Conditions: Atopic Dermatitis Skin Diseases
Keywords: Atopic Dermatitis Orismilast
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 235
Healthy volunteers: no

Brief summary:
This study investigates 3 different doses of orismilast modified release compared to placebo in adult patients with moderate-to-severe atopic dermatitis. The purpose of the study is to assess the effect of orismilast modified release in moderate-to-severe atopic dermatitis and assess the safety aspects of these 3 different doses. The patients will receive an oral treatment of either orismilast modified release tablets or placebo tablets 2 times a day for 16 weeks.

Detailed description:

Arms:
arm 1: Oral, twice daily morning and evening arm 2: Oral, twice daily morning and evening arm 3: Oral, twice daily morning and evening arm 4: Oral, twice daily morning and evening

Interventions: intervention 1: Orismilast modified release tablets intervention 2: Placebo
Intervention descriptions: intervention 1: Orismilast modified release is a next generation PDE4 inhibitor with high selectivity for the PD4 subtypes linked to inflammation.

Other Names:

* UNI50001
* LEO32731 intervention 2: Placebo matching tablets

Protocol document:
Prot_002.pdf: 




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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Phase 2b Dose-Ranging Study to Evaluate the Efficacy and Safety of 
orismilast in Adults With Moderate to Severe Atopic Dermatitis 
Protocol Number: 
UNI50001-202 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
• I, the undersigned, have reviewed this protocol (and any amendments), including 
appendixes, and I will conduct the study as described in compliance with this protocol 
(and any amendments), GCP, and relevant International Council for Harmonisation (ICH) 
guidelines. 
• I am thoroughly familiar with the appropriate use of the study drug, as described in this 
protocol and any other information provided by UNION therapeutics A/S including, but 
not limited to, the current investigator’s brochure. 
• Once the protocol has been approved by the independent ethics committee 
(IEC)/institutional review board (IRB), I will not modify this protocol without obtaining 
prior approval of UNION therapeutics A/S and of the IEC/IRB. I will submit the protocol 
amendments and/or any Informed Consent Form modifications to UNION therapeutics 
A/S and the IEC/IRB, and approval will be obtained before any amendments are 
implemented. 
• I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the UNION therapeutics A/S study drug and of their delegated 
study-related duties and functions as described in the protocol. 
• I ensure that source documents and trial records that include all pertinent observations on 
each of the site’s trial patients will be attributable, legible, contemporaneous, original, 
accurate, and complete. 
• I understand that all information obtained during the conduct of the study with regard to 
the patients’ state of health will be regarded as confidential. No patients’ names will be 
disclosed. All patients will be identified by assigned numbers on all case report forms, 
laboratory samples, or source documents forwarded to the Sponsor. Clinical information 
may be reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the patient before disclosure of patient information to a third party. 
• Information developed in this clinical study may be disclosed by UNION therapeutics 
A/S to other clinical investigators, regulatory agencies, or other health authority or 
government agencies as required. 


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<Name> 
<Title> 
Investigator Signature 
Date (DD-Mmm-YYYY) 
Institution 
 
 


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1 
SYNOPSIS 
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 2b 
Dose-Ranging Study to Evaluate the Efficacy and Safety of orismilast in Adults 
With Moderate to Severe Atopic Dermatitis 
Protocol Number: 
UNI50001-202 
Investigators/Study Sites: 
48 centers in Europe and the United States 
Phase of Development: 
Phase 2b 
Objectives: 
Primary Objective: 
• 
The primary objective is to evaluate the efficacy and safety of a 
modified-release orismilast tablet versus placebo in adults with moderate to 
severe atopic dermatitis (AD). 
Secondary Objectives: 
• 
The secondary objectives are to evaluate the dose response of orismilast and 
identify the dose to be further evaluated in a Phase 3 program. 
Exploratory Objectives: 
The exploratory objectives are to: 
• 
Evaluate pharmacokinetic (PK) and pharmacodynamic parameters relevant to 
AD 
• 
Evaluate the effect of orismilast on the pulmonary status and course of the 
disease in patients with asthma 
Study Endpoints: 
Primary endpoint: 
• 
The primary endpoint of this study is the percentage change in Eczema Area 
and Severity Index (EASI) score from Baseline at Week 16. 
Key secondary endpoints: 
The key secondary endpoints are as follows: 
• 
Patients achieving 75% reduction in EASI (EASI75) response at Week 16 
• 
Patients achieving a score of clear (0) or almost clear (1) and at least a 2-point 
improvement in Investigator Global Assessment for AD (IGA-AD) at Week 16 
Other secondary endpoints: 
The other secondary endpoints of this study are as follows: 
• 
Patients achieving a score of clear (0) or almost clear (1) and at least a 2-point 
improvement in IGA-AD at Weeks 2, 4, 8, 12, and 20 
• 
Patients achieving EASI75 at Weeks 2, 4, 8, 12, and 20 
• 
Patients achieving 50% reduction in EASI (EASI50) and 90% reduction in 
EASI (EASI90) response at Weeks 2, 4, 8, 12, 16, and 20 
• 
Percent change from Baseline in EASI at Weeks 2, 4, 8, 12, and 20 
• 
Change from Baseline in the peak pruritus numerical rating scale (NRS) score 
at Weeks 1, 2, 4, 8, 12, 16, and 20 
• 
Patients achieving at least a 4-point improvement in the peak pruritus NRS 
from baseline at Weeks 1, 2, 4, 8, 12, 16, and 20 
• 
Change from Baseline in affected body surface area (BSA) at Weeks 2, 4, 8, 
12, 16, and 20 


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• 
Change from Baseline in Dermatology Life Quality Index score at Weeks 8, 
16, and 20 
• 
Change from Baseline in Patient Oriented Eczema Measure score at Weeks 2, 
4, 8, 12, 16, and 20 
• 
Change from Baseline in Patient Global Impression of Severity score at Weeks 
2, 4, 8, 12, 16, and 20 
• 
Change from Baseline in Patient Global Impression of Change score at Weeks 
2, 4, 8, 12, 16, and 20 
• 
Change from Baseline in sleep disturbance NRS score at Weeks 1, 2, 4, 8, 12, 
16, and 20 
• 
Change from Baseline in skin pain NRS score at Weeks 1, 2, 4, 8, 12, 16, and 
20 
Safety endpoints: 
The safety endpoints of this study are as follows: 
• 
The occurrence, severity, and seriousness of treatment-emergent adverse events 
reported over the 16-week Treatment Period and the 4-week Follow-up Period 
• 
Changes from Baseline in physical examination findings; vital signs 
measurements (body temperature, respiration rate, heart rate, and systolic and 
diastolic blood pressure measurements); and body weight over the 16-week 
Treatment Period and the 4-week Follow-up Period 
• 
Clinically significant abnormal changes in electrocardiogram (ECG) findings 
over the 16-week Treatment Period 
• 
Changes from Baseline in safety laboratory values (hematology, serum 
chemistry, and urinalysis) over the 16-week Treatment Period 
• 
Change from Baseline in Hospital Anxiety and Depression Scale score at each 
visit except Week 1 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) score at each visit except 
Week 1 
Exploratory endpoints: 
The exploratory endpoints of this study are as follows: 
• 
Change from Baseline in skin biomarkers at Week 16 collected via tape 
stripping and analyzed using proteomic methods 
• 
Patients achieving at least a 2-point improvement in the peak pruritus NRS 
from baseline at Weeks 1, 2, 4, 8, 12, 16, and 20 
• 
Plasma levels of the drug and its metabolites at Weeks 4, 8, and 16 
• 
Change from Baseline in pulmonary status NRS in patients with asthma at 
Weeks 4, 8, 12, 16, and 20 
Study Design: 
This multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
Phase 2b dose-ranging study is designed to assess the efficacy and safety of 
modified-release orismilast compared with placebo in patients aged at least 18 years 
with moderate to severe AD. Efficacy and safety outcomes will be evaluated to 
select an appropriate orismilast dose for subsequent Phase 3 studies. The study will 
be conducted at approximately 48 centers in Europe and United States. 
After a Screening visit up to 28 days before Baseline, approximately 210 patients 
will be assigned randomly in a 1:1:1:1 ratio to receive 1 of the 3 orismilast doses 
(20 mg, 30 mg, or 40 mg) or placebo twice daily (BID) for 16 weeks, with a 4-week 
follow-up visit. Administration will begin at Baseline with a dose titration period of 


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up to 2 weeks’ duration depending on the dose level. The maximum duration of 
study participation for each patient is approximately 24 weeks. 
Patients will be seen at the site at Screening, Baseline (Day 1), and Weeks 1, 2, 4, 8, 
12, 16 (End-of-Treatment visit), and 20 (Follow-up visit, 4 weeks after treatment 
completion or discontinuation). The visit at Week 1 can be conducted via a 
telemedicine procedure at the Investigator’s discretion. 
Patients who have been diagnosed with moderate to severe AD for a minimum of 1 
year (before the Screening visit) using the Hanifin and Rajka criteria with affected 
BSA of at least 10%, EASI score of at least 16, and IGA-AD grade of at least 3 at 
the screening and baseline visits will be included in the study. Patients must also 
have a documented history of inadequate response to treatment with topical 
medications given for at least 4 weeks (at least 2 weeks for high potency topical 
corticosteroids), or as labeled, or for whom topical treatments are otherwise 
medically inadvisable. 
At Baseline and at each visit from Week 2 onwards, EASI, affected BSA, and IGA-
AD will be assessed. BSA is defined as all areas with eczematous lesional skin and 
does not include xerosis (dryness), ichthyosis, keratosis pilaris, urticaria, infection 
(unless there is underlying eczema), or post inflammatory pigmentation changes. If 
patients need to manage areas with dry skin and/or pruritus, they are allowed to 
continue using their current emollient (however, emollients that contain 
pharmacologically active ingredients such as lactic acid, salicylic acid, urea, alpha-
hydroxy acids, or fruit acids are not allowed from the Screening visit). The severity 
of itch will be assessed by peak pruritus NRS at each visit from baseline to end of 
the treatment. Disease symptoms will be assessed by Patient Oriented Eczema 
Measure scores at Baseline and at the Weeks 2, 4, 8, 12, 16, and 20 visits. Quality of 
life related to the disease will be assessed by Dermatology Life Quality Index scores 
at Baseline and at the Weeks 8, 16, and 20 visits. Pulmonary disease status will be 
assessed in patients with asthma by pulmonary status NRS at Baseline and at the 
Weeks 4, 8, 12, 16, and 20 visits. The severity of disease will be assessed by Patient 
Global Impression of Severity and Patient Global Impression of Change scores at 
Baseline and at the Weeks 2, 4, 8, 12, 16, and 20 visits. In addition, the sleep 
disturbance NRS and skin pain NRS will be administered at Baseline and at the 
Weeks 1, 2, 4, 8, 12, 16, and 20 visits. 
Safety evaluations include medical history, adverse events (AEs), laboratory and 
vital sign assessments, physical examination including body weight and height, 12-
lead ECG, and mood change evaluations by the patient (Hospital Anxiety and 
Depression Scale score) and suicidal behavior and ideation evaluation by the 
Investigator (C-SSRS). 
Before administration of the study drug at Baseline and Weeks 4, 8, and 16, blood 
will be collected for orismilast and the major human metabolite LEO 40815 PK 
concentration determination. In addition, noninvasive superficial skin sampling 
using tape stripping will be conducted on a target lesion (lesional and nonlesional 
skin sample) at Baseline and Week 16 (only lesional skin sample) in all patients for 
proteomic analysis. 
Selection of Patients 
Main Inclusion Criteria: 
Patients are eligible to be included in the study only if all of the following criteria 
apply at both the screening and baseline visits: 
1. 
Capable of giving signed informed consent, which includes compliance with 
the requirements and restrictions listed in the Informed Consent Form (ICF) 
and in the protocol 
2. 
Male and female patients at least 18 years of age at the time of signing the ICF 
3. 
Body weight of greater than 40 kg at the time of signing the ICF 
4. 
Diagnosis of AD for a minimum of 1 year (before the Screening visit) using 
the Hanifin and Rajka criteria 
5. 
Moderate to severe AD (affected BSA at least 10%, IGA-AD grade of at least 
3, and EASI score of at least 16) at the screening and baseline visits 
6. 
Candidate for systemic treatment or phototherapy for AD 


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7. 
Patients having a documented history of inadequate response to treatment with 
topical medications given for at least 4 weeks (at least 2 weeks for high 
potency topical corticosteroids), or as labeled, or for whom topical treatments 
are otherwise medically inadvisable 
8. 
Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test result at the Screening visit and a negative urine pregnancy test 
result at the Baseline visit. In addition, sexually active WOCBP must agree to 
use a highly effective method of contraception throughout the study and until 
at least 4 weeks after the end of study treatment. Highly effective methods of 
contraception are those that have a failure rate of less than 1% per year (when 
implemented consistently and correctly and when applicable, in accordance 
with the product label) and include hormonal contraceptives (combined oral 
contraceptive, patch, vaginal ring, injectable, or implantable); progestogen-
only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable); intrauterine devices or 
systems; self or partner vasectomy; or bilateral tubal ligation. Patients must 
have been on a stable dose of hormonal contraceptives for at least 4 weeks 
before the Baseline visit. Abstinence from heterosexual intercourse is an 
accepted method of contraception if it is the patient’s lifestyle and is practiced 
for the duration of the study. 
Note: A woman of nonchildbearing potential is defined as a woman with 
surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or a woman in a postmenopausal status, defined as cessation of 
menses for at least 12 consecutive months without an alternative medical cause 
and a confirmatory follicle-stimulating hormone test result or as cessation of 
menses for at least 24 consecutive months without an alternative medical 
cause. 
Main Exclusion Criteria: 
1. 
Individuals meeting any of the following criteria at screening or baseline are 
ineligible to participate in this study: Therapy-resistant AD, defined as  ≥2  
treatment failures due to inadequate efficacy within the past 2 years of any  
biologic therapy, JAK inhibitor treatment or phototherapy administered at an 
adequate dose and duration according to the label or local/national guidelines. 
(Patients who stopped systemic treatment for reasons not related to lack of 
efficacy are not excluded.) 
2. 
Unstable AD with acute deterioration, requiring rescue therapy for AD within 
4 weeks of the Screening visit or expected to require rescue therapy within 
2 weeks after randomization 
3. 
History of allergy or hypersensitivity to any component of the study treatment 
4. 
Currently have active forms of other inflammatory skin disease or have 
evidence of skin conditions (eg, psoriasis, seborrheic dermatitis, lupus) at the 
Baseline visit that would interfere with evaluation of AD or response to 
treatment 
5. 
Active infection (eg, bacterial, viral, fungal) requiring treatment with systemic 
antibiotics within 4 weeks of the Screening visit 
6. 
Malignancy or history of malignancy except for treated (ie, cured) basal cell 
skin carcinoma 
7. 
Any chronic or recurrent medical condition associated with serious 
gastrointestinal diseases, such as inflammatory bowel disease 
8. 
Any medical or psychiatric condition (eg, current major depression with a 
score for depressive symptoms ≥15 of Hospital Anxiety and Depression Scale 
[HADS] at baseline, schizophrenia, suicidal behavior, psychiatric 
hospitalization within the prior year) that, in the Investigator’s opinion, would 
preclude the patient from adhering to the protocol, completing the study per-
protocol, and/or would place the patient at unacceptable risk while receiving 
the investigational therapy 
9. 
Individuals with severe or uncontrolled asthma or any other concomitant 
condition that is likely to require systemic corticosteroid bursts during the 
study 


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10. Any therapies and systemic treatments as described in Table 3 “Nonallowed 
therapies and treatments” that do not comply with the indicated washout 
interval 
11. Any previous treatment with orismilast or failure of treatment for AD with 
apremilast or any other systemic phosphodiesterase-4 inhibitor. 
12. Any condition, including laboratory or ECG abnormalities, that places the 
patient at unacceptable risk to participate in the study or confounds the ability 
to interpret data from the study 
13. Severe hepatic impairment based upon medical history and laboratory 
abnormalities (eg, low albumin and abnormal bilirubin levels) 
14. Any of the following abnormalities in clinical laboratory test results at 
Screening, as assessed by the study-specific laboratory and confirmed by a 
single repeat test, if deemed necessary: 
• 
Absolute neutrophil count of less than the lower normal range of the 
Central Laboratory (LNR) i.e. 1.7 x 109/L (1700/mm3) 
• 
Hemoglobin of less than 10.0 g/dL or hematocrit less than 30% 
• 
Platelet count of less than 100,000 mm3 
• 
Absolute lymphocyte count of less than the lower normal range of the 
Central Laboratory (LNR) i.e. 0,9 x 109/L (900/mm3) 
• 
Total bilirubin greater than 1.5 × the upper limit of normal (ULN); 
patients with a history of Gilbert’s syndrome may have direct bilirubin 
measured and would be eligible for this study provided the direct bilirubin 
result is less than or equal to the ULN 
• 
Alanine aminotransferase or aspartate aminotransferase greater than 2.5 × 
the ULN 
• 
Serum creatinine greater than or equal to 1.5 mg/dL. For patients with a 
value of greater than or equal to 1.5 mg/dL, if their creatinine clearance is 
at least 60 mL/min (calculated using the Chronic Kidney Disease 
Epidemiology Collaboration creatinine equation) enrollment may be 
allowed 
15. History or evidence of hepatitis B virus infection at Screening. Patients with a 
positive hepatitis B surface antigen result are excluded. For patients with an 
isolated positive antihepatitis B core antibody result, the hepatitis B surface 
antibody result must also be positive to be eligible for this study. 
16. History or positive test result for hepatitis C virus (HCV) antibody, indicating 
ongoing infection, at Screening. Confirmatory testing for HCV RNA will be 
conducted for patients who have a positive test result. Patients who have a 
negative result for HCV RNA will be eligible to participate in the study. 
17. History of positive HIV test result or congenital or acquired immunodeficiency 
(eg, common variable immunodeficiency disease). Patients who are positive 
for HIV antibodies (HIV-1 or HIV-2) at Screening are excluded from the 
study. 
18. Suicidal ideation or behavior in the past 12 months as indicated by a positive 
response (yes) to questions 4 or 5 on the C-SSRS completed at the Screening 
visit or at Baseline 
19. Pregnant or breastfeeding 
20. History of alcohol or substance abuse within 6 months before Baseline that, in 
the opinion of the Investigator, will preclude participation in the study 
21. Institutionalized by court order or by local authority 
22. Regular use (more than 2 visits per week) of a tanning booth/parlor 
Planned Sample Size: 
Approximately 210 patients will be randomly assigned to receive orismilast 20 mg, 
30 mg, or 40 mg BID or placebo for 16 weeks. 
This sample size is based on assumptions that there is a difference of 25.0% in the 
percent change from baseline in EASI scores between each orismilast dose group 
with placebo, respectively, and that the common standard deviation in the percent 
change from baseline in EASI score is 43%. Using 2-sided 2-sample t-test, 
47 patients in each treatment group (188 in total) will achieve a power of 80% at the 


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significance level of 5%. To account for an early dropout of approximately 10%, an 
additional 22 patients will be randomized. 
Investigational Therapy: 
Name: orismilast 
Unit doses strength and dose formulation: 20 mg (2 × 10-mg tablets), 30 mg 
(1 × 30-mg tablet and 1 placebo tablet), and 40 mg (1 × 10-mg tablet and 1 × 30-mg 
tablet) 
Route and frequency of administration: oral, 2 tablets BID (approximately every 12 
hours) 
Use: experimental 
Sourcing: provided centrally by the Sponsor 
Packaging and labeling: provided in individually labeled wallet cards with blistered 
tablets. Each card will be labeled as required per country requirement. 
Reference Therapy: 
Matching placebo tablets 
Treatment Duration: 
The Treatment Period for this study is 16 weeks, with a 4-week Follow-up visit. 
Refer to Table 2 for the dose titration schedule. 
Pharmacokinetics: 
Blood samples for PK analysis of orismilast and its major metabolite levels will be 
collected at the time points indicated in the Schedule of Assessments (Table 4). The 
actual date and time of each blood sample collection will be recorded. Patients will 
be offered optional participation in specific blood sampling for calculation of PK 
profiles. 
Details of PK blood sample collection, processing, storage, and shipping procedures 
are provided in a separate laboratory manual. 
The concentration of study drug and main metabolite will be determined from the 
plasma samples using a validated analytical method. Details of the method 
validation and sample analysis will be included with the final clinical study report. 
Pharmacodynamics: 
Stratum corneum skin samples will be collected at the time points indicated in the 
Schedule of Assessments (Table 4) using the tape stripping method to evaluate 
biomarker expression levels. Tape stripping is a minimally invasive, nonscarring 
approach using serial adhesive films to capture the stratum corneum and the upper 
part of the granular layer. 
At Baseline, before administration of study drug, 1 lesional and 1 nonlesional area 
will be identified, and 20 consecutive skin samples will be collected from each area. 
At Week 16, the same procedure will be repeated only from the same lesional areas 
sampled at Baseline. 
Details of stratum corneum skin samples storage, and shipping procedures are 
provided in a separate laboratory manual. 
Statistical Methods and Planned 
Analyses: 
Details of the statistical analysis will be provided in a separate Statistical Analysis 
Plan. For inferential analyses of primary and secondary efficacy endpoints, each 
active treatment group will be compared with the placebo group. 
Primary and secondary efficacy endpoints are to be assessed in the intent-to-treat 
(ITT) population. Missing data for primary and key secondary endpoints will be 
handled with the multiple imputation method. For a categorical efficacy endpoint 
based on a continuous variable, the multiple imputation will be first done for the 
continuous variable, then the category will be determined using the imputed values. 
Analyses will be repeated on the per-protocol population for primary and key 
secondary endpoints. 
When appropriate, the raw parameter, its change from Baseline, and percentage 
change from Baseline will be summarized. 


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The primary endpoint, percentage change from Baseline to Week 16 in EASI score, 
will be analyzed using an analysis of covariance with treatment group as the factor 
and Baseline EASI score as the covariate. The mixed model for repeated measures 
may be used as a supportive analysis. Each active treatment dose will be compared 
with placebo. No adjustment for multiplicity will be made, and the 0.05 level of 
significance will be used to claim efficacy compared with placebo. Least square 
means and the 95% CI of the difference between each active treatment and placebo 
will be calculated. The primary analysis set will be the ITT population with a 
multiple imputation approach to handle missing values. The same analyses will be 
repeated backward at earlier visits. 
The key secondary and other binary endpoints (IGA-AD success, EASI50, EASI75, 
EASI90, and 4-point improvement in the peak pruritus NRS) will be analyzed using 
the Mantel-Haenszel (MH) test, comparing each active treatment group with 
placebo in the ITT population. 
For categorical endpoints, the MH procedure, with ridit scores, will be used; this test 
is the same as the nonparametric Wilcoxon test and enhances the analysis when the 
parameter is not normally distributed. Graphics will be added to facilitate 
interpretation. IGA-AD scores/full scale will be analyzed using the MH test and the 
row mean score statistics with the ridit transformation. 
The other continuous secondary endpoints will be analyzed using mixed model for 
repeated measures. 
The above endpoints (EASI changes and percentage changes, IGA-AD success, 
EASI50, EASI75, and EASI90) and the percentage change of BSA will be presented 
graphically over time from Baseline to Week 20. In addition, shift tables will be 
provided between Baseline and each visit for the IGA-AD distribution. The EASI 
percentage changes from Baseline will be plotted to identify where the best 
separation between treatments occurs. 
All exploratory endpoints, including change from baseline in pulmonary status NRS 
in patients with asthma and skin biomarkers at Week 16, and patients achieving at 
least a 2-point improvement in peak pruritis NRS from baseline will be summarized 
descriptively in the ITT population or a subgroup. 
All safety analyses will be conducted using the safety population. AE data will be 
presented and tabulated according to Medical Dictionary for Regulatory Activities 
classification. Reported AEs will be summarized by the number of patients 
reporting the events, as well as by system organ class (SOC) and preferred term 
(PT); SOC, PT, and severity; and SOC, PT, and relationship to study product. 
Laboratory (chemistry, urinalysis and hematology) parameters, 12-lead ECG values, 
and vital signs will be tabulated by visit using descriptive statistics and shift tables. 
The value at each visit, as well as the change from Baseline, will be presented. 
The plasma levels of the drug and its metabolites will be summarized descriptively 
by visit in this study. 
No interim analysis is planned in this study. 
 
