Clinical trial NCT03948334
Conditions: Atopic Dermatitis
Keywords: atopic dermatitis AD eczema itch pruritus H4R ZPL389
Sponsor: Novartis Pharmaceuticals
Start date: 2019-04-04; Completion date: 2020-08-25
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

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

Arms: arm 1: 30mg of ZPL389 + TCS and/or TCI for patients re-randomized from the core study (received placebo/ZPL389 3mg/ 10mg in the core study) and for patients continuing in the same arm from the core study arm 2: 50mg of ZPL389 + TCS and/or TCI for patients re-randomized from the core study (received placebo/ZPL389 3mg/ 10mg in the core study) and for patients continuing in the same arm from the core study
Interventions: intervention 1: ZPL389 30mg intervention 2: ZPL389 50mg intervention 3: TCS and/or TCI
Intervention descriptions: intervention 1: 30mg of ZPL389; once daily intervention 2: 50mg of ZPL389; once daily intervention 3: Topical corticosteroids (TCS) and /or topical calcineurin inhibitors (TCI) were used concomitantly or intermittently based on disease severity.

Protocol documents:
Prot_000.pdf: 
 
 
 
Novartis Research and Development 
ZPL389 
Clinical Trial Protocol CZPL389A2203E1 / NCT03948334 
A randomized, double blind, multicenter extension to 
CZPL389A2203 dose-ranging study to assess the short-
term and long-term safety and efficacy of oral ZPL389 with 
concomitant or intermittent use of TCS and/or TCI in adult 
patients with atopic dermatitis (ZEST Extension) 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2018‐000595‐15 
Version number: 
00 (Original Protocol) 
Clinical Trial Phase: 
II 
Release date: 
27-Nov-2018 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 9 
Protocol summary .............................................................................................................. 11 
1 
Introduction ....................................................................................................................... 13 
1.1 
Background ............................................................................................................ 13 
1.2 
Purpose .................................................................................................................. 14 
2 
Objectives and endpoints ................................................................................................... 14 
3 
Study design ...................................................................................................................... 15 
4 
Rationale ............................................................................................................................ 16 
4.1 
Rationale for study design ..................................................................................... 16 
4.1.1 
Rationale for choice of background therapy ......................................... 17 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 17 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 17 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 17 
4.5 
Risks and benefits .................................................................................................. 18 
5 
Population .......................................................................................................................... 19 
5.1 
Inclusion criteria .................................................................................................... 20 
5.2 
Exclusion criteria ................................................................................................... 20 
6 
Treatment ........................................................................................................................... 21 
6.1 
Study treatment ...................................................................................................... 21 
6.1.1 
Investigational and control drugs .......................................................... 21 
6.1.2 
Additional study treatments .................................................................. 21 
6.1.3 
Treatment arms/group ........................................................................... 23 
6.1.4 
Treatment duration ................................................................................ 23 
6.2 
Other treatments ..................................................................................................... 23 
6.2.1 
Concomitant therapy ............................................................................. 23 
6.2.2 
Prohibited medication ........................................................................... 23 
6.2.3 
Rescue medication ................................................................................ 24 
6.3 
Subject numbering, treatment assignment, randomization .................................... 25 
6.3.1 
Subject numbering ................................................................................ 25 
6.3.2 
Treatment assignment, randomization .................................................. 25 
6.4 
Treatment blinding ................................................................................................. 26 


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6.5 
Dose escalation and dose modification .................................................................. 26 
6.5.1 
Dose modifications ................................................................................ 26 
6.5.2 
Follow-up for toxicities ......................................................................... 27 
6.6 
Additional treatment guidance ............................................................................... 27 
6.6.1 
Treatment compliance ........................................................................... 27 
6.6.2 
Emergency breaking of assigned treatment code .................................. 27 
6.7 
Preparation and dispensation ................................................................................. 28 
6.7.1 
Handling of study treatment and additional treatment .......................... 28 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 29 
7 
Informed consent procedures ............................................................................................ 29 
8 
Visit schedule and assessments ......................................................................................... 30 
8.1 
Screening ............................................................................................................... 34 
8.1.1 
Information to be collected on screening failures ................................. 34 
8.2 
Subject demographics/other baseline characteristics ............................................. 34 
8.3 
Treatment exposure and compliance ..................................................................... 34 
8.4 
Efficacy .................................................................................................................. 35 
8.4.1 
Appropriateness of efficacy assessments .............................................. 35 
8.4.2 
IGA ........................................................................................................ 35 
8.4.3 
EASI ...................................................................................................... 35 
8.4.4 
SCORAD............................................................................................... 37 
8.5 
Safety ..................................................................................................................... 38 
8.5.1 
Laboratory evaluations .......................................................................... 39 
8.5.2 
Electrocardiogram (ECG) ..................................................................... 39 
8.5.3 
Pregnancy and assessments of fertility ................................................. 40 
8.6 
Additional assessments .......................................................................................... 40 
 
 40 
8.6.2 
Patient e-Diary ...................................................................................... 40 
 
 42 
 
 42 
9 
Study discontinuation and completion .............................................................................. 42 
9.1 
Discontinuation ...................................................................................................... 42 
9.1.1 
Discontinuation of study treatment ....................................................... 42 
9.1.2 
Withdrawal of informed consent ........................................................... 44 
9.1.3 
Lost to follow-up ................................................................................... 44 
9.1.4 
Early study termination by the sponsor ................................................. 44 
9.2 
Study completion and post-study treatment .......................................................... 45 
10 Safety monitoring and reporting ........................................................................................ 45 


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10.1 
Definition of adverse events and reporting requirements ...................................... 45 
10.1.1 
Adverse events ...................................................................................... 45 
10.1.2 
Serious adverse events .......................................................................... 47 
10.1.3 
SAE reporting........................................................................................ 48 
10.1.4 
Pregnancy reporting .............................................................................. 49 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 49 
10.2 
Additional Safety Monitoring ................................................................................ 50 
10.2.1 
Liver safety monitoring ......................................................................... 50 
10.2.2 
Renal safety monitoring ........................................................................ 51 
10.2.3 
Cardiac safety monitoring ..................................................................... 51 
10.2.4 
Data Monitoring Committee ................................................................. 51 
10.2.5 
Adjudication committee ........................................................................ 52 
11 Data Collection and Database management ...................................................................... 52 
11.1 
Data collection ....................................................................................................... 52 
11.2 
Database management and quality control ............................................................ 52 
11.3 
Site monitoring ...................................................................................................... 53 
12 Data analysis and statistical methods ................................................................................ 54 
12.1 
Analysis sets .......................................................................................................... 54 
12.2 
Subject demographics and other baseline characteristics ...................................... 54 
12.3 
Treatments ............................................................................................................. 55 
12.4 
Analysis of the primary endpoint .......................................................................... 55 
12.4.1 
Definition of primary endpoint ............................................................. 55 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 55 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 55 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 56 
12.5 
Analysis of secondary endpoints ........................................................................... 56 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint ........................................ 56 
12.5.2 
Safety endpoints .................................................................................... 57 
 
 58 
 
 58 
 
 58 
 
 58 
 
 58 
 
 58 
 
 59 
12.7 
Interim analyses ..................................................................................................... 59 
12.8 
Sample size calculation .......................................................................................... 59 


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13 Ethical considerations and administrative procedures ...................................................... 60 
13.1 
Regulatory and ethical compliance ........................................................................ 60 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 60 
13.3 
Publication of study protocol and results............................................................... 60 
13.4 
Quality Control and Quality Assurance ................................................................. 61 
14 Protocol adherence ............................................................................................................ 61 
14.1 
Protocol Amendments ........................................................................................... 61 
15 References ......................................................................................................................... 63 
16 Appendices ........................................................................................................................ 65 
16.1 
Appendix 1: Clinically Notable Laboratory Values and Vital Signs .................... 65 
16.2 
Appendix 2: Liver Event and Laboratory Trigger Definitions and Follow-up 
Requirements ......................................................................................................... 65 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions ........................................ 67 
16.4 
Appendix 4: Hepatitis Serology Criteria ............................................................... 68 
16.5 
Appendix 5: Investigator Global Assessment (IGA) ............................................. 68 
16.6 
Appendix 6: Subject e-diary .................................................................................. 69 
 
