation this estimand will also help to address the 
question of whether ZPL389 is effective under the worst case assumption about what response 
would have been if patients had remained on treatment.  
2.6 
Analysis of secondary objectives 
Secondary objectives for the core study are to characterize the dose-response in terms of EASI 
and to evaluate efficacy over time. 
 
 
 
For the extension study the secondary objectives are to evaluate the efficacy of ZPL389 when 
used with concomitant or intermittent TCS and/or TCI. 
2.6.1 
Dose-response for EASI50 response and EASI75 response at week 16 
The dose-response analyses for EASI50 response and EASI75 response will follow similar 
principles as those for the IGA response. The primary estimand and the three supportive 
estimands will be considered in order to investigate the effect of different methods of handling 
data in the cases of intercurrent events. 
2.6.2 
Dose-response for percentage change from baseline in EASI at week 
16 
A secondary objective for core study is to characterize the dose-response relationship in terms 
of percentage change from baseline EASI score after 16 weeks of treatment. 
The primary clinical question of interest is: What is the effect of ZPL389 versus placebo on 
EASI after the full 16 weeks of treatment in patients with moderate or severe atopic dermatitis, 
who do not use confounding therapy that may affect their AD or the assessment of it, regardless 
of their use of protocol-allowed concomitant medicatons? 
This estimand will enable assessment of the effect of ZPL389 in the absence of confounding 
medication (such as rescue medication) and after the intended 16 weeks of treatment.  
The main estimand is described by the following attributes: 
Population: Adult moderate to severe atopic dermatitis patients as defined by the study 
inclusion and exclusion criteria who were randomized to treatment, and not mis-randomized 
in the IRT. This implies that analyses will be based on the full analysis set.  
Endpoint: Percentage change from baseline in EASI scores at week 16. 
Treatment of interest: the randomized treatment (ZPL389 or placebo) plus medications as 
allowed by the protocol but with no further treatment for patients who discontinue study 
treatment due an AE or lack of efficacy. 


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Handling of remaining intercurrent events: 
• Use of confounding medication: set data after use of confounding medication to missing 
• Treatment discontinuations for any reason: set data after discontinuation to be missing 
The summary measure: difference in means between ZPL389 and placebo. 
This estimand differs from that intended by the protocol in that the definition data recorded after 
the intercurrent events of use of confounding medication or treatment discontinuation are 
ignored in the analysis. The protocol had specified inclusion of all data as recorded regardless 
of use of confounding medication or discontinuation of treatment. This change was made to 
allow for an estimand for the analysis of dose-response for EASI that followed similar principles 
as that for the IGA response. 
The following supportive estimand will also be considered to address the question of what 
would be the effect of ZPL389 versus placebo after treatment for up to 16 weeks and when 
confounding medication is allowed. 
Supportive estimand 4: 
Population: Adult moderate to severe atopic dermatitis patients as defined by the study 
inclusion and exclusion criteria who were randomized to treatment, and not mis-randomized 
in the IRT. This implies that analyses will be based on the full analysis set.  
Endpoint: Percentage change from baseline in EASI scores at week 16. 
Treatment of interest: the randomized treatment (ZPL389 or placebo) plus medications as 
allowed by the protocol but with no further treatment for patients who discontinue study 
treatment. 
Handling of remaining intercurrent events: 
• No intercurrent events are considered. 
The summary measure: difference in means between ZPL389 and placebo. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.6.5 
Efficacy over time up to week 16 
The principles laid out for the primary estimand will be followed in calculating the summary 
measures for each endpoint at each time point. 
The underlying clinical question in general is: What is the effect of the study treatment versus 
placebo on the endpoint at each week, in patients with moderate or severe atopic dermatitis, 
who do not use confounding therapy that may affect their AD or the assessment of it, regardless 
of their use of protocol-allowed concomitant medicatons, and who have received the full 
intended duration of treatment at that timepoint? 
Other questions that may have been of interest in the case of an effective treatment, such as 
when is a treatment effect first seen, or how long is the treatment effect maintained for, will not 
be addressed. 
The main secondary estimands are described by the following attributes: 
Population: Adult moderate to severe atopic dermatitis patients as defined by the study 
inclusion and exclusion criteria who were randomized to treatment, and not mis-randomized 
in the IRT. This implies that analyses will be based on the full analysis set.  
Endpoints: 
IGA response at each week, where IGA response is defined as an IGA score of 0 or 1 with at 
least a 2 point improvement compared to baseline and no use of confounding therapy before the 
assessment time point. 
Percentage change from baseline in EASI at each week 
EASI50 response at each week, where EASI50 response is defined as a reduction from baseline 
of ≥ 50% in EASI score and no use of confounding therapy before the assessment time point.  
EASI75 response at each week, where EASI75 response is defined as a reduction from baseline 
of ≥ 75% in EASI score and no use of confounding therapy before the assessment time point.  
 
 
 
 
Change from baseline in peak pruritus score at each week 
Treatment of interest: the randomized treatment (ZPL389 or placebo) plus medications as 
allowed by the protocol but with no further treatment for patients who discontinue study 
treatment due an AE or lack of efficacy. 
Handling of remaining intercurrent events: 
• Treatment discontinuations for lack of efficacy or adverse event: consider as non-
responder 
• Treatment discontinuations for any other reason: set data after discontinuation to be 
missing 
The summary measure: difference in response rates or means between ZPL389 and placebo. 


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As for the primary estimands, three further supportive estimands will be considered in order to 
investigate the effect of different methods of handling data in the cases of intercurrent events. 
2.6.6 
Efficacy over time in the presence of TCS and/or TCI use after week 16 
The underlying clinical question in general is: What is the effect of the study treatment plus use 
of TCS and/or TCI as needed on endpoint at each week after week 16, in patients with moderate 
or severe atopic dermatitis, and who have received the full intended duration of treatment at 
that timepoint? 
The secondary estimands are described by the following attributes: 
Population: Adult moderate to severe atopic dermatitis patients as defined by the study 
inclusion and exclusion criteria who were randomized to treatment, and not mis-randomized 
in the IRT, and who had received 16 weeks of ZPL389 or placebo treatment and who entered 
the extension study. This implies that analyses will be based on the subset of the extension 
study set.  
Endpoints: 
IGA response at each week after week 16, where IGA response is defined as an IGA score of 0 
or 1 with at least a 2 point improvement compared to baseline. 
Percentage change from baseline in EASI at each week after week 16 
EASI50 response at each week, where EASI50 response is defined as a reduction from baseline 
of ≥ 50% in EASI score.  
EASI75 response at each week, where EASI75 response is defined as a reduction from baseline 
of ≥ 75% in EASI score.  
 
 
 
 
Change from baseline in peak pruritus score at each week after week 16 
Treatment of interest: the randomized treatment (ZPL389 or placebo) plus medications as 
allowed by the protocol including TCS or TCI and including rescue medication but with no 
further treatment for patients who discontinue study treatment due an AE or lack of efficacy. 
Handling of remaining intercurrent events: 
• Treatment discontinuations for lack of efficacy or adverse event: consider as non-
responder 
• Treatment discontinuations for any other reason: set data after discontinuation to be 
missing 
The summary measure: difference in response rates or means between ZPL389 and placebo. 
This estimand is different to that implied in the protocol for the extension study which planned 
to consider patients who use rescue medication (TCS of higher potency than that included in 
the standardized regimen of intermittent of concomitant TCS and/or TCI use) as non-responders. 


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This change is justified given that the study has been stopped and detailed consideration of the 
impact of rescue medication use on efficacy after week 16 is no longer required. 
2.6.7 
Statistical hypothesis, model, and method of analysis 
For all estimands based on binary response rates (e.g. IGA response, EASI50 response, EASI75 
response) the simple response rates for each treatment group will be calculated (i.e. number of 
responders (after imputation as necessary) / the number of subjects in that treatment group.  
Differences in response rates between ZPL389 dose groups and placebo will be calculated, and 
the respective 95% confidence intervals derived using a normal approximation. 
For estimands based on continuous data (e.g. percentage change from baseline in EASI, 
 
) a mixed effect repeated measures model (MMRM) 
approach will be used. The model will contain treatment group, baseline EASI score, 
geographical region if possible, baseline IGA score, visit, baseline value*visit and treatment 
group*visit as covariates, and will use an unstructured covariance matrix. Estimates of the mean 
responses for each visit and treatment group, and of the differences between treatment groups 
at week 16 will be obtained from this model, together with 95% confience intervals. 
2.6.8 
Handling of missing values/censoring/discontinuations 
Where data for a binary response endpoint are are missing, either because the underlying score 
was not recorded or because the response was set to missing as part of the handling of 
intercurrent events, the underlying score (IGA, or EASI) will be imputed using multiple 
impuation methods and the response derived from this imputed score. 
The multiple imputation model will include scores from all visits from randomization up to the 
time point of imputation. 
For endpoints that are analyzed as continuous variables (for example EASI score % change 
from baseline), missing values will not be imputed. In this cases the MMRM analysis approach 
is used to handle the missing data.  
If a baseline value is missing and required to derive an endpoint, the baseline value will be 
imputed by the mean of the respective treatment group in the respective randomization stratum. 
2.7 
Safety analyses 
Safety will be assessed based on the safety set of patients. 
2.7.1 
Adverse events (AEs) 
Adverse events will be coded according to the MedDRA dictionary. The actual MedDRA 
version used for reporting the adverse events will be described in a footnote of the CSR 
tables. 
Only treatment emergent AEs will be presented. Treatment emergent adverse events are those 
events that 
• started after the first dose of study treatment, or  
• were present prior to the first dose of study treatment but increased in severity based on 
preferred term. 


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AEs observed four weeks or more after last study treatment intake will not be considered as 
treatment-emergent.   
The purpose of the AE summaries are to understand what AEs are reported within different 
time periods relative to start of treatment. Thus AEs will be summarized for different time 
periods to cover the core and extension studies. Since AEs reported in a period may also be 
affected by AEs in any previous periods of treatment, the treatment groups for periods after 16 
weeks will separate subjects who received placebo and the lower ZPL389 doses for the first 16 
weeks of their treatment from those who had already received 30mg or 50mg ZPL389 for 16 
weeks. 
Therefore AEs will be summarized across the following time periods 
• AEs with onset date during the first 16 weeks of treatment – where treatment group is the 
treatment group in the core study. This summary will be based on the full safety set. 
• AEs with onset date after week 16 but before week 32 of study treatment. This summary 
will be based on the subset of the safety set comprised of patients who have on study 
treatment data after week 16. Treatment groups for this summary are  
1. Placebo and low dose ZPL389 followed by 30mg ZPL389 (for subjects who received 
placebo 3mg or 10mg ZPL389 in the core study) 
2. Placebo and low dose ZPL389 followed by 50mg ZPL389 (for subjects who received 
placebo 3mg or 10mg ZPL389 in the core study) 
3. 30mg ZPL389 (for subjects who received 30mg ZPL389 in the core study) 
4. 50mg ZPL389 (for subjects who received 50mg ZPL389 in the core study) 
• AEs with onset date after week 32 of study treatment. This summary will be based on the 
subset of the safety set comprising patients who have on study treatment data after week 
32. By week 32 it is expected that the treatment received in the core study will have less 
direct influence and therefore treatment groups for this summary are 
1. 30mg ZPL389 
2. 50mg ZPL389 
AE summaries will show, for each treatment group, the number and percentage of subjects 
• having any AE, 
• having an AE in each primary system organ class 
• having each individual AE (preferred term). 
Summaries will also be presented for AEs by severity and for study treatment related AEs. 
If a subject reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a subject reported more than one adverse 
event within the same primary system organ class, the subject will be counted only once with 
the greatest severity at the system organ class level, where applicable. 
AEs leading to discontinuation of the study drug will be summarized in a similar way. 
Serious adverse events will also be summarized. 
Separate summaries will be provided for deaths, serious adverse events, and other significant 
adverse events leading to discontinuation. 


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2.7.1.1 
Adverse events of special interest / grouping of AEs 
Summary tables showing the effects of ZPL389 in the core study on QTc and liver events will 
be produced following standard tables. 
Additionally since part of the study was conducted during the COVID-19 pandemic, a listing 
of patients with suspected or confirmed SARS-COV-2 infection will be produced.  
2.7.2 
Deaths 
Should any deaths be recorded, these will be listed 
2.7.3 
Laboratory data 
Abnormal laboratory results that meet the criteria for adverse events will be summarized as part 
of the AE reporting.  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.12 
Interim analysis 
An interim analysis of the core study was performed with database lock in May 2020 based on 
approximately 187 patients who had completed to week 16 or discontinued the study.  This IA 


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was planned to support decision making concerning future trials in the ZPL389 development 
program and focused on efficacy in terms of IGA response, EASI and pruritus. It was not the 
intention to stop the trial. The interim analysis charter described the steps takes to restrict the 
knowledge of the results of the study so as not to bias the trial conduct post interim analysis. 
Once the results were seen, the decision made to stop the core and extension studies.  
3 
Sample size calculation 
The planned sample size for the core study was 360 subjects. Since the study was stopped early 
the final sample size will be less than this. 
The sample size was determined with the software ADDPLAN DF, version 3.1.8, with settings 
for minimum power function and model based contrasts. 
The sample size was derived to detect a dose-response with 90% power and a one-sided alpha 
of 2.5%. A placebo response rate of 10% was assumed. A maximum treatment effect for 
ZPL389 of 20%-points higher than placebo wass assumed. An unbalanced allocation ratio of 
2:1:1:2:2 corresponding to treatment arms placebo: 3 mg: 10 mg: 30 mg: 50 mg, with more 
subjects allocated to placebo and the higher doses, was chosen to increase the precision of the 
estimate for the treatment effect at doses in the expected efficacious dose range. 
Under these assumptions, a sample size of 360 subjects in total will be required, randomized to 
90:45:45:90:90 subjects corresponding to placebo: 3 mg: 10 mg: 30 mg: 50 mg treatment arms. 
4 
Change to protocol specified analyses 
A change was made to the primary estimand regarding adjuidcation of confounding medication 
use. This change was made following the interim analysis where it was established that handling 
use of confounding medication did not affect the overall conclusions and so it was decided not 
to perform the adjudication. 
Following the interim analysis results which showed no treatment effect of ZPL389 on efficacy 
and the subsequent early stopping of the trial, the dose-response analysis using MCP-Mod 
methods as described in the protocol will not be performed. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Any partial dates will be imputed as follows: 
Take the earlier day of  
• The last day in the month and  
• The end day of the corresponding epoch. 


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5.1.2 
Concomitant medication date imputation 
Impute concomitant medication (CM) end date:  
1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of treatment end date and the last day of the month.  
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of treatment end date and the end of the year (31DECYYYY).  
3. If imputed CM end date is less than the CM start date, use the CM start date as the imputed 
CM end date.  
Impute CM start date:  
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date.  
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore:  
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY).  
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).  
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:  
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY).  
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY).  
4. If the CM start date year value is equal to the treatment start date year value:  
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date.  
b. Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY).  
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY).  
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date.  
5.1.3 
Prior therapies date imputation 
See Section 5.1.2. 


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5.1.4 
Post therapies date imputation 
See Section 5.1.2. 
5.1.5 
First diagnosis date imputation 
1. If first diagnosis date is complete then imputed first diagnosis date = first diagnosis date.  
2. If only year is present in the first diagnosis date then do the following: 
a. If the year part of the first diagnosis date is equal to the year part of the inform consent 
date then imputed first diagnosis date = Jan 1 of the year of the first diagnosis date 
b. Otherwise imputed first diagnosis date = Jul 1 of the year of the first diagnosis date 
3. If only month and year part are present in the first diagnosis date then do the following: 
a. If the month and year part of the first diagnosis date is equal to the month and year 
part of the inform consent date then imputed first diagnosis date = 1st of the month of 
the year of the first diagnosis date 
b. Otherwise imputed first diagnosis date = 15th of the month of the year of the first 
diagnosis date. 
5.2 
Statistical models 
5.2.1 
Analysis of continuous data 
Mixed model repeated measures (MMRM) 
Continuous variables analyzed via mixed model repeated measures (MMRM) assume that data 
are missing at random (MAR) assumption.  
Treatment group, visit, baseline IGA and geographical region will be fitted as factors and 
baseline values will be fitted as continuous covariates. Treatment group by visit and visit by 
baseline value will be included as interaction terms in the model. A term for visit will be 
included in the repeated statement (in SAS PROC MIXED or PROC GLM) and an unstructured 
covariance matrix will be used thus allowing adjustment for correlations between time points 
within patients. The denominator degrees of freedom will be calculated using the Kenward-
Roger method.  
The model described above allows the relationship to baseline to vary for each visit, but 
assumes that the effects of baseline IGA and geographical region will remain constant over all 
visits. From this analysis, the adjusted means for each treatment group and at each timepointt, 
the difference between the adjusted means (ZPL389 groups vs placebo) at each timepoint, 95% 
confidence interval around these differences. 
 