 
 


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2 
TABLE OF CONTENTS 
1 
SYNOPSIS ........................................................................................................................5 
2 
TABLE OF CONTENTS ................................................................................................12 
3 
LIST OF ABBREVIATIONS .........................................................................................18 
4 
INTRODUCTION ...........................................................................................................20 
4.1 
Background on Atopic Dermatitis ..............................................................................20 
 
Rationale for the Clinical Development of Orismilast for Atopic Dermatitis ...22 
4.2 
Background on Orismilast ..........................................................................................22 
 
Nonclinical Studies ............................................................................................23 
 
Clinical Studies ..................................................................................................24 
4.3 
Clinical Risks/Benefits of Orismilast .........................................................................28 
 
Common PDE-4inhibition related side effects ..................................................28 
 
Monitoring of Cardiovascular, Psychiatric, Hepatic, and Metabolic Risks .......28 
 
Tape Stripping ....................................................................................................28 
 
Stopping of Current Treatment ..........................................................................28 
4.4 
Study Rationale ..........................................................................................................29 
 
Dose Rationale ...................................................................................................29 
5 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................31 
5.1 
Study Objectives .........................................................................................................31 
 
Primary Objective ..............................................................................................31 
 
Secondary Objectives .........................................................................................31 
 
Exploratory Objectives ......................................................................................31 
5.2 
Study Endpoints..........................................................................................................31 
 
Primary Endpoint ...............................................................................................31 
 
Secondary Endpoints ..........................................................................................31 
 
Safety Endpoints ................................................................................................32 
 
Exploratory Endpoints .......................................................................................32 
6 
INVESTIGATIONAL PLAN .........................................................................................34 
6.1 
Description of Overall Study Design and Plan...........................................................34 
6.2 
Discussion of Study Design........................................................................................35 
6.3 
Follow-up Period ........................................................................................................36 
6.4 
End of Study ...............................................................................................................36 
7 
SELECTION OF STUDY POPULATION .....................................................................38 
7.1 
Inclusion Criteria ........................................................................................................38 


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7.2 
Exclusion Criteria .......................................................................................................39 
7.3 
Rescreening ................................................................................................................41 
7.4 
Treatment Discontinuation and Withdrawal ..............................................................41 
8 
TREATMENTS ...............................................................................................................43 
8.1 
Details of Study Treatments and Dosage Schedule ....................................................43 
8.2 
Measures to Minimize Bias: Study Treatment Assignment and Blinding .................43 
 
Method of Study Treatment Assignment ...........................................................43 
 
Blinding 44 
8.3 
Planned Dosing Schedule and Adjustments ...............................................................44 
 
Planned Dosing Schedule – Titration over a Maximum of 2 Weeks .................45 
 
Short Dose Reduction During the Titration Period ............................................45 
 
Dose Reductions and Temporary Treatment Discontinuations After the Titration 
Period 45 
8.4 
Treatment Accountability and Compliance ................................................................46 
8.5 
Prior and Concomitant Therapy .................................................................................46 
 
Emmolients ........................................................................................................46 
 
Supportive Treatment for Side Effects ...............................................................47 
 
Restricted Medications .......................................................................................47 
 
Drug-Drug Interactions ......................................................................................48 
9 
STUDY PROCEDURES .................................................................................................49 
9.1 
Informed Consent .......................................................................................................53 
9.2 
Study Procedures ........................................................................................................53 
10 
EFFICACY ASSESSMENTS .........................................................................................54 
10.1 Investigator Assessments............................................................................................54 
 
Eczema Area and Severity Index .......................................................................54 
 
The Investigator Global Assessment for Atopic Dermatitis ..............................54 
 
Body Surface Area .............................................................................................54 
10.2 Patient-Reported Outcomes ........................................................................................55 
 
Peak Pruritus Numerical Rating Scale ...............................................................55 
 
Skin Pain Numerical Rating Scale .....................................................................55 
 
Sleep Disturbance Numerical Rating Scale .......................................................55 
 
Patient Oriented Eczema Measure .....................................................................55 
 
Patient Global Impression of Severity Scale ......................................................55 
 
Patient Global Impression of Change Scale .......................................................56 


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Dermatology Life Quality Index ........................................................................56 
 
Pulmonary Status Numerical Rating Scale in Patients with Asthma .................56 
11 
SAFETY ASSESSMENTS .............................................................................................57 
11.1 Medical History ..........................................................................................................57 
11.2 Vital Signs and Body Weight .....................................................................................57 
11.3 Physical Examination .................................................................................................57 
11.4 Electrocardiograms .....................................................................................................58 
11.5 Laboratory Assessments .............................................................................................58 
11.6 The Hospital Anxiety and Depression Scale ..............................................................59 
11.7 The Columbia-Suicide Severity Rating Scale ............................................................59 
11.8 Adverse Events ...........................................................................................................60 
 
Adverse Events ..................................................................................................60 
 
Adverse Events of Special Interest (AESI) ........................................................63 
 
Serious Adverse Events .....................................................................................64 
 
Serious Adverse Event Reporting ......................................................................64 
 
Suspected Unexpected Serious Adverse Reactions ...........................................65 
 
Pregnancy ...........................................................................................................66 
 
Overdose ............................................................................................................67 
12 
PHARMACOKINETICS ................................................................................................68 
12.1 Pharmacokinetic Sampling .........................................................................................68 
 
Blood Samples ...................................................................................................68 
12.2 Pharmacokinetic Analytical Methodology .................................................................68 
13 
PHARMACODYNAMICS .............................................................................................69 
13.1 Superficial Skin Sampling Using Tape Stripping ......................................................69 
14 
STATISTICAL ANALYSIS ...........................................................................................70 
14.1 Determination of Sample Size ....................................................................................70 
14.2 Analysis Populations ..................................................................................................70 
14.3 Efficacy Analysis........................................................................................................71 
 
Analysis of the Primary Efficacy Endpoint .......................................................71 
 
Analysis of Secondary Efficacy Endpoints ........................................................71 
 
Analysis of Exploratory Endpoints ....................................................................72 
14.4 Safety Analysis ...........................................................................................................72 
14.5 Pharmacokinetic Analysis ..........................................................................................72 
14.6 Interim Analysis .........................................................................................................72 
15 
STUDY MANAGEMENT ..............................................................................................73 


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15.1 Approval and Consent ................................................................................................73 
 
Regulatory Guidelines ........................................................................................73 
 
Institutional Review Board/Independent Ethics Committee ..............................73 
 
Informed Consent ...............................................................................................74 
15.2 Data Handling .............................................................................................................74 
15.3 Source Documents ......................................................................................................75 
15.4 Record Retention ........................................................................................................75 
15.5 Monitoring ..................................................................................................................75 
15.6 Quality Control and Quality Assurance .....................................................................76 
15.7 Protocol Amendment and Protocol Deviation ............................................................76 
 
Protocol Amendment .........................................................................................76 
 
Protocol Deviations ............................................................................................76 
15.8 Ethical Considerations ................................................................................................76 
15.9 Financing and Insurance .............................................................................................76 
15.10 Publication Policy/Disclosure of Data........................................................................77 
16 
REFERENCES ................................................................................................................78 
17 
APPENDIXES .................................................................................................................80 
Appendix 1: Rajka and Hanifin Criteria for Atopic Dermatitis ...............................................81 
Appendix 2: Eczema Area Severity Index ...............................................................................84 
Appendix 3: Investigator Global Assessment for Atopic Dermatitis ......................................85 
Appendix 4: Body Surface Area ..............................................................................................86 
Appendix 5: Peak Pruritus Numerical Rating Scale ................................................................87 
Appendix 6: Skin Pain Numerical Rating Scale ......................................................................88 
Appendix 7: Sleep Disturbance Numerical Rating Scale ........................................................89 
Appendix 8: Patient Oriented Eczema Measure ......................................................................90 
Appendix 9: Patient Global Impression of Severity Scale.......................................................91 
Appendix 10: Patient Global Impression of Change Scale ......................................................92 
Appendix 11: Dermatology Life Quality Index .......................................................................93 
Appendix 12: Pulmonary Status Numerical Rating Scale in Patients with Asthma ................95 
Appendix 13: The Columbia-Suicide Severity Rating Scale ...................................................96 
Appendix 14: The Hospital Anxiety and Depression Scale...................................................104 
Appendix 15: Protocol Amendment Summary ......................................................................105 


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List of In-text Tables 
Table 1. Study Treatment and Dosage Schedule .....................................................................43 
Table 2. Dose Titration Schedule.............................................................................................45 
Table 3. Nonallowed Therapies and Treatments .....................................................................47 
Table 4. Schedule of Assessments ...........................................................................................50 
Table 5. Laboratory Assessments ............................................................................................58 
Table 6. Selected unique clinical descriptions of severity of AEs from National Cancer Institute 
Common Terminology Criteria for Adverse Events version 5.0 ............................61 
Table 7. National Cancer Institute Common Terminology Criteria for Adverse Events general 
guideline for classification version 5.0 ...................................................................62 
Table 8. Classification of Adverse Events by Relationship to Study Drug .............................63 
 
 
 


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List of In-text Figures 
Figure 1. Study Design .......................................................................................................35 
Figure 2. Pharmacokinetic Blood Sample Collection ........................................................68 
 


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3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
AUC 
area under the curve 
BID 
twice daily 
BSA 
body surface area 
cAMP 
cyclic adenosine monophosphate 
Cmax 
maximum (or peak) serum concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
DLQI 
National Cancer Institute Common Terminology Criteria for Adverse Events 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI50 
50% reduction in Eczema Area and Severity Index 
EASI75 
75% reduction in Eczema Area and Severity Index 
EASI90 
90% reduction in Eczema Area and Severity Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HADS 
Hospital Anxiety and Depression Scale 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IFN 
interferon 
IGA-AD 
Investigator Global Assessment for Atopic Dermatitis 
IL 
interleukin 
IRB 
institutional review board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 


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Abbreviation 
Definition 
JAK 
Janus kinase inhibitors 
LS 
least squares 
MH 
Mantel-Haenszel 
NRS 
numerical rating scale 
PASI 
Psoriasis Area and Severity Index 
PD 
pharmacodynamic 
PDE 
phosphodiesterase 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
pharmacokinetic 
POEM 
Patient Oriented Eczema Measure 
PRO 
patient-reported outcomes 
PT 
preferred term 
SAE 
serious adverse event 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
Th 
T helper 
tmax 
time drug was present at the maximum concentration in serum 
TNF 
tumor necrosis factor 
TSS 
total sign score 
WOCBP 
women of childbearing potential 
ULN 
upper limit of normal 


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4 
INTRODUCTION 
4.1 
Background on Atopic Dermatitis 
Atopic dermatitis (AD) is a chronic inflammatory disease characterized by eczematous lesions 
and intense itching. Inflammatory infiltrates in these cutaneous lesions consist of T-lymphocytes, 
neutrophils, eosinophils, monocytes, macrophages, and mast cells (Cooper KD, 1994). High 
levels of phosphodiesterase (PDE)-4 activity are also found in leukocytes of these patients 
(Butler JM, 1983). AD usually begins in childhood. It is estimated that 50% of patients with AD 
have additional allergy symptoms within the first year of life, and up to 85% have symptoms that 
begin before the age of 5 years. Patients often outgrow the condition in late childhood, with 
approximately 70% of patients experiencing spontaneous remission before adolescence. Early 
childhood AD, on the other hand, is often the first sign that a child may develop asthma and/or 
allergic rhinitis (hay fever) later in life (Spergel JM, 2010). The prevalence of adult AD has been 
reported to range from 2.1% to 4.9% across countries, and patients with severe AD represent a 
small proportion of the overall AD population regardless of measure or region (Barbarot S, 
2018). 
There is a limited number of treatments available for moderate to severe AD. Current treatments 
include phototherapy (eg, ultraviolet A light with or without psoralen, ultraviolet B light 
narrowband or broadband) and systemic immunotherapies (eg, corticosteroids, cyclosporine, 
methotrexate, and dupilumab) (Slater NA, 2015; Newsom M, 2020). More recently, systemic 
therapy options for moderate to severe AD have increased after the approval of the Janus kinase 
inhibitors baricitinib and upadacitinib and the anti–interleukin (IL)-13 monoclonal antibody 
tralokinumab (Bieber T, 2021). 
AD is treated primarily with topical therapies, mainly with intermittent, preventive application of 
topical corticosteroids and/or topical calcineurin inhibitors, paired with daily emollient use 
(McGregor SP, 2017). Intermittent topical corticosteroid use poses risk of 
corticosteroid-associated adverse effects like skin atrophy, striae formation in sensitive or thin-
skinned areas, and systemic effects that limit their long-term use (Hanifin J, 2002). The rate of 
long-term adherence to topical therapy, however, is low (Snyder A, 2015). Off-label use of other 
conventional systemic oral immunomodulatory agents, such as azathioprine and methotrexate, in 
adults with AD can be effective, but patients have reported adverse events (AEs) or 
ineffectiveness as reasons for discontinuation of treatment; use of these drugs poses well-known 
safety limitations and requires regular laboratory monitoring (Roekevisch E, 2018; Sidbury R, 
2014). Moderate to severe AD is often refractory to first-line topical treatments; while systemic 
immunosuppressants are efficacious, they have significant adverse effects. The desire for new 
treatments along with an improved understanding of the pathophysiology of AD has spurred the 
development of novel treatments targeting IL-13, IL-31, and the Janus kinase family of proteins 
(Silverberg JI, 2017). Thus, there is interest in investigating a systemic approach for more severe 
forms of AD. 


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PDEs constitute a superfamily of enzymes catalyzing the hydrolysis of the intracellular second 
messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate that 
play key roles in mediating biological responses generated by a variety of extracellular signals. 
Eleven families of PDE enzymes have been identified, with the PDE4 family constituting 
approximately 20 members (Houslay MD, 2005). PDEs represent the only cellular pathway for 
the degradation of cyclic nucleotides, which emphasizes their critical role in the regulation of the 
intracellular levels of these secondary messengers and, consequently, various functional 
responses of cells (Dastidar SG, 2007). PDE4 is a cAMP specific PDE expressed by immune and 
inflammatory cells, including T-lymphocytes, neutrophils, eosinophils, monocytes, dendritic 
cells, and macrophages (Spina D, 2008). In these cells, PDE4 is the predominant PDE form, and 
PDE4 inhibitors increase cAMP levels. High cAMP levels tend to decrease proliferation and 
cytokine production, whereas low concentrations have the opposite effect. In allergic skin 
disease, PDE4 inhibitors inhibit the migration of skin dendritic cells, and this inhibition is 
accompanied by an inhibition of matrix metalloproteinase 9 activity in epidermis and dermis. 
Furthermore, cytokine secretion (tumor necrosis factor [TNF]-α, IL-1β and IL-12) of human 
dendritic cells is inhibited by PDE4 inhibitors, and an inhibition of T cell activation is also 
demonstrated in vitro. Both T helper (Th)1 and Th2 cytokines are reduced by PDE4 inhibitors in 
vitro and in inflamed murine skin (Jin SL, 2012). 
Inhibition of PDE4 has therapeutic potential in the treatment of psoriasis and other skin diseases 
with an immuno-inflammatory component (Dastidar SG, 2007). Several PDE4-specific 
inhibitors are in late stages of clinical development or have recently been marketed. For example, 
the oral PDE4 inhibitor roflumilast (Daxas®/Daliresp®) is approved in the United States and 
Europe to reduce the risk of exacerbation in patients with chronic obstructive pulmonary disease 
and chronic bronchitis (Roflumilast Summary of Product Characteristics). The oral PDE4 
inhibitor apremilast (Otezla®) is approved in the United States and Europe for psoriatic arthritis 
and psoriasis (Apremilast Summary of Product Characteristics) and it has been studied for AD 
and other chronic inflammatory diseases (Samrao A, 2012). Anacor Pharmaceuticals (a 
subsidiary of Pfizer) has developed a topical PDE4 inhibitor for treatment of mild to moderate 
AD (Crisaborole [AN 2728]), which has been approved in the United States (under the 
tradename Eucrisa®) and in Europe (under the tradename Staquis®) (Crisaborole – Pfizer Adis 
Insight; Staquis – Assessment Report). 
One of the key challenges for an effective PDE4 therapy has been the narrow therapeutic 
window. Most of the programs investigating PDE4 inhibitors failed because of safety issues, up 
until the approval of roflumilast and apremilast some years later. Both therapies had tolerability 
issues affecting, primarily but not exclusively, the gastrointestinal (GI) tract, characterized by 
nausea and diarrhea. These undesired GI effects were consistently observed from the beginning 
of treatment, and this led to the titration of those drugs (apremilast over 1 week, roflumilast over 
1 month) to reduce side effects (Roflumilast Summary of Product Characteristics; Apremilast 
Summary of Product Characteristics). 


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 Rationale for the Clinical Development of Orismilast for Atopic Dermatitis 
A study in Japan looked at the effects of PDE4 inhibitors, cilomilast, roflumilast, and rolipram 
on induced dermatitis in mice models. Cilomilast, roflumilast, and, to a lesser extent, rolipram 
suppressed myeloperoxidase activity, a quantitative index of neutrophils accumulating in skin 
associated with chronic inflammation. After 18 days of treatment, cilomilast and roflumilast 
showed a 47% and 36% recovery in skin severity score, respectively. This effect was more 
potent than the 25% recovery seen with cyclosporine A, especially in the earlier stages of 
treatment (Harada D, 2008). 
An open-label prospective trial of oral apremilast in 16 patients with moderate to severe AD was 
conducted to assess the safety, efficacy, and possible mechanism of action of apremilast in AD 
(Samrao A, 2012). The study showed a trend towards an improvement of AD following 
treatment with apremilast. One cohort consisted of 6 patients treated with apremilast 20 mg twice 
daily (BID) for 3 months, while the second cohort consisted of 10 patients treated with 
apremilast 30 mg BID for 6 months. Patients in the study were required to remain on topical 
triamcinolone acetonide 0.1% for 2 weeks before the start of the study as well as throughout the 
trial. Nausea, the most common AE, appeared to be dose related was rated as mild and improved 
over the course of the study in all patients. After 3 months of treatment, a significant reduction of 
itch from baseline and improvement in quality of life (assessed via Dermatology Life Quality 
Index [DLQI] score) was seen in cohort 1 (P =.02 and P =.003, respectively), while Eczema 
Area and Severity Index (EASI) and DLQI scores improved in cohort 2 (P =.008 and P =.01, 
respectively). At 6 months, statistically significant improvement was seen in all outcomes in 
cohort 2, including the itch visual analog scale (P =.03), DLQI (P =.03), and EASI (P =.002). 
A placebo-controlled study showed only modest efficacy for oral apremilast 40 mg BID versus 
placebo, which was not seen at the 30 mg BID dose. In addition, there were increased rates of 
AEs (6 cases of cellulitis) in the apremilast 40 mg BID group versus none in the placebo or 
30 mg BID group, and thus, treatment with 40 mg BID was halted in this trial (Simpson EL, 
2019). 
4.2 
Background on Orismilast 
Orismilast is a PDE4 inhibitor currently in Phase 2 of clinical development for oral treatment of 
various inflammatory skin diseases including hidradenitis suppurativa, plaque-type psoriasis, and 
AD. During initial development (Phase 1/2a), different oral formulations were tested in the 
clinic. Because the immediate-release tablet appeared to be less well tolerated compared with the 
drug in capsule formulation, newly developed oral orismilast formulation concepts were tested, 
and a modified-release formulation was selected for further development. This new formulation 
was shown to improve GI tolerability without change in systemic exposure. 