 69 
 
 70 
16.6.3 
Tracking study medication intake, emollient, TCS and/or TCI and 
rescue medication .................................................................................. 70 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 14 
Table 6-1 
Investigational drug ............................................................................... 21 
Table 6-2 
Prohibited medication/therapy .............................................................. 24 
Table 6-3 
Study medication dispensing................................................................. 29 
Table 8-1 
Assessment Schedule ............................................................................ 32 
Table 8-2 
EASI: severity descriptions ................................................................... 36 
Table 8-3 
EASI score calculation .......................................................................... 37 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 50 
Table 12-1 
Sample size in the study ........................................................................ 59 
Table 12-2 
The chances to detect at least one AE in this study .............................. 60 
Table 16-1 
Liver Event and Laboratory Trigger Definitions .................................. 65 
Table 16-2 
Follow-up Requirements for Liver Events and Laboratory Triggers .... 65 
Table 16-3 
Specific Renal Alert Criteria and Actions ............................................. 67 
Table 16-4 
Hepatitis B Serology Result, Interpretation and Subject Eligibility ..... 68 


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List of figures 
Figure 3-1 
Study Design CZPL3892203E1 ............................................................ 16 
Figure 6-1 
Regimen for TCS/TCI concomitant or intermittent use and rescue 
TCS ....................................................................................................... 22 
 


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List of abbreviations 
ACR 
albumin-creatinine ratio 
AD 
Atopic dermatitis 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BSA 
Body surface area 
CFR 
Code of federal regulation 
CRO 
Contract research organization 
CTCAE 
Common terminology criteria for adverse event 
CYP2D6  
Cytochrome P450 2D6  
 
 
DMC 
Data monitoring committee 
EASI 
Eczema area and severity index 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European medical agency 
 
 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H4R 
Histamine-4 receptor 
HIV 
Human immunodeficiency virus 
 
 
IB 
Investigator’s Brochure  
ICH 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent ethics Committee 
IGA 
Investigator's Global Assessment 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IN 
Investigator notification 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
 
 
o.d. 
Once daily 
PCR 
Protein-creatinine ratio 
PD 
Pharmacodynamic(s) 
 
 
 
 
 
 
PoC 
Proof of concept 
PRO 
Patient reported outcome 


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QTcF 
Corrected QT interval (by Frediricia’s formula) 
SAE 
Serious adverse event 
 
 
SUSAR 
Suspected unexpected serious adverse reactions 
TBL 
Total bilirubin 
TCI 
Topical calcineurin inhibitors  
TCS 
Topical corticosteroid  
Th2 
T-helper 2 cells 
TSLP 
Thymic stromal lymphopoietin 
ULN 
upper limit of normal 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
WOCBP 
Women of child-bearing potential 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. topical corticosteroids and/or topical 
calcineurin inhibitors will be given concomitantly to ZPL389 as a regimen anticipated to 
be reflective of a real world setting) 
Assessment 
A procedure used to generate data required by the study 
Biological Samples 
A biological specimen including, for example, blood (plasma, serum), urine, etc. taken 
from a study subject. 
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. 
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 (e.g. 
rescue medication) up to the assessment time point. 
Investigational 
drug/treatment 
The drug whose properties are being tested in the study. 
Medication number 
A unique identifier on the label of medication kits. 
Mis-randomized 
subjects 
Mis-randomized subjects are those who were not qualified for randomization and who 
did not take study treatment but have been inadvertently randomized into the study. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy like rescue TCS). 
Patient 
An individual with the condition of interest for the study. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis. 
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. 
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned completion of all 
study drug administration and assessments; at this time all study drug administration is 
discontinued and no further assessments are planned. 
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 completion 
Point/time at which the subject came in for a final evaluation visit or when study drug 
was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when subject permanently stops taking study drug for any reason; may or 
may not also be the point/time of premature subject withdrawal. 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the defined study 
treatment completion date 
Subject 
A patient participating in this study. 
Subject number 
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to identify 
the subject throughout the study for all data collected, sample labels, etc. 


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


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Protocol summary 
Protocol number 
CZPL389A2203E1 
Full Title 
A randomized, double blind, multicenter extension to CZPL389A2203 dose-ranging 
study to assess the short-term and long-term safety and efficacy of oral ZPL389 with 
concomitant or intermittent use of TCS and/or TCI in adult patients with atopic dermatitis 
(ZEST Extension) 
Brief title 
A study to assess the safety and efficacy of ZPL389 with concomitant or intermittent use 
of TCS and/or TCI in atopic dermatitis patients.  
Sponsor and 
Clinical Phase 
Novartis, Phase 2 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to assess short-term and the long-term safety and efficacy 
of oral ZPL389 (30 mg once daily (o.d.) and 50 mg o.d.) when used concomitantly or 
intermittently with topical corticosteroid (TCS) and/or topical calcineurin inhibitors (TCI) 
(according to a standardized regimen,  depending on atopic dermatitis lesion severity, in 
line with common/ real world practice) for up to approximately 2 years in adult patients 
with atopic dermatitis who previously completed 16 weeks of treatment in the core study 
(CZPL389A2203).  
Primary 
Objective(s) 
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. 
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 investigator's global assessment 
(IGA) response over time. 
● 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 eczema area and severity index 
(EASI) over time. 
Study design 
This 2-year study is a randomized, double blind, parallel group, 2-arm study in up to 
approximately 270 to 306 subjects with atopic dermatitis (AD) who have completed 16 
weeks of treatment in the CZPL389A2203 (core study). In this extension study, subjects 
who have been receiving ZPL389 30 mg o.d. or 50 mg o.d. doses in the core study, will 
continue to receive the same doses. Subjects who were receiving ZPL389 3 mg, 10 mg 
or placebo in the core study will be randomized into 30 mg o.d. or 50 mg o.d. ZPL389 in 
a 1:1 ratio. All subjects will receive concomitant or intermittent TCS and/or TCI along 
with ZPL389. 
Subjects, after completing 100 weeks of treatment during extension study (i.e. up to 
Week 116 starting from Week 16 of the core study), will enter a treatment-free follow-up 
period for 4 weeks. 
Population 
The study population will consist of adult atopic dermatitis patients, female and male, 
who completed 16 weeks of treatment in the core study (CZPL389A2203). Patients who 
enter this extension study should be able to use concomitant or intermittent TCS and/or 
TCI therapy, and comply with inclusion and exclusion criteria for this study.  
Key Inclusion 
criteria 
● Signed informed consent must be obtained before any assessment is performed. 
● Female and male subjects with atopic dermatitis who have participated in and 
completed 16 weeks of study treatment in CZPL389A2203 study. 
● Willing and able to comply with scheduled visits, treatment plan, laboratory tests, diary 
completion and other study procedures. 


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Key Exclusion 
criteria 
● Inability to use TCS and/or TCI concomitantly or intermittently due to history of 
important side effects of topical medication (e.g. intolerance to treatment, 
hypersensitivity reactions, significant skin atrophy, systemic effects), as assessed by the 
investigator or subject’s treating physician. 
● Subjects who met any study and/or treatment discontinuation criteria during the 
CZPL389A2203 study.  
● 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). 
● Subjects taking medications prohibited by the protocol. 
● Pregnant or nursing (lactating) women. 
● Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, unless they use required methods of contraception 
during dosing and for 4 weeks after stopping of investigational medication. 
● 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. 
Study treatment 
ZPL389 will be administered orally in capsules in one of the two following treatment 
arms:  
ZPL389 30 mg o.d. + TCS and/or TCI 
ZPL389 50 mg o.d. + TCS and/or TCI 
Efficacy 
assessments 
Investigator's global assessment; Eczema Area and Severity Index 
Key safety 
assessments 
Adverse event (AE) monitoring, physical examinations including vital signs, monitoring 
of laboratory markers in blood and urine and electrocardiograms (ECG). 
Other 
assessments 
 
Data analysis 
Descriptive statistics will be provided for this study. 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. 
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 (Williams et al 1994, Eichenfield 2004). 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 affects 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 (Emerson et al 1998, Hanifin et al 2007). 
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 (TCI) 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 patients. 
Currently the only other systemic therapy approved is dupilumab (anti-Interleukin (IL) 4 
Receptor alpha antibody) for treatment moderate to severe AD, but is expected to be reserved 
for the most recalcitrant patients. 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 
a half-minimal (50%) inhibitory concentration (IC) 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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The chronic and recurrent inflammatory nature of AD requires long-term use of any treatment 
option; hence, it is essential to investigate long-term safety profile of ZPL389. 
1.2 
Purpose 
The purpose of this study is to assess short-term and long-term safety (frequency of AEs) and 
efficacy of one of the two doses (30 mg o.d. and 50 mg o.d.) of ZPL389 when used 
concomitantly or intermittently with topical corticosteroid and/or topical calcineurin inhibitors 
(according to a standardized regimen in line with common / real world practice that depends on 
atopic dermatitis lesion severity) for up to approximately 2 years (100 weeks of treatment and 
4 weeks of follow-up) in atopic dermatitis adult patients who previously completed treatment 
in core study (CZPL389A2203). 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary objective 
Endpoints for primary objective 
● 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). 
Secondary objectives 
Endpoints for 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). 
IGA response is defined as achievement of an 
IGA score of 0 or 1 with a 2-point reduction from 
core study baseline without use of confounding 
therapy (e.g. rescue medication) up to the 
assessment time point. 
● 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). 
EASI-50/EASI-75 response over time: EASI-
50/EASI-75 response is defined as achieving ≥ 
50%/≥ 75% improvement (reduction) in EASI 
score compared to baseline without use 
of confounding therapy (e.g. rescue medication) 
up to the assessment time point. 