SAS code for mixed model: 
proc mixed data=aaa; 
class TRT USUBJID AVISITN IGA_BASELINE GEOGRAPHY; 


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model CHG=TRT AVISITN IGA_BASELINE GEOGRAPHY BASE TRT*AVISITN 
BASE*AVISITN 
           / s ddfm=kr; 
lsmeans TRT*AVISITN / diff cl; 
repeated AVISITN / type=un subject=USUBJID; 
run; 
In case the MMRM model does not converge the following sequential steps will be used: 
1. change ddfm=kr to ddfm=bw. If still no convergence, perform step 2. 
2. change type=un to type=cs. If still no convergence, perform step 3. 
3. remove covariates in the following order until convergence: GEOGRAPHY, 
BASE*AVISITN. 
5.2.2 
Analysis of binary data 
Risk difference and 100*(1-α)% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g., placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event, the risk difference is estimated as p1-p0 with p1= x1/n1 and p0=x0/n0.  
Exact unconditional confidence limits for the risk difference will be obtained with SAS 
procedure PROC FREQ and option RISKDIFF in the TABLES statement, specifying the 
RISKDIFF option also in the EXACT statement.  
Logistic regression 
Where logistic regression is specified, the binary outcome variable will be evaluated using a 
logistic regression model with treatment regimen, baseline IGA, geographical region (if 
possible).  
All p-values reported on linear hypotheses about regression coefficients will be based on the 
Wald tests from Type III analyses. In the SAS procedure PROC GENMOD, a Type III analysis 
will be performed by adding the model options: TYPE3, DIST=BIN, and LINK=LOGIT. 
Logistic regression will be applied to response variables at each visit, and the following steps 
will be performed: 
1. Run the PROC GENMOD procedure;  
2. If convergence not reached, remove the covariates from the model one by one until 
convergence is reached; start with removing region, followed by baseline IGA;  
3. If convergence not reached, perform Fisher’s exact test. 
It should be noted that this model might not converge if response rates are too low. 
SAS code for logistic regression: 
 
proc logistic data=aaa; 
 
class TRT STRATA / param=glm; 
 
Model AVAL (event='1') = TRT WEIGHT STRATA; 


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LSMEANS TRT / diff cl exp ilink; 
 
run; 
5.2.3 
Multiple imputations for response variables 
Where multiple imputation is specified, the missing data will be imputed based on the individual 
treatment arm information.  
Multiple imputation (MI) is a simulation based approach where missing values are replaced by 
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets.  
Missing values will be imputed simultaneously based on an underlying joint normal distribution 
and using a Markov Chain Monte Carlo (MCMC) method.  
The imputations will be done separately for each treatment group including baseline IGA, 
geographical region, baseline EASI score as additional covariates.  
The number of imputations will be set to 100, the seed for the random function will be set to 
3892203 for this study. To generate the multiple imputed data sets, the SAS procedure MI can 
be used as follows: 
The input data set should have one record per subject with baseline EASI score and IGA score 
as well as the variables to be imputed (e.g. changes from baseline in EASI, or  post-baseline 
IGA score). 
 
ODS OUTPUT MissPattern=msgpat VarianceInfo=varinfo ParameterEstimates=param; 
PROC MI DATA=<easi_iga> OUT=<impdata> SEED=3892203  NIMPUTE=100; 
 VAR  <baseline EASI> <baseline IGA>  
     <change from baseline EASI week 1> - <change from baseline EASI week primary endpoint> 
     <IGA week1> - <IGA week primary endpoint>; 
  BY <treatment group>; 
RUN; 
 
Programming notes: 
• The SAS procedure MIANALYZE expects a variable called “_IMPUTATION_” 
which is generated by the MI procedure. It might be needed to set the SAS option 
“VALIDVARNAME=UPCASE” temporarily in the program before the MI call, this 
option should be reset after the MIANALYZE call to VALIDVARNAME=V6.  
• In case there are no missings in one treatment group, the MI procedure does not 
impute any values. In this case the corresponding data need to be imputed manually 
outside PROC MI and added to the dataset <impdata>. 
 
The imputed data are saved in data set <impdata>. The outcomes of interest, i.e. the EASI 
50/75  response and IGA 0 or 1 response will be calculated, e.g. as follows: 
The treatment differences for each imputed data set will then be evaluated by Logistic 
regression and ODDS ratio as described in Section 5.4.2.2. This analysis will be done by 
_IMPUTATION_ for the comparison to the placebo treatment group. The model should be 
estimating response probability = 1 by using DESECENDING option. Using the ESTIMATE 


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option in the GENMOD procedure and the ODS OUTPUT data set “Estimates” provides the 
estimate for the odds ratio and confidence intervals. 
 
PROC GENMOD <option>; 
CLASS <stratum> <treatment>; 
MODEL <response> = <explanatory variables> / link=logit dist=bin type3; 
BY <by-variables); 
ESTIMATE “OR. AIN 300 mg VS. Placebo” <treatment> 1 -1/exp;  
ODS OUTPUT Estimates=Estimates; 
RUN; 
The MIANALYZE procedure expects the parameter estimate in the variables ESTIMATE, and 
the corresponding standard error in the variable STDERR. Measurements can be obtained from 
“Estimates” dataset by selecting the row with ODDS ratio estimates.  
 
Data <modified dataset>; 
  set Estimates; 
  if substr(label,1,3)= “Exp”; 
  ESTIMATE=LBetaEstimate; 
  STDERR=StdErr; 
  effect= “OR”; 
  if missing(ESTIMATE) or missing(STDERR) then delete; 
RUN;  
 
The estimates and standard errors based on the 100 imputed data are then combined by applying 
Rubin’s rules for multiple imputed data sets, see Little and Rubin (2002).  
Programming notes:  
• The variables ESTIMATE and STDERR in the input data set for the MIANALYZE 
procedure may not be missing. Records with missing values need to be deleted and the 
variable _IMPUTATION_ needs to be renumbered and regenerated since for each by-
group the procedure expects consecutive numbers starting at 1. 
• The ESTIMATE and STDERR in terms of odds ratios from logistic regressions will be 
transformed to follow a normal distribution before MIANALYZE procedure. They will 
be transformed back to Odds Ratio to get the corrected ESTIMATE and corresponding 
CIs.   
The SAS procedure MIANALYZE will be applied as follows: 
Step 1: 
DATA <modified dataset_t>; 
 
SET <modified dataset>; 
 
estimate=log(ESTIMATE); 
 
stderr=(log(LBETAUPPERCL)-log(LBETALOWERCL))/(2*1.96); 
RUN ; 
 
ODS LISTING CLOSE; 
ODS OUTPUT ParameterEstimates=<results> VarianceInfo=<varinfo> ModelInfo=<modelinfo>; 
PROC MIANALYZE PARMS=<modified dataset>; 
  BY <by-variables>; 
  MODELEFFECTS OR; 
RUN; 


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ODS LISTING; 
 
data <results_back>; 
 
set <results>; 
 
estimate=exp(ESTIMATE); 
 
LCLMEAN=estimate*exp(-1.96*stderr); 
 
UCLMEAN=estimate*exp(+1.96*stderr); 
RUN ; 
 
 

Prot_000.pdf: 
 
 
 
Global Clinical Development - General Medicine 
ZPL389 
Clinical Trial Protocol CZPL389A2203 / NCT03517566 
A randomized, double-blind, placebo-controlled multicenter 
dose-ranging study to assess the safety and efficacy of 
multiple oral ZPL389 doses in patients with moderate to 
severe atopic dermatitis (ZEST trial) 
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
2017-002176-75 
Version number: 
03 clean 
Clinical Trial Phase: 
II 
Release date: 
02-SEP-2019 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.4 (May 2017) 
 


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Protocol No. CZPL389A2203 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
 10 
Glossary of terms ............................................................................................................... 11 
Amendment 3 (02 September 2019) .................................................................................. 13 
Amendment 2 (11 September 2018) .................................................................................. 15 
Amendment 1 (30 January 2018) ...................................................................................... 17 
Protocol summary .............................................................................................................. 18 
1 
Introduction ....................................................................................................................... 20 
1.1 
Background ............................................................................................................ 20 
1.2 
Purpose .................................................................................................................. 21 
2 
Study objectives and endpoints ......................................................................................... 21 
2.1 
Objectives and related endpoints ........................................................................... 21 
3 
Investigational plan ........................................................................................................... 23 
3.1 
Study design........................................................................................................... 23 
3.2 
Rationale for study design ..................................................................................... 24 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 24 
3.4 
Rationale for choice of comparator ....................................................................... 25 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 25 
3.6 
Risks and benefits .................................................................................................. 25 
4 
Population .......................................................................................................................... 26 
4.1 
Inclusion criteria .................................................................................................... 27 
4.2 
Exclusion criteria ................................................................................................... 27 
4.3 
Inclusion criteria 
 ................................................................ 30 
4.4 
Exclusion criteria 
 ............................................................... 30 
5 
Treatment ........................................................................................................................... 30 
5.1 
Treatment assignment and randomization ............................................................. 30 
5.2 
Study treatment ...................................................................................................... 31 
5.2.1 
Investigational and control drugs .......................................................... 31 
5.2.2 
Additional treatment .............................................................................. 31 
5.3 
Treatment arms ...................................................................................................... 31 
5.4 
Treatment blinding ................................................................................................. 32 
5.5 
Treating the subject ................................................................................................ 32 
5.5.1 
Subject numbering ................................................................................ 32 


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5.5.2 
Dispensing the study drug ..................................................................... 32 
5.5.3 
Handling of study and additional treatment .......................................... 33 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 33 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 34 
5.5.6 
Rescue medication ................................................................................ 34 
5.5.7 
Concomitant medication ....................................................................... 35 
5.5.8 
Prohibited medication ........................................................................... 35 
5.5.9 
Emergency breaking of assigned treatment code .................................. 37 
5.6 
Study completion and discontinuation ................................................................... 38 
5.6.1 
Study completion and post-study treatment .......................................... 38 
5.6.2 
Discontinuation of study treatment ....................................................... 38 
5.6.3 
Withdrawal of informed consent ........................................................... 39 
5.6.4 
Loss to follow-up .................................................................................. 40 
5.6.5 
Early study termination by the sponsor ................................................. 40 
6 
Visit schedule and assessments ......................................................................................... 40 
6.1 
Information to be collected on screening failures .................................................. 45 
6.2 
Subject demographics/other baseline characteristics ............................................. 45 
6.2.1 
Screening for HIV/Hep B and Hep C ................................................... 45 
6.3 
Treatment exposure and compliance ..................................................................... 45 
6.3.1 
ZPL389 / placebo .................................................................................. 45 
6.3.2 
Rescue medication and emollient .......................................................... 46 
6.4 
Efficacy .................................................................................................................. 46 
6.4.1 
Appropriateness of efficacy assessments .............................................. 46 
6.4.2 
IGA ........................................................................................................ 46 
6.4.3 
EASI ...................................................................................................... 46 
 
48 
6.5 
Safety ..................................................................................................................... 49 
6.5.1 
Physical exam ........................................................................................ 49 
6.5.2 
Body Weight and height ........................................................................ 49 
6.5.3 
Electrocardiogram (ECG) ..................................................................... 49 
6.5.4 
Vital Signs ............................................................................................. 50 
6.5.5 
Laboratory evaluations .......................................................................... 50 
6.5.6 
Pregnancy Test ...................................................................................... 51 
6.6 
Other assessments .................................................................................................. 51 
6.6.1 
Clinical Outcome Assessments ............................................................. 51 
6.6.2 
Resource utilization ............................................................................... 53 
 
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 54 
 
 54 
 
 55 
 
 56 
 
 56 
7 
Safety monitoring .............................................................................................................. 56 
7.1 
Adverse events ....................................................................................................... 56 
7.2 
Serious adverse events ........................................................................................... 58 
7.2.1 
Definition of SAE ................................................................................. 58 
7.2.2 
SAE reporting........................................................................................ 59 
7.3 
Liver safety monitoring ......................................................................................... 60 
7.4 
Renal safety monitoring ......................................................................................... 61 
7.5 
Cardiac safety monitoring ...................................................................................... 61 
7.6 
Reporting of study treatment errors including misuse/abuse ................................ 61 
7.7 
Pregnancy reporting ............................................................................................... 62 
8 
Data review and database management ............................................................................. 62 
8.1 
Site monitoring ...................................................................................................... 62 
8.2 
Data collection ....................................................................................................... 63 
8.3 
Database management and quality control ............................................................ 63 
8.4 
Data Monitoring Committee .................................................................................. 64 
8.5 
Adjudication Committee ........................................................................................ 65 
9 
Data analysis ...................................................................................................................... 65 
9.1 
Analysis sets .......................................................................................................... 65 
9.2 
Subject demographics and other baseline characteristics ...................................... 65 
9.3 
Treatments ............................................................................................................. 66 
9.4 
Analysis of the primary variable(s) ....................................................................... 66 
9.4.1 
Primary Variable(s) ............................................................................... 66 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 67 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 68 
9.4.4 
Sensitivity analyses ............................................................................... 69 
9.5 
Analysis of secondary variables ............................................................................ 69 
9.5.1 
Efficacy variables .................................................................................. 69 
9.5.2 
Safety variables ..................................................................................... 72 
9.5.3 
Resource utilization ............................................................................... 73 
 
 73 
 
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 74 
 
74 
9.7 
Interim analyses ..................................................................................................... 76 
9.8 
Sample size calculation .......................................................................................... 76 
10 Ethical considerations ........................................................................................................ 77 
10.1 
Regulatory and ethical compliance ........................................................................ 77 
10.2 
Informed consent procedures ................................................................................. 77 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 78 
10.4 
Publication of study protocol and results............................................................... 78 
10.5 
Quality Control and Quality Assurance ................................................................. 78 
11 Protocol adherence ............................................................................................................ 79 
11.1 
Protocol Amendments ........................................................................................... 79 
12 References ......................................................................................................................... 79 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 81 
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ..................................................................................................................... 82 
15 Appendix 3: Specific Renal Alert Criteria and Actions .................................................... 84 
16 Appendix 4: Hepatitis serology criteria ............................................................................. 85 
17 Appendix 5: Investigator Global Assessment (IGA) ......................................................... 85 
18 Appendix 6: Patient e-diary ............................................................................................... 86 
 
 86 
 
 87 
18.3 
Tracking study medication intake, emollient and rescue medication .................... 88 
 
 
 88 
 
 88 
 
 88 
 
 88 
 
 89 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 21 
Table 5-1 
Prohibited medication/therapy .............................................................. 35 
Table 6-1 
Assessment Schedule ............................................................................ 41 
 
 44 
Table 6-3 
EASI: severity descriptions ................................................................... 47 


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Table 6-4 
EASI calculation ................................................................................... 48 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 62 
Table 14-1 
Liver Event and Laboratory Trigger Definitions .................................. 82 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 82 
Table 15-1 
Specific Renal Alert Criteria and Actions ............................................. 84 
Table 16-1 
Hepatitis B serology result, interpretation and subject eligibility ......... 85 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 23 
Figure 9-1 
Candidate models for IGA response at Week 16 .................................. 68 
Figure 9-2 
Candidate models for percent change from baseline EASI score at 
Week 16 ................................................................................................ 71 
 


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List of abbreviations 
γ-GT 
Gamma-glutamyl transferase 
ACR 
albumin-creatinine ratio 
AD 
atopic dermatitis 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
Anti-HBc 
Anti-Hepatitis B core antigen antibody 
Anti-HBs 
Anti-Hepatitis B surface antigen antibody 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
BUN 
blood urea nitrogen 
 
 
CFR 
Code of Federal Regulation 
CI 
confidence interval 
CK 
creatinine kinase 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
Cytochrome P450 
DDI 
Drug-Drug Interaction 
DILI 
Drug induced Liver injury 
 
 
DMC 
Data Monitoring Committee 
EASI 
Eczema area and severity index 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMA 
European Medical Agency 
EOT 
End of Treatment 
 
 
 
 
 
 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
h 
hour 
H4R 
Histamine-4 receptor 


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HBsAg 
Hepatitis B surface Antigen 
HIV 
human immunodeficiency virus 
 
 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IGA 
Investigator's Global Assessment 
IL 
Interleukin 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
i.v. 
intravenous 
LDH 
Lactate Dehydrogenase 
LFT 
Liver function test 
 
 
MCPMod 
Multiple Comparison Procedures – Modelling 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
MI 
Multiple imputation 
mL 
milliliter(s) 
MMRM 
Mixed effect Model Repeat Measurement 
 
 
NOAEL 
No observed adverse effect level 
NRS 
Numerical rating scale 
o.d. 
once daily 
PCR 
Protein creatinine ratio 
PD 
Pharmacodynamic(s) 
 
 
 
 
 
 
PoC 
Proof of Concept 
PRO 
Patient Reported Outcome 
PSW 
Premature Subject Withdrawal 
PT 
Prothrombin time 
 
 
QTc(F) 
Corrected QT interval (by Frediricia’s formula) 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 


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sCR 
serum Creatinine 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
 
 
TBL 
Total Bilirubin 
TCS 
Topical Corticosteroids 
TD 
Treatment discontinuation 
TdP 
Torsades de Pointes 
Th2 
T-helper 2 cells 
TSLP 
Thymic stromal lymphopoietin 
ULN 
upper limit of normal 
 
 
 
 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of consent 
WOCBP 
Women of child bearing potential 


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Glossary of terms 
Baseline 
Day 1: subjects who are eligible will be randomized 
Control drug 
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 30 mg 
once daily) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point 
of care. 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (e.g. prior to starting any of the procedures described in the 
protocol) 
Investigational drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
IGA Response 
IGA response is defined as achieving an IGA score of 0 (clear) or 1 (almost 
clear) and at least 2 points reduction from Baseline and no use of 
confounding therapy as adjudicated up to the assessment time point. 
Medication pack 
number 
A unique identifier on the label of each investigational drug package 
Patient 
A person with the condition of interest being studied 
Period 
Interval of time in the planned conduct of a study. A period is associated with 
a purpose (e.g. screening, treatment, follow-up), which applies across all 
arms of a study. 
Personal data 
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples. 
Subject 
A patient participating in this study 
Subject number  
A unique number assigned to each subject upon signing the informed 
consent  
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource. 
Study drug/ 
treatment 
Any single drug or combination of drugs administered to the subject as part 
of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy 
Study Treatment 
Discontinuation (TD) 
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study 


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Withdrawal of study 
consent (WoC) 
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data 
 
 


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Protocol No. CZPL389A2203 
 
Amendment 3 (02 September 2019) 
Amendment rationale  
Per the original protocol, even though chronic toxicity studies showed no hepatotoxic effects, 
due to the fact there was at the time limited human data with ZPL389, subjects were not allowed 
to have any value of AST/ALT/ALP above the upper limit of normal in order to join this phase 
2 study.  With the recent results from phase 1 study in healthy volunteers (CZPL389A2101) 
that tested high exposures of ZPL389, no liver abnormalities were seen. Therefore, exclusion 
limit for AST/ALT/ALP have been increased to 1.5 ULN to allow patients with only minor 
elevations of AST/ALT/ALP into the study and to prevent unnecessary exclusion of subjects 
from the study participation. Subjects would still need to fulfill other criteria (e.g. absence of 
HBV, HCV, prior liver disease, hepatotoxic concomitant medication) in order to be eligible for 
the study, and will be closely monitored for LFT during the study, therefore safety of subjects 
would not be  compromised. 
A clarification about the use of H1 antihistamines has been added. Unless these have a potential 
for QT interval prolongation (prohibited for all subjects) or have a sedative effect 
 
, these are allowed if on a stable dose or 
used short term (e.g. to treat allergies). 
Changes to the protocol 
The sponsor has also used this opportunity to make operationally relevant or typographical 
modifications and/ or provide clarifications. 
All changes made to the protocol are listed in the table below. 
 