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 Nonclinical Studies 
Both oral and topical administration of orismilast exhibited anti-inflammatory effects in the 
chronic oxazolone mouse model, an animal model that shares some similarities with human AD 
and chronic skin inflammation. Oral administration of orismilast to mice also reduced levels of 
TNF-α in this model. 
The selectivity of orismilast has been investigated using a panel of 76 G protein coupled 
receptors, 40 kinase assays, and patch-clamp tests with 8 cardiac ion channels, and no effects 
were seen, except some inhibition of the human ether-à-go-go–related gene ion channel current 
amplitudes at 10 μM. 
The pharmacokinetics (PK) of orismilast have been investigated in mice, rats, rabbits, and 
minipigs after administration by oral gavage. In rats, the area under the curve (AUC) and 
maximum (or peak) serum concentration (Cmax) generally increased in proportion to dose in the 
tested range (0.5 to 1.75 mg/kg), with female rats having AUC and Cmax values 1.5 to 3 times 
higher than those in male rats. In mice, rabbits, and minipigs, AUC and Cmax increased less than, 
or proportional to, the investigated doses (5 to 500 mg/kg, BID dosing, and 1.0 to 30 mg/kg, 
respectively), and AUC and Cmax values were generally comparable in females and males. In a 
minipig telemetry study, mean concentrations increased less than proportionally to the 
investigated doses (1.0 to 10 mg/kg) and were lower in females than in males. There was little or 
no accumulation in mice, rats, rabbits, or minipigs. Orismilast was excreted mainly via the feces 
in rats and minipigs. 
The in vitro plasma protein binding of orismilast was low to moderate (35% to 67%) in a variety 
of species tested (mouse, rat, rabbit, minipig, and human). The in vitro metabolism of orismilast 
has been investigated using hepatocytes from mouse, rat, hamster, rabbit, minipig, dog, 
marmoset, cynomolgus monkey, and human. The extent of metabolism was generally low. 
In safety pharmacology assessments, the in vitro assessment of the effect on human ether-à-go-
go–related gene tail current recorded from human embryonic kidney-293 cells gave a half 
maximal inhibitory concentration value of 11.4 μM. In conscious telemetered minipigs, oral 
administration of orismilast produced no treatment-related effects on heart rate; body 
temperature (measured in the ear); QRS, QT, or QTcR intervals; or electrocardiogram (ECG) 
morphology. An increase in systolic blood pressure was observed in minipigs at the highest dose 
level only (10 mg/kg). No effect was observed on the central nervous system in a modified Irwin 
test or on respiratory parameters in rats. 
The outcome and assessment of nonclinical data showed that neither orismilast (LEO 32731) nor 
its major metabolite LEO 40815 have been found to be genotoxic in the standard battery of 
genotoxicity testing that included in vitro Ames and mouse lymphoma assay testing and in vivo 
micronucleus testing (LEO 32731). In addition, reproductive toxicity studies on fertility and 
early embryonic development, as well as embryo fetal development, have been conducted across 
a range of time courses, dose, and exposure levels in rats, mice, minipigs, and rabbits. The 


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weight of evidence from these nonclinical studies indicates that neither orismilast nor its major 
metabolite LEO 40815 are teratogenic or have adverse effects on male and female fertility or the 
female reproductive system. The no observed adverse effect levels, as well as safety margins, are 
based on AUC from these studies for the highest proposed clinical dosing regimen of 40 mg BID 
(80 mg/kg/day). 
Overall, treatment was well tolerated at 1 mg/kg. Refer to the investigator’s brochure for further 
details on orismilast nonclinical studies. 
 Clinical Studies 
As of 01 October 2021, the orismilast clinical development program consists of 8 completed 
trials with an oral formulation (including 7 Phase 1 trials in healthy subjects and 1 Phase 2a trial 
in patients with moderate to severe plaque-type psoriasis) and 1 Phase 1 trial with a topical 
formulation. 
Oral program: The completed trials include 2 dose-finding and PK trials using a solution and a 
capsule formulation (drug in capsule; trials LP0058-S01 and LP0058-1114), a PK trial using a 
capsule (drug in capsule) and modified-release tablets (3 different release profiles; trial 
LP0058-1005), a PK trial in healthy Japanese men using a tablet formulation (immediate-release; 
trial LP0058-1362), a PK trial evaluating the PK and safety/tolerability profiles of several new 
formulations (trial LP0058-1442), 2 drug-drug interaction trials using an orismilast 
immediate-release tablet formulation and midazolam (trials LP0058-1267 and LP0058-1324), 
and a proof-of-concept Phase 2a trial in psoriasis using an immediate-release tablet formulation 
(trial LP0058-1072). Only one trial (LP0058-1442) used the modified-release tablet selected for 
further development. 
Topical program: One Phase 1 proof-of-concept study (LP0108-1082) was conducted in male 
adult patients with mild to moderate AD. 
4.2.2.1 Clinical Pharmacology 
Oral Program 
After single and multiple oral dosing of up to 60 mg BID of the initial capsule formulation, in the 
fasted state or after a standard breakfast, orismilast was steadily absorbed with a median time 
drug was present at the maximum concentration in serum (tmax) of 2 to 4 hours. Systemic 
exposure to orismilast increased in an approximately dose-proportional manner. Estimates of 
elimination half-lives varied across studies, from 4 to 6 hours (for dose levels up to 30 mg 
3 times a day) and up to 10 hours (for the 60-mg BID dose level). After multiple dosing of up to 
30 mg 3 times a day, steady state was attained within 2 days. Minimal accumulation of orismilast 
was observed. Dosing after a high-fat meal delayed tmax by 2 hours and increased AUC0-∞ by 
40% compared with dosing in the fasted state. 
Formation of the human-specific metabolite LEO 40815 was rapid, with median tmax occurring 
approximately 1 hour after that of orismilast. The disposition of the metabolite mirrored that of 


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orismilast, suggesting formation rate-limited elimination of LEO 40815. The ratio of metabolite 
to parent compound was relatively constant across doses and upon repeated dosing, indicating 
that systemic exposure to LEO 40815 was approximately 53% to 75% lower than to orismilast. 
The PK profile for the orismilast immediate-release tablet formulation, used in trial 
LP0058--1267, appeared similar to the PK profile for the immediate-release capsule formulation 
used in the first 3 clinical trials. Furthermore, no differences in the PK profile of orismilast 
between races (LP0058-1362) or sex (LP0058-1114) has been identified. 
Data from the LP0058-1324 trial showed that the exposure of midazolam was more than 
30% higher when midazolam was administered at steady state (Day 17) after administration of 
30 mg orismilast BID compared with midazolam alone (geometric means of 132% for AUC0-t 
and 137% for Cmax). These results classify orismilast as a weak inhibitor of CYP3A4. 
Pharmacodynamic (PD) evaluation from trial LP0058-S01 using an ex vivo cytokine release 
assay indicated that orismilast inhibited the secretion of TNF-α and interferon (IFN)-γ. 
Maximum inhibition generally occurred between 4 to 6 hours post dose. There was no clear 
dose-relationship in the maximal response or duration of inhibitory response. Mean decreases 
from Baseline to Day 7 ranged from approximately 67% to 70% for TNF-α and 52% to 77% for 
IFN-γ levels across dose groups receiving 10, 20, and 30 mg orismilast 3 times a day. In 
accordance, reduced levels of TNF-α, IFN-γ, macrophage inflammatory protein-1α, and 
macrophage inflammatory protein-1βwere observed in lipopolysaccharide -stimulated blood 
from patients treated with orismilast in the LP0058-1072 trial, suggesting that pharmacologically 
relevant levels of orismilast were present. 
4.2.2.2 Efficacy in Atopic Dermatitis 
A single-center, prospective, randomized, vehicle-controlled, double-blinded, intra-individual 
trial was conducted to compare the effect of orismilast cream 20 mg/g and cream vehicle when 
applied BID for 3 weeks on 2 small treatment areas in adults with mild to moderate AD 
(right/left design, on symmetrically located lesions). Efficacy assessments were performed at 
baseline, Days 8, 15, and 22 on site with the primary endpoint being the total sign score (TSS) 
assessed at the End-of-Treatment (EOT). The TSS was defined as the sum of the individual sign 
scores: erythema, edema/papulation, oozing/crusting, excoriations, lichenification, and dryness. 
A total of 30 subjects were randomized and treated with at least 1 application/dose of orismilast 
cream; 29 subjects completed the trial (ie, attended visit 5), but all 30 subjects did complete the 
full treatment period. The TSS at the end of the treatment was 5.2 (least squares [LS] mean: 5.1) 
for orismilast cream 20 mg/g and 6.2 (LS mean: 6.3) for the cream vehicle. This corresponds to a 
reduction in disease severity (TSS) of approximately 39% in the orismilast cream 20 mg/g 
treatment and of approximately 25% for the vehicle treatment. The vehicle-effect subtracted 
difference in LS means accounted to -1.2 (95% CI ranging from -2.2 to -0.3), providing evidence 
for a statistically significant difference (P =.014) between both treatments. This result was 
confirmed by the analyses of the secondary efficacy endpoints. The administration of orismilast 
cream 20 mg/g was found to be safe and well tolerated in patients with AD. No clinically 


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relevant effects in any vital sign parameters, ECG, or laboratory safety values (hematology, 
biochemistry, urinalysis) were detected. 
4.2.2.3 Efficacy in Other Dermatological Disorders 
To date, 1 efficacy trial (LP0058-1072) with orismilast immediate-release tablets has been 
completed. A total of 36 patients with moderate to severe plaque-type psoriasis were randomized 
in the trial in a 1:1 ratio to treatment with either 30 mg orismilast or placebo, administered orally 
as 3 tablets BID for 16 weeks (1-week dose escalation followed by 15-week full dose treatment). 
After 16 weeks of treatment, the mean Psoriasis Area and Severity Index (PASI) score (primary 
endpoint) was statistically significantly lower in patients treated with orismilast tablets (LS 
mean: 7.1) compared with patients in the placebo group (LS mean: 13.1). Mean PASI at entry 
was 14.9. A higher proportion of patients achieved a 75% improvement in PASI in the orismilast 
group (44.4%) versus placebo (5.6%; P =.019). In addition, treatment success (defined as clear 
or almost clear) according to Physician’s Global Assessment of disease severity at Week 16 was 
higher in the orismilast group (7 of 18 patients, 38.9%) than in the placebo group (1 of 18 
patients, 5.6%). The estimated itch score was numerically lower at Week 16 in the orismilast 
group (LS mean: 3.4) compared with the placebo group (LS mean: 5.7). 
Approximately half of the patients in both treatment groups were withdrawn from the 
LP0058-1072 trial, mainly owing to tolerability issues in the orismilast group and lack of 
efficacy in the placebo group, respectively. Although the bias introduced by this attrition had an 
effect on the estimated efficacy, it was not considered to disqualify the clear difference observed 
between the 2 treatments. 
4.2.2.4 Safety 
Extent of Exposure 
As of 01 October 2021, the oral orismilast clinical development program for an oral formulation 
consists of 8 completed trials including 7 Phase 1 trials in healthy subjects and 1 Phase 2a trial in 
patients with moderate to severe plaque-type psoriasis. There are 343 participants in the 
8 completed trials. There were 307 healthy subjects in Phase 1 trials, 274 of whom were exposed 
to orismilast, and 36 patients with moderate to severe plaque-type psoriasis in the Phase 2a trial, 
18 of whom were exposed to orismilast. Of 343 participants, orismilast was given to 
290 patients, while the other 53 patients received placebo. Among the 290 patients, 171 patients 
received a single dose and 119 patients received multiple doses of orismilast (up to 16 weeks). 
Only 1 study examined the new modified-release formulation in 63 healthy subjects (see Section 
4.3). 
Safety Profile 
Orismilast administered as capsules was safe and well tolerated in single doses up to 45 mg and 
in multiple doses up to 30 mg 3 times a day after an up-titration period of 7 days in trial 
LP0058-S01. Orismilast was moderately well tolerated in multiple doses up to 50 mg BID, after 


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gradual up-titration to the 50 mg BID level over 8 days in trial LP0058-1114. In both studies 
LP0058-S01 and LP0058-1114, poor tolerability at the 60-mg dose level was due to an increased 
incidence and severity of GI AEs. This was probably related to high local concentrations of 
orismilast in the GI tract, as the symptoms at the 60-mg dose level generally started before tmax 
and were markedly greater than at lower doses, despite mean systemic exposure being 
comparable to that seen at 45 mg. 
Orismilast administered as immediate-release tablets was relatively well tolerated at the 20-mg 
BID level but was poorly tolerated when up-titrated to the 40-mg and 50-mg BID levels in trial 
LP0058-1267. Six patients were withdrawn from the trial by the Investigator because of AEs. 
Likewise, in the LP0058-1072 trial, orismilast tablets (30 mg BID) were poorly tolerated in 
patients with moderate to severe plaque-type psoriasis. AEs leading to withdrawal from the trial 
were reported for 50% of the patients in the orismilast group compared with 16.7% in the 
placebo group. In the orismilast group, the majority of withdrawals were due to GI disorders. 
A total of 5 serious AEs (SAEs) were reported across all trials; 3 SAEs in 3 patients in the 
LP0058-1072 trial in patients with moderate to severe plaque-type psoriasis and 2 SAEs in 
1 patient in the LP0058-1324 trial. In the LP0058-1072 trial, 2 patients in the orismilast group 
had 1 SAE each (ureterolithiasis, considered not related to the treatment, and erysipelas on the 
arm, considered possibly related to the treatment), and 1 patient in the placebo group had 1 SAE 
(“condition aggravated”, relating to pre-existing Scheuermann's disease and considered not 
related to the treatment). In the LP0058-1324 trial, 1 patient-reported SAEs (abdominal pain and 
abdominal cramps, considered possibly related to the treatment). 
The reported AEs were consistent with reports from other PDE4 inhibitors with nausea, diarrhea 
and headache being the most frequently side effects reported. Most nonserious AEs were of mild 
intensity and considered possibly or probably related to orismilast. Generally, the incidence, 
frequency, and severity of AEs increased with increasing doses of orismilast. The most 
frequently reported orismilast-related AEs were GI disorders (particularly nausea and diarrhea), 
nervous system disorders (particularly headache and dizziness), and musculoskeletal and 
connective tissue disorders (particularly back pain). The GI tolerance appears to be improved 
with titration and low-fat meals. 
Data from 2nd generation modified release tablet from the unblinded phase 2 trial UNI50001-203 
(under reporting) in psoriasis indicate that the side effect profile of orismilast, with diarrhoea, 
nausea and headache, is similar to the two marketed oral PDE4-inhibitors (apremilast, 
roflumilast). The majority of these adverse events had an onset during the initial 4 weeks of 
treatment and very few of these events had an onset after 8 weeks of treatment.  
In addition, seven cases of elevated ALT were observed and one patient in the orismilast 40 mg 
group had self-injurious behavior without suicidal intent at week 16. No deaths or serious 
infections were reported in UNI50001-203. 
 


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4.3 
Clinical Risks/Benefits of Orismilast 
 Common PDE-4inhibition related side effects 
Data from 2nd generation modified release tablet from the unblinded phase 2 trial UNI50001-
203 (under reporting) in psoriasis indicate that the side effect profile of orismilast, with 
diarrhoea, nausea and headache, is similar to the two marketed oral PDE4-inhibitors (apremilast, 
roflumilast). The majority of these adverse events had an onset during the initial 4 weeks of 
treatment and very few of these events had an onset after 8 weeks of treatment. Thus, it is 
important that patients are adequately informed about these common side effects, and that the 
side effects are handled similarly to how they are handled for e.g. apremilast (Tello ED).  
Occurrence and severity of GI disorders will be identified by monitoring the patients for any 
signs of abdominal discomfort, abdominal distension, abdominal pain, nausea, vomiting, loss of 
appetite, and diarrhea. Depending on their severity, these adverse events may qualify as an AE of 
special interest (AESI). On the basis of the occurrence of GI or other AEs considered to have a 
causal relationship with study treatment, the Investigator might consider decreasing the daily 
dosing regimen or stopping the treatment for a few days, until recovery (see Section 8.3.1). 
 Monitoring of Cardiovascular, Psychiatric, Hepatic, and Metabolic Risks 
In the unblinded phase 2 trial UNI50001-203 (under reporting) in psoriasis, seven cases of 
elevated ALT were observed, and one patient in the orismilast 40 mg group had self-injurious 
behavior without suicidal intent at week 16. No deaths or serious infections were reported in 
UNI50001-203. Hepatic laboratory parameters will be monitored. All patients will be monitored 
for any cardiovascular manifestations using vital signs and 12-lead ECG at scheduled visits. 
Drug class potential effects, such as weight loss and major depression, will be monitored during 
the study. Patients with major depression, presenting major psychiatric disorders or at risk for 
suicide will be excluded from enrollment, and suicidal ideation and depressive symptoms will be 
assessed in the course of the study by the Columbia-Suicide Severity Rating Scale (C-SSRS) and 
Hospital Anxiety and Depression Scale (HADS), respectively. Patients will be informed of the 
potential increased risk of depression or suicidal thoughts of this class of drugs, and 
recommended to promptly contact their study doctor in case of such event. 
 Tape Stripping 
Risks associated with skin tape stripping, theoretically, include the rare possibility of an allergic 
reaction to the tape or a skin infection. The risk of skin infection is extremely low because only 
superficial skin layers are removed. A bandage could be applied to the area of tape stripping to 
reduce the small likelihood of an infection. 
 Stopping of Current Treatment 
Risks associated with stopping the use of protocol-prohibited medications/procedures may 
include worsening of the condition being treated and will be reported as such. In an effort to 


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minimize these risks, patients with moderate to severe AD who may have difficulty tolerating 
periods without medication/procedure will be excluded from participating in the study, per 
exclusion criteria (see Section 7.2). If patients need to manage areas with dry skin and/or 
pruritus, they are allowed to continue using their current emollient. However, emollients that 
contain pharmacologically active ingredients such as lactic acid, salicylic acid, urea, alpha-
hydroxy acids, or fruit acids are not allowed from the Screening visit. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of orismilast may be found in the recent version of the investigator’s brochure. 
4.4 
Study Rationale 
PDE4 inhibitors have demonstrated efficacy in psoriasis and/or AD, with 2 drugs having reached 
the market: apremilast, an oral agent for the treatment of plaque-type psoriasis, and crisaborole, a 
topical agent for the treatment of AD. Orismilast is a novel PDE4 inhibitor being developed for 
the oral treatment of moderate to severe AD that requires a systemic therapeutic approach. 
The purpose of this study is to assess the efficacy and safety of 3 different dose levels (20 mg, 
30 mg, or 40 mg) of orismilast versus placebo administered orally BID over a period of 16 weeks 
in patients with moderate to severe AD. Efficacy and patient outcome will be assessed through a 
set of validated measures for AD. In addition, safety, PK, and PD evaluations will be conducted. 
The results of the study will inform the design and the dose level(s) of the subsequent Phase 3 
program. 
 Dose Rationale 
The modified-release formulation was studied in 1 clinical trial (LP0058-1442) and administered 
in a total of 36 healthy volunteers: 18 in part 1, 9 in part 2, and 9 in part 3. Twenty-seven (27) 
healthy volunteers received a single administration of 30 mg orismilast, and 9 subjects received 
multiple administrations over a period of 17 days with an up-titration up to a maximum of 60 mg 
BID.  
Part 1 of this study was to evaluate the key PK parameters of the new modified-release 
formulation compared to the reference capsule formulation with immediate-release. Orismilast 
was rapidly absorbed from both formulations with median tmax values of 3.00 hours postdose for 
the immediate-release capsule and 2.52 hours postdose for the modified-release tablet. The 
individual tmax ranges were approximately 1 to 6 hours postdose for the immediate-release 
capsule and 1 to 4 hours postdose for the modified-release tablet. Following tmax, the plasma 
concentrations of orismilast declined in a generally biphasic manner for both formulations with 
geometric mean terminal half-life (t1/2) values of 6.48 and 6.67 hours for the modified-release 
tablet and immediate-release capsule, respectively. With a geometric mean value of 507 ng.h/mL 
for AUC0-∞, systemic exposure to orismilast following administration of the modified-release 
tablet was comparable to the one of the immediate-release capsules (506 ng.h/mL). Statistical 
analyses comparing key PK parameters of orismilast for both formulations did not show any 


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significant difference. Exposure to LEO 40815 and LEO 32731, the main metabolites, appeared 
generally similar for the modified-release tablet and the immediate-release formulation. 
It can thus be concluded that the systemic exposure following administration of the modified-
release formulation is not different from the one following the administration of the immediate-
release formulation. It can therefore be reasonably assumed that the safety profile resulting from 
systemic effects can be extrapolated from studies having investigated the immediate-release 
formulation and in particular, study LP0058-1072, a Phase 2a study including 36 patients with 
moderate to severe psoriasis vulgaris.  
In that study, patients received orismilast 30 mg BID or placebo for 16 weeks. The efficacy in 
psoriasis was confirmed on each predefined endpoint. No significant safety concerns were 
identified during the trial, and no adverse reaction not already seen with PDE4 inhibitors was 
reported. However, there was a high level of intolerance in the orismilast group. Most subjects 
treated with orismilast had treatment-induced AEs related to GI functions, predominantly nausea 
and diarrhea, throughout the treatment period. These tolerability issues resulted in half of the 
subjects in the orismilast group being withdrawn from the trial. 
The hypothesis was that this high incidence of GI side effects was related to high local 
concentration of orismilast in the stomach, thus the formulation work to identify a slow-release 
formulation that would reduce local concentration of active compound in the stomach while 
preserving a similar systemic exposure for maintaining efficacy. 
Study LP0058-1442 in healthy volunteers has confirmed these characteristics by showing a 
similar PK profile and an improved safety profile. Following multiple dosing up to 60 mg BID, 
the orismilast modified-release tablet was safe and well tolerated. There were no clinically 
relevant findings in the vital signs data, clinical laboratory evaluations, 12-lead ECG parameters, 
or physical examinations for any subject, and there were no deaths or SAEs during any part of 
the trial. A total of 113 AEs were reported: 12 AEs in 3 subjects randomized to placebo and 101 
AEs in 9 subjects following administration of up to 60 mg orismilast BID modified-release 
tablet. Headache, nausea, dizziness, pain in extremity, and diarrhea were the most commonly 
reported AEs. Of the 14 AEs of headache reported in subjects receiving orismilast, 6 occurred at 
the 40 mg dose level. Dizziness was only reported following dosing of 30 mg orismilast or 
above. Nausea was reported in 5 subjects receiving LEO 32731, with the majority of events 
occurring at the 60 mg dose level. Only 2 participants experienced nausea at a dose equal or 
lower to 40 mg, and these side effects lasted approximately 1 day before spontaneously 
disappearing, despite dosing and up-titration being maintained. 
It was thus concluded that 40 mg BID was the maximal tolerated dose with 30 mg BID being the 
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5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Study Objectives 
 Primary Objective 
The primary objective is to evaluate the efficacy and safety of a modified-release orismilast 
tablet versus placebo in patients aged at least 18 years with moderate to severe AD. 
 Secondary Objectives 
The secondary objectives are to evaluate the dose response of orismilast and identify the dose to 
be further evaluated in a Phase 3 program. 
 Exploratory Objectives 
The exploratory objectives are to: 
• Evaluate PK and PD parameters relevant to AD 
• Evaluate the effect of orismilast on the pulmonary status and course of the disease in 
patients with asthma 
5.2 
Study Endpoints 
 Primary Endpoint 
The primary endpoint of this study is the percentage change in EASI score from Baseline at 
Week 16. 
 Secondary Endpoints 
5.2.2.1 Key Secondary Endpoints 
The key secondary endpoints are as follows: 
• Patients achieving 75% reduction in EASI (EASI75) response at Week 16 
• Patients achieving a score of clear (0) or almost clear (1) and at least a 2-point 
improvement in Investigator Global Assessment for AD (IGA-AD) at Week 16 
5.2.2.2 Other Secondary Endpoints 
The other secondary endpoints of this study are as follows: 
• Patients achieving a score of clear (0) or almost clear (1) and at least a 2-point 
improvement in IGA-AD at Weeks 2, 4, 8, 12, and 20 
• Patients achieving EASI75 at Weeks 2, 4, 8, 12, and 20 
• Patients achieving 50% reduction in EASI (EASI50) and 90% reduction in EASI 
(EASI90) response at Weeks 2, 4, 8, 12, 16, and 20 
• Percent change from Baseline in EASI at Weeks 2, 4, 8, 12, and 20 


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• Change from Baseline in the peak pruritus numerical rating scale (NRS) score at 
Weeks 1, 2, 4, 8, 12, 16, and 20 
• Patients achieving at least a 4-point improvement in the peak pruritus NRS from baseline 
at Weeks 1, 2, 4, 8, 12, 16, and 20 
• Change from Baseline in affected body surface area (BSA) at Weeks 2, 4, 8, 12, 16, and 
20 
• Change from Baseline in DLQI score at Weeks 8, 16, and 20 
• Change from Baseline in Patient Oriented Eczema Measure (POEM) score at Weeks 2, 4, 
8, 12, 16, and 20 
• Change from Baseline in Patient Global Impression of Severity (PGIS) score at Weeks 2, 
4, 8, 12, 16, and 20 
• Change from Baseline in Patient Global Impression of Change (PGIC) score at Weeks 2, 
4, 8, 12, 16, and 20 
• Change from Baseline in sleep disturbance NRS score at Weeks 1, 2, 4, 8, 12, 16, and 20 
• Change from Baseline in skin pain NRS score at Weeks 1, 2, 4, 8, 12, 16, and 20 
 Safety Endpoints 
The safety endpoints of this study are as follows: 
• The occurrence, severity, and seriousness of treatment-emergent AEs (TEAEs) reported 
over the 16-week Treatment Period and the 4-week Follow-up Period 
• Changes from Baseline in physical examination findings; vital signs measurements (body 
temperature, respiration rate, heart rate, and systolic and diastolic blood pressure 
measurements); and body weight over the 16-week Treatment Period and the 4-Week 
Follow-up Period 
• Clinically significant abnormal changes in ECG findings over the 16-week Treatment 
Period 
• Changes from Baseline in safety laboratory values (hematology, serum chemistry, and 
urinalysis) over the 16-week Treatment Period 
• Change from Baseline in HADS score at each visit except Week 1 
• C-SSRS score at each visit except Week 1 
 Exploratory Endpoints 
The exploratory endpoints of this study are as follows: 
• Change from Baseline in skin biomarkers at Week 16 collected via tape stripping and 
analyzed using proteomic methods 
• Patients achieving at least a 2-point improvement in the peak pruritus NRS from baseline 
at Weeks 1, 2, 4, 8, 12, 16, and 20 
• Plasma levels of the drug and its metabolites at Weeks 4, 8, and 16 


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• Change from Baseline in pulmonary status NRS in patients with asthma at Weeks 4, 8, 
12, 16, and 20. 