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Objectives 
Endpoints 
3 
Study design 
This 2-year study is a randomized, double blind, parallel group, 2-arm study in up to 
approximately 270 to 306 subjects, considering a projected discontinuation rate of 15% to 25% 
in the CZPL389A2203 (core study), with AD who have completed 16 weeks of treatment in the 
core study. In this extension study, subjects who have been receiving ZPL389 30 mg o.d. or 50 
mg o.d. doses in the core study, will continue to receive the same doses in double-blinded 
fashion. Subjects who were receiving ZPL389 3 mg, 10 mg or placebo in the core study, will 
be randomized into 30 mg o.d. or 50 mg o.d. of ZPL389 in a 1:1 ratio. All subjects will receive 
concomitant or intermittent TCS and/or TCI along with ZPL389. 
After completing 100 weeks of study treatment during extension study (i.e. up to Week 116 
including 16 weeks of the core study), subjects will enter the 4 weeks treatment-free follow-up 
period. 
 
 


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Figure 3-1 
Study Design CZPL3892203E1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
Rationale 
4.1 
Rationale for study design 
This study is planned to collect short-term and long-term safety and efficacy data of ZPL389 
by continuing treatment in AD subjects who have completed 16 weeks of treatment in the core 
study. ZPL389 doses (30 mg o.d. and 50 mg o.d.) selected for the extension phase are 
anticipated to be most efficacious and tolerable. 
The study is a parallel assignment and double blinded to prevent bias in this extension study 
and to protect the integrity of the core study. Subjects from the core study will roll over into the 
extension in a manner in which they will not be able to know the dose they received previously 
in the core study and neither what they receive in this study.  
Subjects who previously received either 30 mg or 50 mg ZPL389 in the core study will continue 
to receive these doses respectively until end of the extension study, this way cumulative data of 
30 mg and 50 mg will be generated continuously for a long period. In addition, they will receive 
standardized TCS/TCI regimen (see Section 4.1.1). 
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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Subject who previously received either 3 mg, 10 mg or placebo for 16 weeks in the core study 
will be randomized in a 1:1 ratio to receive either 30 mg or 50 mg of ZPL389. Data from these 
arms will allow confirmation of the added benefit of 30 mg and 50 mg over the lower doses 
(i.e. 3 mg, 10 mg) or concomitant or intermittent use of TCS/TCI (see Section 4.1.1). 
4.1.1 
Rationale for choice of background therapy 
Topical corticosteroids and/or topical calcineurin inhibitors will be used concomitantly or 
intermittently to ZPL389 as a regimen anticipated to be reflective of a common / real world 
clinical practice and depending on the severity of atopic dermatitis lesions. 
4.2 
Rationale for dose/regimen and duration of treatment 
The ZPL389 doses of 30 mg o.d. and 50 mg o.d. were selected as monotonic response is 
expected for ZPL389 and these are expected to provide better efficacy and will support robust 
characterization of the long-term safety profile. Additionally, subjects previously receiving 
lower doses of ZPL389 (3 mg o.d. and 10 mg o.d.) or placebo in the core study will have an 
opportunity to receive the higher once daily 30 mg and 50 mg doses of ZPL389 in this extension 
study.  
Continuing therapy for two years beyond the core study offers trial participants continued 
access to a potentially beneficial therapy. Additionally, treatment in this study for 
approximately 2 years is based on the need for efficacy and safety information during chronic 
treatment in subjects suffering from AD and for assessing the benefit-to-risk profile of ZPL389 
for the long-term management of AD. 
Since AD is a systemic inflammatory disease, long-term use of ZPL389 in all patients rolling 
over to the extension study would allow assessment of the benefit of ZPL389 on one of the most 
important and prevalent comorbidities of AD which is asthma.  
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
The study does not contain a control drug or combination drug. To support this extension study's 
purpose and objectives, two doses of ZPL389 will be assigned in parallel and double blinded 
fashion and this design will offer long-term safety and efficacy characterization of ZPL389 
without use of placebo or active control arm. In addition, the use of placebo is not advisable for 
long-term periods. 
4.4 
Purpose and timing of interim analyses/design adaptations 
No formal interim analysis is planned. The primary analysis will be performed after all subjects 
complete the Week 32 visit. Study modifications are not planned based on this primary analysis. 
An analysis after all subjects have completed Week 68 visit may be conducted to support drug 
development decision. A final analysis will be performed after all subjects have completed 
Week 120 visit (or discontinued prior to Week 120). Investigators, subjects and site personnel 
will remain blinded until the final database lock has been achieved. 


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4.5 
Risks and benefits 
Considering efficacy observed in the Proof of Concept (PoC) study, overall safety observed in 
studies to date, and the absence of approved oral agent for atopic dermatitis (AD), the 
benefit/risk of ZPL389 appears to be positive. 
In the AD PoC study, subjects receiving a dose of 30 mg o.d. ZPL389 achieved a 50% reduction 
in EASI score on average over 8 weeks vs. 27% for placebo. Improvements in SCORAD and 
IGA were observed as well as reductions in body surface area (BSA) affected and lower use of 
rescue medication in the ZPL389 arm compared to placebo. 
In the AD PoC study (N = 98), the safety profile of ZPL389 (30 mg o.d.) was comparable to 
placebo and the percentages of subjects who reported AEs 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. 
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 single ascending dose and multiple ascending dose 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 this study, the single ascending dose part has completed with 49 healthy volunteers exposed 
to ZPL389 up to doses of 400 mg. All adverse events occurring after intake of ZPL389 were 
rated as mild and frequencies of AEs were similar between ZPL389 and placebo. The 
pharmacokinetic (PK) exposure at steady-state of a dose of 50 mg o.d. is expected to be 
comparable to the PK exposure of a 200 mg single dose. Therefore, multiple doses of up to 50 
mg o.d. are considered safe. 
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, and no clinically significant 
changes in ECG parameters including QTc interval prolongation have been observed following 
single doses of up to 400 mg and multiple doses of up to 50 mg o.d. 
Interim analysis data from the ongoing study CZPL389A2101 showed clinically relevant 
increases of corrected QT interval (by Frediricia’s formula) (QTcF) at single doses of 300 and 
400 mg ZPL389 (exposures exceeding those expected with 50 mg o.d). 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 effects at a 
level of regulatory concern (i.e. an upper bound of the 90% confidence interval (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.  


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Based on in vitro data and Drug-Drug Interaction (DDI) simulations, the highest clinically 
relevant exposure is predicted to occur in a poor metabolizer of Cytochrome P450 
2D6 (CYP2D6) treated with a strong inhibitor of CYP1A2. Therefore, in the currently planned 
extension study, the scenario of highest clinically relevant exposure at a dose of 50 mg o.d. will 
be prevented by implementing the same measures as in core study:  
1. Prohibiting the use of strong CYP1A2 inhibitors for all subjects 
2. Prohibiting use of moderate CYP1A2 inhibitors in subjects identified as CYP2D6 poor 
metabolizers during the core study screening 
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. 
Long-term toxicity studies have been completed and no further risks have been identified. 
In pivotal embryo-fetal development study, there were rare fetal abnormalities and minor 
maternal toxicity at the highest tested dose, which corresponds to exposure 22 times over the 
expected exposure in humans with 50 mg once daily (50 mg dose is the highest dose planned 
in the clinical study).  There were no adverse effects in rats, maternal or fetal, at exposures 12 
times over the expected exposure in humans with 50 mg once daily. In rabbits, there were no 
findings. The translatability of the findings in rats to humans is unknown. ZPL389 should not 
be administered to females of childbearing 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 childbearing 
potential (WOCBP) will be required to have monthly 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, the benefit/risk appears to be positive. 
5 
Population 
The study population will consist of adult patients with atopic dermatitis, female and male, who 
have completed 16 weeks of treatment in the core study (CZPL389A2203). They will 
use concomitant or intermittent TCS and/or TCI therapy, and comply with inclusion and 
exclusion criteria for this study. 