Section 
Changes made 
Section 3.5, Section 5.4 
and Section 9.7 
Addition of a potential interim analysis 
Section 3.6 
Updated with results of pivotal Embryo-fetal development 
toxicology studies and CZPL389A2101 study 
Section 4 
Number of study sites has been updated 
Section 4.2 
Clarification added to Exclusion criterion #2 on skin infection 
Exclusion criterion #10 has been modified to  
• 
include subjects with AST/ALT/ALP up to 1.5 upper limit 
of normal (ULN) 
• 
clarify abnormal values for Potassium and Magnesium 
• 
Allow one central lab retest for lab abnormalities outside 
the respective cut-off criteria during screening period 
Clarification added to Exclusion criterion #11 on basal cell 
carcinoma of the skin 
Clarification added on the form of hormonal contraception allowed 
in Exclusion criterion #15 
Section 5.2.2 and Table 5-1 
Removal of Vitamin E as prohibited component of moisturizers 
Section 5.5.4 
Clarification on the number of doses to be taken until week 16 visit  


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Section 5.5.6 
Clarification added for use of an alternative TCS as rescue 
medication 
Section 5.5.8, Table 5-1 
For subjects who discontinued early, action taken on prohibited 
medication during follow up period has been modified 
Clarification on the use of H1 Antihistamines  
Information on use of ibuprofen or topical NSAID has been added 
Section 6.2 
Clarification added for collection of subject’s baseline 
characteristics 
Section 6.2.1 
Clarification on the type of test done for Hep C 
Section 6.5.5.1 and Table 
14-2 
PT/INR has been added to unscheduled visit 
Section 6.5.6.1 
Microscopy result entry in CRF has been removed as the result 
will be available in central laboratory data 
Section 6.6.4 
Clarification on the requirement of availability of CYP2D6 test 
results before randomization for subjects taking moderate 
CYP1A2 inhibitor and adherence to wash out period 
 
 
Section 7.3 
In case of a Liver event, requirement of completion of applicable  
questionnaire for adjudication has been added 
Section 7.5 
Any increase from Baseline of 30 msec in QTcF (Fridericia) 
interval for males and females has been added to the definition of 
a notable QTc value 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 
 


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Protocol No. CZPL389A2203 
 
Amendment 2 (11 September 2018) 
Amendment rationale  
The protocol is amended to incorporate changes following interim results from Phase I trial in 
healthy volunteers (CZPL389A2101). 
  
Based on the Phase I study results and potential drug-drug interaction risk, the protocol is 
amended to include a precautionary measure to minimize the risk of higher exposure to ZPL389 
that may occur in subjects who are poor CYP2D6 metabolizers. This measure includes 
identifying subjects that are poor CYP2D6 metabolizers prior to study treatment start and 
prohibiting use of moderate inhibitors of CYP1A2 (including hormonal contraception), in these 
subjects (CYP2D6 metabolizers). As per previous protocol, strong CYP1A2 inhibitors are still 
prohibited for all subjects. Additionally Phase I study results have shown that more time is 
needed to achieve 
 than shown by previous studies, therefore the timing of the post dose 
ECG is changed from 0.5h to 2h. On days of site visits, subjects are asked to fast 3 hours before 
the visit, 
 ECG parameters may be impacted by the intake of food. However, due to 
no food effect seen on overall drug exposure in Phase I study, fasting before and after drug 
intake on non-visit days is no longer necessary. 
 
 
Changes to the protocol 
 
 
   
All changes made to the protocol are listed in the table below. 
 
Section 
Changes made 
 
 
 
 
 
 
 
 
 
Section 3.1, Figure 3-1 and 
Table 6-1 
The screening period has been extended up to 4 weeks (to allow 
time to get the 
), 
extending the total study duration from 23 to 24 weeks 
Section 3.4, Section 4.1, 
Section 5.2.2 and Section 6 
The use of bland emollient has been changed to once daily instead 
of twice 
Section 3.3 and Section 3.6 
Updated with relevant interim data from study CZPL389A2101 
Section 3.4 
Removal of the sentence referring to the extension study as this 
was misplaced 


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Section 4.2 
Exclusion criteria #15 has been modified to prohibit hormonal 
contraception for poor CYP2D6 metabolizers (as hormonal 
contraception is moderate inhibitor of CYP1A2) 
Deletion of the text about additional exclusion applied by 
investigator 
Section 4.3 and Section 4.4 
 
 
Section 5.4 
Clarification on when unblinding would occur 
Section 5.5.4 and Section 6 
Fasting requirement before and after taking study medication at 
home has been removed.  
Section 5.5.6 
Allowing hydrocortisone 2.5% ointment as rescue medication for 
sensitive areas    
Section 5.5.8 
Addition of moderate CYP1A2 inhibitors as prohibited concomitant 
medication for CYP2D6 poor metabolizers 
Clarification that eye drops are not considered systemic 
immunosuppressive treatment. 
Section 5.6 
Clarification on EOT, Withdrawal of consent and early study 
termination    
Section 6 
Clarification that subjects should be fasted 3 hours before site visits 
and until the last ECG is performed 
Visit days for Week 16 and Week 20 visits have been updated to 
113 and 141 days respectively. Therefore dosing at site on Week 
16 visit has been removed. A clarification has been added on when 
 sample will be collected at Week 16 visit 
Unplanned ECG has been added in the table of assessment and 
time of Post dose ECG at Baseline and Week 4 changed from 0.5h 
to 2 hours postdose 
 
Section 6.6.1 and Section 
8.3 
Allowing Patient Reported Outcomes (PROs) to be collected on 
paper should the electronic device not be working 
 
 
 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment 


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Amendment 1 (30 January 2018) 
Rationale 
The original protocol is amended to incorporate health authority feedback prior to the start of 
enrolment as listed in the table below. 
 
Section 
Changes made 
 
 
 
Section 4.1 
EASI score at Screening visit for inclusion into trial changed from 12 
to 16 
Section 4.2 and Section 7.5 
Exclusion threshold and notable value for resting QTcF for female 
changed from ≥460 to ≥470 msec 
 Section 5.6 and Section 7.5 
Discontinuation criteria for cardiac disorders aligned with CTCAE 
grade 2 events 
Section 6 
Time of Post dose ECG at Baseline and Week 4 changed to 30 
mins postdose 
 
 
The sponsor has used this opportunity to simplify and update sections regarding sample size 
and statistical analysis. Other minor corrections were made such as adding the requirement for 
fasting 1 hour before ECG measurements. 
All changes from the original protocol v00 are indicated in red underlined text (insertions) or 
red strikethrough (deleted text) in the track changes version of this protocol amendment. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 


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Protocol summary 
Protocol 
number 
CZPL389A2203 
Full Title 
A randomized, double-blind, placebo-controlled multicenter dose ranging study to 
assess the safety and efficacy of multiple oral ZPL389 doses in patients with 
moderate to severe atopic dermatitis (ZEST Trial) 
Brief title 
A study to assess the safety and efficacy of ZPL389 doses in patients with moderate 
to severe atopic dermatitis 
Sponsor and 
Clinical 
Phase 
Novartis, Phase 2 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to determine the dose-response relationship of ZPL389 
for key efficacy and safety parameters in order to define the most appropriate dose(s) 
for further development of ZPL389 in subjects with moderate to severe atopic 
dermatitis. 
Primary 
Objective(s)  
To characterize the dose-response relationship of ZPL389 in subjects with moderate 
to severe atopic dermatitis assessed by Investigator's global assessment response 
at Week 16 
Secondary 
Objectives 
1. To characterize the dose-response relationship of ZPL389 in subjects with 
moderate to severe atopic dermatitis assessed using the percent change from 
Baseline in Eczema Area and Severity Index after 16 weeks of treatment 
2. To evaluate the efficacy across different dose levels as assessed by Eczema Area 
and Severity Index and Investigator's global assessment compared to placebo over 
time 
3. To assess the safety and tolerability of different doses of ZPL389 as compared to 
placebo 
Study design 
This is a randomized, double-blind, placebo-controlled, parallel-group study to 
assess safety and efficacy of ZPL389 in subjects with moderate to severe atopic 
dermatitis with a total study duration up to 24 weeks 
Population 
The study population will consist of female and male subjects aged 18 years or 
older with moderate or severe atopic dermatitis 
Key 
Inclusion 
criteria 
• 
Written informed consent 
• 
Chronic atopic dermatitis (according to American Academy of Dermatology 
Consensus Criteria), that has been present for at least 1 year before Baseline. 
• 
Moderate to severe atopic dermatitis defined as: 
• 
Eczema Area and Severity Index ≥16 at Screening and at Baseline 
• 
Investigator's global assessment 3 or 4 on a 5-point scale (at screening 
and Baseline) 
• 
Body Surface Area involvement ≥10% at Screening and Baseline 
• 
Average peak pruritus score ≥3 as assessed by numerical rating scale over the 
last 7 days prior to Baseline 
• 
Documented recent history (within 6 months before the screening visit) of 
inadequate response to treatment with topical medications or for whom topical 


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treatments are otherwise medically inadvisable (e.g., because of important side 
effects or safety risks) 
• 
Candidate for systemic treatment 
Key 
Exclusion 
criteria 
• 
Any skin disease that, in the opinion of the investigator, including infection, 
would confound the diagnosis or evaluation of atopic dermatitis disease activity 
• 
Use of other investigational drugs within 5 half-lives of enrollment, or within 30 
days /until the expected pharmacodynamic effect has returned to baseline, 
whichever is longer. 
• 
History of hypersensitivity to any of the study drug constituents or to drugs of 
similar chemical classes. 
• 
Risk factors for Torsades de Pointes including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia or any of the following:  
• 
Long QT syndrome, family history of idiopathic sudden death or congenital 
long QT syndrome 
• 
Concomitant medication(s) with a “Known Risk of Torsades de Pointes” 
that cannot be discontinued or replaced by safe alternative medication. 
• 
Resting QTcF ≥450 msec (male) or ≥470 msec (female) at screening or 
baseline or inability to determine the QTcF interval 
• 
Cardiac or cardiac repolarization abnormality 
• 
Subjects with pre-existing conditions that may confound ability to diagnose 
drug-induced liver injury (DILI) or subjects with factors that increase 
susceptibility to DILI 
• 
Participation in prior ZPL389 studies 
Study 
treatment 
ZPL389 in one of 4 dosing levels or placebo will be administered orally in capsules 
in the following dosing groups: 
• 
Placebo once daily 
• 
ZPL389 dose 1 once daily 
• 
ZPL389 dose 2 once daily 
• 
ZPL389 dose 3 once daily 
• 
ZPL389 dose 4 once daily 
Efficacy 
assessments 
Investigator's global assessment; Eczema Area and Severity Index 
Key safety 
assessments 
Adverse event monitoring, physical examinations including vital signs, monitoring of 
laboratory markers in blood and urine and electrocardiograms 
Other 
assessments 
 
Data 
analysis 
The Multiple Comparison Procedures-Modelling methodology will be used to 
determine an overall dose-response signal with respect to Investigator's global 
assessment response at Week 16. Summary statistics for continuous variables will 
include N, mean, standard deviation, minimum, lower quartile, median, upper 
quartile, maximum. Summary statistics for discrete variables will be presented in 
contingency tables and will include absolute and relative frequencies. If not otherwise 
specified, p-values will be presented as two-sided p-values and two-sided 
confidence intervals will be displayed. 
Key words 
atopic dermatitis, AD, eczema, atopic eczema, itch, pruritus, histamine 4 receptor 
antagonist, H4R, ZPL389 


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1 
Introduction 
1.1 
Background 
Atopic dermatitis (AD) is a chronic inflammatory skin disease that commonly presents first 
during early infancy and childhood. It is characterized by poorly defined erythema with edema, 
vesiculation, and weeping in the acute stage and skin thickening (lichenification) in the chronic 
stage (Eichenfield 2004, Williams et al 1994). These symptoms result in a severely reduced 
quality of life (QOL). In particular, itching (pruritus), that continues throughout the day and 
worsens at night causes sleep loss and impacts everyday activities and psychosocial wellbeing 
(Bieber 2010, Weidinger and Novak 2016). AD is commonly associated with other atopic and 
inflammatory disorders, such as asthma, allergic rhinitis and food allergy. Usually the disease 
regresses during adolescence but symptoms may also persist into adulthood. 
Two to ten percent of adults and up to 20% of children have AD, of which approximately 70% 
and 16%, respectively, are moderate to severe (Hanifin et al 2007, Emerson et al 1998). 
Depending on the severity of the disease different therapeutic options may be proposed. The 
basis of AD treatment is emollients in patients of all severity stages. Additionally in patients 
suffering from milder forms of the disease, treatment with either topical corticosteroids (TCS) 
or topical calcineurin inhibitors is used. Patients suffering from more severe disease and failing 
to sustain response to topical agents are generally treated with phototherapy and systemic 
immunosuppressive drugs like cyclosporine and oral corticosteroids (Ring et al 2012, 
Eichenfield et al 2014, Sidbury et al 2014). Cyclosporine is approved as systemic therapy for 
severe AD in Europe, but renal toxicity and other adverse events (AEs) limit its long term use. 
Phototherapy carries the risk of future skin cancer and is not practical for many subjects. 
Currently the only systemic therapy approved is dupilumab (anti-Interleukin 4 Receptor alpha 
antibody) for treatment of moderate to severe AD, but is expected to be reserved for the most 
recalcitrant subjects. Thus, there is a high unmet medical need for an oral treatment in moderate 
to severe AD patients. 
The histamine 4 receptor (H4R) is the newest member of the histamine receptor family. It is 
predominantly expressed on a variety of immune cells such as T cells, mast cells, eosinophils 
and dendritic cells. There is a large body of evidence demonstrating that the H4R is intimately 
linked to many inflammatory responses mediated by histamine, including chemotaxis and cell 
recruitment, up-regulation of adhesion molecule expression and modulation of cytokine and 
chemokine release (Thurmond 2015; Zhang et al 2007). In particular, there is growing 
preclinical evidence and emerging clinical data supporting the utility of H4R antagonists in the 
treatment of pruritus and atopic skin inflammation (Dunford et al 2007). For example, H4R 
agonists have been described to upregulate the T-helper 2 (Th2) cells and itch inducing cytokine 
IL-31 (Gutzmer et al 2009), contribute to Th2 polarization by suppressing IL-12 in antigen-
presenting cells (Cowden et al 2010) and to induce proliferation and thymic stromal 
lymphopoietin (TSLP) production in human keratinocytes. 
ZPL389 is a potent and selective H4R antagonist with in vitro binding potency of 6.2 nM and 
an IC50 value of 5.7 nM. Functional antagonism has been observed with native human H4R 
against a variety of endpoints associated with the chemotactic and inflammatory responses in 
primary human eosinophils. 