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6 
INVESTIGATIONAL PLAN 
6.1 
Description of Overall Study Design and Plan 
This multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2b 
dose-ranging study is designed to assess the efficacy and safety of modified-release orismilast 
compared with placebo in patients aged at least 18 years with moderate to severe AD. Efficacy 
and safety outcomes will be evaluated to select an appropriate orismilast dose for subsequent 
Phase 3 studies. The study will be conducted at approximately 48 centers in Europe and the 
United States. 
After a Screening visit up to 28 days before Baseline, approximately 210 patients will be 
assigned randomly in a 1:1:1:1 ratio to receive 1 of the 3 orismilast doses (20 mg, 30 mg, or 
40 mg) or placebo BID for 16 weeks, with a 4-week follow-up visit. Administration will begin at 
Baseline with a dose titration period of up to 2 weeks’ duration depending on the dose level. The 
maximum duration of study participation for each patient is approximately 24 weeks. 
Patients will be seen at the site at Screening, Baseline (Day 1), and Weeks 1, 2, 4, 8, 12, 16 (EOT 
visit), and 20 (Follow-up visit, 4 weeks after treatment completion or discontinuation). The visit 
at Week 1 can be conducted via a telemedicine procedure at the Investigator’s discretion. 
Patients who have been diagnosed with moderate to severe AD for a minimum of 1 year (before 
the Screening visit) using the Hanifin and Rajka criteria with affected BSA of at least 10%, EASI 
score of at least 16, and IGA-AD grade of at least 3 at the screening and baseline visits will be 
included in the study. Patients must also have a documented history of inadequate response to 
treatment with topical medications given for at least 4 weeks (at least 2 weeks for high potency 
topical corticosteroids), or as labeled, or for whom topical treatments are otherwise medically 
inadvisable. 
At Baseline and at each visit from Week 2 onwards, EASI, affected BSA, and IGA-AD will be 
assessed. BSA is defined as all areas with eczematous lesional skin and does not include xerosis 
(dryness), ichthyosis, keratosis pilaris, urticaria, infection (unless there is underlying eczema), or 
post inflammatory pigmentation changes. If patients need to manage areas with dry skin and/or 
pruritus, they are allowed to continue using their current emollient. However, emollients that 
contain pharmacologically active ingredients such as lactic acid, salicylic acid, urea, alpha-
hydroxy acids, or fruit acids are not allowed from the Screening visit. The severity of itch will be 
assessed by peak pruritus NRS at each visit from baseline to end of the treatment. Disease 
symptoms will be assessed by POEM scores at Baseline and at the Weeks 2, 4, 8, 12, 16, and 20 
visits. Quality of life related to the disease will be assessed by DLQI scores at Baseline and at the 
Weeks 8, 16, and 20 visits. Pulmonary disease status will be assessed in patients with asthma by 
pulmonary status NRS at Baseline and at the Weeks 4, 8, 12, 16, and 20 visits. The severity of 
disease will be assessed by PGIS and PGIC scores at Baseline and at the Weeks 2, 4, 8, 12, 16, 
and 20 visits. In addition, the sleep disturbance NRS and skin pain NRS will be administered at 
Baseline and at the Weeks 1, 2, 4, 8, 12, 16, and 20 visits. 


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Safety evaluations include medical history, AEs, laboratory and vital sign assessments, physical 
examination including body weight and height, 12-lead ECG, and mood change evaluations by 
the patient (HADS score) and suicidal behavior and ideation evaluation by the Investigator (C-
SSRS). 
Before administration of the study drug at Baseline and Weeks 4, 8, and 16, blood will be 
collected for orismilast and the major human metabolite LEO 40815 for PK concentration 
determination. In addition, noninvasive superficial skin sampling using tape stripping will be 
conducted on a target lesion (lesional and nonlesional skin sample) at Baseline and Week 16 
(only lesional skin sample) in all patients for proteomic analysis. See Figure 1 for the study 
design. 
Figure 1. 
Study Design 
 
 
6.2 
Discussion of Study Design 
A double-blind, randomized, placebo-controlled study is considered the gold standard for 
conducting an interventional and dose-finding study. A sample size of approximately 47 patients 
per treatment arm is also adequate to obtain robust outcome data for comparisons between 
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Titration of oral apremilast was shown to improve the GI tolerance and overall acceptability of 
the drug (Zerilli, 2015). Similarly, a slow increase in orismilast dose was associated with fewer 
GI side effects when compared with a rapid increase. Consistent with this approach, this study 
will titrate the study treatment dose over a period of maximum 2 weeks. If tolerability issues 
arise during the treatment or titration period, a short dose reduction is allowed. For a detailed 
titration schedule, refer to Section 8.3.1. 
AD is a chronic condition requiring long-term therapy. Primary efficacy assessments of AD 
clinical trials are usually performed at 12 or 16 weeks after initiation of study treatment. Because 
of the initial titration period of up to 3 weeks’ duration, a treatment duration of 16 weeks, with 
the primary endpoint being evaluated at this time point, is therefore considered the optimal 
strategy for this study. A 16-week treatment period was also deemed acceptable for the placebo 
arm because AD is not a life threatening disease warranting immediate treatment. A follow-up 
period is established after the end of the treatment period to assess efficacy and safety, including 
risk of rebound AD (see Section 6.3). 
In addition to the AD assessments of the EASI, IGA-AD, BSA, peak pruritus NRS, PGIS, PGIC, 
sleep disturbance NRS, and skin pain NRS, the effects of study treatment on the pulmonary 
status and course of the disease in patients with asthma will be explored. A number of patient-
reported outcomes (PROs) will be administered to explore the patient’s perception of his or her 
condition and the related quality of life, as recommended by regulatory agencies. This 
comprehensive evaluation of the AD condition of patients will contribute to the selection of the 
most suitable dose for the Phase 3 clinical program. 
Conduct of superficial skin sampling by tape stripping is considered a minimally invasive 
technique that can allow for evaluation of a panel of skin biomarkers to better characterize the 
biological activity of orismilast. 
6.3 
Follow-up Period 
A follow-up period is established after the end of the treatment period to assess efficacy, safety, 
and the risk of rebound (ie, flaring with worse severity than before treatment). During the follow-
up period, no other treatments are permitted, except topical emollients (between the EOT and the 
follow-up visit). If the investigator determines that additional treatment must be initiated during 
the follow-up period, the patient will end participation in the trial and the last follow-up visit 
should be performed before adding new treatment and withdrawing the patient from the trial. 
If the patient is withdrawn because of initiation of a nonallowed treatment, as described above, 
the patient will be considered a study completer if the full 16-week treatment period is 
completed, including the follow-up visit upon initiation of the nonallowed treatment. 
6.4 
End of Study 
The end of the study will be the last patient’s last visit as indicated in the Schedule of 
Assessments (Table 4). 


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A patient will have fulfilled the requirements for study completion if/when the patient has 
completed all study periods, including the Follow-up visit or the last scheduled visit, as indicated 
in the Schedule of Assessments (Table 4). 


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7 
SELECTION OF STUDY POPULATION 
7.1 
Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria apply at both the 
screening and baseline visits: 
1. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the Informed Consent Form (ICF) and in the 
protocol 
2. Male and female patients aged at least 18 years at the time of signing the ICF 
3. Body weight of greater than 40 kg at the time of signing the ICF 
4. Diagnosis of AD for a minimum of 1 year (before the Screening visit) using the Hanifin 
and Rajka criteria 
5. Moderate to severe AD (affected BSA of at least 10%, IGA-AD grade of at least 3, and 
EASI score of at least 16) at the screening and baseline visits 
6. Candidate for systemic treatment or phototherapy for AD 
7. Patients having a documented history of inadequate response to treatment with topical 
medications given for at least 4 weeks (at least 2 weeks for high potency topical 
corticosteroids), or as labeled, or for whom topical treatments are otherwise medically 
inadvisable 
8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
result at the Screening visit and a negative urine pregnancy test result at the Baseline 
visit. In addition, sexually active WOCBP must agree to use a highly effective method of 
contraception throughout the study and until at least 4 weeks after the end of study 
treatment. Highly effective methods of contraception are those that have a failure rate of 
less than 1% per year (when implemented consistently and correctly and when applicable, 
in accordance with the product label) and include hormonal contraceptives (combined 
oral contraceptive, patch, vaginal ring, injectable, or implantable); progestogen-only 
hormonal contraception associated with inhibition of ovulation (administration may be 
oral, injectable, or implantable); intrauterine devices or systems; self or partner 
vasectomy; or bilateral tubal ligation. Patients must have been on a stable dose of 
hormonal contraceptives for at least 4 weeks before the Baseline visit. Abstinence from 
heterosexual intercourse is an accepted method of contraception if it is the patient’s 
lifestyle and is practiced for the duration of the study. Note: A woman of nonchildbearing 
potential is defined as a woman with surgical sterilization (hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) or a woman in a postmenopausal status, 
defined as cessation of menses for at least 12 consecutive months without an alternative 
medical cause and a confirmatory follicle-stimulating hormone test result or as cessation 
of menses for at least 24 consecutive months without an alternative medical cause. 


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7.2 
Exclusion Criteria 
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study: 
1. Therapy-resistant AD, defined as ≥2 treatment failures due to inadequate efficacy within 
the past 2 years of any biologic therapy, JAK inhibitor treatment or phototherapy  
administered at an adequate dose and duration according to the label or local/national 
guidelines. (Patients who stopped systemic treatment for reasons not related to lack of 
efficacy are not excluded.) 
2. Unstable AD with acute deterioration, requiring rescue therapy for AD within 4 weeks of 
the Screening visit or expected to require rescue therapy within 2 weeks after 
randomization 
3. History of allergy or hypersensitivity to any component of the study treatment. 
4. Currently have active forms of other inflammatory skin disease or have evidence of skin 
conditions (eg, psoriasis, seborrheic dermatitis, lupus) at the Baseline visit that would 
interfere with evaluation of AD or response to treatment 
5. Active infection (eg, bacterial, viral, fungal) requiring treatment with systemic antibiotics 
within 4 weeks of the Screening visit 
6. Malignancy or history of malignancy except for treated (ie, cured) basal cell skin 
carcinoma 
7. Any chronic or recurrent medical condition associated with serious GI diseases, such as 
inflammatory bowel disease 
8. Any medical or psychiatric condition (eg, current major depression with a score for 
depressive symptoms ≥15 of HADS at baseline, schizophrenia, suicidal behavior, 
psychiatric hospitalization within the prior year) that, in the Investigator’s opinion, would 
preclude the patient from adhering to the protocol, completing the study per-protocol, 
and/or would place the patient at unacceptable risk while receiving the investigational 
therapy 
9. Individuals with severe or uncontrolled asthma or any other concomitant condition that is 
likely to require systemic corticosteroid bursts during the study 
10. Any therapies and systemic treatments as described in Table 3 “Nonallowed therapies 
and treatments” that do not comply with the indicated washout interval 
11. Any previous treatment with orismilast or failure of treatment for AD with apremilast or 
any other systemic PDE4 inhibitor 
12. Any condition, including laboratory or ECG abnormalities, that places the patient at 
unacceptable risk to participate in the study or confounds the ability to interpret data from 
the study 
13. Severe hepatic impairment based upon medical history and laboratory abnormalities (eg, 
low albumin and abnormal bilirubin levels) 


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14. Any of the following abnormalities in clinical laboratory test results at Screening, as 
assessed by the study-specific laboratory and confirmed by a single repeat test, if deemed 
necessary: 
• Absolute neutrophil count of less than the lower normal range of the Central 
Laboratory (LNR) i.e. 1.7 x 109/L (1700/mm3) 
• Hemoglobin of less than 10.0 g/dL or hematocrit less than 30% 
• Platelet count of less than 100,000 mm3 
• Absolute lymphocyte count of less than  the lower normal range of the Central 
Laboratory (LNR) i.e. 0,9 x 109/L (900/mm3) 
• Total bilirubin greater than 1.5 × the upper limit of normal (ULN); patients 
with a history of Gilbert’s syndrome may have direct bilirubin measured and 
would be eligible for this study provided the direct bilirubin result is less than 
or equal to the ULN 
• Alanine aminotransferase or aspartate aminotransferase greater than 2.5 × the 
ULN 
• Serum creatinine greater than or equal to 1.5 mg/dL. For patients with a value 
of greater than or equal to 1.5 mg/dL, if their creatinine clearance is at least 
60 mL/min (calculated using the Chronic Kidney Disease Epidemiology 
Collaboration creatinine equation), enrollment may be allowed. 
15. History or evidence of hepatitis B virus infection at Screening. Patients with a positive 
hepatitis B surface antigen result are excluded. For patients with an isolated positive 
antihepatitis B core antibody result, the hepatitis B surface antibody result must also be 
positive to be eligible for this study. 
16. History or positive test result for hepatitis C virus (HCV) antibody, indicating ongoing 
infection, at Screening. Confirmatory testing for HCV RNA will be conducted for 
patients who have a positive test result. Patients who have a negative result for HCV 
RNA will be eligible to participate in the study. 
17. History of positive HIV test result or congenital or acquired immunodeficiency (eg, 
common variable immunodeficiency disease). Patients who are positive for HIV 
antibodies (HIV-1 or HIV-2) at Screening are excluded from the study. 
18. Suicidal ideation or behavior in the past 12 months as indicated by a positive response 
(yes) to question 4 or 5 on the C-SSRS completed at the Screening visit or at Baseline 
19. Pregnant or breastfeeding 
20. History of alcohol or substance abuse within 6 months before Baseline that, in the 
opinion of the Investigator, will preclude participation in the study 
21. Institutionalized by court order or by local authority 
22. Regular use (more than 2 visits per week) of a tanning booth/parlor 


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7.3 
Rescreening 
Individuals who sign the ICF to participate in the study but who do not subsequently meet all the 
requirements as outlined in the inclusion and exclusion criteria and therefore do not enroll 
(screen failures) may be rescreened. Such individuals may be allowed to rescreen up to one timet 
the investigator’s discretion (period from screen failure to rescreening to be determined by the 
investigator). If rescreening is performed, the individual must sign a new ICF and will be 
assigned a new identification number. Additionally, all screening procedures must be conducted 
at rescreening to ensure all eligibility criteria are met. 
7.4 
Treatment Discontinuation and Withdrawal 
An additional 22 patients will be randomized to account for an estimated early dropout rate of 
approximately 10%. 
If a patient discontinues study treatment prematurely or is withdrawn from the study for any 
reason, the study site must immediately notify the Medical Monitor. The date and the reason for 
treatment discontinuation or study withdrawal must be recorded on the electronic case report 
form (eCRF). Patients who discontinue treatment prematurely will be asked to complete the 
assessments corresponding to Week 16 at the time of treatment discontinuation. The patient will 
be asked to return to the study site within 4 weeks of the last administration of study drug to 
complete the follow-up visit and have the assessments corresponding to the Week 20 
assessments done (Table 4). If possible and deemed safe by the investigator, the patient should 
thereafter be offered to stay in the trial with no treatment and complete study visits as planned. If 
a patient withdraws from the study, attempts should be made to have him or her return to the 
study site within 4 weeks of the last administration of study drug to complete follow-up visit 
assessments. 
In the event that a patient discontinues treatment prematurely because of a TEAE or serious 
TEAE ,this will be followed up until it resolves (returns to normal or baseline values) or 
stabilizes, or until it is judged by the Investigator to no longer be clinically significant. The 
patient will also be asked to return to the study site for the follow-up visit within 4 weeks of the 
last administration of study drug to have the assessments corresponding to the Week 20 
assessments done (Table 4). 
Once withdrawn from the study, the patient cannot re-enter the study. 
A patient may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following circumstances: 
• unacceptable toxicity or AE 
• patient withdrawal of consent: at any time, a patient’s participation in the study may be 
terminated at his/her request or on the basis of the investigator’s clinical judgment. The 
reason for patient withdrawal will be noted on the eCRF 


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• intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the patient’s termination from the 
study 
• general or specific changes in the patients’ condition that renders him/her ineligible for 
further treatment according to the inclusion/exclusion criteria 
• patient fails to adhere to the protocol requirements (eg, drug noncompliance, failure to 
return for defined number of visits) 
• lost to follow-up: the patient stopped coming for visits, and study personnel were unable 
to contact the patient 
• pregnancy, as indicated in Section 11.8.5. 
If a patient withdraws from the study, the Sponsor may retain and continue to use any data 
collected before the withdrawal for the purpose of the study or scientific research. 
Additionally, the Sponsor may stop the study at any time for safety, regulatory, legal, or other 
reasons aligned with Good Clinical Practice (GCP). This study may be terminated at the 
discretion of the Sponsor or any regulatory agency. An Investigator may elect to discontinue or 
stop the study at his or her study site for any reason, including safety or low enrollment. 


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8 
TREATMENTS 
8.1 
Details of Study Treatments and Dosage Schedule 
The study treatment is formulated as modified-release tablets (10 mg and 30 mg) or placebo 
tablets for oral administration. Tablets should be taken in the morning and in the evening, 
approximately every 12 hours. The minimum time interval between 2 consecutive doses is 
6 hours. The first dose of the study drug should be taken in the evening of Day 1 (Baseline visit). 
PK studies have shown no difference in PK properties whether the product is taken under fasted 
condition or with a low-fat meal. Intake with a high-fat meal leads to a higher incidence of GI 
side effects and should therefore be avoided. Refer to Table 1 for details about study treatment 
and dosage schedule. 
Table 1. Study Treatment and Dosage Schedule 
Arm name 
Orismilast 20 mg 
BID 
Orismilast 30 mg 
BID 
Orismilast 40 mg 
BID 
Placebo 
Drug name 
Orismilast 
Orismilast 
Orismilast 
Placebo 
Type 
Drug 
Dose formulation 
10 mg and 30 mg tablet or matching placebo tablet 
Frequency 
BID (approximately every 12 hours) 
Administered 
tablets 
2 × 10-mg 
orismilast tablets 
BID 
1 × 30-mg 
orismilast tablet and 
1 placebo tablet 
BID 
1 × 10-mg and 
1 × 30-mg 
orismilast tablets 
BID 
2 × placebo tablets 
BID 
Route 
Oral 
Use 
Experimental 
Placebo 
Sourcing 
Provided centrally by the Sponsor 
Packaging and 
labeling 
Investigational medicinal product will be provided in individually labeled wallet cards 
with blistered tablets. Each card will be labeled as required per country requirement. 
Abbreviation: BID, twice daily. 
 
8.2 
Measures to Minimize Bias: Study Treatment Assignment and Blinding 
 Method of Study Treatment Assignment 
At the investigational site, each screened patient will be assigned a patient identifier number 
during Screening that will be used on all patient documentation. The patient identifier number 
will contain the site number and the patient number and will be assigned in numerical order at 
the Screening visit on the basis of chronological order of Screening dates (eg, 01-010 for the 
10th patient screened at Site No. 01). 
Randomization will occur before the first study treatment administration, at the Baseline visit. 
Patients will be assigned randomly in a 1:1:1:1 ratio to 1 of 3 orismilast dose groups (20 mg, 


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30 mg, or 40 mg) or placebo. All patients will be assigned to randomized study treatment using 
an Interactive Web Response System (IWRS). Further guidance and information can be obtained 
in the study manual. 
 Blinding 
To facilitate the double blinding, the tablets will be packaged in the same type of blister, and the 
active and placebo tablets will have the same appearance (in terms of size, form, weight, and 
color). One dose consists of 2 identical tablets (a 10-mg or 30-mg orismilast tablet or a matching 
placebo tablet). 
Before the study is initiated, each site will be provided with an email address and/or telephone 
number as well as call-in directions for the log-in information and IWRS directions. 
The IWRS will be programmed with blind-breaking instructions. Blinding codes should only be 
broken in emergency situations for reasons of patient safety. In case of an emergency, the 
Investigator has the sole responsibility for determining whether unblinding of a patient’s 
treatment assignment is warranted. Patient safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the Sponsor or its designee before unblinding a 
patient’s treatment assignment unless this could delay emergency treatment of the patient. If a 
patient’s treatment assignment is unblinded, the Investigator should promptly inform the Medical 
Monitor and the Sponsor within 24 hours after breaking the blind. When the blind for a patient 
has been broken, the date and reason that the blind was broken must be fully documented in the 
source document and eCRF. The primary reason for discontinuation (the event or condition that 
led to the unblinding) will be recorded, as applicable. Also, documentation of breaking the blind 
should be recorded using the IWRS with the date/time and reason why the blind was broken and 
the names of the personnel involved. 
The patient for whom the blind has been broken will be discontinued from the study and undergo 
the procedures for premature treatment discontinuation. 
Study drug will be dispensed at the study visits summarized in the Schedule of Assessments 
(Table 4). Returned study drug should not be redispensed to the patients. 
The Sponsor’s safety staff may unblind the study drug assignment for any patient with an SAE. 
If the SAE requires that an expedited regulatory report be sent to 1 or more regulatory agencies, 
a copy of the report identifying the patient’s study drug assignment may be sent to investigators 
in accordance with local regulations and/or Sponsor policy. 
8.3 
Planned Dosing Schedule and Adjustments 
If GI or other AEs considered probably or definitely related to the study drug are reported with a 
severity not compatible with maintaining the treatment as per-protocol, the Investigator might 
consider temporarily decreasing the dosage regimen, as described in Section 8.3.2 and 
Section 8.3.3. 




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up to 7 days before reinitiating twice daily dosing.  
 
If treatment has been temporarily discontinued due to side effect related circumstances (e.g. 
nausea) for up to 3 days, treatment re-initiation is done by administration of the evening dose or 
morning dose only for up to 7 days before reinitiating twice daily dosing. 
 