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The subject discontinuation rate in the core study is estimated to be 15 % to 25% of all 
randomized subjects; therefore, approximately 270 to 306 subjects are expected to be part of 
this extension study. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained before any assessment is performed. 
2. Female and male subjects with atopic dermatitis who have participated in and completed 
16 weeks of treatment in CZPL389A2203 study. 
3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, diary 
completion and other study procedures. 
5.2 
Exclusion criteria 
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study: 
1. Inability to use TCS and/or TCI concomitantly or intermittently due to history of 
important side effects of topical medication (e.g., intolerance to treatment, hypersensitivity 
reactions, significant skin atrophy, systemic effects), as assessed by the investigator or 
subject’s treating physician. 
2. Subjects who met any study and/or treatment discontinuation criteria during the 
CZPL389A2203 study (Section 9.1). 
3. 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) 
4. Subjects taking medications prohibited by the protocol (see Section 6.2.2) 
5. Pregnant or nursing (lactating) women 
6. Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, unless they use 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 (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has 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 
• Use of oral, injected or implanted hormonal methods of contraception, except in poor 
CYP2D6 metabolizers. In the case of this method, the addition of a male condom 
is required 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) 


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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 informed consent form (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 childbearing potential. 
7. 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.  
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF. 
6 
Treatment 
6.1 
Study treatment 
Study treatment includes investigational drug (30 mg and 50 mg formulation of ZPL389) which 
will be provided by Novartis. 
6.1.1 
Investigational and control drugs 
ZPL389 will be administered as powder in capsules and dispensed as 30 mg and 50 mg capsules.  
Table 6-1 
Investigational drug 
Investigational 
Drug (Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply type 
Sponsor (global or 
local) 
ZPL389 30 mg 
Capsule 
Oral 
Blinded 
Global 
ZPL389 50 mg 
Capsule 
Oral 
Blinded 
Global 
6.1.2 
Additional study treatments 
TCS/TCI 
TCS and/or TCI as available locally will be provided in an open-label type packing. 
Starting at Baseline of extension study, all subjects will initiate treatment with TCS (or TCI 
in sensitive areas) using a standardized regimen and continue the regimen through the end of 
the study (Figure 6-1). 
 


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Figure 6-1 
Regimen for TCS/TCI concomitant or intermittent use and rescue TCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In areas of active lesions: 
• Apply medium potency TCS once daily to areas with active lesions. 
• Low potency TCS or TCI should be used once daily on areas of thin skin (face, neck, 
intertriginous, and genital areas, areas of skin atrophy, etc.) or for areas where continued 
treatment with medium potency TCS is considered unsafe. 
For lesions under control (clear or almost clear): 
• After lesions are under control (clear or almost clear), initiate or switch to low potency 
TCS (TCI for sensitive area) and treat once daily for 7 days, then stop. 
If active lesions return, resume treatment with medium potency TCS, with the step-down 
approach described above upon lesion resolution. 
Continue for 7 
days 
Stop 
TCS/TCI 
Low 
potency 
TCS once 
daily (TCI 
on sensitive 
area) 
Lesions rated as 
clear or almost 
clear 
Continue 
until lesions 
clear or 
almost clear 
If lesions 
return 
Lesions rated as 
active lesions 
Medium potency 
TCS once daily  
 
(Low potency TCS 
or TCI on thin skin 
or sensitive area)  
Only if medically 
justified: RESCUE 
with high/super high 
TCS.  


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Mometasone furoate 0.1% cream or Triamcinolone acetonide 0.1% cream are recommended 
for medium potency, and hydrocortisone 1% cream for low potency.  
If use of rescue medication is medically justified, mometasone furoate 0.1% ointment is 
recommended as a high potency TCS and either betamethasone dipropionate 0.05% ointment 
or clobetasol propionate 0.05% cream for super high potency TCS. For decision making 
regarding TCS use, the location of the lesion(s) also needs to be taken into account; please see 
Section 6.2.3 for details on rescue medication. 
Bland emollients: 
The use of a bland emollient is required throughout the study and is 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. 
6.1.3 
Treatment arms/group 
Subjects will be assigned, at Baseline of extension study (Week 16 from Baseline of the core 
study) visit into one of the following 2 treatment arms in a ratio of 1:1: 
• ZPL389 30 mg o.d. + TCS and/or TCI 
• ZPL389 50 mg o.d. + TCS and/or TCI 
TCS and TCI will be sourced locally in each of the participating the countries. 
6.1.4 
Treatment duration 
The planned duration of treatment is approximately 2 years (100 weeks of treatment in 
extension study), double-blinded treatment period and a 4 weeks treatment-free follow-up 
period. Subjects may be discontinued from treatment earlier due to unacceptable toxicity, 
disease progression and/or at the discretion of the investigator or the subject.  
6.2 
Other treatments 
6.2.1 
Concomitant therapy 
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 on appropriate electronic case 
report form (eCRF). 
Each concomitant drug must be individually assessed against the prohibited medication table 
(Table 6-2). If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue participation in the study. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the below table is NOT allowed during the period specified 
below in Table 6-2. 


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Table 6-2 
Prohibited medication/therapy 
Medication 
Prohibition period 
Action taken 
● Topical treatment for atopic 
dermatitis such as crisaborole, tar 
etc., OTHER than those part of the 
protocol. 
● Initiation of treatment of AD with 
prescription moisturizers or 
moisturizers containing active 
ingredients such as ceramides, 
lactic acid, urea, α-hydroxy- or fruit 
acids, vitamins A, D or E 
a) Treatment period 
a) Discontinue prohibited medication and 
continue study treatment 
● 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 
● Oral antihistamines 
a) Treatment period 
a) 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 the study treatment must be 
discontinued. 
b) Follow-up period 
b) Discontinue prohibited medication 
unless there is a specific safety risk for 
the subject, in the opinion of the 
investigator. 
● Phototherapy or tanning booths 
a) Treatment period 
a) Discontinue prohibited 
medication/therapy, and continue study 
treatment 
● Any investigational treatment 
a) Treatment period 
a) Discontinue subject from study 
treatment 
b) Follow-up period 
b) Discontinue prohibited medication 
● Any drug known to prolong QTc 
interval (See 
https://crediblemeds.org/ for 
details) 
● Drugs known to be hepatotoxic 
(please see protocol 
supplementary guidance) 
● 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) 
a) Within 5 half-lives of 
Baseline or until 
pharmacodynamic effect has 
disappeared, whichever is 
longer 
a) subject is not eligible for this study 
b) Treatment period 
b) Discontinue study treatment and enter 
follow-up 
c) Follow-up period 
c) Discontinue prohibited medication 
* 2-chlorobenzylidene malononitrile (CS) nasal sprays and eye drops are not considered systemic 
immunosuppressive treatment. 
i.v.: intravenous; i.m.: intramuscular; JAK: Janus kinase. 
6.2.3 
Rescue medication 
Only if medically necessary (i.e. to control intolerable AD symptoms), as assessed by 
investigator, rescue medication may be provided to study subjects. Rescue treatment in this 
study is TCS of higher potency than that of previously used when the need for rescue was 