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1.2 
Purpose 
The purpose of this study is to determine the dose-response relationship of ZPL389 for key 
efficacy and safety parameters in order to define the most appropriate dose(s) for further 
development of ZPL389. Investigator's global assessment (IGA) will be assessed after treatment 
with 4 different ZPL389 doses or placebo administered orally once daily for 16 weeks in 
subjects with moderate to severe atopic dermatitis. 
2 
Study objectives and endpoints 
2.1 
Objectives and related endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To characterize the dose-response relationship 
of ZPL389 in subjects with moderate to severe 
AD assessed by IGA response after 16 weeks 
of treatment 
• 
IGA response at Week 16 
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
• 
To characterize the dose-response relationship 
of ZPL389 in subjects with moderate to severe 
AD assessed using the percent change from 
Baseline in Eczema Area and Severity Index 
(EASI) score after 16 weeks of treatment 
• 
Percent change from baseline 
EASI score at Week 16 
• 
To evaluate the efficacy across different dose 
levels as assessed by EASI and IGA compared 
to placebo over time 
• 
At each visit:  
• 
IGA score 
• 
IGA response 
• 
EASI score (absolute and 
percent change from 
Baseline)  
• 
EASI50 response, EASI75 
response 
• 
To assess the safety and tolerability of different 
doses of ZPL389 as compared to placebo 
• 
Frequency of adverse events 


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3 
Investigational plan 
3.1 
Study design 
This is a randomized, double blind, placebo controlled, parallel group, 5-arm study in at least 
360 subjects with moderate to severe AD. Unbalanced randomization ratio will be utilized, to 
result in approximately 90 subjects randomized in each of the 30 mg/day and 50 mg/day dose 
arms as well as in the placebo arm, and 45 subjects in each of the 3 mg/day and 10 mg/day arms. 
The study consists of a screening period of up to 4 weeks (depending on current medication use 
and associated washout period), and a 16-week double blinded treatment period. After the end 
of treatment visit, subjects may be offered ongoing treatment in an extension study, or enter the 
4 week treatment-free follow up period (Figure 3-1). 
The total study duration will be up to 24 weeks. The details of the study design and procedures 
of the extension study will be described in a separate protocol. 
Figure 3-1 
Study design 
 
 


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3.2 
Rationale for study design 
This randomized, double-blind, parallel-group, placebo-controlled design supports the 
assessment of efficacy as well as safety of ZPL389 in moderate to severe AD subjects. Four 
dose levels were chosen to characterize the dose-response curve. An unbalanced allocation of 
2:1:1:2:2 for placebo: 3 mg: 10 mg: 30 mg: 50 mg with more subjects on placebo and the higher 
doses of ZPL389 is chosen to increase the precision of the estimate for the treatment effect at 
doses in the expected efficacious dose range. The treatment length of 16 weeks (for primary 
endpoint) was chosen to understand when efficacy responses plateau. Additionally, this 
treatment length is comparable to clinical studies of other investigational treatments for 
moderate to severe AD patients (Simpson et al 2016). 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
The doses of ZPL389 selected for this study are 3 mg, 10 mg, 30 mg, and 50 mg o.d. for 112 
days. 
ZPL389 is rapidly absorbed following oral administration of single and multiple doses. The 
estimated terminal half-life of 70-100 hours supports daily dosing of ZPL389. 
The safety margins with toxicology findings and current clinical data support the use of the 
proposed doses. In oral toxicity studies, ZPL389 was well tolerated in rats and cynomolgus 
monkeys of up to 26 and 39 weeks duration, respectively. The no-observed-adverse-effect 
levels (NOAELs) could be established at 30 mg/kg/d in rats and 20 mg/kg/day in monkeys 
which result in safety margins of 20 and 60 for rats and monkeys, respectively, compared to 
human exposures at 50 mg dose o.d. 
Interim analysis results from an ongoing phase 1 study (CZPL389A2101) which investigated 
single doses up to 400 mg ZPL389 and multiple doses of 50 mg/day and 100 mg/day ZPL389 
(administered as drug in capsule formulation for 21 days) in 75 healthy subjects, supports the 
current dose selection. 
Although good efficacy was observed for some endpoints in the AD proof of concept (PoC) 
study at 30 mg o.d., other endpoints did not show a sufficient differentiation from placebo. 
Given the dose of 50 mg has already been administered in healthy volunteers and the large 
safety margin of this dose, the maximum proposed dose in this study is 50 mg o.d. 
The 30 mg dose is chosen to investigate whether there is sufficiently increased efficacy at 50 mg 
vs. 30 mg (the dose used in the AD PoC study). Finally, to enable exploration of the dose 
response curve, ½ log dose reductions of 30 mg are used, providing a mid-dose of 10 mg and a 
low dose of 3 mg. Overall, a more than 16-fold dose range is explored. 
A dosing period of 16 weeks is expected to result in additional efficacy compared to the AD 
PoC study, as, unlike placebo, the efficacy of ZPL389 had not plateaued by the end of the 8-
week dosing period in the PoC study. 
Novartis anticipates that the proposed doses, and hence range of plasma exposures obtained 
from the study, will enable characterization of the dose and concentration response curves for 
ZPL389 in atopic dermatitis subjects. 


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3.4 
Rationale for choice of comparator 
Placebo is an appropriate comparator for the objectives of this study as it will provide the robust 
assessment of the efficacy and safety of ZPL389 in atopic dermatitis population. 
All subjects will use a bland emollient once daily. 
In addition, subjects from all treatments groups, including placebo, will have access to a 
standardized rescue medication if medically necessary (i.e., to control intolerable AD 
symptoms), as assessed by investigator and after at least 4 weeks post Baseline. 
3.5 
Purpose and timing of interim analyses/design adaptations 
An interim analysis may be performed to support decision making concerning the current 
clinical study or project. As a consequence the study sample size may be reduced, e.g. size of 
lower dose arms may be reduced by approximately 30%.  
3.6 
Risks and benefits 
To date, 289 subjects (including asthma, psoriasis and AD patients and healthy volunteers) have 
been treated with at least one dose of ZPL389. The longest treatment duration to date occurred 
in a study of ZPL389 30 mg/day for 12 weeks in subjects with moderate to severe plaque 
psoriasis. In an ongoing study (CZPL389A2101), 75 healthy subjects received ascending single 
doses up to 400 mg ZPL389 and multiple doses of 50 mg/day and 100 mg/day for 21 days. 
In the AD Phase 2a PoC study (N = 98), safety profile of ZPL389 (30 mg o.d.) was comparable 
to placebo and the percentages of subjects who reported adverse events were similar following 
8 weeks of treatment with ZPL389 or placebo. The most common adverse events in the Phase 
2a study were nasopharyngitis (12/65 [19%] subjects in the ZPL389 group and 8/33 [24%] 
subjects in the placebo group) and headache (7/65 [11%] subjects in the ZPL389 group and 
4/33 [12%] subjects in the placebo group). No serious adverse events (SAEs) were reported 
following treatment with ZPL389. 
Due to preclinical findings suggesting ZPL389 might prolong the corrected QT (QTc) interval 
when administered at several fold multiples of the intended clinical dose, 12-lead ECG 
monitoring was conducted in five completed clinical studies performed to date, and no clinically 
significant changes in ECG parameters including QTc interval prolongation have been observed 
following single doses of up to 48 mg and multiple doses of up to 50 mg o.d.  
Interim analysis data from the ongoing study CZPL389A2101 showed clinically relevant 
increases of QTcF at single doses of 300 and 400 mg ZPL389 (plasma concentrations  
exceeding the concentration at Cmax,ss of a 50 mg o.d regimen). All elevations of QTcF and 
QT were asymptomatic. There were no QTcF or QT values ≥ 500 msec and no changes in QTcF 
≥ 60 msec.  
The concentration-QTcF analysis of the 50 mg o.d. regimen did not show QTcF results at a 
level of regulatory concern (i.e., an upper bound of the 90% CI of the QTcF effect for the highest 
clinically relevant exposure achieved with 50 mg o.d. was below 10 msec), therefore further 
supporting the use of a 50 mg o.d. regimen in this study.  
Based on in vitro data and DDI simulations, the highest clinically relevant exposure is predicted 
to occur in a poor metabolizer of CYP2D6 treated with a strong inhibitor of CYP1A2. Therefore, 


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in the currently planned study, the scenario of highest clinically relevant exposure at a dose of 
50 mg o.d. will be prevented by implementing the following measures:  
1. Prohibiting the use of strong CYP1A2 inhibitors for all subjects 
2. Genotyping all subjects for CYP2D6 polymorphism prior to treatment start; for those 
subjects identified as CYP2D6 poor metabolizers, moderate CYP1A2 inhibitors will 
also be prohibited 
Additionally, any drug known to prolong QTc interval will be prohibited in this study.  Subjects 
with clinically significant cardiovascular disease or close family history of long QT syndrome 
and subjects with QTc prolongation at screening or baseline will be excluded from this study 
protocol, and 12-lead ECGs will be recorded at regular intervals for subjects receiving study 
drug. 
Preclinically, there was no signal of liver toxicity. However, due to a case indicating most 
probably hepatitis A infection, as a safety precaution, subjects with abnormalities of liver 
function will be excluded from this study, and liver function will be monitored regularly in 
subjects randomized into the study. In the multi-part study CZPL389A2101 in healthy 
volunteers, no clinically relevant changes of liver parameters in subjects treated with ZPL389 
were observed. 
In the GLP embryo-fetal development toxicology in rats, thoracic and abdominal situs inversus 
were noted in three fetuses at the highest dose tested (120 mg/kg/day). The dose of 120 
mg/kg/day corresponds to 22 to 27 fold exposure over the human exposure with 50 mg o.d. 
Such findings can occur spontaneously but are rare. Minor maternal toxicity was seen at the 
same dose 120 mg/kg/day, therefore maternal and fetal NOAEL in this study in rats was 
considered to be 60 mg/kg/day (12 to 17 fold exposure over the human exposure with 
50 mg o.d.). In the GLP embryo-fetal development toxicology in rabbits, no effects were noted, 
including at the highest dose tested, 15 mg/kg/day. ZPL389 should not be administered to 
females of child-bearing potential in long-term clinical studies unless protocol-specified 
contraceptive measures are implemented. Sexually active males and females must use 
appropriate contraception as indicated in the clinical protocol. Women of child-bearing 
potential (WOCBP) will be required to have monthly serum pregnancy tests. It is unknown 
whether ZPL389 is excreted in human breast milk and hence ZPL389 should not be 
administered to lactating females. 
Full details of the preclinical and clinical data are summarized in the Investigator’s Brochure 
(IB). There are unknown risks to ZPL389 which may be serious. 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, including a data monitoring committee (DMC) 
and study drug discontinuation rules. Considering efficacy observed in the PoC study, overall 
safety observed in studies to date, and the absence of approved oral agent for AD, the 
benefit/risk appears to be positive. 
4 
Population 
The study population will consist of female and male subjects aged 18 years or older with 
moderate to severe AD. It is planned to randomize approximately 360 subjects globally. The 


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screen failure rate is estimated to be 30% and thus a total of around 515 subjects are expected 
to be screened in approximately 110-140 investigational sites. 
4.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Females and males aged 18 years or older at the time of Screening 
3. Chronic AD; according to American Academy of Dermatology Consensus Criteria 
(Eichenfield et al 2014), that has been present for at least 1 year before the baseline visit. 
4. Moderate to severe AD defined as: 
• Eczema Area and Severity Index (EASI) ≥16 at Screening and at Baseline 
• IGA 3 or 4 on a 5-point scale (where 3 is moderate and 4 is severe) at Screening and 
Baseline 
• BSA involvement ≥10% at Screening and Baseline 
5. Average peak pruritus score ≥3 as assessed by NRS over the last 7 days prior to Baseline 
6. Documented recent history (within 6 months before the screening visit) of inadequate 
response to treatment with topical medications for AD or for whom topical treatments are 
otherwise medically inadvisable (e.g., because of important side effects or safety risks).  
7. Candidate for systemic treatment 
8. Have applied a stable dose of bland topical emollient once daily for at least the 7 
consecutive days immediately before the baseline visit 
9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, diary 
completion and other study procedures. 
4.2 
Exclusion criteria 
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study: 
1. Any skin disease that, in the opinion of the investigator, would confound the diagnosis or 
evaluation of AD disease activity (e.g., Netherton Syndrome, Cutaneous T-Cell 
Lymphoma, extensive contact dermatitis, chronic actinic dermatitis) 
2. Current active skin infection at Baseline, that in the opinion of the investigator, would 
confound the diagnosis or evaluation of AD disease activity  
3. Use of other investigational drugs within 5 half-lives of enrollment, or within 
30 days /until the expected PD effect has returned to baseline, whichever is longer. 
4. History of hypersensitivity to any of the study drug constituents or to drugs of similar 
chemical classes. 
5. Subjects taking medications prohibited by the protocol (see Table 5-1) 
6. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia or any of the following: 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome 


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• Concomitant medication(s) with a “Known Risk of Torsades de Pointes” that cannot 
be discontinued or replaced by safe alternative medication. 
7. Resting QTcF ≥450 msec (male) or ≥470 msec (female) at Screening or Baseline or 
inability to determine the QTcF interval 
8. Cardiac or cardiac repolarization abnormality, including any of the following: 
• History of myocardial infarction, angina pectoris, or coronary artery bypass graft 
within 6 months prior to starting study treatment 
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, 
Mobitz type II and third degree AV block)  
9. Subjects with pre-existing conditions that may confound ability to diagnose drug-induced 
liver injury (DILI) or subjects with factors that increase susceptibility to DILI, including 
but not limited to: 
• Ongoing liver disease 
• Cirrhosis, compensated or decompensated 
• History of hepatitis B or C 
• Positive hepatitis B surface antigen (HBsAg), antiHB core antigen antibody (anti-
HBc) or anti-HB surface antigen antibody (anti-HBs) or positive hepatitis C test result 
(Subjects positive for anti-HBs after Hep B vaccination but negative for HBsAg and 
anti-HBc are eligible; Table 16-1) 
• Hepatitis A or B vaccination in last 3 months 
• Unhealthy alcohol use 
• Known gallbladder or bile duct disease 
• Acute or chronic pancreatitis 
• Acute decompensated heart failure 
• Chronic treatment with medication with hepatotoxic potential 
10. Subjects who have a laboratory abnormality at Screening as follows: 
• ALT/AST/ALP above 1.5 upper limit of normal (ULN), or TBL above upper limit of 
normal (ULN) 
• Total white blood cell count (WBC) <2.5 x 109cells/L 
• Absolute neutrophil count (ANC) <1.5 x 109/L  
• Hemoglobin <11.0 g/dL 
• Platelets <100.0 x 109/L 
• Potassium or magnesium below normal range 
• Estimated Glomerular Filtration Rate by the Modification of Diet in Renal Disease 
(MDRD)  equation <60 mL/minute/1.73 m2 
Note: One central lab retest will be allowed for lab abnormalities outside the above 
mentioned respective cut-off criteria during the screening period, if the investigator 
believes the abnormality is transient and not clinically significant 
11. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for skin Bowen’s disease, completely 


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treated and resolved non-metastatic squamous or basal cell carcinoma of the skin or 
actinic keratosis that has been treated with no evidence of recurrence in the past 12 weeks; 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been 
removed) 
12. Past medical history record of, or current infection with, human immunodeficiency virus 
(HIV) 
13. Any surgical, medical (e.g., uncontrolled hypertension, heart failure or diabetes), 
psychiatric or additional physical condition that the Investigator feels may jeopardize the 
subject in case of participation in this study 
14. Pregnant or nursing (lactating) women 
15. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using required methods of contraception during dosing 
and for 4 weeks after stopping of investigational medication. Required contraception 
methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (bilateral oophorectomy with or without hysterectomy, total 
hysterectomy or tubal ligation) at least six weeks before taking investigational drug. 
In case of oophorectomy alone, the reproductive status of the woman must have been 
confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 
• Placement of an intrauterine device (IUD) or intrauterine system 
• Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that are considered highly effective (i.e. failure rate <1%), 
i.e. for oral contraceptives only hormonal contraception associated with inhibition of 
ovulation is allowed.  
In the case of this method, the addition of a male condom is required.  
In case of use of oral contraception women should have been stable on the same pill for 
a minimum of 3 months before taking investigational drug. 
In subjects who are poor CYP2D6 metabolizers, hormonal contraception is not 
allowed and other contraceptive options as per the protocol should be followed. 
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF. 
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered not 
of child bearing potential. 


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16. Sexually active males unless they use a condom during intercourse while taking drug and 
for 4 weeks after stopping investigational medication and should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid. In case local regulations deviate from the 
contraception methods listed above, local regulations apply and will be described in the 
ICF. 
17. Prior exposure to ZPL389 treatment. 
 
 
 
4.3 
Inclusion criteria 
 
Subjects eligible for inclusion in this substudy must fulfill all of the following criteria: 
10. Subjects eligible for the main study who consent to participate in the substudy 
11. Subjects residing in a country where the substudy will be conducted. 
4.4 
Exclusion criteria 
 
Subjects fulfilling any of the following criteria are not eligible for inclusion in this substudy: 
 
 
 
 
 
 
 
 
5 
Treatment 
5.1 
Treatment assignment and randomization 
At Baseline, all eligible subjects will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the subject is eligible according to the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the subject, which will be used to link the subject to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the subject. The randomization number will not be communicated to the 
caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 


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randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s). 
In the proof of concept study, response to treatment was related to the Baseline IGA score and 
therefore randomization will be stratified by Baseline IGA moderate (3) or severe (4). In 
addition, randomization will be stratified by geographical region. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group. 
5.2 
Study treatment 
5.2.1 
Investigational and control drugs 
ZPL389 and placebo will be administered in hydroxypropyl methylcellulose capsules. The 
capsule's size is "0" (21.7 x 7.6 mm) and is pink in color. 
ZPL389 will be dispensed as 3 mg, 10 mg, 30 mg and 50 mg capsules. 
5.2.2 
Additional treatment 
The use of a bland emollient is required throughout the study and to be applied once a 
day on the entire body. Subjects should use the same emollient throughout the study. To 
allow adequate assessment of skin dryness, emollient should not be applied on the area(s) 
of non-lesional skin designated for such assessments for at least 8 hours before each clinic 
visit. 
During the screening period, investigators are to evaluate the emollient used by the subjects to 
ensure it is a bland emollient, i.e. emollients not containing ingredients such as ceramides, lactic 
acid, urea, α-hydroxy- or fruit acids, vitamins A or D. 
Subjects are requested to enter their daily use of emollients in the e-diary described in 
Section 6.6.1.6. 
5.3 
Treatment arms 
Subjects will be assigned at Baseline to one of the following 5 treatment arms in a ratio of 
2:1:1:2:2. 
• Placebo o.d. 
• ZPL389 3 mg o.d. 
• ZPL389 10 mg o.d. 
• ZPL389 30 mg o.d. 
• ZPL389 50 mg o.d. 