If treatment has been temporarily discontinued due to non-side effect related circumstances (e.g. 
forgetting medication at home while on a weekend trip), re-initiation is done by resuming the 
planned twice daily dosing schedule without compensating for missing doses.  
8.4 
Treatment Accountability and Compliance 
The patients will receive the study drug at the site directly from the Investigator or designee. The 
date of the first dose should be recorded in the source documents and recorded in the eCRF. At 
all site visits beginning with the Week 2 visit, patients will return all study drug, including 
packaging, dispensed at the previous visit, and it will be documented using the IWRS. 
The patients will self-administer the study drug at home, and compliance with the protocol will 
be assessed at each visit beginning with the Week 2 visit. Compliance will be assessed by direct 
questioning and counting returned tablets during the site visits and documented in the source 
documents and relevant form. Deviation from the prescribed dosage regimen should be recorded. 
A record of the quantity of study drug dispensed to and administered by each patient must be 
maintained and reconciled with study drug and compliance records. Study drug administration 
dates, including dates for administration delays and/or dose reductions, will also be recorded. 
Discontinuation for noncompliance is at the investigator’s discretion and is to be noted on the 
eCRF. 
8.5 
Prior and Concomitant Therapy 
Any concomitant medication, supplement, or procedure within 6 months before Baseline or 
received during the study must be recorded, along with: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information, including dose and frequency 
Patients may take any medication that is not restricted by the protocol and would not be expected 
to interfere with the conduct of the study or affect assessments. Chronic medication should be 
dosed on a stable regimen. 
 Emmolients 
Emollients can be used at patient discretion for managing dry skin on noneczematous areas or for 
reducing pruritus on eczematous areas. The use of emollients is to be recorded as concomitant 


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treatment. In order not to generate local tolerance issues, patients should only use emollients that 
they have already used (and that they tolerated well) and refrain from initiating treatment with a 
new emollient. Emollients that contain pharmacologically active ingredients such as lactic acid, 
salicylic acid, urea, alpha-hydroxy acids, or fruit acids are not allowed from the Screening visit. 
 Supportive Treatment for Side Effects 
Over the course of this trial, additional medications may be required to manage adverse events 
from trial treatment. At the discretion of the Investigator antiemetic or anti-diarrheic 
medications, or mild analgesics for headaches, may be administered. This approach is well 
established for other PDE4-inhibitors, and described by Tello ED et al. 2021 In brief: 
The common PDE4-inhibition related side effect of secretory diarrhea is due to stimulation of the 
CFTR, a fluid transporter in the intestine. Usually, the diarrhea transforms to loose stools instead 
of diarrhea within a couple of weeks, but initial medical treatment with anti-diarrheic 
medications, e.g. loperamide, may support the patient during treatment initiation.     
The common PDE4-inhibition related side effect of nausea is related to delayed gastric 
emptying, thus also related to large meals and energy dense meals. The patients should be 
advised to adjust their meals to be smaller and less fatty and less sugary and drink more water. 
Despite the advice, temporary use of antiemetic medications, e.g. metoclopramide, may support 
the patient during treatment initiation. 
The advice to use mild analgesics (e.g. acetylsalicylic acid/aspirin or paracetamol/acetaminophen 
and NSAIDs) for the common PDE4-inhibition related side effect of headache may support the 
patient during treatment initiation.  
 Restricted Medications 
Restricted prior therapies are provided in Table 3. In addition, patients with any prior treatment 
with orismilast or failure of treatment for AD with apremilast or any other systemic PDE4 
inhibitor are ineligible. 
Table 3. Nonallowed Therapies and Treatments 
Compound 
Washout and Prohibition During the 
Study 
Topical medications/treatments that could affect AD or study 
evaluations (eg, antihistamines, corticosteroids, tazarotene, 
pimecrolimus, tacrolimus, or PDE4 inhibitor) 
≥2 weeks before Baseline and 
throughout the study 
Systemic treatment with medications other than biologics with a 
possible effect on AD, like apremilast, corticosteroids, retinoids, and 
systemic immunosuppressants (eg, methotrexate, azathioprine, 
cyclosporine, Janus kinase inhibitors)  
≥4 weeks before Baseline or 5 half-lives 
(whichever is longer) and throughout 
the study  
Investigational drugs other than the study drug 
≥4 weeks before Baseline, or 5 half-
lives, if known (whichever is longer) 
and throughout the study  


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Compound 
Washout and Prohibition During the 
Study 
Use of phototherapy or prolonged sun exposure or use of tanning 
booths or other ultraviolet light sources (ie, ultraviolet B, psoralens, 
and long-wave ultraviolet radiation) 
≥4 weeks before Baseline and 
throughout the study  
Dupilumab or any biologic targeting the immune system 
≥12 weeks before Baseline and 
throughout the study 
Concomitant medication mainly metabolized via the cytochrome 2D6 
isozyme and with a narrow therapeutic window, such as tricyclic 
antidepressants (eg, nortriptyline, amitriptyline, imipramine, and 
desipramine) or type 1C antiarrhythmics (propafenone, flecainide, and 
encainide) 
≥4 weeks before Baseline and 
throughout the study 
Systemic antibiotics 
≥4 weeks before Screening visit 
Initiation of new emollient or emollients containing pharmacologically 
active ingredients (such as lactic acid, salicylic acid, urea, alpha-
hydroxy acids, or fruit acids) and regular use (more than 2 visits per 
week) of a tanning booth/parlor 
From the Screening and throughout the 
study 
Abbreviations: AD, atopic dermatitis; PDE, phosphodiesterase. 
Concomitant medication mainly metabolized via cytochrome 3A4 and with a narrow therapeutic window (such as 
anticoagulant or digoxine) are not to be excluded but require close medical monitoring. 
The Medical Monitor should be contacted for questions regarding concomitant or prior therapy. 
 
 Drug-Drug Interactions 
From clinical studies, orismilast can be considered a weak inhibitor of CYP3A4, and 
concomitant use of orismilast with CYP3A4 substrates may increase the systemic exposure to 
these medicinal products. Patients receiving orismilast concurrently with these medicinal 
products should be monitored for related AEs, especially if they have a narrow therapeutic 
window. Refer to the following link for examples of clinical inhibitors for P450-mediated 
metabolisms: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers#table3-2. 
In vitro orismilast is a competitive direct inhibitor of CYP2D6. Concomitant use of orismilast 
with other drugs mainly metabolized by the cytochrome CYP2D6 has not been studied clinically. 
Because of a potential increase of systemic exposure to medicinal products metabolized by 
CYP2D6 when concomitantly administered with orismilast, patients should be monitored for 
AEs related to these medicinal products. Coadministration of drugs with a narrow therapeutic 
index, such as tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine, and 
desipramine) or type 1C antiarrhythmics (propafenone, flecainide, and encainide) is prohibited 
(see Table 3). 


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9 
STUDY PROCEDURES 
Table 4 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 11.5 specifies laboratory assessment samples to be obtained. See Section 10 and 
Section 11 for additional details regarding efficacy assessments and safety assessments, 
respectively. 
 


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Table 4. Schedule of Assessments 
 
Screening 
Treatment Period 
Follow-up 
Procedure 
Between Day 
-28 and -7 
Day 1 
(Baseline) 
W1 
(±1 d)a, b 
W2 
(±1 d)a 
W4 
(±3 d)a 
W8 
(±3 d)a 
W12 
(±3 d)a 
W16 
(EOT/ET; 
±3 d)a 
W20 
(±3 d)a or 
4 weeks 
after 
EOT/ET; 
±3 da 
Informed consent (before any study procedures) 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history, including medications, alcohol consumption, and 
smoking history (last 6 months) 
X 
 
 
 
 
 
 
 
 
Concurrent medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion and exclusion criteria review 
X 
X 
 
 
 
 
 
 
 
Physical examination c 
X 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECG (single measurement) 
X 
 
 
 
X 
X 
 
X 
 
Vital signs d 
X 
X 
 
 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
BMI 
 
X 
 
 
 
X 
 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for serology (HIV antibody, HBV, HCV, HBsAg, 
HBcAb, HBsAb) 
X 
 
 
 
 
 
 
 
 
Safety laboratory assessments (hematology, serum chemistry, 
urinalysis)  
X 
X 
 
 
X 
X 
X 
X 
 
Pregnancy test e 
X 
X 
 
X 
X 
X 
X 
X 
 
Blood samples for drug and metabolite PK analysis: plasma levels  
 
X 
 
 
X 
X 
 
X 
 
Optional: blood samples for drug PK profile 
 
 
 
 
X 
 
 
X 
 


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Screening 
Treatment Period 
Follow-up 
Procedure 
Between Day 
-28 and -7 
Day 1 
(Baseline) 
W1 
(±1 d)a, b 
W2 
(±1 d)a 
W4 
(±3 d)a 
W8 
(±3 d)a 
W12 
(±3 d)a 
W16 
(EOT/ET; 
±3 d)a 
W20 
(±3 d)a or 
4 weeks 
after 
EOT/ET; 
±3 da 
Superficial skin sample using tape stripping f 
 
X 
 
 
 
 
 
X 
 
IGA-AD, BSA, and EASI assessments 
X 
X 
 
X 
X 
X 
X 
X 
X 
Peak pruritus NRS, sleep disturbance NRS, and skin pain NRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
PGIS, PGIC 
 
X 
 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
 
X 
X 
X 
X 
X 
X 
DLQI 
 
X 
 
 
 
X 
 
X 
X 
POEM 
 
X 
 
X 
X 
X 
X 
X 
X 
HADS 
 
X 
 
X 
X 
X 
X 
X 
X 
Pulmonary status NRS g 
 
X 
 
 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
 
X 
X 
X 
X 
 
 
Collect study drug, including packaging 
 
 
 
X 
X 
X 
X 
X 
 
Compliance check 
 
 
Xh 
X 
X 
X 
X 
X 
 
Abbreviations: BMI, body mass index; BSA, body surface area; C-SSRS, Columbia-Suicide Severity Rating Scale; d, day; DLQI, Dermatology Life Quality 
Index; EASI, Eczema Area and Severity Index; ECG, electrocardiogram; EOT, end-of-treatment; ET, early termination; HADS, Hospital Anxiety and 
Depression Scale; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, 
hepatitis C virus; IGA-AD, Investigator Global Assessment for Atopic Dermatitis; NRS, numerical rating scale; PGIC, Patient Global Impression of Change; 
PGIS, Patient Global Impression of Severity; PK, pharmacokinetic; POEM, Patient Oriented Eczema Measure; W, week. 
 
a The time window is defined in relation to the baseline visit date. In addition, if the investigator determines that additional treatment is required for the patient 
because of a flare, a follow-up visit should be scheduled before adding new treatment and withdrawing the patient from the trial. 
b Visit can be conducted via a telemedicine procedure at Investigator’s discretion. 
c A complete physical examination will be performed at Screening (Visit 1) and Week 16. A limited physical examination will be conducted at Day 1 and Weeks 
4, 8, 12, and 20. 
d All vital signs will be measured after the patient has been resting in a sitting position for at least 5 minutes. 
e Serum β-human chorionic gonadotropin testing will occur at Screening. Urine pregnancy testing will occur at all other visits. If required per local regulations 
and/or institutional guidelines, pregnancy testing can occur at other times during the study Treatment Period. 


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f At Baseline, before administration of study drug, 1 lesional and 1 nonlesional area will be identified, and 20 consecutive skin samples will be collected from 
each area. At Week 16, the same procedure will be repeated only from the same lesional area sampled at Baseline. 
g Only for patients diagnosed with asthma. 
h Compliance check is performed only on-site. 
 


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9.1 
Informed Consent 
Before performing any study-related procedures, the Investigator (or designee) will obtain 
written informed consent from the patient. 
In the event that rescreening occurs, the individual is required to sign a new ICF and must be 
assigned a new identification number. 
9.2 
Study Procedures 
Assessments and their timing are to be performed as outlined in the Schedule of Assessments 
(Table 4). Section 11.5 specifies laboratory assessment samples to be obtained. 
All PROs (Section 10.2) should be administered before any other visit procedure. Vital signs, 
weight measurement, and ECG must be done before blood sampling, except visits where blood 
sampling for PK analysis is done.  
Efficacy assessments are described in Section 10 and include the EASI, IGA-AD, and BSA and 
the PROs of POEM, peak pruritus NRS, PGIS, PGIC, sleep disturbance NRS, skin pain NRS, 
pulmonary status NRS (only in patients with asthma), and DLQI. 
Safety assessments are described in Section 11 and include medical history, vital signs and body 
weight, physical examinations, ECGs, laboratory assessments, HADS, C-SSRS, and AEs. PK 
assessments are described in Section 12 and superficial skin sampling using tape stripping is 
described in Section 13. 


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10 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 4) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
Assessors must be trained and certified by the Sponsor or delegate before conducting the 
Investigator’s assessments. The same assessor should perform all evaluations for the same 
patient at Baseline and Week 16. 
10.1 Investigator Assessments 
 Eczema Area and Severity Index 
The EASI is an investigator-assessed instrument measuring the severity of clinical signs and the 
percentage of affected BSA in patients with AD. The EASI is a composite scoring system used 
by the AD clinical evaluator to evaluate the degree of erythema, induration/papulation, 
excoriation, and lichenification (each scored separately) for each of 4 body regions, with 
adjustment for the percentage of BSA involved for each body region and for the proportion of 
the body region to the whole body (Hanifin JM, 2001). 
EASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, 
induration/papulation, excoriation, and lichenification are scored on a scale of 0 (absent) to 
3 (severe) for each body region: head and neck, upper limbs (including the external axillae and 
hands), trunk (including the internal axillae and groin), and lower limbs (including the buttocks 
and feet). The extent of affected skin in each body region is scored on a scale of 0 (no 
involvement) to 6 (90% to 100% involvement). The EASI assessment will exclude the scalp, 
palms, and soles from scoring. 
 The Investigator Global Assessment for Atopic Dermatitis 
The IGA-AD is a measure used by physicians to determine a patient’s overall severity of disease. 
The static version is used in this trial for measurement at a single point in time, as indicated in 
the Schedule of Assessments (Table 4). The Investigator will rate the severity of the patient’s AD 
on a 5-point scale ranging from 0 (clear) to 4 (severe) (Simpson E, 2020). 
 Body Surface Area 
The BSA assessment estimates the extent of disease or skin affected by AD and is expressed as a 
percentage of total BSA. BSA will be determined by the Investigator or designee using the 
patient’s hand (palm + fingers) = 1% BSA rule. 


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10.2 Patient-Reported Outcomes 
 Peak Pruritus Numerical Rating Scale 
The severity of itch (pruritus) due to AD will be assessed using a horizontal 11-point NRS. 
Patients will be asked to assess their “worst itching due to AD over the past 24 hours” on an 
NRS anchored by the terms “no itching” (0) and “worst possible itching” (10). 
The item will be completed at each visit via an application on an electronic device in the clinic or 
the patient’s own electronic device from baseline through Week 20. 
 Skin Pain Numerical Rating Scale 
The skin pain NRS is a patient-administered, 11-point horizontal scale anchored at 0 and 10, 
with 0 representing "no pain" and 10 representing "worst pain imaginable." Overall severity of a 
participant's skin pain is indicated by selecting the number that best describes the worst level of 
skin pain in the past 24 hours. 
The item will be completed at each visit via an application on an electronic device in the clinic or 
the patient’s own electronic device from baseline through Week 20. 
 Sleep Disturbance Numerical Rating Scale 
The sleep disturbance NRS is a scale used by the patients to report their degree of sleep loss 
related to AD. Patients will be asked the following question in their local language: how would 
you rate your sleep last night? On a scale of 0 to 10, with 0 being “no sleep loss related to 
signs/symptoms of AD” and 10 being “I cannot sleep at all because of the signs/symptoms of 
AD”. Higher scores indicate worse outcomes. 
The item will be completed at each visit via an application on an electronic device in the clinic or 
the patient’s own electronic device from baseline through Week 20. 
 Patient Oriented Eczema Measure 
The POEM is a 7-item, validated questionnaire completed by the patient to assess disease 
symptoms. Patients are asked to respond to questions on frequency of sleep loss and skin 
dryness, itching, flaking, cracking, bleeding, and weeping over the past week. All answers carry 
equal weight, with a total possible score ranging from 0 to 28. A high score is indicative of a 
poor quality of life. 
The item will be completed at each visit via an application on an electronic device in the clinic or 
at the patient’s own electronic device from baseline through Week 20 except Week 1. 
 Patient Global Impression of Severity Scale 
The PGIS scale is a single question asking the patient how he or she would rate his or her overall 
AD symptoms over the past 24 hours. The 5 categories of responses are (0) “no symptoms", (1) 
“very mild", (2) “mild", (3) “moderate", and (4) “severe." 


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The item will be completed at each visit via an application on an electronic device in the clinic or 
the patient’s own electronic device from baseline through Week 20 except Week 1. 
 Patient Global Impression of Change Scale 
The PGIC scale measures change in clinical status of AD. The PGIC is based on a 7-point scale, 
and the patient will rate the change from the start of treatment as 1 “very much improved,” 2 
“much improved,” 3 “minimally improved,” 4 “no change,” 5 “minimally worse,” 6 “much 
worse,” and 7 “very much worse.” 
The item will be completed at each visit via an application on an electronic device in the clinic or 
the patient’s own electronic device from baseline through Week 20 except Week 1. 
 Dermatology Life Quality Index 
The DLQI is a 10-item validated questionnaire completed by the patient and used to assess the 
effect of skin disease on the patient’s quality of life during the previous week. The 10 questions 
cover the following topics: symptoms; embarrassment; interference with shopping and home 
care, clothing choices, social and leisure activities, sports participation, work or study, close 
relationships, and sex; and treatment. Each question is scored from 0 to 3 (“not at all,” “a little,” 
“a lot,” and “very much,” respectively), giving a total score ranging from 0 to 30. A high score is 
indicative of a poor quality of life. 
The item will be completed at each visit via an application on an electronic device in the clinic or 
the patient’s own electronic device at baseline and Weeks 8, 16, and 20. 
 Pulmonary Status Numerical Rating Scale in Patients with Asthma 
Pulmonary disease status will be assessed in patients with asthma using a horizontal NRS. 
Patients will be asked to assess their “symptoms due to asthma over the past 7 days” on an NRS 
anchored by the terms (0) “no symptoms” and (10) “very bad symptoms”.  
The item will be completed at each visit via an application on an electronic device in the clinic or 
the patient’s own electronic device at baseline and Weeks 4, 8, 12, 16, and 20. 


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11 SAFETY ASSESSMENTS 
Safety assessments (medical history, vital signs and body weight, physical examinations, ECGs, 
clinical laboratory results [routine hematology, urinalysis and biochemistry], HADS, C-SSRS, 
and AEs) are to be performed at protocol-specified visits, as specified in the Schedule of 
Assessments (Table 4). 
11.1 Medical History 
Medical history will be recorded at Screening. Investigators should document the occurrence, 
signs, and symptoms of the patient’s pre-existing conditions, including any psychiatric treatment 
or hospitalization, covering all prior significant illnesses up to and including 6 months before 
screening. Additional pre-existing conditions present at the time when informed consent is given, 
and up to the time of first dosing (Visit 1), are to be regarded as concomitant. Medical history 
will include medications, alcohol consumption and smoking history, if applicable. 
Illnesses first occurring or detected during the study, and/or worsening of a concomitant illness 
during the study, are to be documented as AEs on the eCRF in accordance with Section 11.8.1. 
All changes not present at Baseline or described in the past medical history (last 6 months) and 
identified as clinically noteworthy must be recorded as AEs. 
Additionally, demographic data will be collected for all patients and include date of birth or age 
according to applicable regulations, sex, ethnicity, etc. 
11.2 Vital Signs and Body Weight 
Vital signs (body temperature [measured in the ear], respiration rate, heart rate, and systolic and 
diastolic blood pressure measurements) will be evaluated at the visits indicated in the Schedule 
of Assessments (Table 4). All vital signs will be measured after the patient has been resting in a 
sitting position for at least 5 minutes. Blood pressure measurements are to be taken in the same 
arm for the duration of the study. Body weight (without shoes) will be recorded whenever vital 
signs are recorded; height (without shoes) will be recorded at Baseline only. A weight reduction 
of least 5% from baseline should be reported as a TEAE. 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range blood pressure, respiratory rate, or heart rate measurements will be repeated 
at the Investigator’s discretion. Any confirmed, clinically significant vital sign measurements 
must be recorded as AEs on the eCRF. 
11.3 Physical Examination 
A complete physical examination (a check of the head, eyes, ears, nose, and throat; heart; lungs; 
abdomen; skin; cervical and axillary lymph nodes; and neurological and musculoskeletal 
systems) will be performed at Screening (Visit 1) and Week 16. A limited physical examination 
will be conducted at Day 1 and Weeks 4, 8, 12, and 20 to verify continued patient eligibility and 


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to follow-up regarding any change in medical history. Physical examinations will be performed 
by a physician at the visits indicated in the Schedule of Assessments (Table 4). 
11.4 Electrocardiograms 
A 12-lead, resting ECG will be conducted at the visits indicated in the Schedule of Assessments 
(Table 4). 
At Screening, the Investigator will examine the ECG traces for signs of cardiac disease that 
could exclude the patient from the study. An assessment of normal or abnormal results will be 
recorded; if the ECG is considered abnormal, the abnormality will be documented on the eCRF, 
and the ECG will be repeated if clinically significant abnormalities are observed or artifacts are 
present. 
11.5 Laboratory Assessments 
Laboratory assessment samples (Table 5) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 4).  
Table 5. Laboratory Assessments 
Hematology  
Serum Chemistry  
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count (% reticulocytes) 
WBC count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils)  
Albumin 
ALT 
ALP 
AST 
BUN 
Creatinine 
Electrolytes (sodium, potassium, chloride, calcium, 
phosphorus) 
GGT 
LDH 
Total bilirubin 
Direct bilirubin 
Total IgE 
Other Screening Tests 
Urinalysis (Dipstick) 
HIV antibody 
HBV 
HCV 
HCV RNA 
HBsAg 
HBcAb 
HBsAb 
FSH (confirmatory test for female patients in a 
postmenopausal status defined as cessation of menses 
for at least 12 months without an alternative medical 
cause)  
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urine hCG (premenopausal females only) 
Urobilinogen 
Pregnancy test: A serum pregnancy test will be performed on all WOCBP at Screening, and a urine pregnancy 
test will be performed at all other visits as indicated in Table 4.  


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Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, 
blood urea nitrogen; FSH, follicle-stimulating hormone; GGT, gamma-glutamyl transpeptidase; Hb, hemoglobin; 
HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, 
hepatitis B virus; hCG, human chorionic gonadotropin; Hct, hematocrit; HCV, hepatitis C virus; IgE, 
Immunoglobulin E; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular 
hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell; WBC, white blood cell; WOCBP, 
women of childbearing potential. 
 
Blood and urine samples will be analyzed at a central laboratory facility. Urine samples will be 
analyzed by dipstick at clinical site, and a microscopic analysis will be performed if the results of 
dipstick indicate abnormalities to be further investigated. All laboratory reports must be 
reviewed, signed, and dated by the investigator. A legible copy of all reports must be filed with 
both the patients’ eCRF and medical record (source document) for that visit. Any laboratory test 
result considered by the Investigator to be clinically significant should be considered an AE 
(clinically significant AEs include those that require an intervention). Clinically significant 
abnormal values occurring during the study will be followed up until repeat test results return to 
normal, stabilize, or are no longer clinically significant. 
11.6 The Hospital Anxiety and Depression Scale 
The HADS is a PRO, comprises 7 questions for anxiety and 7 questions for depression, with 
each answer being graded from 0 to 3 with a higher score indicating a worse condition. For each 
group of questions, scores of 7 or less indicate cases without anxiety or depression, whereas 
scores of 8 to 10, 11 to 14, and 15 to 21 indicate mild, moderate, and severe cases, respectively. 
The HADS is one of the tools recommended by the National Institute for Health and Care 
Excellence for diagnosis of depression and anxiety. 
Any patient with a score for depressive symptoms ≥ 15 at baseline will not be eligible for 
enrollment in the study. Patients with a clinically significant worsening of depressive symptoms 
or new occurrence of clinically significant depression during the study may be referred to a 
mental health specialist (psychiatrist or clinical psychologist) for further evaluation. After a 
mental health specialist evaluation, the final decision on restarting or permanently discontinuing 
study treatment will be at the discretion of the Investigator in consultation with the mental health 
specialist. These cases should be reported as an AESI. Refer to Section 11.8.2.  
11.7 The Columbia-Suicide Severity Rating Scale 
The C-SSRS, Investigator-administered version, was designed to provide a prospective, 
standardized measure of suicidality. The scale allows clinicians and researchers alike to assess 
the severity and lethality of suicidal behaviors and ideations and can be used to monitor 
treatment outcomes and establish suicide risk in a variety of research and clinical settings. 
Requiring approximately 5 minutes for completion, the C-SSRS is administered in the form of a 
clinical interview. 