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determined by the investigator. Subjects should continue treatment with study drug ZPL389. 
Novartis will provided/reimbursed the rescue medication. 
• For lesions persisting or worsening under once daily treatment with medium potency TCS, 
subjects may be treated (rescued) with high or super-high potency TCS, unless higher 
potency TCS are considered unsafe. 
• The subject is to be monitored for signs of local or systemic TCS toxicity and step-down 
or stop treatment as necessary. 
If use of rescue medication is medically justified, mometasone furoate 0.1% ointment is 
recommended as a high potency TCS and either betamethasone dipropionate 0.05% ointment 
or clobetasol propionate 0.05% cream for super-high potency TCS. 
Investigator 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 
negatively affect the validity of study results. Use of rescue medication must be stopped as 
soon as the investigator determines that it is not needed anymore. 
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-
diary (Section 16.6.3). 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. Rescue medication 
tubes/container will be weighed at the time of dispensing and every subsequent visit and the 
weight used will be recorded in the appropriate eCRF. Up to Week 32, the subject must also 
indicate in the patient e-dairy on a daily basis whether the rescue medication was used or not. 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Subject numbers will remain the same as in the core study. 
The investigator or his/her staff will contact the extension study Interactive Response 
Technology (IRT) system and provide the requested identifying information for the subject to 
be registered in the study. The site must select the Electronic Case Report Form (eCRF) book 
with a matching Subject Number in the electronic data capture (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 
eCRF. 
6.3.2 
Treatment assignment, randomization 
At the baseline visit of this extension study (i.e. Week 16 visit of core study), all eligible 
subjects who have been receiving ZPL389 30 mg o.d. or 50 mg o.d. doses in the core study, 
will continue to receive the same doses, while the subjects who were receiving ZPL389 3 mg, 
10 mg or placebo in the core study, will be re-randomized in a 1:1 ratio via IRT to one of the 
two treatment arms. The investigator or his/her delegate will contact the extension study 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 


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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 
randomization list will be produced by the IRT provider using a validated system that automates 
the 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 Global 
Clinical Supply (GCS) using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s). 
The re-randomization of subjects (who were receiving ZPL389 3 mg, 10 mg or placebo in the 
core study) will be stratified by previous treatment group in core study and geographical region. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group. 
6.4 
Treatment blinding 
Subjects, investigator staff, and persons performing the assessments will remain blind to the 
identity of the treatment from the time of randomization until final database lock, using the 
following 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 6.6.2). (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. 
Unblinding will only occur in the case of subject emergencies (see Section 6.6.2); at the time 
of the primary endpoint at Week 32, and final database lock. After all subjects complete Week 
32, designated sponsor team members will be unblinded, whereas the subjects, investigator 
staff, and persons performing the assessments will remain blinded until end of the study to 
ensure reliable efficacy and safety measures. The randomization codes associated with subjects 
from whom PK samples are taken will be disclosed to PK analysts who will keep PK results 
confidential until database lock.  
6.5 
Dose escalation and dose modification 
6.5.1 
Dose modifications 
For subjects who are unable to tolerate the protocol-specified dosing scheme, dose interruptions 
of investigational drug are permitted in order to keep the subject on study drug and recorded on 
the appropriate eCRF. For example, the study medication may be interrupted when the 
investigator receives an alert for specific parameters and after assessing the subject, is of the 
opinion that the subject should not be taking the study medication until the issue resolves. 
Alternatively, the subject may have a planned surgery and may interrupt drug. However when 
discontinuation criteria are met, the subject must permanently discontinue study medication. 
The interruptions are only allowed if decided by the investigator to be medically necessary. No 
down titration or up titration are allowed in this protocol. 


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6.5.2 
Follow-up for toxicities 
Please refer to Section 10 for safety monitoring of specific events and required follow-up 
actions. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Subjects must be instructed to take one capsule per day at the same time every day in the 
morning (e.g. every day at 8 am). The subject will record the intake of study medication up to 
Week 32 visit 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 study medication (ZPL389) at home on the day of study visits, 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. 
6.6.2 
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/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• subject number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
Country Organization (CO) (or any entity to which it has delegated responsibility for emergency 
code breaks) to ensure that un-blinding can be performed at any time. 


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The appropriate personnel from the study site and Novartis will assess whether study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently for 
any reason. 
Study treatment must be discontinued after emergency unblinding. However, subjects should 
continue the study assessments as per protocol. 
6.7 
Preparation and dispensation 
All ZPL389 kits of study treatment assigned by the IRT will be recorded in the IRT system. 
Each site will be provided ZPL389 30 mg and 50 mg capsules in packaging of identical 
appearance. 
The ZPL389 study drug packaging has a 2-part label. A unique medication number is printed 
on each part of this label corresponding to one of the two 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. 
TCS and/or TCI will be provided locally by the investigator in an open-label manner to all 
eligible subjects at each study visit at the time when ZPL389 is also dispensed to the subjects. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
ZPL389: 
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 (CPO) 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 during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study 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. 


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6.7.1.2 
Handling of additional treatment 
TCS/TCI and emollients: 
Use of TCS and/or TCI as concomitant or intermittent therapy, and/or TCS when used as rescue 
medication (please see Section 6.2.3), subjects must bring all current study medication with 
them to each site visit. 
Study drug compliance will be assessed by the investigator and/or center personnel at 
designated visits by recording the weight of the TCS/TCI 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 are requested to enter their 
daily use of emollients in the e-diary up to Week 32 visit, as per assessment schedule 
(Table 8-1). Above details will be recorded on appropriate eCRF. 
6.7.2 
Instruction for prescribing and taking study treatment 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
ZPL389 will be provided by Novartis as 30 mg or 50 mg powder in capsules. Bottles of capsules 
will be dispensed at study visits as per below schedule. All study drugs will be the same color 
and appearance; they will be supplied in identical bottles, thereby maintaining double-blind 
conditions. 
Study medication will be supplied to the subject as follows: 
Table 6-3 
Study medication dispensing 
Number of bottles 
At Each Site Visit on Week 
1 bottle  
16 
20 
24 
28 
 
3 bottles 
32 
44 
56 
68 
80 
92 
104 
Subjects must be instructed to take one capsule per day at the same time every day 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 up to Week 32 visit. On days of a scheduled study visit, 
subjects must be instructed to: 
• bring all current study medication with them to the visit. 
• not to take study medication (ZPL389) at home on the day of study visits, but must take it 
when instructed by study personnel at the investigational site (just prior to PK sampling 
and/or after ECG).  
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing signed (witnessed, where 
required by law or regulation), Institutional Review Board/Independent ethics Committee 
(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(s) gives consent (if allowed according to local requirements), the subject must 
be informed about the study to the extent possible given his/her understanding. If the subject is 


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capable of doing so, he/she must indicate agreement by personally signing and dating the 
informed consent document. 
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 Good Clinical Practice (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. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). 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 investigational drug 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 then must be discussed with the subject. 
Women of childbearing 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. 
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. 
Informed consent must be obtained before conducting any study-specific procedures listed in 
this protocol. 
8 
Visit schedule and assessments 
The Assessments Schedule (Table 8-1) lists all the assessments and indicates when they are 
performed. All data obtained from these assessments must be supported in the subject’s source 
documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1). Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study treatment for any reason should be scheduled for a visit as 
soon as possible, at which time all of the assessments listed for the visit Week 116 will be 
performed. At this visit, all dispensed investigational product should be reconciled and the 
adverse event and concomitant medications reconciled on the appropriate eCRF. Subjects must 
return for the follow-up visit Week 120. 
Site visits are performed as specified in the assessment schedule (Table 8-1). Subjects must be 
reminded to be fasting for at least 3 hours before the site visits and to bring their study 


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medication including any TCS/TCI dispensed previously as well as their e-diaries with them to 
the site. On days of site visits, subjects should not eat until the ECG is performed. 


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Table 8-1 
Assessment Schedule 
Period 
Treatment 
End of 
Treatment/TD 
Follow-
up/TD/PSW  Unplanned  
Weeks (starting from baseline of core study) 
16 
20 
24 
28 
32 
44 
56 
68 
80 
92 
104 
116  
120 
0 
Days 
113 
141 
169 
197 
225 
309 
393 
477 
561 
645 
729 
813 
841 
- 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Electrocardiogram (ECG) 1, Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Hematology, Clinical Chemistry, Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (serum) 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Pregnancy Test (urine) 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
 
Adverse Events, Concomitant medications / 
Surgeries or medical procedures,
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IGA, EASI, 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient e-Diary daily entry2
X 
 
 
 
 
 
 
 
 
 
Patient e-Diary Review 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Drug dispensation 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing at site 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study Disposition 
X 
1 All ECGs are to be performed under fasted conditions (subjects should fast at least 3 hours before the site visit and remain fasted until the ECG is done). ECG should be done after 10 min 
rest in supine position, followed by vital signs while supine and then blood samples. 