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5.4 
Treatment blinding 
Subjects, investigator staff, and persons performing the assessments will remain blinded to the 
identity of the treatment from the time of randomization until database lock (note that if the 
patient rolls over into the extension study, this will be at the completion of the double blind 
period of the extension study) using below methods: (1) Randomization data are kept strictly 
confidential until the time of unblinding, and will not be accessible by anyone else involved in 
the study except in the case of subject emergencies (see Section 5.5.9). (2) the identity of the 
treatments will be concealed by the use of study drug that are all identical in packaging, labeling, 
schedule of administration, appearance, taste and odor. 
Data analysts and core clinical trial team members will remain blinded to the identity of the 
treatment from the time of randomization until database lock of the core study using similar 
methods mentioned above. In case an interim analysis is performed, designated Novartis team 
members will be unblinded, however core Novartis team reviewing study data will remain 
blinded until the final database lock.   
Unblinding will only occur in the case of subject emergencies (see Section 5.5.9), and at the 
completion of the study. 
 
 
  
5.5 
Treating the subject 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
5.5.1 
Subject numbering 
Each subject is uniquely identified by a Subject Number assigned by Novartis. The Subject 
number is composed of a site number and a sequential number. Once assigned to a subject, the 
Subject Number will not be reused. 
Upon signing the informed consent form, the subject is assigned the next sequential number 
available in the electronic data capture (EDC) system. The investigator or his/her staff will 
contact the IRT and provide the requested identifying information for the subject to register 
them into the IRT. The site must select the Case Report Form (CRF) book with a matching 
Subject Number in the EDC system to enter data. 
If the subject fails to be treated for any reason, the IRT must be notified within 2 days that the 
subject was not treated. The reason for not being treated will be entered on the appropriate CRF. 
Subjects can be re-screened only once and no study-related re-screening procedure should be 
performed prior to written re-consent by the subject. 
Mis-randomized subjects are defined as cases where IRT randomization was performed by the 
site either prematurely or inappropriately prior to confirmation of the subject’s final 
randomization eligibility and no study medication was administered to the subject. 
5.5.2 
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance. 


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The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 5 treatment arms and a specific dose. 
Investigator staff will identify the study drug package(s) to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). Immediately before dispensing the package 
to the subject, investigator staff will detach the outer part of the label from the packaging and 
affix it to the source document (Drug Label Form) for that subject’s unique subject number. 
5.5.3 
Handling of study and additional treatment 
5.5.3.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis Country Pharma 
Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors. Subjects will be asked to return all unused study treatment at each visit and at the end 
of treatment or at the time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
5.5.3.2 
Handling of additional treatment 
Subjects are requested to enter their daily use of emollients in the e-diary. Rescue medication 
is discussed in Section 5.5.6. 
5.5.4 
Instructions for prescribing and taking study treatment 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT. 
ZPL389 will be provided as 3 mg, 10 mg, 30 mg and 50 mg powder in capsules.  Placebo will 
be provided as visually matched capsules. Bottles of capsules will be dispensed at study visits 
occurring at Baseline and every 4 weeks thereafter. All study drugs will be supplied in identical 
bottles and will be the same color and appearance, thereby maintaining double-blind conditions. 
Study medication will be supplied to the subject at: 
• Baseline visit (Day 1): 1 bottle of ZPL389 or matching placebo 
• Week 4 (Day 29): 1 bottle of ZPL389 or matching placebo 
• Week 8 (Day 57): 1 bottle of ZPL389 or matching placebo 


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• Week 12 (Day 85): 1 bottle of ZPL389 or matching placebo 
Note: Investigators must check the number of doses already taken by the subject, and ensure 
that the Week 16 visit is scheduled such that the subjects take approximately 112 capsules in 
total. 
Subjects must be instructed to take one capsule per day at the same time every day 
preferably in the morning (e.g. every day at 8 am). The subject will record the intake of 
study medication on a daily basis on the subject e-diary. On days of a scheduled study 
visit, subjects must be instructed to: 
• bring all current study medication with them to the visit 
• not take the investigational treatment at home on the day of a study visit but must 
take it when instructed by study personnel at the investigational site 
 
 
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Investigational treatment dose adjustments are not permitted. Treatment might be interrupted 
as per guidance in the safety monitoring Sections 14 and 15. 
Changes must be recorded on the appropriate CRF. 
5.5.6 
Rescue medication 
Only after four weeks post Baseline and only if medically necessary (i.e., to control 
intolerable AD symptoms), as assessed by investigator, rescue treatment for AD may be 
provided to study subjects. The rescue therapy may not be dispensed as a precaution. If 
the need for rescue therapy arises between scheduled study visits, the subject needs to 
come for an unplanned visit for the investigator to assess the subject. 
The following rescue medication will be provided/reimbursed by Novartis: mometasone furoate 
cream 0.1% (TCS). The rescue medication may only be used to treat AD symptoms. If patients 
have tolerance issues with mometasone furoate cream 0.1% or in countries where mometasone 
furoate cream 0.1% is not available for the relief of AD symptoms or its use is restricted by its 
label, an alternative TCS of similar potency will be provided. If and only when the use of 
mometasone furoate cream 0.1% is not deemed appropriate for problem areas, e.g., face, neck, 
intertriginous and genital areas, then hydrocortisone 2.5% ointment or topical calcineurin 
inhibitors could be used instead in these areas only. Any other TCS/TCI use is prohibited. 
Investigators must remind subjects that they should use rescue medication only if really needed 
and only when instructed by the investigator because the use of rescue medication may affect 
the validity of study results negatively. Rescue medication use must be stopped as soon as not 
needed anymore as assessed by the investigator. 
Subjects should allow adequate time for absorption after each rescue medication 
application before applying an emollient and record their rescue medication use in the e-


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diary (see Section 6.6.1). At each study visit, after a subject was given rescue medication, the 
subject will have to bring the rescue medication tube/ container to the site and the investigator 
will review the e-diary. Rescue medication tubes/container will be weighed at the time of 
dispensing and every subsequent visit and the weight used recorded in the appropriate CRF. 
5.5.7 
Concomitant medication 
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the subject was enrolled into the study must be recorded in the appropriate CRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. 
5.5.8 
Prohibited medication 
Use of the treatments displayed in the below table is NOT allowed during the period specified 
below in Table 5-1. 
Table 5-1 
Prohibited medication/therapy 
Medication/therapy 
Prohibited period 
Action taken 
Topical corticosteroids (TCS) 
Topical calcineurin inhibitors 
(TCI) 
Other topical treatment for AD 
such as crisaborole, tar etc. 
Initiation of treatment of AD 
with prescription moisturizers 
or moisturizers containing 
ingredients such as ceramides, 
lactic acid, urea, α-hydroxy- or 
fruit acids, vitamins A or D 
a) Within 1 week prior to 
Baseline 
 
b) Treatment period  
 
 
 
 
 
 
c) Follow up period 
a) Delay randomization to achieve 
1-week wash out or discontinue 
subject from trial 
b) Discontinue prohibited 
medication and continue study 
treatment  
OR 
If the subject meets criteria for 
rescue medication and only after 4 
weeks post Baseline, follow 
instructions in Section 5.5.6** 
c) Discontinue prohibited 
medication, unless patient is in the 
follow up period after early 
treatment discontinuation 
Systemic immunosuppressive 
treatments* including but not 
limited to systemic 
corticosteroids (e.g.,  i.v., i.m. 
or oral), cyclosporine, 
tacrolimus, cyclophosphamide, 
azathioprine, methotrexate, 
mycophenolate mofetil, JAK 
inhibitors, apremilast, biologic 
therapies (like dupilumab, 
etanercept, adalimumab, 
infliximab, omalizumab), 
chinese traditional medicine 
a) Within 4 weeks prior to 
Baseline for non biologics 
/ within 3 months prior to 
Baseline for biologic 
treatments 
or  
within 5 half-lives of 
Baseline, whichever is 
longer 
 
 
a) Discontinue subject from trial 
and rescreen subject after wash-
out and if recruitment period is still 
ongoing 
 
 
 
 


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Medication/therapy 
Prohibited period 
Action taken 
b) Treatment period 
 
 
 
 
c) Follow up period 
b) Discontinue prohibited 
medication and continue study 
treatment unless there is a specific 
safety risk for the subject, in the 
opinion of the investigator in which 
case study treatment must be 
discontinued 
c) Discontinue prohibited 
medication 
Oral antihistamines  
(H1 antihistamines are allowed 
if the subject is on a stable 
dose or used short term to, for 
example, treat allergies) 
a) Within 1 week prior to 
Baseline 
 
b) Treatment period 
 
 
 
 
c) Follow up period 
a) Delay randomization to achieve 
1-week wash out or discontinue 
subject from trial 
b) Discontinue the prohibited 
therapy, and continue study 
treatment unless there is a specific 
safety risk for the subject, in the 
opinion of the investigator in which 
case study treatment must be 
discontinued 
c) Discontinue prohibited 
medication 
Phototherapy or tanning booths 
Bleach baths 
a) 4 weeks prior to Baseline 
 
 
 
b) Treatment period 
 
 
c) Follow up period 
a) Discontinue subject from study 
and rescreen subject after wash-
out if the recruitment period is still 
ongoing  
b) Discontinue prohibited 
medication/therapy, and continue 
study treatment 
c) Discontinue prohibited 
medication 
Any investigational treatment  
a) Within 5 half-lives of 
Baseline or until the 
expected pharmacodynamic 
effect has disappeared, 
whichever is longer 
 
b)Treatment period 
 
c) Follow up period 
a) Discontinue subject from trial 
and rescreen subject after wash-
out if the recruitment period is still 
ongoing 
 
 
b) Discontinue subject from study 
treatment 
c) Discontinue prohibited 
medication 
Any drug known to prolong 
QTc interval (See 
https://crediblemeds.org/ for 
details as well as protocol 
supplementary guidance) 
Drugs known to be hepatotoxic 
(please see protocol 
supplementary guidance)# 
a) Within 5 half-lives of 
Baseline or until 
pharmacodynamic effect 
has disappeared, whichever 
is longer 
b) Treatment period 
 
 
 
a) Discontinue subject from study 
and rescreen subject after wash-
out if the recruitment period is still 
ongoing 
 
b) Discontinue study treatment 


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Medication/therapy 
Prohibited period 
Action taken 
Strong (Potent) CYP1A2 
inhibitors (see protocol 
supplementary guidance) for all 
subjects  
For subjects that are poor 
CYP2D6 metabolizers, strong 
and moderate  CYP1A2 
inhibitors (see protocol 
supplementary guidance) 
c) Follow up period  
c) Discontinue prohibited 
medication (unless taken 4 weeks 
after early treatment 
discontinuation where it can be 
allowed if medically necessary) 
 
Patients participating in 
 must not 
take
 
 
 
a) Within 2 weeks of 
Baseline 
b) Treatment period 
c) Follow up period 
a) Patient is not eligible for 
substudy and will not participate 
b) Discontinue prohibited 
treatment 
c) Discontinue prohibited 
medication 
*CS nasal sprays and eye drops are not considered systemic immunosuppressive treatment 
**Rescue therapy used as per Section 5.5.6 (only if medically necessary i.e., to control intolerable AD 
symptoms, as assessed by investigator and only after at least 4 weeks post Baseline) is not 
considered a prohibited medication. 
# short course of ibuprofen or topical NSAID may be allowed if investigator is of the opinion that it is in 
the best interest of the subject and that no hepatotoxicity is expected. 
 
5.5.9 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the Study Team that the code has 
been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 
• subject number 
In addition, oral and written information on how to contact his/her backup in cases of emergency, 
or when he/she is unavailable, must be provided to the subject to ensure that un-blinding can be 
performed at any time. 
The subject must be followed up and continue the study visit schedules. 


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5.6 
Study completion and discontinuation 
5.6.1 
Study completion and post-study treatment 
 The study will be completed once all subjects have either entered the extension trial or have 
completed the Week 20 visit. 
Subjects may be offered participation in an extension study. The details of the study design and 
procedures of the extension study will be described in a separate protocol. If the subject does 
not enter the extension study, the investigator and/or referring physician must ensure that 
continuing care is provided. 
When the subject has completed all scheduled study assessments or prematurely withdrawn 
from the study, the investigator must contact the IRT to record the subject completion 
/discontinuation and complete applicable CRF. 
5.6.2 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would negatively impact the subject or in the event the subject is 
unwilling or unable to comply with study requirements. 
Study treatment must be discontinued under the following circumstances: 
• Subject wishes to withdraw consent 
• Pregnancy (Section 7.7) 
• Use of prohibited treatment as per recommendations in Table 5-1 
• Any situation in which study participation might result in a safety risk to the subject 
• QTcF >500 msec, confirmed by repeat ECG measurements 
• QRS >110 msec and increase >25% from Baseline (Day 1) 
• Cardiac abnormalities of CTCAE v4.03 severity grade ≥2, including: 
o Resting heart rate <60 or >100 bpm confirmed by repeat measurement and 
associated with symptoms, indicating medical intervention  
o Ventricular fibrillation, or any clinically significant cardiac arrhythmia 
o New complete heart block (Grade III AV block)  
o Second degree AV block Mobitz type II associated with symptoms, indicating 
medical intervention 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study 
• Liver and renal events requiring treatment discontinuation as per  Table 14-2 and Table 
15-1 
• Laboratory abnormalities indicating blood and lymphatic system disorders of CTCAE 
v4.03 of severity grade ≥2 including: 
• Anemia: Hemoglobin <10 g/dL 


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• Febrile neutropenia (ANC <1000/mm3 with a single temperature of >38.3 ºC (101 ºF) 
or a sustained temperature of ≥38 ºC (100.4 ºF) for more than 1 hour 
• Leukocytes >100,000/mm3 
• Lymph node pain of at least moderate intensity 
• Spleen disorder requiring prophylactic antibiotics 
• Thrombotic thrombocytopenic purpura 
If discontinuation of study treatment occurs, the subject should not receive additional doses. 
Subjects should remain in the study and be followed at least until the adverse event resolves / 
stabilizes, or until the end of the study, whichever is longer.  I.e. After study treatment 
discontinuation, the subject should remain in the study and attend study visits as normal in Table 
6-1 (without contacting IRT /drug dispensing). Subjects who discontinue treatment and wish to 
discontinue the study should at a minimum return for the End of Treatment visit (Week 16 visit) 
and the Follow up visit (Week 20 visit), as detailed in Table 6-1, and assessment should be 
completed and recorded in the appropriate CRF. The investigator must determine the primary 
reason for the subject’s premature discontinuation of study treatment and record this 
information on the CRF. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
5.6.3 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore,  
and 
• Does not  allow further collection of personal data 
 In this situation, the investigator must make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. Prior to 
withdrawal, evaluation should be made as detailed in the assessment table (End of Treatment 
Week 16 visit). All e-diaries and devices and study medication must be returned to the site at 
this visit. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.  


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For United States and Japan: All biological samples not yet analyzed at the time of withdrawal 
may still be used for further testing/analysis in accordance with the terms of this protocol and 
of the informed consent form.   
For European Union and Rest of World: All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements. 
5.6.4 
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit has passed. 
5.6.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason.  
Reasons for early termination: 
• Unexpected, significant or unacceptable safety risk to subjects enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. If the study is terminated prematurely the investigator or treating physician 
must ensure appropriate ongoing care is provided to the patient. The investigator will be 
responsible for informing IRBs/IECs of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments/actions and indicates with an “x” or “S” at which visits 
they are performed. 
Subjects must be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits should not lead to automatic discontinuation. Subjects who prematurely 
discontinue from the study should have at the time of discontinuation all of the assessments 
listed for the End of Treatment Week 16 visit, and a Follow-up Week 20 visit. All e-diaries and 
devices and study medication must be returned to the site at this visit. At this final visit, all 
dispensed investigational product should be reconciled and the adverse event and concomitant 
medications reconciled on the CRF. 
Subjects should be reminded to be fasting for at least 3 hours before the visits and to bring 
their medication and their e-diaries. They should not eat at least until the last ECG is 
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Table 6-1 
Assessment Schedule 
Period Screening 
Treatment 
Follow-up 
(EOS/PSW) Unplanned 
Visit Day 
-28 to -1 
1 
15 
29 
43 
57 
85 
1131 
141 
- 
Weeks 
-4 to -1 
0 
2 
4 
6 
8 
12 
16 
20 
0 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demography, AD medical 
history, Medical history/current 
medical conditions, Smoking 
history 
X 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Electrocardiogram (ECG)2 
X 
X (predose AND 
2h postdose)3 
X 
X (predose AND  
2h postdose)3 
X 
X 
X 
X3 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Height 
X 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Hepatitis screen, HIV screen 
X 
 
 
 
 
 
 
 
 
 
Hematology, Clinical Chemistry, 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (Serum)  
X 
X 
 
X 
 
X 
X 
X 
X 
 
Pregnancy Test (Urine) 
 
S 
 
 
 
 
 
 
 
 
Concomitant medications/ 
Surgical or Medical Procedure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Period Screening 
Treatment 
Follow-up 
(EOS/PSW) Unplanned 
Visit Day 
-28 to -1 
1 
15 
29 
43 
57 
85 
1131 
141 
- 
Weeks 
-4 to -1 
0 
2 
4 
6 
8 
12 
16 
20 
0 
Patient e-Diary daily entry4 
X 
Patient e-Diary Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IGA, EASI (incl. BSA), 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensation5 
 
X 
 
X 
 
X 
X 
 
 
 
Drug accountability 
 
 
 
X 
 
X 
X 
X 
 
 
Dosing at site6 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Disposition 
X 
 
1Visit must be the day after the last day of dosing i.e. Day 113; End of treatment visit (EOT) or treatment discontinuation (TD) 
2All ECGs are to be performed under fasted conditions (subjects should fast at least 3 hours before the site visit and remain fasted until the last ECG is done). ECG should be done after 10 min rest in supine position, 
followed by vital signs while supine and then blood samples 
3Triplicate standard 12-lead ECGs will be performed at: Baseline (triplicate before intake of drug and triplicate 2 hours post dose), Week 4 (triplicate before intake of drug and triplicate 2 hours post dose), and at Week 
16 (triplicate before intake of drug).  Single standard ECGs should be done at all other visits. 
4Starting 1 week prior to Baseline. The investigational site staff must make a phone call to the patient to remind them to switch on the device and start completion. Patient e-Diary will include 
 
daily use of emollients, study drug and rescue therapy (if any). 
5Subjects should be instructed to take study medication every day at the same time preferably in the morning except on study visit days. The subject will record the intake of study medication on a daily basis on the 
subject e-diary. 
6 On days of a study visit, subjects should not take the investigational treatment at home; instead they will take it when instructed by study personnel at the investigational site 
. 
Note: The use of a bland emollient is required throughout the study and to be applied once a day on the entire body. Subjects should use the same emollient throughout the study. To allow adequate assessment of 
skin dryness, emollient should not be applied on the area(s) of non-lesional skin designated for such assessments for at least 8 hours before each clinic visit. Tube/container of rescue medication (if any; only when 
medically justified) will be weighed at the time of dispensing and at every subsequent visit while the rescue medication is used and the weight used recorded. 