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This C-SSRS is available in 2 versions: 1 for use at screening referring to the past year and 1 for 
use throughout the rest of the study referring to the time since the prior visit. 
If at screening or baseline there are “yes” answers on item 4 or 5, the patient will not be included 
in the study.  
Any patient with a positive response at subsequent visits (answers “yes” to questions 1-5) should 
be referred to a mental health specialist (psychiatrist or clinical psychologist) for further 
evaluation, and the study medication should be paused. After a mental health specialist 
evaluation, the final decision on restarting or permanently discontinuing study treatment will be 
at the discretion of the Investigator in consultation with the mental health specialist. These cases 
should be reported as an AESI. Refer to Section 11.8.2. 
11.8 Adverse Events 
AEs will be collected throughout the study as shown in the Schedule of Assessments (Table 4). 
 Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening, worsens during the study, regardless of the suspected cause of the 
event. All medical and psychiatric conditions (except those related to the indication under study) 
present at screening will be documented in the medical history eCRF. Changes in these 
conditions and new symptoms, physical signs, syndromes, or diseases should be noted on the AE 
eCRF during the rest of the study. Clinically significant laboratory abnormalities should also be 
recorded as AEs. Surgical procedures that were planned before the patient enrolled in the study 
are not considered AEs if the conditions were known before study inclusion; the medical 
condition should be reported in the patient’s medical history. 
Any AEs that occur before dosing at Baseline will be categorized as pretreatment events. TEAEs 
will be defined as those AEs that occur or worsen in severity after initial dosing and up to 7 days 
after the last dose of study drug. 
Patients will be instructed to report AEs at each study visit. All AEs are to be followed up until 
resolution or a stable clinical endpoint is reached. 
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to study drug, action taken with study drug, treatment of event, and 
outcome. Furthermore, each AE is to be classified as being serious or nonserious. Changes in 
AEs and resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time the patient gives informed consent until the follow-up visit. Follow-up of the AE, even after 
the date of therapy discontinuation, is required if the AE persists until the event resolves or 
stabilizes at a level acceptable to the investigator. 


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When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
All AEs must be graded by using the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) grading system version 5.0 (CTCAE- Version 5.0) with reference 
to the unique clinical descriptions of severity for each AE in the guidance document. Please see 
Table 6 for selected unique clinical descriptions of severity of AEs. Only if an AE is not 
uniquely described in the CTCAE grading system, the general guidance for classification is to be 
used. Please see Table 7 for the general guideline for classification.  
If a patient experiences a TEAE assessed as Grade 3 or higher using the unique clinical 
descriptions of severity (Grade 2 or higher for the SOC of cardiac disorders) according to 
CTCAE version 5, the patient should be permanently discontinued from the study drug and not 
receive additional doses.   
Specific guidelines for classifying AEs by intensity are given in Table 6 and  Table 7 and 
relationship to study drug are given in Table 8. 
Table 6. Selected unique clinical descriptions of severity of AEs from National Cancer 
Institute Common Terminology Criteria for Adverse Events version 5.0 
CTCAE Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
Grade 5    
Diarrhea 
Increase of <4 
stools per day 
over baseline; 
mild increase in 
ostomy output 
compared to 
baseline 
Increase of 4 - 6 
stools per day 
over baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline; 
limiting 
instrumental 
ADL 
Increase of >=7 
stools per day 
over baseline; 
hospitalization 
indicated; 
severe increase 
in ostomy 
output 
compared to 
baseline; 
limiting self 
care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Nausea 
Loss of appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration or 
malnutrition 
Inadequate oral 
caloric or fluid 
intake; tube 
feeding, TPN, 
or 
hospitalization 
indicated 
 - 
 - 
Vomiting 
Intervention not 
indicated 
Outpatient IV 
hydration; 
medical 
intervention 
indicated 
Tube feeding, 
TPN, or 
hospitalization 
indicated 
Life-threatening 
consequences 
Death 


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Headache 
Mild pain 
Moderate pain; 
limiting 
instrumental 
ADL 
Severe pain; 
limiting self 
care ADL 
 - 
 - 
Alanine 
aminotransferase 
increased 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 
- 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 5.0 x 
ULN if baseline 
was normal; 
>3.0 - 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
- 
Aspartate 
aminotransferase 
increased 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 
- 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 5.0 x 
ULN if baseline 
was normal; 
>3.0 - 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
 - 
Other AEs 
For other AEs not in this table, please refer to the CTCAE grading system version 5.0, with 
reference to the unique clinical descriptions of severity for each AE. Only if an AE is not 
uniquely described in the CTCAE grading system, the general guidance (see Table 7) for 
classification is to be used. 
 
Table 7. National Cancer Institute Common Terminology Criteria for Adverse Events 
general guideline for classification version 5.0 
GRADE 1: Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.  
GRADE 2: Moderate: minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
GRADE 3: Severe or medically significant but not immediately life threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care ADL. 
GRADE 4: Life threatening consequences; urgent intervention indicated. 
GRADE 5: Death related to an AE. 
Abbreviations: ADL, activities of daily living; AE, adverse event. 


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Table 8. Classification of Adverse Events by Relationship to Study Drug 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc).  
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the test drug but for 
which no extraneous cause may be found. An AE may be considered unlikely to be related to study drug if or 
when it meets 2 of the following criteria: (1) it does not follow a reasonable temporal sequence from 
administration of the test drug; (2) it could readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient; (3) it does not follow a 
known pattern of response to the test drug; or (4) it does not reappear or worsen when the drug is 
readministered.  
POSSIBLY: This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty. An AE may be considered possibly related if or when 
it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the 
drug; (2) it could not readily have been produced by the patients’ clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; or (3) it follows a known pattern of response to 
the test drug.  
PROBABLY: This category applies to those AEs that the Investigator feels with a high degree of certainty 
are related to the test drug. An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the patients’ clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; (3) it disappears or decreases on cessation or 
reduction in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or (4) it follows a known pattern of response to the test drug.  
DEFINITELY: This category applies to those AEs that the Investigator feels are incontrovertibly related to 
test drug. An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the patients’ clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a known 
pattern of response to the test drug.  
Abbreviation: AE, adverse event. 
 
 Adverse Events of Special Interest (AESI) 
An AESI (serious or nonserious) is one of scientific and medical concern, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor could be appropriate. 
AESIs must be reported within 24 hours of occurrence or when the Investigator becomes aware 
of the event, following SAE reporting procedures (Section 11.8.4). Such an event might require 
further investigation to characterize and understand it. Depending on the nature of the event, 
rapid communication by the trial Sponsor to other parties (eg, regulators) might also be 
warranted. 


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In this trial, the following AEs are to be considered AESI: 
• any AE of occurrence of suicidal ideation or behavior, including a positive response to 
question 1 to 5 of C-SSRS, 
• a depression assessed as moderate or worse by the investigator or a score ≥ 15 in the 
HADS score, 
• any grade 3 or higher psychiatric condition, and/or  
• any of the following GI TEAEs: vomiting, diarrhea with an increase of at least 4 stools 
per day over baseline (Grade 2 CTCAE) for at least 3 days. 
• any signal that may arise from Sponsors ongoing safety review during the trial that may 
need closer monitoring. 
 Serious Adverse Events 
An SAE is any untoward medical occurrence, in the view of either the Investigator or Sponsor, 
that: 
• results in death, 
• is life threatening, 
• results in inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, and/or 
• is a congenital anomaly/birth defect. 
Other important medical events that may not be immediately life threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the patient and/or require medical or surgical intervention to prevent one of 
the outcomes defining an SAE. SAEs are critically important for the identification of significant 
safety problems; therefore, it is important to take into account both the investigator’s and the 
Sponsor’s assessment. If either the Sponsor or the Investigator believes that an event is serious, 
the event must be considered serious and evaluated by the Sponsor for expedited reporting. 
 Serious Adverse Event Reporting 
An SAE occurring from the time informed consent is obtained, during the study, or within 
30 days of stopping the treatment must be reported to the Syneos Health Safety and 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE due to any 
cause, whether or not related to the study drug, must be reported within 24 hours of occurrence 
or when the Investigator becomes aware of the event. Notification can be made using the 
dedicated fax line or email for the Syneos Health Safety and Pharmacovigilance group: 
Syneos Health Safety and Pharmacovigilance fax number: +1 (877) 464-7787 
Syneos Health Safety and Pharmacovigilance email address: safetyreporting@syneoshealth.com 


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If the Investigator contacts the Syneos Health Safety and Pharmacovigilance group by telephone, 
then a written report must follow within 24 hours and is to include a full description of the event 
and sequelae in the format detailed in the SAE reporting form. 
The event must also be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the Investigator considers the event to 
be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. Clinical, laboratory, and diagnostic measures should be employed as needed to 
determine the etiology of the problem. The Investigator must report all additional follow-up 
evaluations to the Syneos Health Safety and Pharmacovigilance group within 24 hours of 
becoming aware of the additional information or as soon as is practicable. All SAEs will be 
followed up until the Investigator and Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the patient’s 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the study 
drug or procedures. 
 Suspected Unexpected Serious Adverse Reactions 
AEs that meet all of the following criteria will be classified as suspected unexpected serious 
adverse reactions (SUSARs) and reported to the appropriate regulatory authorities in accordance 
with applicable regulatory requirements for expedited reporting: 
• serious 
• unexpected (ie, the event is not consistent with the safety information in the investigator’s 
brochure) 
• there is at least a reasonable possibility that there is a causal relationship between the 
event and the study treatment 
The Investigator will assess whether an event is causally related to study treatment. Syneos 
Health will consider the Investigator’s assessment and determine whether the event meets the 
criteria for being reportable as a 7-day or 15-day safety report. SUSARs that are fatal or life 
threatening must be reported to the regulatory authorities and the independent ethics committee 
(IEC)/institutional review boards (IRBs) (where required) within 7 days after the Sponsor (or 
Syneos Health) has first knowledge of them, with a follow-up report submitted within a further 
8 calendar days. Other SUSARs must be reported to the relevant regulatory authorities and the 
IEC/IRBs within 15 calendar days after the Sponsor (or Syneos Health) first has knowledge of 
them. 


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The Sponsor (or Syneos Health) is responsible for reporting SUSARs, and any other events 
required to be reported in an expedited manner to the regulatory authorities and for informing 
investigators of reportable events, in compliance with applicable regulatory requirements within 
specific timeframes. Investigators will notify the relevant IEC/IRBs of reportable events within 
the applicable timeframes. 
 Pregnancy 
WOCBP must have a negative serum pregnancy test at Screening and are required to use 1 of the 
highly effective contraception methods (listed in Inclusion Criterion 8). Women on hormone 
replacement therapy, and whose menopausal status is in doubt, will be required to use 1 of the 
highly effective contraception methods. Highly effective contraception is defined as having a 
failure rate of less than 1% per year when used consistently and correctly and, when applicable, 
in accordance with the product label. 
Women of nonreproductive potential are defined as those with surgical sterilization 
(hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) and those in a 
postmenopausal status, defined as cessation of menses for at least 12 consecutive months without 
an alternative medical cause and a confirmatory follicle-stimulating hormone test or as cessation 
of menses for at least 24 consecutive months without an alternative medical cause. 
After administration of study drug, any known cases of pregnancy in female patients will be 
reported until the patient completes or withdraws from the study. The pregnancy will be reported 
immediately by faxing/emailing a completed pregnancy report to Syneos Health Safety and 
Pharmacovigilance within 24 hours of knowledge of the event. If any patient becomes pregnant 
during the study, she is to immediately discontinue any Sponsor-supplied study drug and to have 
only safety assessments performed. The Investigator will follow-up with the patient until 
completion of the pregnancy and must assess the outcome in the shortest possible time but not 
more than 30 days after completion of the pregnancy. The Investigator should notify Syneos 
Health Safety and Pharmacovigilance of the pregnancy outcome by submitting a follow-up 
pregnancy report. If the outcome of the pregnancy involved spontaneous or therapeutic abortion 
(any congenital anomaly detected in an aborted fetus is to be documented), stillbirth, neonatal 
death, or congenital anomaly, the Investigator will report the event by faxing/emailing a 
completed pregnancy report form to Syneos Health and Pharmacovigilance within 24 hours of 
knowledge of the event. 
If the Investigator becomes aware of a pregnancy occurring in the partner of a patient 
participating in the study, the pregnancy should be reported to Syneos Health Safety and 
Pharmacovigilance within 24 hours of knowledge of the event. Information regarding the 
pregnancy must only be submitted after obtaining written consent from the pregnant partner. The 
Investigator will arrange counseling for the pregnant partner by a specialist to discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus. 


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Upon discontinuation from the study, only those procedures that would not expose the patient to 
undue risk will be performed. The Investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. If a patient is subsequently found 
to be pregnant after inclusion in the study, any pregnancy will be followed to term, and the status 
of mother and child will be reported to Syneos Health Safety and Pharmacovigilance after 
delivery. 
 Overdose 
The Investigator must immediately notify the Sponsor of any occurrence of overdose with study 
drug. 


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12 PHARMACOKINETICS 
12.1 Pharmacokinetic Sampling 
 Blood Samples 
Blood samples for PK analysis of orismilast and its major metabolite levels will be collected at 
the time points indicated in the Schedule of Assessments (Table 4). The actual date and time of 
each blood sample collection will be recorded.  
Blood sampling for measuring plasma levels: The patients will be instructed to self-administer 
the study drug approximately 12 hours prior to the planned blood collection for PK analysis. The 
date and time of the dose taken prior to the PK blood sampling will be collected and registered.  
Blood sampling for calculation of PK profiles: In addition to the sample collected for measuring 
plasma levels, patients will be offered optional participation in specific blood sampling for 
calculation of PK profiles. This additional procedure is voluntary for patients and a separate 
informed consent will be obtained before collection of the blood samples. For PK profiling, 4 or 
5 additional blood samples will be collected during each visit at W4 and W16. The patient will 
be instructed to take the next dose of the study drug in the clinic and blood samples will be taken 
at the following timepoints: 45 min, 2.5 hours (estimated Cmax), 4 hours and 6 hours after intake 
of the study drug, as shown in the figure below. An additional optional 8-hour blood sample will 
be collected if the patient agrees. The actual date and time of the study drug administration in the 
clinic and each blood sample collection will be recorded. See Figure 2 for the details of PK blood 
sample collection. 
Figure 2. 
Pharmacokinetic Blood Sample Collection 
Details of PK blood sample collection, processing, storage, and shipping procedures are provided 
in a separate laboratory manual. 
12.2 Pharmacokinetic Analytical Methodology 
The concentration of study drug and main metabolite will be determined from the plasma 
samples using a validated analytical method. Details of the method validation and sample 
analysis will be included with the final clinical study report. 


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13 PHARMACODYNAMICS 
13.1 Superficial Skin Sampling Using Tape Stripping 
Stratum corneum skin samples will be collected at the time points indicated in the Schedule of 
Assessments (Table 4) using the tape stripping method to evaluate biomarker expression levels. 
Tape stripping is a minimally invasive, nonscarring approach using serial adhesive films to 
capture the stratum corneum and the upper part of the granular layer. 
At Baseline, before administration of study drug, 1 lesional and 1 nonlesional area will be 
identified, and 20 consecutive skin samples will be collected from each area. At Week 16, the 
same procedure will be repeated only from the same lesional areas sampled at Baseline. 
Details of stratum corneum skin samples storage, and shipping procedures are provided in a 
separate laboratory manual. 


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14 STATISTICAL ANALYSIS 
A statistical analysis plan will be prepared after the protocol is approved. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives. The statistical analysis plan will serve as a complement to the 
protocol and supersedes it in case of differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of patients, mean, standard deviation, median, minimum, and 
maximum by treatment group. For categorical variables, data will be tabulated with the number 
and proportion of patients for each category by treatment group. 
14.1 Determination of Sample Size 
Approximately 210 patients will be randomly assigned to receive orismilast 20 mg, 30 mg, or 
40 mg BID or placebo for 16 weeks. 
This sample size is based on assumptions that there is a difference of 25.0% in the percent 
change from baseline in EASI scores between each orismilast dose group with placebo, 
respectively, and that the common standard deviation in the percent change from baseline in 
EASI score is 43%. Using a 2-sided 2-sample t-test, 47 patients in each treatment group (188 in 
total) will achieve a power of 80% at the significance level of 5%. To account for an early 
dropout rate of approximately 10%, an additional 22 patients will be randomized. 
14.2 Analysis Populations 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all randomized patients who receive at least 1 
dose of study drug. The treatment group assignment will be designated according to initial 
randomization. The ITT population will serve as the basis for the analysis of efficacy. 
Per-Protocol Population 
The per-protocol population includes all randomized patients who receive at least 1 dose of study 
drug, have at least 1 post-Baseline EASI assessment, and who do not have any major protocol 
deviations affecting efficacy analysis. The treatment group assignment in this population will be 
designated according to initial randomization. 
Safety Population 
The safety population will include all randomized patients who receive at least 1 dose of study 
drug. The treatment group assignment in this population will be defined by the treatment actually 
received. This population will be used for the analysis of safety. 


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14.3 Efficacy Analysis 
For inferential analyses of primary and secondary efficacy endpoints, each active treatment 
group will be compared with the placebo group. 
Primary and secondary efficacy endpoints are to be assessed in the ITT population. Missing data 
for primary and key secondary endpoints will be handled with the multiple imputation method. 
For a categorical efficacy endpoint based on a continuous variable, the multiple imputation will 
be first done for the continuous variable, then the category will be determined using the imputed 
values. Analyses will be repeated on the per-protocol population for primary and key secondary 
endpoints. 
When appropriate, the raw parameter, its change from Baseline, and percentage change from 
Baseline will be summarized. 
 Analysis of the Primary Efficacy Endpoint 
The primary endpoint, percentage change from Baseline to Week 16 in EASI score, will be 
analyzed using an analysis of covariance with treatment group as the factor and Baseline EASI 
score as the covariate. As a supportive analysis, a mixed model for repeated measures will be 
performed with treatment group, visit and treatment-by-visit interaction as factors and baseline 
EASI score by-visit interaction as a covariates. 
Each active treatment dose will be compared with placebo. No adjustment for multiplicity will 
be made, and the 0.05 level of significance will be used to claim efficacy compared with 
placebo. Least square means and the 95% CI of the difference between each active treatment and 
placebo will be calculated. The primary analysis set will be the ITT population with a multiple 
imputation approach to handle missing values. The same analyses will be repeated backward at 
earlier visits. 
 Analysis of Secondary Efficacy Endpoints 
For the continuous secondary efficacy endpoints (peak pruritus NRS, BSA, PGIS, PGIC, sleep 
disturbance NRS, skin pain NRS, DLQI, and POEM examination), a mixed model for repeated 
measures will be performed similar to the supportive MMRM for the primary endpoint. 
The key secondary efficacy endpoints and other binary secondary efficacy endpoints (IGA-AD 
success, EASI50, EASI75, EASI90, and 4-point improvement in the peak pruritus NRS) will be 
analyzed using the Mantel-Haenszel (MH) test, comparing each active treatment group with 
placebo in the ITT population. 
For categorical endpoints, the MH procedure, with ridit scores, will be used; this test is the same 
as the nonparametric Wilcoxon test and enhances the analysis when the parameter is not 
normally distributed. Graphics will be added to facilitate interpretation. IGA-AD scores/full 
scale will be analyzed using the MH test and the row mean score statistics with the ridit 
transformation. 


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The above endpoints (EASI changes and percentage changes, IGA-AD success, EASI50, 
EASI75, and EASI90) and the percentage change of BSA will be presented graphically over time 
from Baseline to Week 20. In addition, shift tables will be provided between Baseline and each 
visit for the IGA-AD distribution. The EASI percentage changes from Baseline will be plotted to 
identify where the best separation between treatments occurs. 
 Analysis of Exploratory Endpoints 
All exploratory endpoints, including change from baseline in pulmonary status NRS in patients 
with asthma and skin biomarkers at Week 16, and patients achieving at least a 2-point 
improvement in peak pruritis NRS from baseline will be summarized descriptively in the ITT 
population or a subgroup. 
14.4 Safety Analysis 
All safety analyses will be conducted using the safety population. AE data will be presented and 
tabulated according to Medical Dictionary for Regulatory Activities classification. Reported AEs 
will be summarized by the number of patients reporting the events, as well as by SOC and 
preferred term (PT); SOC, PT, and severity; and SOC, PT, and relationship to study drug. 
Laboratory (chemistry, urinalysis and hematology) parameters, 12-lead ECG values, and vital 
signs will be tabulated by visit using descriptive statistics and shift tables. The value at each visit, 
as well as the change from Baseline, will be presented. 
14.5 Pharmacokinetic Analysis 
The plasma levels of the drug and its metabolites will be summarized descriptively by visit in 
this study. 
14.6 Interim Analysis 
No interim analysis is planned in this study. 


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15 STUDY MANAGEMENT 
15.1 Approval and Consent 
 Regulatory Guidelines 
This study will be conducted in accordance with the protocol and the following guidelines: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable ICH GCP guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC and reviewed and approved by the 
IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
Protocols and any substantial amendments to the protocol will require health authority approval 
before initiation, except for changes necessary to eliminate an immediate hazard to study 
patients. 
The Investigator will have the following responsibilities: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to the 
requirements of 21 CFR Parts 50, 56, 312, Subpart D; ICH guidelines; the IRB/IEC; 
European regulation 536/2014 for clinical studies (if applicable); and all other applicable 
local regulations 
 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IEC/IRB. Approval is 
required for the study protocol, protocol amendments (if applicable), investigator’s brochure, 
ICFs, recruitment material, and patient information sheets and other patient-facing material. 


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 Informed Consent 
The Investigator is responsible for ensuring that patients do not undergo any study-related 
examination or activity before giving informed consent. 
The Investigator or his/her representative will explain orally and in writing the nature of the 
study, its purpose, procedures, expected duration, alternative therapy available, and the benefits 
and risks involved in study participation to the patient and answer all questions regarding the 
study. The patient must be given every opportunity to clarify any points not understood and must 
be provided with more information as requested. At the end of the interview, the patient may be 
given time to reflect and can request more time if needed. 
Patients must be informed that their participation is voluntary and that they can withdraw from 
the study at any time. Patients will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements (where applicable), and the IRB/IEC or study 
center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be reconsented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient. Patients who are rescreened are required to 
sign a new ICF. 
The ICF will have an additional form that addresses the use of any remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
patient the objectives of the exploratory research. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a patient’s agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate in 
this optional research will not provide this separate signature. 
15.2 Data Handling 
All patient data relating to the study will be recorded on the eCRF unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF. Access to 
the electronic data capture system will be restricted, and users will only be able to access the 
system via authorized individual accounts. Appropriate training will be completed with the 
Investigator and all authorized study site personnel before the study being initiated and any data 
being entered into the eCRF. 


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A comprehensive Data Management Plan will be written outlining the standard operating 
procedures, internal/external security safeguards, system and change controls, and training 
procedures and will be filed in the Sponsor’s trial master file. 
15.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The Investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial patients. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
15.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer period. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, the 
General Data Protection Regulation, Standards for Individually Identifiable Health Information, 
45 CFR, Parts 160 and 164 (the HIPAA of 1996 Privacy Regulation). The Investigator shall 
ensure that study patients authorize the use and disclosure of protected health information in 
accordance with the HIPAA Privacy Regulation (if applicable) and in a form satisfactory to the 
Sponsor. 
15.5 Monitoring 
The study will be monitored according to the Sponsor’s monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits, on-site and remote (telephone) or a combination, and contacts will be made at 
appropriate times during the study. The Investigator will assure he/she and adequate site 
personnel are available throughout the study to collaborate with clinical monitors. Clinical 
monitors must have direct access to source documentation to check the completeness, clarity, 
and consistency of the data recorded in the eCRFs for each patient. 
The Investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the Investigator will 


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work closely with the clinical monitor and as needed, provide him or her appropriate evidence 
that the study is being conducted in accordance with the protocol, applicable regulations, and 
GCP guidelines. 
15.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the Investigator generating the data. 
15.7 Protocol Amendment and Protocol Deviation 
 Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of patients or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IEC/IRB for information only. The Sponsor will ensure that 
acknowledgment is received and filed. Amendments that are classed as substantial amendments 
must be submitted to the appropriate regulatory authorities and the IECs/IRBs for approval and 
will not be implemented at sites until such approvals are received, other than in the case of an 
urgent safety measure. 
 Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IRB/IEC and in accordance with applicable 
regulatory authority mandates is an Investigator responsibility. 
15.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki, and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; EU 536/2014, Annex 1, D, 17 (a); and in compliance with 
GCP guidelines. 
IECs/IRBs will review and approve this protocol and the ICF. All patients are required to give 
written informed consent before participation in the study. 
15.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the Investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the Investigator (or the institution 
signatory) and the Sponsor (or its designee). 