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2 The investigational site staff must make a phone call to the patient to remind them to switch on the device and start completion of e-Diary. Patient e-Diary will include 
 
daily use of emollients, study drug, TCS and/or TCI use and rescue therapy (if any). 
 
 
4 Subjects should be instructed to take study medication every day at the same time preferably in the morning except on study visit days. Up to week 32 visit, the subject will record the intake 
of study medication on a daily basis on the subject e-diary. 
5 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:  
• Patient reported outcomes must be done before physician assessments (IGA, then EASI 
). 
• The use of a bland emollient is required throughout the study and is 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. 
PWS: Premature Subject Withdrawal; TD: Treatment Discontinuation; X: Assessment to be recorded in the clinical database or received electronically from a vendor; S: Assessment to be 
recorded in the source documentation only. 


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8.1 
Screening 
There is no screening period in this study. All eligible subjects will begin their participation in 
this study at Week 16 of the core study; making Week 16 of the core study also the baseline 
visit of this study. At the baseline visit, the investigator will review assessments from Week 0, 
Week 12 and Week 16 visits of the core study to ensure that eligibility criteria are met.  
Subjects who are not able to rollover to the extension study at Week 16 visit, due to delayed 
start of the study at the site, may still enter the extension study within any time during the 4 
weeks follow-up period of the core study. In such cases, the “Follow-up (EOS/PWS)” visit 
assessments from the core study and baseline assessments required for extension study should 
be performed. 
8.1.1 
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, inclusion/exclusion, informed consent, withdrawal of consent (if subject 
withdrew consent), AE and SAE data collected. AEs that are not SAEs will be followed by the 
investigator or primary care physician and collected only in the source data. 
Subjects who are randomized and fail to start/continue treatment, e.g. subjects randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate eCRF. 
8.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data that was collected as a part of the core 
study will be used for this extension study; therefore this data (except for body weight that need 
to be collected as specified in the assessment schedule) is not required to be collected again at 
baseline of this extension study. 
8.3 
Treatment exposure and compliance 
ZPL389: 
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 up to Week 32 visit. 
Study personnel will review the e-diary entries at each visit up to Week 32 visit, as noted in the 
assessment schedule (Table 8-1) for study drug intake and discuss with subject any missed 
doses. Study personnel will also review the amount of study medication returned by the subject 
at each visit throughout the duration of the study. The total number of doses of study drug intake 
since the last dispensing visit will be recorded in the appropriate eCRF based on the returned 
study medication and discussion with the subject. 


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TCS/TCI: 
Subjects must bring the study medication, including emptied tubes/containers of TCS/TCI, to 
the site at every visit. Study drug compliance will be assessed by the investigator and/or center 
personnel at designated visits by recording the weight of the TCS/TCI container(s). 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. 
8.4 
Efficacy 
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. 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 must be performed in an order; IGA then EASI 
. 
8.4.1 
Appropriateness of efficacy assessments 
The efficacy measurements are standard for this indication (Eichenfield et al 2014). 
8.4.2 
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 (Table 8-1). Whenever possible, the IGA assessments should be performed 
by the same evaluator throughout the study. Please see Section 16.5 for details. 
8.4.3 
EASI 
The EASI (Eczema Area and Severity Index) will be used to make an assessment of the extent 
and severity of AD (Hanifin et al 2001). The Investigator or trained qualified designee will 
complete the EASI assessment on each of the visits as outlined in the assessment schedule 
(Table 8-1). 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: 
• 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 8-2 EASI: severity descriptions. 


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• 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 8-3.  
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 & neck, 0.3 for trunk, 0.2 for upper limbs and 0.4 for lower limbs).  
Table 8-2 
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 
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 


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Table 8-3 
EASI score calculation 
Body 
region 
Erythema 
(E) 
Induration / 
Papulation 
(P) 
Excoriation 
(Ex) 
Lichenificati
on (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% to <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% to <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% to <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% to <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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8.5 
Safety 
In addition to the below listed safety assessments, safety monitoring must be done at every visit, 
as per Section 10, as well as review of concomitant medications with reference to prohibited 
medications (Table 6-2). The safety assessments and monitoring is in accordance with the risks 
associated with ZPL389 and/or unknown information. 
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 eCRF. Significant findings made after the signing of the 
informed consent, which meet the definition of an AE, must be recorded on the AE eCRF. 
Body Weight:  
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. 
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. 


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8.5.1 
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. 
Clinical Chemistry: 
The Chemistry Panel 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 (γGT), 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 Modification of Diet in Renal 
Disease (MDRD) formula. 
If the TBL concentration is increased above 1.5 x upper limit of normal (ULN), direct and 
indirect reacting bilirubin should be differentiated. 
Hematology: 
Hemoglobin, hematocrit, red blood cell count, white blood cells (WBC) count with differentials 
and platelet count will be measured. 
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 eCRF. 
Microscopy must be assessed following an abnormal dipstick test with results captured in the 
eCRF. 
8.5.2 
Electrocardiogram (ECG) 
ECGs will be analyzed centrally and performed with ECG machines supplied by the central 
provider. 
ECGs must be recorded after at least 3 hours of fasting and after 10 minutes rest in the supine 
position. The preferred 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 single 12-lead ECGs will be performed as indicated in the assessment schedule. 
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 eCRF. 


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8.5.3 
Pregnancy and assessments of fertility 
For all WOCBP, pregnancy tests are required at scheduled visits as per Table 8-1. A serum 
pregnancy test will be performed at Week 68 visit and at the end of the study. Additionally, a 
urine pregnancy assessment should be done and the result must be evaluated prior to enrollment 
in to the extension study but only captured on source document. 
From Week 32 visit onwards site will dispense pregnancy test kits to the subjects and advice to 
perform the test at home at an interval of every 4 weeks until next clinic visit. 
If a urine pregnancy test is positive, confirmation is required by performing a serum pregnancy 
testing. In case of urine pregnancy testing conducted at home is positive, the serum sample must 
be collected at the next site visit. The study treatment must be interrupted unless the serum 
pregnancy results are available.  
When pregnancy occurs in a subject in this study, the study drug must be discontinued, return 
to the site to perform assessments as per end of treatment Week 116 visit 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. 
8.6 
Additional assessments 
8.6.1 
Clinical Outcome Assessments (COAs) 
 
. All 
the patient reported outcomes (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. 
8.6.2 
Patient e-Diary 
Subjects will be asked to complete an e-diary on a daily basis until Week 32. The subject e-
diary will be dispensed at baseline visit of the core study to all subjects. The device will remind 
the subjects to complete the questions. Subjects must bring their e-diaries with them to every 
scheduled visit. The subject e-diary will be checked by a designated study staff member at each 
visit; in case of incomplete e-diary entry, the study site staff will counsel the subject on the 
correct use and frequency of the subject e-diary. Please see Section 16.6 for subject diary 
questions. 
Daily entries will be completed until Week 32 (see Table 8-1) 
 
 
 
 
• Study medication intake 
• Emollient use 


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• TCS and/or TCI and rescue medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
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 affect the subject or in the event the subject is 
unwilling or unable to comply with study requirements. 


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Study treatment must be discontinued under the following circumstances: 
• Subject wishes to withdraw consent 
• Pregnancy (Section 10.1.5) 
• Need for continuing prohibited treatment as per Table 6-2. 
• 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 Common Terminology Criteria for Adverse Event (CTCAE) 
v4.03 severity grade ≥2, including:  
• Resting heart rate <60 or >100 bpm confirmed by repeat measurement and associated 
with symptoms, indicating medical intervention 
• Ventricular fibrillation, or any clinically significant cardiac arrhythmia 
• New complete heart block (Grade III AV block) 
• 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 Appendix 2 and 
Appendix 3 
• Laboratory abnormalities indicating blood and lymphatic system disorders of CTCAE 
v4.03 of severity grade ≥2 including:  
• Anemia: Hemoglobin <10 g/dL 
• Febrile neutropenia: Absolute Neutrophil Count: (ANC) <1000/mm3 with a single 
temperature of >38.3ºC (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 8-1 (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 
116 visit) and the Follow-up visit (Week 120 visit), as detailed in Table 8-1, and assessments 
should be completed and recorded in the appropriate eCRF. The investigator must determine 
the primary reason for the subject’s premature discontinuation of study treatment and record 
this information on the appropriate eCRF. 