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Period Screening 
Treatment 
Follow-up 
(EOS/PSW) Unplanned 
Visit Day 
-28 to -1 
1 
15 
29 
43 
57 
85 
1131 
141 
- 
Weeks 
-4 to -1 
0 
2 
4 
6 
8 
12 
16 
20 
0 
 
 
Note: Patient reported outcomes must be done before physician assessments (IGA, then EASI and BSA 
) 
EOS = End of Study. PSW = Premature study withdrawal.  X = will be captured in systems for study data collection; S = source capture only 


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6.1 
Information to be collected on screening failures 
All subjects who have signed informed consent but not entered into the next period will have 
the disposition, demographics, inclusion/exclusion, informed consent, rescreening, withdrawal 
of consent (if subject withdrew consent) and serious adverse event (SAE) data collected. 
Adverse events that are not SAEs will be followed by the investigator or primary care physician 
and collected only in the source data. 
6.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race, ethnicity, smoking history, relevant medical history/family history or current medical 
condition present before signing informed consent. When possible, diagnoses and not 
symptoms will be recorded.
 
 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. Information about characteristics and history of subjects’ AD including previous 
treatment received will be collected. 
6.2.1 
Screening for HIV/Hep B and Hep C 
• All subjects will be screened for hepatitis B surface antigen (HBsAg), anti-HBs, and anti-
HBc. Subjects testing positive for any of the serologic markers will not be eligible for 
randomization, with the exception of anti-HBs due to previous vaccination against Hep B 
(unless vaccination was in the past 3 months). Table 16-1 provides detailed Hep B 
serology result interpretations. 
• Screening for hepatitis C will be based on hepatitis C virus antibodies; if the qualitative 
test result is positive, it will be verified by a second technique (e.g. HCV RNA 
quantification) 
• Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a 
second technique available at the laboratory site, e.g., Western blot. 
Appropriate counseling will be made available by the Investigator in the event of a positive 
finding. Results will be available as source data and will not be recorded within the CRF. All 
samples will be shipped to the central laboratory. 
6.3 
Treatment exposure and compliance 
6.3.1 
ZPL389 / placebo 
Study drug compliance will be assessed by the investigator and/or center personnel at 
designated visits by recording capsule counts from the previously dispensed container. This 
information should be captured in the source document at each designated visit. All study 
treatment dispensed and returned must be recorded in the Drug Accountability Log. 
Subjects must be requested to record in the e-diary their intake of study medication on a daily 
basis. 


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Study personnel will review the e-diary entries at each visit for study drug intake and discuss 
with patient any missed doses. Study personnel will also review the amount of study medication 
returned by the subject. The total number of doses of study drug intake since the last dispensing 
visit will be recorded in the appropriate CRF based on the returned study medication and 
discussion with the patient. 
6.3.2 
Rescue medication and emollient 
Subjects are requested to record in the e-diary their use of emollient. If the subject needed rescue 
medication and it was dispensed by the investigator, the subject needs to enter rescue 
medication use on a daily basis in the e-diary. 
In addition, Investigators will weigh the rescue medication container at the time of dispensing 
and at the time of return at the next study visit. The information will be recorded in the 
appropriate CRF. 
6.4 
Efficacy 
The investigator assessments should be performed by the same member of study site staff 
throughout the study. Adequate time should be scheduled allowing for a complete examination. 
The IGA, EASI, 
 evaluations require a full-body examination - subjects must be 
undressed. Observations must also be made in a well-lit area. 
Assessments performed by the investigator are to be conducted after the subject has completed 
the on-site reported outcome assessments, and should be performed in the following order: IGA, 
then EASI 
. 
6.4.1 
Appropriateness of efficacy assessments 
The efficacy measurements are standard for this indication (Eichenfield et al 2014). 
6.4.2 
IGA 
The IGA rating scale is used to determine the severity of AD symptoms and clinical response 
to treatment. It reflects a subject’s overall disease severity for the whole body based on a 5-
point scale. The 5-point scale includes: clear, almost clear, mild, moderate, and severe disease. 
It is a static scale and does not refer to previous status of the subject. The Investigator or trained 
qualified designee will complete the IGA assessment on each of the visits as outlined in the 
assessment schedule. Whenever possible, the IGA assessments should be performed by the 
same evaluator throughout the study. Please, see Section 17 for details. 
6.4.3 
EASI 
The EASI (Eczema Area and Severity Index) will be used to make an assessment of the extent 
and severity of AD (Hanifin 2001). The Investigator or trained qualified designee will complete 
the EASI assessment on each of the visits as outlined in the assessment schedule. Whenever 
possible, the EASI assessments should be performed by the same evaluator throughout the study.  
Each body region (head/neck [H], upper limbs [UL], trunk [T], and lower limbs [LL]) will be 
assessed for: 


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• Severity of AD: the average degree of the following key signs of AD (erythema, 
induration/papulation, excoriation, and lichenification) will each be assigned a score of 
0, 1, 2 or 3 indicating none (0), mild (1), moderate (2), and severe (3) expression of the 
clinical sign, as indicated in Table 6-3 EASI: severity descriptions.  
• Extent of AD: Based on the extent of AD in a particular body region (when each body 
region is considered as a whole or 100%), an Area score will be assigned to that body 
region. 
Please note: 
• Only inflamed areas should be included in the assessment, dry skin or post inflammatory 
pigmentation changes should not be included. 
• The neck is assessed as part of the head region. 
• The axillae and groin are assessed as part of the trunk. 
• The buttocks are assessed as part of the lower limbs. 
For a calculation of EASI score (ranging from 0 to 72), please see Table 6-4. 
Calculation of BSA (total body surface area affected by AD): percentage of each body region 
affected by AD will be multiplied by its respective body region corresponding factor (0.1 for 
head, 0.3 for trunk, 0.2 for upper limbs and 0.4 for lower limbs). 
Total BSA affected by AD = 0.1xHead area % + 0.2xUpper limbs area % + 0.3xTrunk area % 
+ 0.4xLower limbs area %. 
Table 6-3 
EASI: severity descriptions 
Sign score 
Grading 
Description 
Erythema (E) 
0 
None 
N/A 
1 
Mild 
Faintly detectable erythema: very light pink 
2 
Moderate 
Dull red, clearly distinguishable 
3 
Severe 
Deep/dark red 
Induration / Papulation (P) 
0 
None 
N/A 
1 
Mild 
Barely perceptible elevation 
2 
Moderate 
Clearly perceptible elevation but not extensive 
3 
Severe 
Marked and extensive elevation 
Excoriations (Ex) 
0 
None 
N/A 
1 
Mild 
Scant evidence of excoriations with no signs of deeper skin 
damage (erosion, crust) 
2 
Moderate 
Several linear marks of skin with some showing evidence of deeper 
skin injury (erosion, crust) 
3 
Severe 
Many erosive or crusty lesions 
Lichenification (L) 
0 
None 
N/A 


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1 
Mild 
Slight thickening of the skin discernible only by touch and with skin 
markings minimally exaggerated 
2 
Moderate 
Definite thickening of the skin with skin markings exaggerated so 
that they form a visible crisscross pattern 
3 
Severe 
Thickened indurated skin with skin markings visibly portraying an 
exaggerated crisscross pattern 
Table 6-4 
EASI calculation 
Body 
region 
Erythema 
(E) 
Induration / 
Papulation(P) 
Excoriation 
(Ex) 
Lichenification 
(L) 
Area score (A) 
EASI 
calculation 
Head & 
neck  
(H) 
0=none  
1=mild 
2=moderate 
3=severe 
0=none  
1=mild   
2=moderate 
3=severe 
0=none  
1=mild 
2=moderate 
3=severe 
0=none  
1=mild   
2=moderate 
3=severe 
0= 0% 
1= >0 - <10% 
2=10% to <30% 
3=30% to <50% 
4=50% to <70% 
5=70% to <90% 
6=90% to 100% 
(E+P+Ex+L) 
x A x 0.1 
Trunk 
(T) 
 
0=none 
1=mild 
2=moderate 
3=severe 
0=none 
1=mild 
2=moderate 
3=severe 
0=none 
1=mild 
2=moderate 
3=severe 
0=none 
1=mild 
2=moderate 
3=severe 
0=0% 
1=>0 - <10% 
2=10% to <30% 
3=30% to <50% 
4=50% to <70% 
5=70% to <90% 
6=90% to 100% 
(E+P+Ex+L) 
x A x 0.3 
Upper 
limbs 
(UL) 
0= none 
1= mild 
2=moderate 
3=severe 
0=none 
1=mild 
2=moderate  
3=severe 
0= none 
1= mild 
2=moderate 
3= severe 
0= none 
1= mild 
2=moderate 
3=severe 
0= 0% 
1= >0 - <10% 
2=10% to <30% 
3=30% to <50% 
4=50% to <70% 
5=70% to <90% 
6=90% to 100% 
(E+P+Ex+L) 
x A x 0.2 
Lower 
limbs 
(LL) 
0=none  
1=mild 
2=moderate 
3=severe 
0=none  
1=mild 
2=moderate 
3=severe 
0=none 
1=mild 
2=moderate  
3=severe 
0=none  
1=mild 
2=moderate  
3= severe 
0= 0% 
1= >0 - <10% 
2=10% to <30% 
3=30% to <50% 
4=50% to <70% 
5=70% to <90% 
6=90% to 100% 
(E+P+Ex+L) 
x A x 0.4 
EASI score = 
sum of the 
above 4 
scores 
 
 
 
 
 


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6.5 
Safety 
In addition to the below listed safety assessments, safety monitoring must be done at every visit 
as per Section 7 as well as review of concomitant medications with reference to prohibited 
medications (Table 5-1). The safety assessments and monitoring is in accordance with the risks 
associated with ZPL389 and/or unknown information. 
6.5.1 
Physical exam 
A physical examination, including general appearance, will be performed at every visit. If 
indicated, based on medical history and/or symptoms, additional exams will be performed at 
the discretion of the investigator. If possible, assessments for an individual subject should be 
performed by the same member of the study site staff throughout the study. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the subject signing informed consent 
must be included in the medical history CRF. Significant findings made after the signing of the 
informed consent which meet the definition of an AE must be recorded on the AE CRF. 
6.5.2 
Body Weight and height 
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at the visits specified in the table of assessments. 
Height in centimeters (cm) will be measured at the visit specified in the assessments schedule. 
6.5.3 
Electrocardiogram (ECG) 
ECGs will be analyzed centrally and performed with ECG machines supplied by the central 
provider. 


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ECGs should be done in fasting conditions (subjects should fast for at least 3 hours before the 
site visit) and after 10 minutes rest in the supine position.  The sequence of cardiovascular data 
collection during study visits is ECG collection first, followed by vital signs and then blood 
sampling. The Fridericia QT correction formula (QTcF) should be used for clinical decisions. 
Standard 12-lead ECGs will be performed as indicated in the assessment schedule; triplicates 
standard ECG at Baseline, Week 4 and Week 16 visits and single standard ECGs at all other 
visits. Subjects must remain fasted until the last ECG is performed. 
In the event that the central cardiologist reports that an ECG is abnormal, then the investigator 
must comment as to whether the ECG abnormality is either clinically significant or clinically 
insignificant. If necessary, a local cardiologist may be consulted. 
Clinically significant abnormalities should be recorded on the relevant section of the 
appropriate CRF. 
6.5.4 
Vital Signs 
Measurements will include pulse rate, supine systolic and diastolic blood pressure. 
On visits where an ECG is also being performed, the blood pressure measurement should be 
done after the ECG measurements while the subject is in the supine position. Pulse rate (heart 
rate) will be done as part of the ECG measurement, if taken at the visit at which ECG is done. 
After the subject has been resting in supine position for approximately 10 minutes, systolic and 
diastolic blood pressure will be measured twice using an automated validated device, e.g. 
OMRON, with an appropriately sized cuff. The repeat measurements will be made at 1 to 2 
minute intervals and the mean of the two measurements will be used. In case the cuff sizes 
available are not large enough for the subject's arm circumference, a sphygmomanometer with 
an appropriately sized cuff may be used. 
6.5.5 
Laboratory evaluations 
A central laboratory will be used for analysis of all blood specimens detailed in this section, 
unless otherwise specified. Samples will be collected according to the assessment schedule. 
Details on the collections, shipment of samples, and reporting of results by the central laboratory 
will be provided to Investigators in the central laboratory manual. 
6.5.5.1 
Clinical Chemistry 
The chemistry panel will include: albumin, alkaline phosphatase (ALP), total bilirubin (TBL), 
calcium, chloride, total cholesterol, LDL-cholesterol, HDL-cholesterol, creatinine, creatine 
kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-
glutamyltransferase (γ-GT), glucose, sodium, potassium, inorganic phosphorus, total protein, 
lactate dehydrogenase (LDH), triglycerides, magnesium, blood urea nitrogen (BUN), and uric 
acid. Estimated creatinine clearance will be calculated using the MDRD formula. Lipase and 
amylase will be included at Screening and Baseline. PT/INR (Prothrombin time/ International 
Normalized Ratio) must be included in unscheduled visits.  
If the TBL concentration is increased above 1.5 x ULN, direct and indirect reacting bilirubin 
should be differentiated. 


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6.5.5.2 
Hematology 
Hemoglobin, hematocrit, red blood cell count, WBC count with differentials and platelet count 
will be measured. 
6.5.6 
Pregnancy Test 
For all WOCBP, a serum pregnancy test is required at Screening, Baseline and at monthly 
intervals during treatment (at scheduled visits). A serum pregnancy test will also be performed 
at the end of the study. Additionally, at Baseline a urine pregnancy assessment should be done 
and the result must be evaluated prior to randomization but only captured on source documents. 
6.5.6.1 
Urinalysis 
Dipstick measurements for protein, blood, and WBC/leukocytes will be performed. 
If dipstick measurement results are positive (abnormal), results will be captured in the CRF. 
Microscopy must be assessed following an abnormal dipstick test. 
6.6 
Other assessments 
6.6.1 
Clinical Outcome Assessments 
 
 All the PROs should 
be completed by the subject before they see the study physician (investigator or designee) who 
will perform the investigator assessments. Exceptionally, if the electronic device is not working, 
the questionnaires might be completed on paper. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.6.1.6 
Patient e-diary 
Subjects will be asked to complete an e-diary. The patient e-diary will be dispensed at Screening 
to all subjects. They will complete entries on a daily basis at home starting one week prior to 


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their scheduled Baseline visit. The device will remind the subjects to complete the questions 
however, the site staff must make a telephone call to each subject one week prior to their 
scheduled Baseline visit to remind them to charge and switch on the device and to complete the 
e-dairy on a daily basis in order for the inclusion criterion 5 to be evaluated on the day of 
Baseline. Subjects must bring their e-diaries with them to every scheduled visit. The patient e-
diary will be checked by a designated study staff member at each visit; in case of incomplete e-
dairy entry, the study site staff will counsel the subject on the correct use and frequency of the 
patient e-diary. 
Daily entries starting 1 week prior to the scheduled Baseline visit: 
 
 
 
 
• Emollient use (see Section 5.2.2) 
In addition, daily entry starting on the day of the Baseline visit will also include: 
• Intake of study medications (see Section 18) 
Rescue medication use, if applicable (see Section 5.5.6) will be entered on the e-diary. Note: 
rescue therapy can only be used starting at least 4 weeks after Baseline and if found necessary 
by the Investigator. 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Resource utilization 
Not applicable. 


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7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign, 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. 


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In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1. 
Adverse events must be recorded in the appropriate CRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, accompanied by the following information: 
• the severity grade 
mild: usually transient in nature and generally not interfering with normal activities 
moderate: sufficiently discomforting to interfere with normal activities 
severe: prevents normal activities 
• its relationship to the study treatment 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
• whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met. 
• action taken regarding investigational treatment 
All adverse events must be treated appropriately. Action taken with investigational treatment 
may include one or more of the following: 
• no action taken (e.g. further observation only) 
• investigational treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given 
• non-drug therapy given 
• subject hospitalized/subject’s hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• its outcome (not recovered/not resolved; recovered/resolved, recovered/resolved with 
sequelae; fatal; or unknown) 


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Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the subject. 
The investigator must also instruct each subject to report any new event (beyond the protocol 
observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing)) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
o elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention. 
All malignant neoplasms except non-melonoma skin cancer will be assessed as serious under 
“medically significant” if other seriousness criteria are not met. 