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The Investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide no-exclusion insurance coverage for the clinical 
study as required by national regulations. 
15.10 Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such clinical study agreement. To facilitate 
such ownership, investigators will be required to assign all such inventions either to their 
institution or directly to the Sponsor or its designee, as will be set forth in the clinical study 
agreement. 


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16 REFERENCES 
1. Apremilast. Summary of Product Characteristics. Accessed October 2021. 
https://www.medicines.org.uk/emc/product/10709/smpc. 
2. Barbarot S, Auziere S, Gadkari A, et al. Epidemiology of atopic dermatitis in adults: 
Results from an international survey. Allergy. 2018;73(6):1284-1293. 
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3. Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat 
Rev Drug Discov. 2021;1-20. doi:10.1038/s41573-021-00266-6 
4. Butler JM, Chan SC, Stevens S, Hanifin JM. Increased leukocyte histamine release with 
elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin 
Immunol. 1983;71(5):490-497. doi:10.1016/0091-6749(83)90467-0 
5. Crisaborole. Pfizer Adis Insight. Accessed August 16, 2018. 
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6. Cooper KD. Atopic dermatitis: recent trends in pathogenesis and therapy. J Invest 
Dermatol. 1994;102(1):128-137. doi:10.1111/1523-1747.ep12371746 
7. Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in 
inflammatory diseases. Curr Opin Investig Drugs. 2007;8(5):364-372. 
8. Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of fluticasone propionate cream 
for reducing the risk of relapse in atopic dermatitis patients. Br J Dermatol. 
2002;147(3):528-537. doi:10.1046/j.1365-2133.2002.05006.x 
9. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area 
and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator 
Group. Exp Dermatol. 2001;10(1):11-18. doi:10.1034/j.1600-0625.2001.100102.x 
10. Harada D, Ikeda Y, Nosaka Y, Kobayashi K, Manabe H. Curative effects of 
phosphodiesterase 4 inhibitors cilomilast, roflumilast, and rolipram in dermatitis mouse 
model. J Dermatol Sci. 2008;51(3):215-219. doi:10.1016/j.jdermsci.2008.04.007 
11. Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a 
therapeutic target. Drug Discov Today. 2005;10(22):1503-1519. doi:10.1016/S1359-
6446(05)03622-6 
12. Jin SL, Ding SL, Lin SC. Phosphodiesterase 4 and its inhibitors in inflammatory 
diseases. Chang Gung Med J. 2012;35(3):197-210. doi:10.4103/2319-4170.106152 
13. McGregor SP, Farhangian ME, Huang KE, Feldman SR. Treatment of atopic dermatitis 
in the United States: analysis of data from the National Ambulatory Medical Care 
Survey. J Drugs Dermatol. 2017;16(3):250-255. 
14. Newsom M, Bashyam AM, Balogh EA, Feldman SR, Strowd LC. New and emerging 
systemic treatments for atopic dermatitis. Drugs. 2020;80(11):1041-1052. 
doi:10.1007/s40265-020-01335-7 
15. Roekevisch E, Schram ME, Leeflang MMG, et al. Methotrexate versus azathioprine in 
patients with atopic dermatitis: 2-year follow-up data. J Allergy Clin Immunol. 
2018;141(2):825-827.e10. doi:10.1016/j.jaci.2017.09.033 
16. Roflumilast. Summary of Product Characteristics. Accessed October 2021. 
https://www.medicines.org.uk/emc/medicine/23416. 


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17. Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase 
inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. 2012;148(8):890-
897. doi:10.1001/archdermatol.2012.812 
18. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic 
dermatitis: section 3. Management and treatment with phototherapy and systemic 
agents. J Am Acad Dermatol. 2014;71(2):327-349. doi:10.1016/j.jaad.2014.03.030 
19. Silverberg JI, Kantor R. The Role of Interleukins 4 and/or 13 in the Pathophysiology and 
Treatment of Atopic Dermatitis. Dermatol Clin. 2017;35(3):327-334. 
doi:10.1016/j.det.2017.02.005 
20. Simpson E, Bissonnette R, Eichenfield LF, et al. The Validated Investigator Global 
Assessment for Atopic Dermatitis (vIGA-AD): the development and reliability testing of 
a novel clinical outcome measurement instrument for the severity of atopic dermatitis. J 
Am Acad Dermatol. 2020;83(3):839-846. doi:10.1016/j.jaad.2020.04.104 
21. Simpson EL, Imafuku S, Poulin Y, et al. A Phase 2 randomized trial of apremilast 
in patients with atopic dermatitis. J Invest Dermatol. 2019;139(5):1063-1072. 
doi:10.1016/j.jid.2018.10.043 
22. Slater NA, Morrell DS. Systemic therapy of childhood atopic dermatitis. Clin Dermatol. 
2015;33(3):289-299. doi:10.1016/j.clindermatol.2014.12.005 
23. Snyder A, Farhangian M, Feldman SR. A review of patient adherence to topical therapies 
for treatment of atopic dermatitis. Cutis. 2015;96(6):397-401. 
24. Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma 
Immunol. 2010;105(2):99-117. doi:10.1016/j.anai.2009.10.002 
25. Spina D. PDE4 inhibitors: current status. Br J Pharmacol. 2008;155(3):308-315. 
doi:10.1038/bjp.2008.307 
26. Staquis. Assessment report. Accessed October 2021. 
https://www.ema.europa.eu/en/documents/assessment-report/staquis-epar-public-
assessment-report_en.pdf. 
27. Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0). 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50 
28. Tello ED, Daudén, et al. Multidisciplinary management of the adverse effects of 
apremilast. Actas Dermo-Sifiliográficas (English Edition), 2021, 112.2: 134-141.  


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17 APPENDIXES 
The assessments and scales included in the appendixes are samples of what may be used during 
the study. The study-specific assessments and scales may be different. 
Appendix 1. Rajka and Hanifin Criteria for Atopic Dermatitis 
Appendix 2. Eczema Area Severity Index (EASI) 
Appendix 3. Investigator Global Assessment for Atopic Dermatitis (IGA-AD) 
Appendix 4. Body Surface Area 
Appendix 5. Peak Pruritus Numerical Rating Scale 
Appendix 6. Skin Pain Numerical Rating Scale 
Appendix 7. Sleep Disturbance Numerical Rating Scale 
Appendix 8. Patient Oriented Eczema Measure (POEM) 
Appendix 9. Patient Global Impression of Severity (PGIS) Scale 
Appendix 10. Patient Global Impression of Change (PGIC) Scale 
Appendix 11. Dermatology Life Quality Index (DLQI) 
Appendix 12. Pulmonary Status NRS in Patients with Asthma 
Appendix 13. The Columbia-Suicide Severity Rating Scale (C-SSRS) 
Appendix 14. The Hospital Anxiety and Depression Scale (HADS) 
Appendix 15. Protocol Amendment Summary 


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Appendix 1: Rajka and Hanifin Criteria for Atopic Dermatitis 
MAJOR FEATURES 
- Pruritus
- Chronic or chronically relapsing dermatitis
- Typical distribution of skin lesion
- Personal and/or family history of atopy
MINOR FEATURES
1. Xerosis: Rough skin surface, often with visible fine scaling, but without erythema, involving
at least 20% of body surface
2a. Ichthyosis vulgaris: Dryness of skin, with small, flaky, or branny scales, most obvious on 
extensor surfaces of limbs and sparing flexural creases 
2b. Palmar hyperlinearity: More than 5 prominent lines longer than 1 cm running across palm 
2c. Keratosis pilaris: More than 20 follicular, keratotic papules involving at least the 
posterolateral aspects of upper arms or thighs 
3. Immediate (type I) skin test reactivity: Positive skin prick test; white or red wheal with an area
of at least 50% of the histamine (10 mg/mL) control and not less than 3 mm (at site of
inoculation) 15 minutes after inoculation (Dreborg S, editor. Skin tests used in type I allergy
testing: position paper. Allergy 1989; Suppl 44:1-59.)
4. Elevated total serum IgE: Determined by fluoroimmunoassay with the following reference
values:
Age  
IgE kU/L 
Newborn  
<0.1 to 1.3 
6 weeks to 2 months  
0.1 to 4.9 
3 to 8 months   
0.4 to 16.3 
9 months to 4 years  
0.4 to 22.3 
5 to 19 years   
1.3 to 263 
Adult  
1.6 to 122 
5. Early age of onset: Symptoms of eczema before the age of 5 years
6a. Tendency toward cutaneous infections: At least 2 episodes of folliculitis, furunculosis, or 
impetiginization requiring antibacterial treatment, or verified herpes simplex infection during the 
past 12 months 
6b. Impaired cell-mediated immunity 
7a. Hand eczema: Pruritic lesions on 1 or both hands with erythema and papules/vesicles or 
scaling, with or without oozing, crusting, fissures, or lichenification 


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7b. Foot eczema: Pruritic lesions on 1 or both feet with erythema and papules/vesicles or scaling, 
with or without oozing, crusting, fissures, or lichenification 
8. Nipple eczema: Pruritic lesions on 1 or both nipples with erythema and papules/vesicles or
scaling, with or without oozing, crusting, fissures, or lichenification
9. Cheilitis: Scaling of 1 or both lips, with or without fissures, erosions, or crusts
10. Recurrent conjunctivitis: Conjunctival hyperemia, generally associated with discharge and
itching, provoked, on at least 2 different occasions, by exposure to airborne allergens
11. Dennie-Morgan infraorbital fold: Secondary crease in the lower eyelid affecting 1 or both
eyes, starting at inner canthus and extending beyond the midline of the pupil when gaze is
directed anteriorly with the head upright
12. Keratoconus: Diagnosed by ophthalmologist
13. Anterior subcapsular cataracts: Diagnosed by ophthalmologist
14. Orbital darkening: Subtle symmetric brownish to grayish or bluish discoloration of
periorbital skin
15a. Facial pallor: Skin pallor, often accentuated perinasally and periorally, as judged by a 
physician 
15b. Facial erythema: Erythema on cheeks, with neither papules nor prominent scaling 
16. Pityriasis alba: Hypopigmented scaling areas with or without erythema, round, or ovoid, with
a diameter exceeding 1 cm
17. Anterior neck folds: Prominent horizontal skin crease(s) on anterior aspect of neck, when
head is upright
18. Itch when sweating: Itching or scratching provoked by sweating, reported by patient, or
observed by parents
19a. Intolerance of wool: Itching or scratching provoked by wool contact, reported by patient, or 
observed by parents 
19b. Intolerance to lipid solvents: Dry and/or itchy skin or deterioration of eczema due to contact 
with lipid solvents (eg, soap, shampoo), reported by patient or observed by parents 
20. Perifollicular accentuation: Dermatitis enhanced around hair follicles in 2 or more areas with
a diameter more than 5 cm
21a. Skin reactions provoked by ingested food: Itching, erythema or whealing, or exacerbation of 
eczema, reported by patient or observed by parents 
21b. Skin reactions provoked by skin contact with food: Itching, erythema or whealing, or 
exacerbation of eczema, reported by patient or observed by parents 


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22a. Course influenced by environmental factors: Deterioration of eczema due to environmental 
factors not mentioned elsewhere in the minor criteria (Hanifin JM, Rajka G. Acta Derm Venereol 
Suppl [Stockh] 1980;92:44-7), such as seasonal variation, or exacerbation caused by upper 
respiratory tract infections, airborne allergens, and excessive water contact 
22b. Course influenced by emotional factors: Deterioration of eczema during periods of 
emotional stress as judged by patient or parents 
23a. White dermographism in nonlesional skin: Linear blanching of skin occurring within 
90 seconds of mechanical stroking of nonlesional skin with blunt instrument, diameter of white 
line exceeding that of instrument 
23b. White dermographism in lesional skin: Linear blanching of skin occurring within 
90 seconds of mechanical stroking of lesional skin with blunt instrument, diameter of white line 
exceeding that of instrument 
23c. Delayed blanch: Delayed blanch provoked (eg, by intradermal injection of methacholine) 
X1. Infra-auricular fissure: Fissure at lower attachment of the earlobe, affecting 1 or both ears, 
length greater than 2 mm 
X2. Angular cheilitis (perlèche): Scaling and fissure(s) at 1 or both corners (commissures) of the 
mouth, with or without crusting 
X3. Eczema of the scalp: Pruritic lesions on the scalp with erythema and papules/vesicles or 
scaling, with or without oozing, crusting, fissures, or lichenification 
X4. Scalp scaling without eczema: Fine, dry scaling on the scalp without erythema 
X5. Pulpite digitale: Dry, scaling, often erythematous skin on finger pulp, sometimes associated 
with fissures 
X6. Juvenile plantar dermatosis: Dry, scaling, often erythematous plantar skin, especially on the 
forefoot and big toe, sometimes associated with fissures 


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Appendix 2: Eczema Area Severity Index 
Eczema Area Severity Index 
The Eczema Area and Severity Index scoring system uses a defined process (Steps 1 to 5 below) 
to grade the severity of the signs of eczema and the extent of body surface area affected. The 
EASI assessment will exclude the scalp, palms, and soles from scoring. 
1. Select a body region:
Four individual body regions are assessed:
•
Head/neck
•
Trunk (includes the internal axillae and groin)
•
Upper limbs (includes the external axillae and hands)
•
Lower limbs (includes the buttocks and feet).
2. Assess the extent of eczema in that body region:
Area of Involvement: Each body region has potentially 100% involvement. Using the 
table below, give each respective body region a score of between 0 and 6 on the basis of 
the percentage involvement. Precise measurements are not required.
Percent 
involvement 
0 
1–9 
10–29 
30–49 
50–69 
70–89 
90–100 
Region score 
0 
1 
2 
3 
4 
5 
6 
3. Assess the severity of each of the 4 signs in that body region:
Erythema
Induration/papulation
Excoriation
Lichenification
4. Grade the severity of each sign on a scale of 0 to 3.
0 
Absent 
•
Take an average if the severity across the involved area.
•
Half points (1.5 and 2.5) may be used. 0.5 is not permitted.
If a sign is present, it should be at least mild. 
• Palpation may be useful in assessing edema/papulation as 
well as lichenification.
1 
Mild 
2 
Moderate 
3 
Severe 
5. Sum the scores for each of the 4 body region scores for a total score = (0-72).
Body 
region 
Erythema 
(0–3) 
Edema/ 
Papulation 
(0–3) 
Excoriation 
(0–3) 
Lichenification 
(0–3) 
Region 
Score 
(0–6) 
Multiplier 
Score 
per body 
region 
Head/ 
neck 
( + 
+ 
+ 
+ ) 
X 
× 0.1 
Trunk 
( + 
+ 
+ 
+ ) 
X 
× 0.3 
Upper 
extremities 
( + 
+ 
+ 
+ ) 
X 
× 0.2 
Lower 
extremities 
( + 
+ 
+ 
+ ) 
X 
× 0.4 
Final Eczema Area and Severity Index score is the sum of the 4 region scores: 
(0–72) 


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Appendix 3: Investigator Global Assessment for Atopic Dermatitis 
Status 
Score Definition 
Clear 
0 
Minor, residual hypopigmentation/hyperpigmentation, no erythema or 
induration/papulation, no oozing/crusting. 
Almost 
clear 
1 
Trace faint pink erythema, no induration/papulation and no 
oozing/crusting. 
Mild 
2 
Faint pink erythema with mild induration/papulation and no 
oozing/crusting. 
Moderate 
3 
Pink-red erythema with moderate induration/papulation with or without 
oozing/crusting. 
Severe 
4 
Deep or bright red erythema with severe induration/papulation with 
oozing/crusting. 
Adapted due to an FDA request from: Simpson E, Bissonnette R, Eichenfield LF, Guttman-Yassky E, King B, 
Silverberg JI, Beck LA, Bieber T, Reich K, Kabashima K, Seyger M, Siegfried E, Stingl G, Feldman SR, Menter A, 
van de Kerkhof P, Yosipovitch G, Paul C, Martel P, Dubost-Brama A, Armstrong J, Chavda R, Frey S, Joubert Y, 
Milutinovic M, Parneix A, Teixeira HD, Lin CY, Sun L, Klekotka P, Nickoloff B, Dutronc Y, Mallbris L, Janes JM, 
DeLozier AM, Nunes FP, Paller AS. The Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-
AD): The development and reliability testing of a novel clinical outcome measurement instrument for the severity of 
atopic dermatitis. J Am Acad Dermatol. 2020 Sep;83(3):839-846.  


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Appendix 4: Body Surface Area 
The BSA assessment estimates the extent of disease or skin involvement with respect to AD and 
is expressed as a percentage of total BSA. 
BSA is defined as all areas with eczematous lesional skin and does not include xerosis (dryness), 
ichthyosis, keratosis pilaris, urticaria, infection (unless there is underlying eczema), or 
postinflammatory pigmentation changes. 
Determine BSA using the patient’s hand (palm + fingers) = 1% BSA rule. 
The patient’s palm is measured from the wrist to the proximal interphalangeal and thumb. 
Estimate the number of palms it takes to cover the area affected by AD. Add up the number of 
palms to give a total estimate of the area covered in AD. 
Additional rules: 
1. When many small lesions are present, try to put several together to make 1 patient palm.
2. Only include the edge of current lesions, not areas that have cleared.
3. Double check to see if the area derived matches the “eyeball method” of estimation.


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Appendix 5: Peak Pruritus Numerical Rating Scale 
Peak Pruritus Numerical Rating Scale 
Numerical Rating Scale 
On a scale of 0 (no itching) to 10 (worst possible itching) …. 
…. how was your worst itching due to AD over the past 24 hours? Please select 1 number. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 


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Appendix 6: Skin Pain Numerical Rating Scale 
Skin Pain Numerical Rating Scale 
Numerical Rating Scale 
On a scale 0 (no pain) to 10 (worst pain imaginable) …. 
…. how was your skin pain in the past 24 hours? Please select 1 number. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 


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Appendix 7: Sleep Disturbance Numerical Rating Scale 
Sleep Disturbance Numerical Rating Scale 
Numerical Rating Scale 
On a scale 0 (no sleep loss related to signs/symptoms of atopic dermatitis to 10 (I cannot 
sleep at all because of the signs/symptoms of atopic dermatitis) …. 
…. how would you rate your sleep last night? Please select 1 number. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 


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Appendix 8: Patient Oriented Eczema Measure 
The Patient Oriented Eczema Measure is a tool used for monitoring atopic eczema severity. It is 
a measurement using patient-reported symptoms in eczema and focuses on the illness as 
experienced by the patient. 
Patient Oriented Eczema Measure 
(Questionnaire for Adults) 
Please circle one response for each of the 7 questions below about your eczema. Please leave 
blank any questions you feel unable to answer. 
1. Over the last week, on how many days has your skin been itchy because of the eczema?
No days  
1-2 days  
3-4 days  
5-6 days  
Every day
2. Over the last week, on how many nights has your sleep been disturbed because of the eczema?
No days  
1-2 days  
3-4 days  
5-6 days  
Every day
3. Over the last week, on how many days has your skin been bleeding because of the eczema?
No days  
1-2 days  
3-4 days  
5-6 days  
Every day
4. Over the last week, on how many days has your skin been weeping or oozing clear fluid
because of the eczema?
No days 
1-2 days
3-4 days
5-6 days
Every day 
5. Over the last week, on how many days has your skin been cracked because of the eczema?
No days  
1-2 days  
3-4 days  
5-6 days  
Every day
6. Over the last week, on how many days has your skin been flaking off because of the eczema?
No days  
1-2 days  
3-4 days  
5-6 days  
Every day
7. Over the last week, on how many days has your skin felt dry or rough because of the eczema?
No days  
1-2 days  
3-4 days  
5-6 days  
Every day.
Total Score (maximum 28): ____ 


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Appendix 9: Patient Global Impression of Severity Scale 
Patient Global Impression of Severity Scale 
Numerical Rating Scale 
On a scale "(0) no symptoms", "(1) very mild", "(2) mild" "(3) moderate", and "(4) 
severe" 
…. how would you describe overall atopic dermatitis symptoms over the past 24 hours on a 
single item? Please select 1 number. 
0 
1 
2 
3 
4 


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Appendix 10: Patient Global Impression of Change Scale 
Patient Global Impression of Change Scale 
Numerical Rating Scale 
On a scale "(1) very much improved, (2) much improved, (3) minimally improved, (4) no 
change, (5) minimally worse, (6) much worse, and (7) very much worse" 
…. how would you describe the change (if any) from the start of treatment in activity 
limitations, symptoms, emotions, and overall quality of life, related to your atopic dermatitis? 
Please select one number. 
1 
2 
3 
4 
5 
6 
7 


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Appendix 11: Dermatology Life Quality Index 
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK. Please tick (X) one box for each question. 
1.
Over the last week, how itchy, sore, painful, or stinging has your skin been?
Very much __ 
A lot__ 
A little__ 
Not at all__ Not relevant_ 
2.
Over the last week, how embarrassed or self-conscious have you been
because of your skin?
Very much__ 
A lot__ 
A little__
Not at all_ Not relevant_ 
3.
Over the last week, how much has your skin interfered with you going
shopping or looking after your home or garden?
Very much__ 
A lot__ 
A little __
Not at all_ Not relevant_ 
4.
Over the last week, how much has your skin influenced the clothes you wear?
Very much__
A lot__ 
A little__
Not at all_ Not relevant_ 
5.
Over the last week, how much has your skin affected any social or leisure
activities?
Very much__
A lot__
A little__
Not at all_ Not relevant_ 
6.
Over the last week, how much has your skin made it difficult for you to do
any sport?
Very much__
A lot__
A little__
Not at all_ Not relevant_
7.
Over the last week, has your skin prevented you from working or studying?
If “No”, over the last week how much has your skin been a problem at work
or studying?
Very much__ 
A lot__
A little__
Not at all_ Not relevant_
8.
Over the last week, how much has your skin created problems with your
partner or any of your close friends or relatives?
Very much__
A lot__
A little__
Not at all_ Not relevant_
9.
Over the last week, how much has your skin caused any sexual difficulties?
Very much__ 
A lot__ 
A little__ 


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Not at all_ Not relevant_ 
10. Over the last week, how much of a problem has the treatment for your skin
been, for example by making your home messy, or taking up time?
Very much__
A lot__
A little__
Not at all_ Not relevant_
__ Please check you have answered EVERY question. Thank you. 


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Appendix 12: Pulmonary Status Numerical Rating Scale in Patients with Asthma 
Numerical rating scale to assess the pulmonary status. Only for patients diagnosed with asthma. 
Pulmonary Status Numerical Rating Scale in Patients with Asthma 
Numerical Rating Scale 
On a scale 0 (no symptoms) to 10 (very bad symptoms) …. 
…. how were your symptoms due to asthma over the past 7 days? Please select 1 number. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 




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The following features should be rated with respect to the most severe type of 
ideation (i.e., 1-5 from above, with 1 being the least severe and 5 being the 
most severe). Ask about time he/she was feeling the most suicidal. 
  