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The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
9.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of study 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 should 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. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
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. 
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 RoW (Rest of the 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. 
9.1.3 
Lost 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. 
9.1.4 
Early study termination by the sponsor 
Novartis can terminate the study 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 


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In taking the decision to terminate, Novartis will always consider subjects' welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely discontinued 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. The investigator will be responsible for informing IRBs/IECs of the early 
termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last subject finishes their Study Completion visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision (e.g. Each subject will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them). 
A subject will be considered to have completed the study when he/she has completed the last 
visit planned in the protocol (i.e. Week 120 visit). 
For all subjects, a safety follow-up visit at Week 120, which is 30 days after the last treatment 
visit (i.e. Week 116), should be conducted as per assessment schedule (Table 8-1). If the subject 
is unable to visit the clinic, then at a minimum the information to be collected (e.g. by telephone) 
at this follow-up visit includes concomitant medications and adverse events. 
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 the applicable eCRF. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
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 the subject volunteers 


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them 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 eCRF 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 10.1.2 for definition of 
SAE) and which seriousness criteria have been met. 
• action taken regarding [investigational] treatment 
All adverse events must be treated appropriately. 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 
• subject hospitalized/subject’s hospitalization prolonged (see Section 10.1.2 for definition 
of SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), 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’s Brochure (IB). This information will be included in the subject 


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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 adverse 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. 
10.1.2 
Serious adverse events 
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 
• life-threatening 
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). 
• 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: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• 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 
• 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 
• 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 to prevent one of the outcomes listed above. 
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 
be considered as “medically significant” are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 


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hospitalization or development of dependency or abuse (please refer to the ICH-E2D 
Guideline). 
All malignant neoplasms except non-melanoma skin cancer will be assessed as serious under 
“medically significant” if other seriousness criteria are not met. 
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 eCRF; SAEs also require individual 
expedited reporting to Novartis Chief Medical Office and Patient Safety as per Section 10.1.3.  
10.1.3 
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 treatment visit (i.e. 30 days after Week 116) should only be 
reported to Novartis safety if the investigator suspects a causal relationship to study treatment. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
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 each specific 
component of study 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 
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. 


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Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of 
its occurrence/receiving follow-up information. 
10.1.4 
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. 
10.1.5 
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. 
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 dose administration record (DAR) eCRF 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. 


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Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dose 
Administration (DAR) 
eCRF (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 
10.2 
Additional Safety Monitoring 
10.2.1 
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 eCRFs. 
Please refer to Table 16-1 for complete definitions of liver laboratory triggers and liver events. 
Every liver laboratory trigger or liver event as defined in Table 16-1 should be followed up by 
the investigator or designated personnel at the trial site as summarized below. Detailed 
information is outlined in Table 16-2. 
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 eCRFs. 
• 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) 


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• An investigation of the liver event, which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, and/or 
hepatologist consultancy, based on the investigator’s discretion and/or consultation with 
Novartis medical monitor. All follow-up information and the procedures performed must be 
recorded on the appropriate eCRFs. 
10.2.2 
Renal safety 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 16-3 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 3. 
10.2.3 
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 – all such ECGs will be flagged by the Central contract research 
organization (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, conduction abnormality of QTcF >500 ms), 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 PK 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 immediately (for example cardioversion). 
Please refer to Appendix 1 for notable vital signs. 
10.2.4 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 


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investigators participating in the study. The DMC will review safety data at defined intervals 
and recommend to the sponsor whether to continue, modify or terminate the study. 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 9). 
A designated CRO or Novartis will prepare the collection and summary of these data. 
Details on the organization and function of the DMC will be described in the DMC charter. 
10.2.5 
Adjudication committee 
An adjudication committee may be used to monitor specific safety events, including, but 
potentially not limited to, clinically significant cardio and liver events and ensure that all 
treatment outcomes are judged uniformly, using standard criteria and processes. The events will 
be blindly reviewed and adjudicated as they occur during the study conduct. 
Details regarding the adjudication process will be available, in the relevant Adjudication 
Committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. The investigator/designee is responsible for assuring that all the 
data (recorded or entered into eCRF) is complete, accurate, and that entry and updates are 
performed in a timely manner. The Investigator must certify that the data entered are complete 
and accurate. After final database lock, the investigator will receive copies of the subject data 
for archiving at the investigational site. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered into the eCRFs 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 investigational site via the EDC system. Designated investigator site staff is 
required to respond to the query and confirm or correct the data. 
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and adverse 


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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). The subject will enter diary data and Patient 
Reported Outcomes into an electronic device. The device will also be used to capture efficacy 
assessments entered by the investigator/delegate. A vendor, who will also manage the database, 
will supply the system. 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 the vendor database.  
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 an Interactive Response Technology (IRT). A vendor, who will 
also manage the database, will supply the system. The database will be sent electronically to 
Novartis (or a designated CRO) at specific timelines. 
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 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. 
11.3 
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 (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and 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 Good Clinical Practice, 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. 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, ECG, and the results of any other tests or assessments. All 
information on eCRFs 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 


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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 eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
The analysis will be conducted on all subject data after all subjects completed the Week 32 visit 
and at the time of the study 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, the data will be analyzed by treatment groups and p-values will be 
presented as two-sided p-values and two-sided confidence intervals will be displayed.  
12.1 
Analysis sets 
Randomized Analysis Set (RAS): All subjects randomized are included in the RAS. 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 by randomization. Following the intent-to-treat principle, subjects will be analyzed 
according to the treatment they have been assigned to during the randomization procedure. Mis-
randomized subjects (mis-randomized in IRT) will be excluded. 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 (SAF): The Safety Set includes all subjects who received at least one dose of study 
treatment. Subjects will be analyzed according to treatment received. 
12.2 
Subject demographics and other baseline characteristics 
Analyses will be based on the Randomized Analysis Set. 
Demographics and baseline characteristics: 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables from core study 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. 


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Medical history: 
Disease-specific medical history and any condition entered as medical history or current 
medical conditions at core baseline will be coded using the MedDRA dictionary. They will be 
summarized by system organ class and preferred term of the MedDRA dictionary. 
12.3 
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. 
TCS/TCI therapy use, duration of use, amount used, proportion of days without TCS/TCI use, 
and potency category (high/medium/low) will be summarized. 
12.4 
Analysis of the primary endpoint 
The primary objective for this study is to analyze the adverse event (AE). All analyses for 
adverse events will be based on the SAF. 
12.4.1 
Definition of primary endpoint 
The primary variable is frequency of AE. Please refer to Section 12.5.2 for detailed analyses. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Only descriptive statistics will be provided, no inferential statistics will be conducted. 
12.4.3 
Handling of missing values/censoring/discontinuations 
For efficacy, variables based on response (e.g. IGA response, EASI-50 response, EASI-75 
response) missing data will be handled as follows: 
1. Subjects with use of confounding therapy (e.g. rescue medication) based on Anatomical 
Therapeutic Chemical (ATC) codes and/or timing of dosing will be considered as non-
responders after application of the therapy. 
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 


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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 as well as all EASI score at baseline and absolute change from baseline 
EASI score for all visits. For each imputed dataset, the logistic regression will be 
performed and results combined for estimation. 
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 other secondary 
 
 the observed values will be used for 
summary statistics, missing values will not be imputed. 
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. 
12.4.4 
Sensitivity and Supportive analyses 
Not applicable. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint 
All analyses for efficacy data will be based on the FAS. 
IGA/EASI-50/EASI-75 response: 
IGA response: subjects achieving an IGA score of 0 or 1 with a 2-point reduction from core 
study baseline without use of confounding therapy; e.g. rescue medication, up to the assessment 
time point. 
EASI-50 response: subjects achieving ≥ 50% improvement (reduction) in EASI score compared 
to baseline (without use of confounding therapy; e.g. rescue medication, up to the assessment 
time point) are defined as EASI-50 responders. 
EASI-75 response: subjects achieving ≥ 75% improvement (reduction) in EASI score compared 
to baseline (without use of confounding therapy; e.g. rescue medication, up to the assessment 
time point) are defined as EASI-75 responders. 
Summary tables for the responses 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. 
Heat map will be provided based on EASI response (no EASI-50 response; EASI-50 response, 
but not EASI-75 response, EASI-75 response, but not EASI-90 response; EASI-90 response).  
IGA score: 
Summary tables will be presented by treatment group and visit, which include absolute and 
relative frequencies. Heat map will be provided for IGA score over time. 