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Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured in the CRF; SAEs also require individual 
expedited reporting to Novartis Chief Medical Office and Patient Safety as per Section 7.2.2. 
7.2.2 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced after the 
30 day period after the last study visit should only be reported to Novartis safety if the 
investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to the investigational 
treatment complete the SAE Report Form in English, and submit the completed form within 24 
hours to Novartis. Detailed instructions regarding the submission process and requirements for 
signature are to be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the subject continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 


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reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of 
its occurrence/receiving follow-up information. 
7.3 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring should be 
entered into the appropriate CRFs. 
Please refer to Table 14-1 for complete definitions of liver laboratory triggers and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 should be followed up by 
the investigator or designated personnel at the trial site as summarized below. Detailed 
information is outlined in Table 14-2. 
For the liver laboratory trigger: 
• Repeating the liver function test (LFT) within the next week to confirm elevation 
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
subject. Repeats of laboratory must then be performed at central laboratory as soon as 
possible. If a liver event is subsequently reported, any local LFTs previously conducted that 
are associated with this event must be reported on the appropriate CRFs. 
• If the elevation is confirmed, close observation of the subject will be initiated, including 
consideration of treatment interruption if deemed appropriate. Based on the investigator’s 
discretion and/or consultation with Novartis medical monitor, further investigations may 
be performed. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the subject if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution 
• Complete questionnaire for adjudication as applicable 
These investigations can include serology tests, imaging and pathology assessments, and/or 
hepatologist consultancy, based on the investigator’s discretion and/or consultation with 


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Novartis medical monitor. All follow-up information and the procedures performed must be 
recorded on the appropriate CRFs. 
7.4 
Renal safety monitoring 
As part of standard renal monitoring, the following two categories of abnormal renal laboratory 
values have to be considered during the course of the study: 
• Serum event: 
• confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status 
• Urine event: 
• new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable) 
• new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 15-1 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Appendix 3. 
7.5 
Cardiac safety monitoring 
For ECGs, a notable QTc value is defined as a QTcF (Fridericia) interval of ≥450 msec for 
males or ≥470 msec for females as well as any increase from Baseline of 30 msec for males and 
females– all such ECGs will be flagged by the Central CRO and require assessment for clinical 
relevance and continuance of the subject by the Investigator. 
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, QTcF >500 msec), a copy of the assessment is sent to the core laboratory for 
expedited review by the central cardiologist if applicable, and the triplicate ECG is repeated to 
confirm the diagnosis. Additionally, the following must be done: 
• Discontinue study treatment 
• Collect a 
 sample 
• Consult a cardiologist and review electrolytes and concomitant medications 
• Perform a follow up ECG 24-48 hours 
• Cardiac enzymes or any other cardiac investigation may be done as appropriate 
If the subject is hemodynamically compromised, the investigator or a medically qualified 
person must initiate appropriate safety procedures without delay (for example cardioversion). 
Please refer to Appendix 1 for notable vital signs. 
7.6 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 


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Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE. 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in CRF 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
7.7 
Pregnancy reporting 
When pregnancy occurs in a subject in this study, the study drug must be discontinued, and the 
subject should stay in the study and follow the assessments. Assessments that are considered as 
a risk during pregnancy must not be performed. The subject should continue all other protocol 
assessments. Pregnancy cases have to be unblinded and the treatment communicated to 
investigator with the request to inform the subject which treatment she was on. This applies also 
when pregnancy occurs in partners of male subjects. 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. Post-natal follow up is required until 3 months after the birth. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements with the investigators and 


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their staff. During the study, Novartis employs several methods of ensuring protocol and Good 
Clinical Practice (GCP) compliance and the quality/integrity of the sites’ data. The field monitor 
will visit the site to check the completeness of subject records, the accuracy of data capture / 
data entry, the adherence to the protocol and to GCP, the progress of enrollment, and to ensure 
that study treatment is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the field monitor during these visits.  Continuous 
remote monitoring of each site’s data may be performed by a centralized Novartis monitoring 
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis Clinical Teams to assist 
with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the subject's file. The 
investigator must also keep the original informed consent form signed by the subject (a signed 
copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs) using fully validated secure web-enabled software that conforms 
to US CFR 21 Part 11 requirements. Designated investigator site staff will not be given access 
to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock or when a site is closed, the investigator will receive copies of the subject data 
for archiving at the investigational site. 
The Principal Investigator is responsible for assuring that the data entered by the site personnel 
into CRF is complete, accurate, and that entry and updates are performed in a timely manner. 
8.3 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 


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investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples and ECG readings will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO). 
Diary data and Patient Reported Outcomes will be entered into an electronic device by the 
subject. The device will also be used to capture efficacy assessments entered by the 
investigator/delegate. The system will be supplied by a vendor(s), who will also manage the 
database. Exceptionally, if the electronic device is not working, the efficacy assessments and 
Patient Reported Outcomes may be completed on paper. The data would then be transcribed in 
the vendor database. The database will be sent electronically to Novartis personnel (or 
designated CRO). 
 The database will be sent 
electronically to Novartis personnel (or designated CRO). 
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using IRT. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management. 
 
 
 
 
 
 
8.4 
Data Monitoring Committee 
A DMC will review cumulative safety data at scheduled meetings. Of note, the clinical safety 
plan for this study includes close monitoring by the investigator for signs of abnormal cardiac 
and hepatic parameters, study entry criteria and treatment discontinuation criteria (Section 5.6). 
The collection and summary of these data will be prepared by a designated CRO or Novartis. 


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Details on the organization and function of the DMC will be described in the DMC charter. 
8.5 
Adjudication Committee 
An adjudication committee will be used to adjudicate rescue therapy and concomitant 
medication that might have an impact on the primary endpoint. Blinded adjudication of rescue 
therapy and concomitant medication will be implemented for the final data base lock by 
considering factors such as the type of medication, indication, timing, frequency and the 
potential impact of the use. Details regarding the adjudication process will be available in the 
relevant Adjudication Committee charter. 
In addition, an adjudication committee might be used to monitor specific safety events, 
including, but potentially not limited to, clinically significant cardio- and liver events. The 
events would be blindly reviewed and adjudicated as they occur during the conduct of a trial. 
Details regarding the adjudication process would be available, as needed, in the relevant 
Adjudication Committee charter. 
9 
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation. 
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented in contingency tables and will include absolute and relative frequencies. If not 
otherwise specified, p-values will be presented as two-sided p-values and two-sided confidence 
intervals will be displayed. 
9.1 
Analysis sets 
Randomized Set: All subjects randomized are included in the Randomized Set. Subjects will be 
analyzed according to the treatment assigned to at randomization. 
Full Analysis Set (FAS): The FAS comprises all subjects to whom study treatment has been 
assigned. Following the intent-to-treat principle, subjects will be analyzed according to the 
treatment assigned to at randomization. Mis-randomized subjects (mis-randomized in IRT) will 
be excluded from FAS. Mis-randomized subjects are defined as cases where IRT contacts were 
made by the site either prematurely or inappropriately prior to confirmation of the subject’s 
final randomization eligibility and no study medication was administered to the subject.  
Safety Set: The Safety Set includes all subjects who received at least one dose of study 
medication. Subjects will be analyzed according to treatment received. 
9.2 
Subject demographics and other baseline characteristics 
Analyses will be based on the Randomized Set. 


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Demographics and baseline characteristics 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group. The number and percentage of subjects in each category 
will be presented for categorical variables for each treatment group and all subjects. 
Medical history 
Disease-specific medical history and any condition entered as medical history or current 
medical conditions at baseline will be coded using the MedDRA dictionary. They will be 
summarized by system organ class and preferred term of the MedDRA dictionary. 
9.3 
Treatments 
Analyses of treatment will be based on the Safety Set. 
Study treatment 
The duration of exposure to study treatment will be summarized by treatment group. In addition, 
the number of subjects with exposure of at least certain thresholds (e.g., any exposure, ≥1 week, 
≥2 weeks, ≥3 weeks, ≥4 weeks, ≥6 weeks, ≥8 weeks, etc.) will be displayed. 
Prior and concomitant medication 
Prior and concomitant medications will be summarized by treatment separated for AD related 
and non-AD related medications. AD-related concomitant medications will be summarized by 
pre-specified categories, route of administration and preferred term. Non-AD related 
concomitant medications will be summarized by the preferred term. 
Rescue therapy (duration of use and amount used) will also be summarized. 
9.4 
Analysis of the primary variable(s) 
All analyses for efficacy data will be based on the FAS. 
The primary objective of this study is to characterize the dose response relationship among 
ZPL389 doses (3, 10, 30 and 50 mg o.d.) and placebo with respect to achievement of IGA 
response after 16 weeks of treatment, and to select an appropriate dose (or range of doses) to 
use in Phase 3 studies. The consecutive steps are therefore (1) to confirm an overall dose-
response signal, (2) to estimate the minimal ZPL389 dose that shows a relevant effect based on 
the selected dose response model. The Multiple Comparison Procedures – Modelling (MCP-
Mod) methodology (Bretz, et al 2005, Pinheiro, et al 2014, Qualification Opinion on MCP-Mod 
EMA 2014, FDA endorsement 2015) will be used to address these goals. 
9.4.1 
Primary Variable(s) 
The primary variable for the study is IGA response after 16 weeks of treatment. 
IGA response is defined as achievement of an IGA score of 0 or 1 with a 2-point reduction from 
baseline and no use of confounding therapy as adjudicated up to the assessment time point. 


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9.4.2 
Statistical model, hypothesis, and method of analysis 
The null hypothesis of a constant dose-response curve for the primary efficacy endpoint will be 
tested at a significance level of 5% against the one-sided alternative hypothesis of a nonconstant 
dose response curve using the MCP-Mod methodology. 
A logistic regression model will be fitted with response as outcome variable and treatment (dose 
as categorical variable) and baseline IGA as covariates. 
The response Yij for subject j in dose group i receiving dose di is modelled as Yij ~ Bin(1, pij) 
with pij = logit-1(δi+xij’β), i=1,…, 5, j=1, …, ni 
where Bin(1,p) denotes the binomial distribution with parameter 1 and p, δi is the effect of dose 
di, β refers to the vector of regression coefficients corresponding to additional covariates xij  
which represent the baseline IGA category. Finally, ni is the number of subjects allocated to 
each treatment group. If the covariate baseline IGA prevents fitting of a model, it will be 
dropped. 
Population-average estimates of the logit of the response probability for each dose will be 
derived based on the results of the logistic regression. This will be a weighted sum of the 
corresponding estimates for each baseline IGA. The weights will be based on the observed 
frequencies of the baseline IGA category in the FAS. 
The covariance matrix of the estimates will also be estimated based on the logistic regression 
results. Using the obtained estimates and estimated covariance matrix generalized MCP-Mod 
(Pinheiro 2014) will be performed. 
The following dose-response shapes are selected as candidates: 
1. Sigmoid Emax model (with fixed Hill parameter): f(d, θ) = E0+Emax*dh/(dh+ED50h) 
• sigEmax1: ED50 = 25 mg, Hill parameter = 4.0 
• sigEmax2: ED50 = 30 mg, Hill parameter = 8.0 
• sigEmax3: ED50 = 1.85 mg, Hill parameter = 3.0 
• sigEmax4: ED50 = 7.5 mg, Hill parameter = 5.0 
2. Emax model: f(d, θ) = E0+Emax*d/(d+ED50) 
• Emax1: ED50 = 15 mg 
• Emax2: ED50 = 45 mg 
3. beta model: E0+Emax*B(δ1, δ2)*xδ1(1-x)δ2 with x=d/scale 
• Scale=71, δ1=1.1, δ2=1.1 


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Figure 9-1 
Candidate models for IGA response at Week 16 
 
For each candidate model a contrast test statistic, based on a linear combination of the treatment 
estimates per dose will be derived. The contrast coefficients will be chosen to maximize the 
power to detect the pre-specified candidate models. The global test decision is based on the 
maximum of the contrast test statistics. A critical value q controlling the type I error rate can be 
derived from the fact that the contrast test statistics approximately follow a multivariate normal 
distribution and that their maximum follows the distribution of the maximum of a multivariate 
normal distribution. If the maximum contrast test statistic exceeds the critical value q, the 
overall null hypothesis of a constant dose-response curve is rejected and one proceeds to the 
further estimation steps to determine the dose-response curve and doses achieving target clinical 
effects using a dose-response model. 
Bootstrap model averaging will be used to estimate the dose-response curve, the target dose and 
to derive confidence intervals. Bootstrap simulation will be performed using the multivariate 
normal distribution of the estimates of the logit of the response probability for each dose and 
generalized least-squares fitting of the resulting simulated values (see Pinheiro et al. 2014). The 
target dose is defined as the dose for which the expected response rate is at least 15% higher 
than the response rate of placebo which is expected to be about 10%. This will be based on the 
estimated dose-response curve. 
9.4.3 
Handling of missing values/censoring/discontinuations 
For efficacy variables based on response (e.g. IGA response, EASI50 response, EASI75 
response) missing data will be handled as follows: 
1. Subjects with use of confounding therapy as adjudicated will be considered as non-
responders after application of the therapy. 


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2. Subjects who discontinue study treatment permanently or discontinue the study due to 
lack of efficacy or due to adverse event will be considered as non-responder after 
discontinuation. 
3. For subjects who discontinue study or treatment due to other reasons than above or have 
missing data due to other reasons, missing-at-random will be assumed. The estimates for 
the logits of the response probabilities as well as the corresponding covariance matrix will 
be derived applying multiple imputation (MI). The MI model will include IGA categories 
from all visits from randomization up to Week 16 as well as all EASI score at baseline and 
absolute change from baseline EASI score for all visits from baseline up to Week 16. For 
each imputed dataset the logistic regression described in Section 9.4.1 will be performed 
and results combined for estimation. 
For the estimation of the IGA response rates at Week 16 for each treatment group, the estimate 
for subjects in (3) above will be combined with the non-responders in (1) and (2) above. These 
combined estimates will be used as input for the MCP-Mod analysis. 
If a baseline value is missing, it will be imputed by the mean of the respective treatment group 
in the respective randomization stratum. 
If not stated otherwise, for the secondary 
 the observed values will be 
used for summary statistics, missing values will not be imputed. When doing inference, any 
missing data will be handled by the respective MMRM model. 
For any percent change from baseline analysis, any baseline values equal to zero will be ignored. 
The total number of zero baseline values will be provided as additional information. 
9.4.4 
Sensitivity analyses 
As a sensitivity analysis, the primary analysis will be repeated on a dataset in which subjects 
who 
• discontinue treatment or study for any reason at any time or 
• who take rescue medication at any time 
will be considered non-responders. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
All analyses will be based on the FAS if not specified otherwise. For handling of missing data 
refer to Section 9.4.3. 
Percent change from baseline EASI score at Week 16 
The null hypothesis of a constant dose-response curve for the EASI score will be tested at a 
significance level of 5% against the one-sided alternative hypothesis of a non-constant dose 
response curve using the MCP-Mod methodology (Bretz, et al 2005, Pinheiro, et al 2014, 
Qualification Opinion on MCP-Mod EMA 2014, FDA endorsement 2015), in analogy to the 
primary endpoint analysis. 


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To allow adjustment for correlations between time points within subjects, a mixed effect model 
for repeated measurements (MMRM) approach is adopted to obtain the least squares means fits. 
The mean responses at each individual dose will be obtained through covariate-adjusted 
treatment effects by modeling the primary efficacy variable using MMRM. The model will 
contain treatment group, baseline EASI score, geographical region, baseline IGA score, visit, 
baseline EASI score*visit, and treatment group*visit as covariates, with unstructured 
covariance matrix. 
The covariance matrix of the estimates will also be estimated based on the MMRM results. 
Using the obtained estimates and estimated covariance matrix generalized MCP-Mod (Pinheiro 
2014) will be performed. 
The following dose-response shapes are selected as candidates: 
 
1. Sigmoid Emax model (with fixed Hill parameter): f(d, θ) = E0+Emax*d^h/(d^h+ED50^h) 
• sigEmax1: ED50 = 25 mg, Hill parameter = 4.0 
• sigEmax2: ED50 = 30 mg, Hill parameter = 8.0 
• sigEmax3: ED50 = 1.85 mg, Hill parameter = 3.0 
• sigEmax3: ED50 = 7.5 mg, Hill parameter = 5.0 
 
2. Emax model: f(d, θ) = E0+Emax*d/(d+ED50) 
• emax1: ED50 = 15 mg 
• emax2: ED50 = 45 mg 
 
3. beta model: E0+Emax*B(δ1, δ2)*xδ1(1-x)δ2 with x=d/scale 
• beta1: Scale=71, δ1=1.1, δ2=1.1 


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Figure 9-2 
Candidate models for percent change from baseline EASI score at 
Week 16 
 
For each candidate model a contrast test statistic, based on a linear combination of the treatment 
estimates per dose will be derived. The contrast coefficients will be chosen to maximize the 
power to detect the pre-specified candidate models. The global test decision is based on the 
maximum of the contrast test statistics. A critical value q controlling the type I error rate can be 
derived from the fact that the contrast test statistics approximately follow a multivariate normal 
distribution and that their maximum follows the distribution of the maximum of a multivariate 
normal distribution. If the maximum contrast test statistic exceeds the critical value q, the 
overall null hypothesis of a constant dose-response curve is rejected and one proceeds to the 
further estimation steps to determine the dose-response curve and doses achieving target clinical 
effects using a dose-response model. 
Bootstrap model averaging will be used to estimate the dose-response curve and to derive 
confidence intervals. Bootstrap simulation will be performed using the multivariate normal 
distribution of the parameter estimates and generalized least-squares fitting of the resulting 
simulated values. 
IGA score 
Summary tables will be presented by treatment group and visit which include absolute and 
relative frequencies. Shifts from baseline IGA score will also be summarized by visit. 