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EASI score: 
Summary tables will be presented by treatment group and visit for EASI score, absolute change 
and percent change from baseline on EASI score. 
12.5.2 
Safety endpoints 
All safety endpoints (i.e. adverse event, laboratory data, vital signs, and ECG) will be 
summarized by treatment for all subjects of the safety set. 
Adverse events: 
Treatment emergent adverse events will be summarized. Only primary paths within MedDRA 
will be considered for adverse event reporting. The definition for “treatment emergent” is as 
follows: 
• Events started on or 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 
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. 
All adverse event including non-treatment emergent adverse events will be listed. 
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 
laboratory test and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post baseline values. For each parameter, the maximum change from 
baseline will be analyzed analogously. Number and percentage of subjects with notable 
abnormalities will be summarized. 
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 


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by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. Number and percentage of subjects with notable 
abnormalities will also be summarized. 
ECG: 
Summary statistics will be provided for ECG parameters. Number and percentage of subjects 
with notable abnormalities will be summarized. 


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12.7 
Interim analyses 
No formal interim analysis is planned. The primary analysis will be performed after all subjects 
have completed Week 32 visit. An analysis after all subjects have completed Week 68 visit may 
be conducted as well. A final analysis will be performed after all subjects have completed Week 
120 visit (or discontinued prior to Week 120). 
12.8 
Sample size calculation 
Assuming the discontinuation rates of 5%, 10%, 20%, and 30% in core study, the sample size 
in each treatment group (ZPL389 50 mg + TCS/TCI, ZPL389 30 mg + TCS/TCI) will be 171, 
162, 144 and 126, respectively in extension study. The approximate subject numbers based on 
different discontinuation rates in core study are listed as below. 
Table 12-1 
Sample size in the study 
Subject number 
in core study 
Discontinuation 
rate 
subject number 
in extension study 
Subject number in each treatment 
group in extension study 
360 
5% 
342 
171 
360 
10% 
324 
162 
360 
20% 
288 
144 
360 
30% 
252 
126 
With a sample size in the extension study receiving ZPL389, the chances for an AE with an underlying 
occurrence rate of 1%, 2.5%, 5%, 10% to be observed at least once for the given doses (ZPL389 50 mg + 
TCS/TCI or ZPL389 30 mg + TCS/TCI) are very high and >71% for all cases, which is shown in Table 12-2. 


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Table 12-2 
The chances to detect at least one AE in this study 
Subject number in each 
treatment group 
AE occurrence rate 
Power to detect at least one AE 
171 
1% 
82.1% 
2.5% 
98.7% 
5% 
99.9% 
10% 
100% 
162 
1% 
80.3% 
2.5% 
98.3% 
5% 
99.9% 
10% 
100% 
144 
1% 
76.5% 
2.5% 
97.4% 
5% 
99.9% 
10% 
100% 
126 
1% 
71.8% 
2.5% 
95.9% 
5% 
99.8% 
10% 
99.9% 
13 
Ethical considerations and administrative procedures 
13.1 
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. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (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. 
13.3 
Publication of study protocol and results 
The key design elements of this protocol will be registered in a publicly accessible database 
such as clinicaltrials.gov and as required in EudraCT. In addition, upon study completion and 


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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 such as the Novartis 
clinical trial results website and all required Health Authority websites (e.g. Clinicaltrials.gov, 
EudraCT etc.). 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) 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 SOPs, and are performed according to written Novartis processes. 
14 
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.  
14.1 
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 required for subject safety 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, Novartis should 


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be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
Bieber T (2010) Atopic dermatitis. Ann Dermatol; 125-37. 
Cowden JM, Zhang M, Dunford PJ, et al (2010) The histamine H4 receptor mediates 
inflammation and pruritus in Th2-dependent dermal inflammation. J. Invest. Dermato; 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; 176-83. 
Eichenfield LF (2004) Consensus guidelines in diagnosis and treatment of atopic dermatitis. 
Allergy; 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; 338-51. 
Emerson RM, Williams HC, Allen BR (1998) Severity distribution of atopic dermatitis in the 
community and its relationship to secondary referral. Br. J. Dermatol; 73-6. 
 
 
 
 
 
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; 619-25. 
Hanifin JM, Reed ML (2007) A population-based survey of eczema prevalence in the United 
States. Dermatitis; 82-91. 
Hanifin JM, Thurston M, Omoto M, et al (2001) The eczema area and severity index (EASI): 
assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp. Dermatol; 11-8. 
Ring J, Alomar A, Bieber T, et al (2012) Guidelines for treatment of atopic eczema (atopic 
dermatitis) part I. J Eur Acad Dermatol Venereol; 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; 327-49. 
Thurmond RL (2015) The histamine H4 receptor: from orphan to the clinic. Front Pharmacol; 
65. 
Weidinger S, Novak N (2016) Atopic dermatitis. Lancet; 1109-1122. 
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; 406-16. 


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Zhang M, Thurmond RL, Dunford PJ (2007) The histamine H(4) receptor: a novel modulator 
of inflammatory and immune disorders. Pharmacol. Ther; 594-606. 


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16 
Appendices 
16.1 
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 
16.2 
Appendix 2: Liver Event and Laboratory Trigger Definitions and 
Follow-up Requirements 
Table 16-1 
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 16-2 
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 eCRF 
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 
ALT or AST 
>8 × ULN 
● Discontinue the study treatment 
immediately 
● Hospitalize if clinically appropriate 
● Establish causality 
● Complete eCRF 
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 eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP, and γGT until resolutionc 
(frequency at investigator 
discretion) 
>5 to ≤8 × ULN 
● Repeat LFT within 48 hours 
● If elevation persists, continue follow-up 
monitoring 
● If elevation persists for more than 2 
weeks, discontinue the study drug 
● Establish causality 
● Complete eCRF 
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 eCRF 
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 
● 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 eCRF 
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 eCRF 
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 eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP, and γGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative 
of a liver toxicity* 
● Consider study treatment interruption or 
discontinuation 
● Hospitalization if clinically appropriate 
● Establish causality 
● Complete eCRF 
Investigator discretion 


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Criteria 
Actions required 
Follow-up monitoring 
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; Alb: Albumin; PT; prothrombin time; INR: international normalized ratio. 
Based on investigator’s discretion, investigation(s) for contributing factors for the liver event 
can include: serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions 
Table 16-3 
Specific Renal Alert Criteria and Actions 
Serum Event 
Actions 
Serum creatinine (sCR) increase 25 – 49% compared 
to baseline 
Confirm 25% increase after 24-48 h 
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 eCRF: 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 
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. 


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16.4 
Appendix 4: Hepatitis Serology Criteria 
Table 16-4 
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 
Anti-HBc: Anti-Hepatitis B core antigen antibody; Anti-HBs: Anti-Hepatitis B surface antigen antibody; HbsAg: 
hepatitis B virus surface antigen; IgM: Immunoglobulin M 
16.5 
Appendix 5: Investigator Global Assessment (IGA) 
The IGA scale used in the study is Validated Investigator Global Assessment scale for Atopic 
Dermatitis (vIGA-ADTM). 
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 
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. 


Novartis 
Confidential 
Page 69 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CZPL389A2203E1 
 
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 - creativecommons.org/licenses/by-
nd/4.0/ 
16.6 
Appendix 6: Subject e-diary 


N o v arti s  
C o nfi d e nti al  
P a g e 7 0  
Cli ni c al Tri al Pr ot o c ol ( V er si o n N o. 0 0)  
 
Pr ot o c ol N o. C Z P L 3 8 9 A 2 2 0 3 E 1  
1 6. 6. 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, T C S a n d/ or T CI 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 E cze ma S y m pt o m a n d I m pact q uesti o ns s h o w n a b o ve, 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  
Di d y o u a p pl y T o pical St u d y Treat me nt ( pr o vi de d b y y o ur st u d y d oct or) 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 o ct or has pr o vi de d y o u wit h a res c ue crea m a n d 
as ke 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 v arti s  
C o nfi d e nti al  
P a g e 7 1  
Cli ni c al Tri al Pr ot o c ol ( V er si o n N o. 0 0)  
 
Pr ot o c ol N o. C Z P L 3 8 9 A 2 2 0 3 E 1  
 
 N o  
 Yes  
 

SAP_001.pdf: 
 
 
 
 
 
Clinical Development 
ZPL389 
CZPL389A2203 and A2203E1 / 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 ;