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IGA/EASI50/EASI75 response 
Summary tables will be presented by treatment group and visit which include absolute and 
relative frequencies. Time courses of the estimated response rate including 95% confidence 
interval will be plotted for each treatment group. For pairwise comparisons between treatment 
groups (individual ZPL389 arms versus placebo), 
• odds ratios and 95% confidence intervals will be derived using logistic regression with 
treatment group, baseline IGA and geographical region as covariate 
• the individual rate differences of the active treatment groups to placebo and the respective 
95% confidence intervals will be derived using a normal approximation. 
EASI score as well as absolute and percent change from baseline EASI score 
Summary statistics will be presented by treatment group and visit. 
To allow for a pairwise comparison between treatment groups, the data will be analyzed using 
a MMRM with treatment group, baseline EASI, geographical region and baseline IGA, visit, 
baseline EASI*visit and treatment group*visit as covariate, with unstructured covariance matrix. 
Time courses of LS means including 95% confidence intervals will be graphically displayed 
for each treatment group. 
BSA will also be summarized analogously to EASI score. 
9.5.2 
Safety variables 
All safety endpoints (i.e. adverse events, laboratory data, vital signs, and ECG) will be 
summarized by treatment for all subjects of the safety set. All data will be included in the 
analysis regardless of rescue medication use. 
Adverse events 
Treatment emergent adverse events (events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term; AEs observed four weeks after last study-drug administration will not be 
considered as treatment-emergent) will be summarized. AEs will be summarized by presenting, 
for each treatment group, the number and percentage of subjects having any AE, having an AE 
in each primary system organ class and having each individual AE (preferred term). Summaries 
will also be presented for AEs by severity and for study treatment related AEs. If a subject 
reported more than one adverse event with the same preferred term, the adverse event with the 
greatest severity will be presented. If a subject reported more than one adverse event within the 
same primary system organ class, the subject will be counted only once with the greatest 
severity at the system organ class level, where applicable. 
Serious adverse events will also be summarized. 
Separate summaries will be provided for deaths, serious adverse events, and other significant 
adverse events leading to discontinuation. 
Non-treatment emergent adverse events will be reported separately. 


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Laboratory data 
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry). Descriptive summary statistics for the change from baseline 
to each study visit will be presented. These descriptive summaries will be presented by test 
group, laboratory test and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post baseline values. Shifts with respect to normal ranges and 
number and percentage of notable abnormalities will also be summarized. For each parameter, 
the maximum change from baseline will be analyzed analogously. 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. Shifts with respect to normal ranges and number 
and percentage of notable abnormalities will also be summarized. 
ECG 
Summary statistics will be provided for ECG parameters. Shifts with respect to normal ranges 
and number and percentage of notable abnormalities will also be summarized. 
9.5.3 
Resource utilization 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.7 
Interim analyses 
An interim analysis may be performed to support decision making concerning the current 
clinical study or project. As a consequence the sample size may be reduced, e.g. size of lower 
dose arms may be reduced by approximately 30%.  
9.8 
Sample size calculation 
The primary objective of this study is to characterize the dose response relationship among 
ZPL389 doses (3, 10, 30 and 50 mg o.d.) and placebo with respect to achievement of IGA 
response after 16 weeks of treatment. The sample size was determined with the software 
ADDPLAN DF, version 3.1.8, with settings for minimum power function and model based 
contrasts. 
The sample size is derived to detect a dose-response with 90% power and a one-sided alpha of 
2.5%. Based on literature data Simpson et al 2017, a placebo response rate of 10% is assumed. 
A maximum treatment effect for ZPL389 of 20%-points higher than placebo is assumed. An 


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unbalanced allocation ratio of 2:1:1:2:2 corresponding to treatment arms placebo: 3 mg: 10 mg: 
30 mg: 50 mg, with more subjects allocated to placebo and the higher doses, is chosen to 
increase the precision of the estimate for the treatment effect at doses in the expected efficacious 
dose range. 
Under these assumptions, a sample size of 360 subjects in total will be required, randomized to 
90:45:45:90:90 subjects corresponding to placebo: 3 mg: 10 mg: 30 mg: 50 mg treatment arms. 
In order to show consistency of the treatment effect in Japanese subjects compared to the non-
Japanese population, it was estimated that approximately 40 Japanese subjects need to be 
recruited, i.e. the trial will include approximately 320 non-Japanese subjects and 40 Japanese 
subjects and the total sample size is 360 subjects. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible subjects may only be included in the study after providing signed (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after such 
consent has been provided by a legally acceptable representative(s) of the subject. In cases 
where the subject’s representative gives consent, the subject must be informed about the study 
to the extent possible given his/her understanding. If the subject is capable of doing so, he/she 
must indicate assent by personally signing and dating* the informed consent document or a 
separate assent form. Informed consent must be obtained before conducting any study-specific 
procedures (e.g. all of the procedures described in the protocol). The process of obtaining 
informed consent must be documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the subject will not reliably comply, they must not be 
entered in the study. 
 
 


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Declining to participate in 
 
, 
will in no way affect the subject’s ability to participate in the main research study. 
10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, documented informed consent form, consent form updates, 
subject recruitment procedures (e.g., advertisements) and any other written information to be 
provided to subjects. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all relevant 
data and records to Novartis monitors, auditors, Novartis Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 
10.5 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management system that includes all activities involved in 
quality assurance and quality control, including the assignment of roles and responsibilities, the 
reporting of results, and the documentation of actions and escalation of issues identified during 
the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures, and are performed according to written 
Novartis processes. 


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11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 
not use it for any purpose other than the study, except for the appropriate monitoring on study 
participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to subjects may be implemented immediately provided the health authorities are subsequently 
notified by protocol amendment and the reviewing IRB/IEC is notified. Notwithstanding the 
need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any subject included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 Safety Monitoring must be followed. 
12 
References 
References are available upon request. 
Bieber T (2010) Atopic dermatitis. Ann Dermatol p. 125-37. 
Bretz F, Pinheiro JC, Branson M (2005) Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics p. 738-48. 
Cowden JM, Zhang M, Dunford PJ, et al (2010) The histamine H4 receptor mediates 
inflammation and pruritus in Th2-dependent dermal inflammation. J. Invest. Dermatol. p. 
1023-33. 
Dunford PJ, Williams KN, Desai PJ, et al (2007) Histamine H4 receptor antagonists are 
superior to traditional antihistamines in the attenuation of experimental pruritus. J. Allergy 
Clin. Immunol. p. 176-83. 
 
 


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Eichenfield LF (2004) Consensus guidelines in diagnosis and treatment of atopic dermatitis. 
Allergy p. 86-92. 
Eichenfield LF, Tom WL, Chamlin SL, et al (2014) Guidelines of care for the management of 
atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J. Am. Acad. 
Dermatol. p. 338-51. 
Ellis C, Luger T, Abeck D, et al (2003) International Consensus Conference on Atopic 
Dermatitis II (ICCAD II): clinical update and current treatment strategies. Br. J. Dermatol. p. 
3-10. 
Emerson RM, Williams HC, Allen BR (1998) Severity distribution of atopic dermatitis in the 
community and its relationship to secondary referral. Br. J. Dermatol. p. 73-6. 
European Medicines Agency (2015) Report from dose finding workshop. Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/Report/2015/04/WC500185864.pdf 
Food and Drug Administration (2016) Determination Letter, 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM508700.pdf 
Gutzmer R, Mommert S, Gschwandtner M, et al (2009) The histamine H4 receptor is 
functionally expressed on T(H)2 cells. J. Allergy Clin. Immunol. p. 619-25. 
Hanifin JM, Reed ML, (2007) A population-based survey of eczema prevalence in the United 
States. Dermatitis p. 82-91. 
 
 
 
 
 
 
 
 
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Stat Med p. 1646-61. 
Ring J, Alomar A, Bieber T, et al (2012) Guidelines for treatment of atopic eczema (atopic 
dermatitis) part I. J Eur Acad Dermatol Venereol p. 1045-60. 
Sidbury R, Davis DM, Cohen DE, et al (2014) Guidelines of care for the management of 
atopic dermatitis: section 3. Management and treatment with phototherapy and systemic 
agents. J. Am. Acad. Dermatol. p. 327-49. 


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Simpson EL, Akinlade B, Ardeleanu M (2017) Two Phase 3 Trials of Dupilumab versus 
Placebo in Atopic Dermatitis. N. Engl. J. Med. p. 1090-1. 
Simpson EL, Bieber T, Guttman-Yassky E, et al (2016) Two Phase 3 Trials of Dupilumab 
versus Placebo in Atopic Dermatitis. N. Engl. J. Med. p. 2335-2348. 
Thurmond RL (2015) The histamine H4 receptor: from orphan to the clinic. Front Pharmacol 
p. 65. 
Weidinger S, Novak N (2016) Atopic dermatitis. Lancet p. 1109-22. 
Williams HC, Burney PG, Pembroke AC, et al (1994) The U.K. Working Party's Diagnostic 
Criteria for Atopic Dermatitis. III. Independent hospital validation. Br. J. Dermatol. p. 406-16. 
Zhang M, Thurmond RL, Dunford PJ (2007) The histamine H(4) receptor: a novel modulator 
of inflammatory and immune disorders. Pharmacol. Ther. p. 594-606. 
Hanifin JM, Thurston M, et al. (2001) The eczema area and severity index (EASI): 
assessment of reliability in atopic dermatitis. Exp Dermatol; 10: 11-18. 
 
 
 
 
 
13 
Appendix 1: Clinically notable laboratory values and vital 
signs 
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate eCRF. 
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined. 
See Appendix 2 for specific liver event and laboratory test trigger definitions and follow-up 
requirements. 
See Appendix 3 for specific renal alert criteria and actions. 
Post-baseline vital signs will be flagged as notable abnormalities as follows: 
1. Systolic/Diastolic blood pressure: ≥25% decrease or ≥25 % increase from baseline 
2. Pulse: ≥110 bpm with ≥15% change from baseline, or <50 bpm with ≥15% change from 
baseline 


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14 
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements 
Table 14-1 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY 
TRIGGERS 
• 
ALT >1.5 x ULN and <5 x ULN 
• 
AST >1.5 x ULN and <5 x ULN 
• 
TBL >1.5 x ULN and <2 x ULN 
LIVER EVENTS 
• 
ALT or AST >5 × ULN 
 
• 
ALP >2 × ULN (in the absence of known bone pathology) 
 
• 
TBL >2 × ULN (in the absence of known Gilbert syndrome) 
 
• 
ALT or AST >3 × ULN and INR >1.5 
 
• 
Potential Hy’s Law cases (defined as ALT or AST >3 × ULN and TBL 
>2 × ULN [mainly conjugated fraction] without notable increase in ALP 
to >2 × ULN) 
 
• 
Any clinical event of jaundice (or equivalent term) 
 
• 
ALT or AST >3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
• 
Any adverse event potentially indicative of a liver toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Complete CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
>8 × ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Complete CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
>3 × ULN and INR >1.5 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Complete CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
>5 to ≤8 × ULN 
• 
Repeat LFT within 48 hours 
(include PT/INR) 
• 
If elevation persists, continue 
follow-up monitoring 
• 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
• 
Establish causality 
• 
Complete CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
>3 × ULN accompanied 
by symptomsb 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Complete CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
>1.5 to ≤5 × ULN 
(subject is asymptomatic) 
• 
Repeat LFT within the next 
week (include PT/INR) 
• 
If elevation is confirmed, 
initiate close observation of 
the subject 
Investigator discretion 
Monitor LFT within 1 to 4 weeks, if 
resolved in 4 weeks, no further 
action 
ALP (isolated) 
 
 
>2 × ULN (in the 
absence of known bone 
pathology) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish 
causality 
• 
Complete CRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
TBL (isolated) 
 
 
>2 × ULN (in the 
absence of known Gilbert 
syndrome) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, 
discontinue the study drug 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Complete CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
>1.5 to ≤2 × ULN 
(subject is asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the subject 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
Jaundice 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the subject 
• 
Establish causality 
• 
Complete CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
Any AE potentially 
indicative of a liver 
toxicity* 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Complete CRF 
Investigator discretion 
aElevated ALT/AST >3 × ULN and TBL >2 × ULN but without notable increase in ALP to >2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 
15 
Appendix 3: Specific Renal Alert Criteria and Actions 
Table 15-1 
Specific Renal Alert Criteria and Actions 
Serum Event 
Serum creatinine increase 
25 – 49% compared to baseline 
Confirm 25% increase after 24-48h 
Follow up within 2-5 days 
Acute Kidney Injury: Serum creatinine increase ≥50% 
compared to Baseline 
Follow up within 24-48h if possible 
Consider study treatment interruption or 
discontinuation 
Consider subject hospitalization 
/specialized treatment 
Urine Event 
New dipstick proteinuria ≥1+ 
Albumin- or Protein-creatinine ratio increase ≥2-fold 
Albumin-creatinine ratio (ACR) ≥30 mg/g or 
≥3 mg/mmol; 
Protein-creatinine ratio (PCR) ≥150 mg/g or 
≥15 mg/mmol 
Confirm value after 24-48h 
Perform urine microscopy 
Consider study treatment interruption / or 
discontinuation 
New dipstick glycosuria ≥1+ not due to diabetes 
Blood glucose (fasting) 
Perform serum creatinine, ACR 
New dipstick hematuria ≥1+ not due to trauma 
Urine sediment microscopy 
Perform serum creatinine, ACR 
For all renal events: 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed 
Monitor subject regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or 


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Event stabilization: sCr level with ± 10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ± 50% variability over last 6 months. 
16 
Appendix 4: Hepatitis serology criteria 
Table 16-1 
Hepatitis B serology result, interpretation and subject eligibility 
Test 
Test result 
Interpretation 
Subject Eligibility 
HBsAg 
Anti-HBc 
Anti-HBs 
Negative 
Negative 
Negative 
Susceptible 
Subject eligible 
HBsAg 
Anti-HBc 
Anti-HBs 
Negative 
Negative 
Positive 
Immune due to hepatitis B 
vaccination 
Subject eligible unless 
vaccination performed within 
three months before baseline 
HBsAg 
Anti-HBc 
Anti-HBs 
Negative 
Positive 
Positive 
Immune due to natural infection 
Not eligible 
HBsAg 
Anti-HBc 
IgM anti-HBc 
Anti-HBs 
Positive 
Positive 
Positive 
Negative 
Acutely infected 
Not eligible 
HBsAg 
Anti-HBc 
IgM anti-HBc 
Anti-HBs 
Positive 
Positive 
Negative 
Negative 
Chronically infected 
Not eligible 
HBsAg 
Anti-HBc 
Anti-HBs 
Negative 
Positive 
Negative 
Interpretation unclear; four 
possibilities: 
1. Resolved infection (most 
common) 
2. False-positive anti-HBc, thus 
susceptible 
3. “Low level” chronic infection 
4. Resolving acute infection 
Not eligible 
17 
Appendix 5: Investigator Global Assessment (IGA) 
The IGA scale used in the study is vIGA-ADTM (Validated Investigator Global Assessment 
scale for Atopic Dermatitis). 
The IGA score is selected using the descriptors below that best describe the overall appearance 
of the lesions at a given time point. It is not necessary that all characteristics under 
Morphological Description be present. 
 
Score 
Morphological Description 


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0 – Clear 
No inflammatory signs of atopic dermatitis (no erythema, no 
induration/papulation, no lichenification, no oozing/crusting). Post-
inflammatory hyperpigmentation and/or hypopigmentation may be present. 
1 – Almost 
clear 
Barely perceptible erythema, barely perceptible induration/papulation, 
and/or minimal lichenification. No oozing or crusting. 
2 – Mild 
Slight but definite erythema (pink), slight but definite 
induration/papulation, and/or slight but definite lichenification. No oozing 
or crusting. 
3 – 
Moderate 
Clearly perceptible erythema (dull red), clearly perceptible 
induration/papulation, and/or clearly perceptible lichenification. Oozing 
and crusting may be present. 
4 – Severe 
Marked erythema (deep or bright red), marked induration/papulation, 
and/or marked lichenification. Disease is widespread in extent. Oozing or 
crusting may be present. 
Notes: 
• In indeterminate cases, please use extent to differentiate between scores.  
For example: Patient with marked erythema (deep or bright red), marked papulation 
and/or marked lichenification that is limited in extent, will be considered “3 – Moderate”. 
• Excoriations should not be considered when assessing disease severity. 
Copyright ©2017 Eli Lilly and Company – Used with the permission of Eli Lilly and Company under a Creative 
Commons Attribution-NoDerivatives 4.0 International License - https://creativecommons.org/licenses/by-nd/4.0/ 
18 
Appendix 6: Patient e-diary 


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N o v arti s  
C o nfi d e nti al  
P a g e 8 8  
A m e n d e d Pr ot o c ol V er si o n 0 3 ( cl e a n ) 
 
Pr ot o c ol N o. C Z P L 3 8 9 A 2 2 0 3  
 
 
1 8. 3   
Tr a c ki n g st u d y m e di c ati o n i nt a k e, e m olli e nt a n d r e s c u e 
m e di c ati o n 
F oll o wi n g t he c o m pleti o n of t he 
, s u bjects 
will be as ke d t o a ns wer t he f oll o wi n g q uesti o ns e ver y e ve ni n g: 
Di d y o u ta ke y o ur st u d y me dicati o ns (ca ps ules) t o da y? 
 N o  
 Yes  
Di d y o u a p pl y a n y e m ollie nt t o da y? 
 N o  
 Yes  
Please a ns wer O N L Y i n case y o ur st u d y d oct or has pr o vi de d y o u wit h a resc ue crea m a n d as k e d 
y o u t o a p pl y it: Di d y o u a p pl y t he resc u e crea m t o da y? 
 N o  
 Yes  
 


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