Lifetime - Most Severe Ideation: _______ Type # (1-5) 
________________________________________ 
Description of Ideation 
 
Past 12 Months - Most Severe Ideation: _______ Type # (1-5) 
________________________________________ 
Description of Ideation 
 
Most 
Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or 
almost daily (5) Many times each day 
 
 
____ 
 
 
____ 
Duration 
When you have the thoughts how long do, they last? 
(1) Fleeting - few seconds or minutes 
(2) Less than 1 hour/some of the time 
(3) 1-4 hours/a lot of time 
(4) 4-8 hours/most of day 
(5) More than 8 hours/persistent or continuous 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you 
want to? 
(1) Easily able to control thoughts 
(2) Can control thoughts with little difficulty 
(3) Can control thoughts with some difficulty 
(4) Can control thoughts with a lot of difficulty 
(5) Unable to control thoughts 
(0) Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - 
that stopped you from wanting to die or acting on thoughts of suicide? 
(1) Deterrents definitely stopped you from attempting suicide 
(2) Deterrents probably stopped you 
(3) Uncertain that deterrents stopped you 
(4) Deterrents most likely did not stop you 
(5) Deterrents definitely did not stop you 
(0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or 
killing yourself? Was it to end the pain or stop the way you were feeling (in 
other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge, or a reaction from others? Or 
both? 
(1) Completely to get attention, revenge, or a reaction from others 
(2) Mostly to get attention, revenge, or a reaction from others 
(3) Equally to get attention, revenge, or a reaction from others and to end/stop 
the pain 
(4) Mostly to end or stop the pain (you could not go on living with the pain or 
how you were feeling) 
(5) Completely to end or stop the pain (you could not go on living with the 
pain or how you were feeling) 
(0) Does not apply  
____ 
____ 










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Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result 
of act. Behavior was in part thought of as method to kill oneself. Intent does not 
have to be 100%. If there is any intent/desire to die associated with the act, then it 
can be considered an actual suicide attempt. There does not have to be any injury or 
harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth, but gun is broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred 
clinically from the behavior or circumstances. For example, a highly lethal act that is 
clearly not an accident so no other intent, but suicide can be inferred (e.g., gunshot to 
head, jumping from window of a high floor/story). Also, if someone denies intent to 
die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself 
(like to relieve stress, feel better, 
get sympathy, or get something else to happen)? (Self-Injurious Behavior without 
suicidal intent) 
If yes, describe: 
 
Has subject engaged in Nonsuicidal Self-Injurious Behavior? 
Yes No 
□ □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the 
potentially self-injurious act (if not for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest 
any pills, this becomes an attempt rather than an interrupted attempt. Shooting: 
Person has gun pointed toward self, gun is taken away by someone else, or is 
somehow prevented from pulling trigger. Once they pull the trigger, even if the gun 
fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed, and 
taken down from ledge. Hanging: Person has noose around neck but has not yet 
started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but 
someone or something stopped you before you actually did anything? 
If yes, describe: 
 
Yes No 
□ □ 
 
 
 
Total # of interrupted 
 
______ 
 
Aborted or Self-Interrupted Attempt: 
When person begins to take steps toward making a suicide attempt but stops 
themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops 
him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life, but 
you stopped yourself before you actually did anything? 
If yes, describe: 
 
Yes No 
□ □ 
 
Total # of 
aborted or self-
interrupted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include 
anything beyond a verbalization or thought, such as assembling a specific method 
(e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., 
giving things away, writing a suicide note). 
Yes No 
□ □ 
 
Total # of preparatory 
acts 
 






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Appendix 15: Protocol Amendment Summary 
Protocol version 1.0 dated 09 Dec 2021 was amended to create Protocol Amendment 1 (Protocol 
version 2.0) dated 05-May-2022; the amended version of the protocol supersedes version 1.0. 
The purpose of this amendment was to update the protocol per FDA recommendations related to 
subject inclusion/exclusion criteria, AESIs, and the Investigator Global Assessment for Atopic 
Dermatitis scale. Additional updates were made to the statistical analyses per the Sponsor’s 
statistician. 
• The definition of therapy-resistant AD was revised in exclusion criteria #1 with the 
following updates: 
o Specification of ≥2 treatment failures was added. 
o “Systemic AD therapy” was changed to “biologic therapy”. 
o (including phototherapy) was changed to “JAK inhibitor treatment or 
phototherapy”. 
• Clarification on the durations for documented history of topical medications was added to 
inclusion criterion #7 – “(at least 2 weeks for high potency topical corticosteroids), or as 
labeled”. 
• Additional information regarding prohibited emollients was included - “(however, 
emollients that contain pharmacologically active ingredients such as lactic acid, salicylic 
acid, urea, alpha-hydroxy acids, or fruit acids are not allowed from the Screening visit)”. 
• The following changes were made to the Schedule of Assessments table due to an 
administrative error in the original protocol. These have been changed to fit the packages 
for the study treatment. 
o A ±3-day window was changed to a ±1-day window (at certain visits). 
o “Optional: blood samples for drug PK profile” was removed from Week 8 and 
added at Week 16. 
o The requirement that patients should be in a fasted condition before sample 
collection at Baseline and Week 16 was removed. 
• The following sentence was added to Vital signs and Body Weight to align with the 
updates made to the AESI definitions– “A weight reduction of least 5% from baseline 
should be reported as a TEAE.”  
• Additional specifics on psychiatric conditions were added to exclusion criterion #8 - “(eg, 
current major depression with a score for depressive symptoms ≥15 of HADS at baseline, 
schizophrenia, suicidal behavior, psychiatric hospitalization within the prior year)”.  
• Additional wording was added to Medical History to emphasize the focus on psychiatric 
conditions “including any psychiatric treatment or hospitalization, covering”. 
• The definitions of AESIs were updated as follows: 
o any AE of occurrence of suicidal ideation or behavior, including a positive 
response to question 1 to 5 of C-SSRS, 
o a depression assessed as moderate or worse by the investigator or a score ≥ 15 in 
the HADS score, 


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o any grade 3 or higher psychiatric condition, and/or  
o any of the following GI TEAEs: vomiting, diarrhea with an increase of at least 4 
stools per day over baseline (Grade 2 CTCAE) for at least 3 days. 
• Additional wording was added to clarify that AESIs should be reported in the same 
manner as SAEs.  
• Dose modification language was revised to clarify that patients will be permanently 
discontinued from the study drug in the event that a TEAE meets the discontinuation 
criteria. 
• A typographical error was corrected in the Pregnancy section. The reference to “Inclusion 
Criterion 9” was changed to “Inclusion Criterion 8”. 
• Collection of PK samples were updated to collect and generate PK-profiles in patient 
within the psoriasis indication as follows: 
o PK samples were revised from “trough” to “plasma”. 
o The number of optional PK blood samples was increased from “4” to “4 or 5”. 
o The date of collection for optional PK samples was revised from Week 8 to Week 
16.  
o PK timepoints were revised from “1.5 hours” to “45 minutes” and “4.5 hours” to 
“4 hours” after intake of the study drug. 
o An additional optional 8-hour blood sample was added. 
• Statistical methods and planned analyses were revised as follows: 
o The ITT population was revised to include “all randomized patients who receive 
at least 1 dose of study drug” as the decision to withdraw patients cannot be 
biased by knowledge of the assigned treatment due to blinding. 
o Efficacy analysis was revised to remove the condition “using observed cases 
only” for consistency with the ITT and PP analyses. The only difference in the 
efficacy analysis should be the number of patients included. 
o The supportive analysis was clarified in the analysis of the primary efficacy 
endpoint. The sentence “The mixed model for repeated measures may be used as 
a supportive analysis.” was changed to “As a supportive analysis, a mixed model 
for repeated measures will be performed with treatment group, visit and 
treatment-by-visit interaction as factors and baseline EASI score by-visit 
interaction as a covariates”. 
o The analysis of secondary efficacy endpoints was revised for consistency and to 
allow for comparison of ITT analysis results between the primary endpoint and 
continuous secondary efficacy endpoints. The sentence “For the continuous 
secondary efficacy endpoints (peak pruritus NRS, BSA, PGIS, PGIC, sleep 
disturbance NRS, skin pain NRS, DLQI, and POEM examination), an analysis of 
covariance, with treatment and disease severity as factors and Baseline value as 
covariate, will be applied. The mixed model for repeated measures may be used 
as a supportive analysis if appropriate.” was changed to “ For the continuous 
secondary efficacy endpoints (peak pruritus NRS, BSA, PGIS, PGIC, sleep 
disturbance NRS, skin pain NRS, DLQI, and POEM examination), a mixed model 


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for repeated measures will be performed similar to the supportive MMRM for the 
primary endpoint. 
o PK analysis was revised from “trough” to “plasma”. 
• Appendix 3 was modified as follows: 
o The definition for Status of “Almost clear” / Score=1 was revised from “Trace 
faint pink erythema, with barely perceptible induration/papulation and no 
oozing/crusting” to “Trace faint pink erythema, no induration/papulation and no 
oozing/crusting”. 
o As a result of the above change to the wording of the scale, the word “Validated” 
was removed from the title of the scale throughout. 
 
Protocol version 2.0 dated 05 May 2022 was amended to create Protocol Amendment 2 (Protocol 
version 3.0) dated 14 April 2023; the amended version of the protocol supersedes version 2.0. 
The purpose of this amendment was to update the protocol per notification letter dated 09-FEB-
2023 for adjustment of laboratory ranges in exclusion criterion No. 14, the update of the 
Investigators Brochure for orismilast version 15, dated 05. April 2023 and learnings from the 
recently completed clinical phase 2b trial, UNI50001-203, with orismilast in patients with 
moderate to severe psoriasis. 
• General safety information regarding the use of orismilast is updated with the overall 
results from the UNI50001-203 trial in psoriasis patients, according to the updated 
Investigators Brochure version 15. 
• The clinical risks and benefits of orismilast has been updated according to the recent 
learnings for the UNI50001-203 trial in patients with psoriasis and update of the 
Investigators Brochure version 15. 
• The exclusion criteria no. 14 on absolute neutrophil count and absolute lymphocyte count 
are by mistake not consistent with the reference range of the central laboratory and was 
corrected per notification letter dated 09. February 2023, as follows:  
o Absolute neutrophil count of less than 3.0x109 /L (less than 3000/mm3) was 
corrected to the lower normal range of the Central Laboratory (LNR) i.e. 1.7 x 
109 /L (1700/mm3). 
o Absolute lymphocyte count of less than 1.0 x 109 /L (less than 1000/mm3) was 
corrected to the lower normal range of the Central Laboratory (LNR) i.e. 0,9 x 
109 /L (900/mm3). 
• The section regarding treatment discontinuation has been updated to more clearly state 
the requirement that if a patient experiences a TEAE assessed as Grade 3 or higher using 
the unique clinical descriptions of severity (Grade 2 or higher for the SOC of cardiac 
disorders) according to CTCAE version 5, the patient should be permanently 
discontinued from the study drug and not receive additional doses. 
• Planned dosing schedule and adjustments has been described in more detail. This to help 
guide the Investigator in case of temporarily decreasing the dosage regimen if GI or other 
AEs considered probably or definitely related to the study drug are reported with a 
severity not compatible with maintaining the treatment as per-protocol. 
o A section for planned dosing schedule – Titration over a maximum of 2 weeks has 
been created. 


UNION therapeutics A/S  
 UNI50001-202 
Orismilast  
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o A section describing the short dose reduction during the titration period has been 
updated. 
o A section describing dose reductions and temporary treatment discontinuations 
after the titration period has been created. 
• A section describing the examples of supportive treatment for side effects and medical 
treatment for tolerability issues that may arise during the treatment (e.g. metoclopramide 
for nausea/vomiting, loperamide for diarrhea, acetaminophen/paracetamol and NASID 
for headache) have been added. 
• Safety blood samples for week 12 have been added in Table 4. Schedule of Assessments, 
to allow for closer monitoring of all safety laboratory assessments (hematology, serum 
chemistry, urinalysis) between weeks 8 and 16. 
• The adverse events section has been updated with details to emphasize that all AEs must 
be graded by using the CTCAE grading system version 5.0, with reference to the unique 
clinical descriptions of severity for each AE in the guidance document.  
• Table 6 has been added for selected unique clinical descriptions of severity of AEs. Only 
if an AE is not uniquely described in the CTCAE grading system, the general guidance 
for classification is to be used. 
• The adverse events of special interest section (AESI) have been updated with an 
additional general criterion to allow sponsor to follow any signal that may arise from 
Sponsors ongoing safety review during the trial that may need closer monitoring. 
• The Screening version of the Columbia Suicide Rating Scale in Annex 13 was the short 
version and initially inserted in error. The correct long version for Screening has been 
inserted. 

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Statistical Analysis Plan for Interventional Studies 
 
 
SAP Version Number: 2.0 
SAP Date: 26-Jul-2023 
 
Sponsor Name: UNION therapeutics A/S 
 
Protocol Number: UNI50001-202 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 2b Dose-
Ranging Study to Evaluate the Efficacy and Safety of Orismilast in Adults With Moderate to Severe Atopic 
Dermatitis 
 
Protocol Version and Date: 3.0, 14-Apr-2023 
 
Syneos Health Project Code: 7025424  
 
Authors: 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to UNION therapeutics A/S. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of UNION therapeutics 
A/S. However, this document may be disclosed to appropriate Institutional Review Board (IRB) and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 
 
 
 
 
 
 
 
 




Statistical Analysis Plan for Interventional Studies 
Sponsor: UNION therapeutics A/S; Protocol No.: UNI50001-202 
 
 
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I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
 
 
Name, Title   
Lead Biostatistician  
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
Name, Title 
Senior Reviewing Biostatistician 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
UNION therapeutics A/S Approval 
  
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 


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Table of Contents
Revision History..........................................................................................................................2
Approvals ..................................................................................................................................3
Glossary of Abbreviations...................................................................................................7
Purpose............................................................................................................................10
Study Objectives ..............................................................................................................11
Study Details/Design........................................................................................................12
Endpoints .........................................................................................................................17
Analysis Populations ........................................................................................................19


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General Aspects for Statistical Analysis ...........................................................................20
Demographic, Other Baseline Characteristics and Medication .........................................22
Efficacy ............................................................................................................................25
Pharmacokinetics.............................................................................................................29
Pharmacodynamics..........................................................................................................30
Safety...............................................................................................................................31


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Interim Analyses...............................................................................................................36
Changes from Analysis Planned in Protocol.....................................................................37
Reference List..................................................................................................................38
Programming Considerations ...........................................................................................39
Quality Control .................................................................................................................44
Index of Tables.................................................................................................................45
Index of Figures................................................................................................................54
Index of Listings ...............................................................................................................56
Shells ...............................................................................................................................58
Appendices ......................................................................................................................59








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Purpose
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives based on Protocol v2.0.
Responsibilities
Syneos Health will perform the statistical analyses and is responsible for the production and quality 
control of all tables, figures and listings.
Timings of Analyses
The primary analysis of safety and efficacy and the pharmacokinetic analysis are planned after all 
patients complete the final study visit or terminate early from the study.


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Study Objectives
Primary Objective
The primary objective is to evaluate the efficacy and safety of a modified-release orismilast tablet versus 
placebo in patients aged at least 18 years with moderate to severe atopic dermatitis (AD). 
Secondary Objectives
The secondary objectives are to evaluate the dose response of orismilast and identify the dose to be 
further evaluated in a Phase 3 program.
Exploratory Objectives
The exploratory objectives are to:
x
Evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters relevant to AD.
x
Evaluate the effect of orismilast on the pulmonary status and course of the disease in patients with 
asthma.


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Study Details/Design
Brief Description
This multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2b dose-ranging 
study is designed to assess the efficacy and safety of modified-release orismilast compared with placebo 
in patients aged at least 18 years with moderate to severe AD. Efficacy and safety outcomes will be 
evaluated to select an appropriate orismilast dose for subsequent Phase 3 studies. The study will be 
conducted at approximately 48 centers in Europe and the United States.
After a Screening visit up to 28 days before Baseline, approximately 210 patients will be assigned 
randomly in a 1:1:1:1 ratio to receive 1 of the 3 orismilast doses (20 mg, 30 mg, or 40 mg) or placebo BID 
for 16 weeks, with a 4-week follow-up visit. Administration will begin at Baseline with a dose titration 
period of up to 2 weeks’ duration depending on the dose level. The maximum duration of study 
participation for each patient is approximately 24 weeks.
Patients will be seen at the site at Screening, Baseline (Day 1), and Weeks 1, 2, 4, 8, 12, 16 (EOT visit), 
and 20 (Follow-up visit, 4 weeks after treatment completion or discontinuation). The visit at Week 1 can 
be conducted via a telemedicine procedure at the Investigator’s discretion.
Patients who have been diagnosed with moderate to severe AD for a minimum of 1 year (before the 
Screening visit) using the Hanifin and Rajka criteria with affected BSA of at least 10%, Eczema Area and 
Severity Index (EASI) score of at least 16, and Investigator Global Assessment for Atopic Dermatitis (IGA-
AD) grade of at least 3 at the screening and baseline visits will be included in the study. Patients must 
also have a documented history of inadequate response to treatment with topical medications given for at 
least 4 weeks (at least 2 weeks for high potency topical corticosteroids), or as labeled, or for whom topical 
treatments are otherwise medically inadvisable.
At Screening, Baseline and at each visit from Week 2 onwards, EASI, affected body surface area (BSA), 
and IGA-AD will be assessed. BSA is defined as all areas with eczematous lesional skin and does not 
include xerosis (dryness), ichthyosis, keratosis pilaris, urticaria, infection (unless there is underlying 
eczema), or postinflammatory pigmentation changes. If patients need to manage areas with dry skin 
and/or pruritus, they are allowed to continue using their current emollient. However, emollients that 
contain pharmacologically active ingredients such as lactic acid, salicylic acid, urea, alpha-hydroxy acids, 
or fruit acids are not allowed from the Screening visit. The severity of itch will be assessed by peak 
pruritus numerical rating scale (NRS) at each visit from baseline to end of the treatment. Disease 
symptoms will be assessed by Patient Oriented Eczema Measure (POEM) scores at Baseline and at the 
Weeks 2, 4, 8, 12, 16, and 20 visits. Quality of life related to the disease will be assessed by Dermatology 
Life Quality Index (DLQI) scores at Baseline and at the Weeks 8, 16, and 20 visits. Pulmonary disease 
status will be assessed in patients with asthma by pulmonary status NRS at Baseline and at the Weeks 4, 
8, 12, 16, and 20 visits. The severity of disease will be assessed by Patient Global Impression of Severity 
(PGIS) at Baseline and at the Weeks 2, 4, 8, 12, 16, and 20 visits and Patient Global Impression of 
Change (PGIC) scores at the Weeks 2, 4, 8, 12, 16, and 20 visits. In addition, the sleep disturbance NRS 
and skin pain NRS will be administered at Baseline and at the Weeks 1, 2, 4, 8, 12, 16, and 20 visits.
Safety evaluations include medical history, AEs, laboratory and vital sign assessments, physical 
examination including body weight and height, BMI, 12-lead ECG, and mood change evaluations by the 
patient (HADS score) and suicidal behavior and ideation evaluation by the Investigator (C-SSRS).
Before administration of the study drug at Baseline (Day 1) and Weeks 4, 8, and 16, blood will be 
collected for orismilast and the major human metabolites LEO 40815 and LEO32728 for PK concentration 
determination. In addition, noninvasive superficial skin sampling using tape stripping will be conducted on 


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a target lesion (lesional and nonlesional skin sample) at Baseline and Week 16 (only lesional skin 
sample) in all patients for proteomic analysis. See Figure 1 Study Design for the study design.
Figure 1 Study Design
Patient Selection
Inclusion Criteria
Patients are eligible to be included in the study only if all the following criteria apply at both the 
screening and baseline visits:
1.
Capable of giving signed informed consent, which includes compliance with the requirements and 
restrictions listed in the Informed Consent Form (ICF) and in the protocol.
2.
Male and female patients aged at least 18 years at the time of signing the ICF.
3.
Body weight of greater than 40 kg at the time of signing the ICF.
4.
Diagnosis of AD for a minimum of 1 year (before the Screening visit) using the Hanifin and Rajka 
criteria.
5.
Moderate to severe AD (affected BSA of at least 10%, IGA-AD grade of at least 3, and EASI 
score of at least 16) at the screening and baseline visits.
6.
Candidate for systemic treatment or phototherapy for AD.
7.
Patients having a documented history of inadequate response to treatment with topical 
medications given for at least 4 weeks (at least 2 weeks for high potency topical corticosteroids), 
or as labeled, or for whom topical treatments are otherwise medically inadvisable.


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8.
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result at 
the Screening visit and a negative urine pregnancy test result at the Baseline visit. In addition, 
sexually active WOCBP must agree to use a highly effective method of contraception throughout 
the study and until at least 4 weeks after the end of study treatment. Highly effective methods of 
contraception are those that have a failure rate of less than 1% per year (when implemented 
consistently and correctly and when applicable, in accordance with the product label) and include 
hormonal contraceptives (combined oral contraceptive, patch, vaginal ring, injectable, or 
implantable); progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable); intrauterine devices or systems; self or 
partner vasectomy; or bilateral tubal ligation. Patients must have been on a stable dose of 
hormonal contraceptives for at least 4 weeks before the Baseline visit. Abstinence from 
heterosexual intercourse is an accepted method of contraception if it is the patient’s lifestyle and 
is practiced for the duration of the study. Note: A woman of nonchildbearing potential is defined 
as a woman with surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or a woman in a postmenopausal status, defined as cessation of menses for at 
least 12 consecutive months without an alternative medical cause and a confirmatory follicle-
stimulating hormone test result or as cessation of menses for at least 24 consecutive months 
without an alternative medical cause.
Exclusion Criteria
Individuals meeting any of the following criteria at screening or baseline are ineligible to participate in 
this study:
1.
Therapy-resistant AD, defined as ≥2 treatment failures due to inadequate efficacy within the past 
2 years of any biologic therapy, JAK inhibitor treatment or phototherapy administered at an 
adequate dose and duration according to the label or local/national guidelines. (Patients who 
stopped systemic treatment for reasons not related to lack of efficacy are not excluded).
2.
Unstable AD with acute deterioration, requiring rescue therapy for AD within 4 weeks of the 
Screening visit or expected to require rescue therapy within 2 weeks after randomization.
3.
History of allergy or hypersensitivity to any component of the study treatment.
4.
Currently have active forms of other inflammatory skin disease or have evidence of skin 
conditions (eg, psoriasis, seborrheic dermatitis, lupus) at the Baseline visit that would interfere 
with evaluation of AD or response to treatment.
5.
Active infection (eg, bacterial, viral, fungal) requiring treatment with systemic antibiotics within 4 
weeks of the Screening visit.
6.
Malignancy or history of malignancy except for treated (ie, cured) basal cell skin carcinoma.
7.
Any chronic or recurrent medical condition associated with serious GI diseases, such as 
inflammatory bowel disease.
8.
Any medical or psychiatric condition (eg, current major depression with a score for depressive 
symptoms ≥15 of HADS at baseline, schizophrenia, suicidal behavior, psychiatric hospitalization 
within the prior year) that, in the Investigator’s opinion, would preclude the patient from adhering 
to the protocol, completing the study per-protocol, and/or would place the patient at unacceptable 
risk while receiving the investigational therapy.
9.
Individuals with severe or uncontrolled asthma or any other concomitant condition that is likely to 
require systemic corticosteroid bursts during the study.
10. Any therapies and systemic treatments as described in protocol Table 3 “Nonallowed therapies 
and treatments” that do not comply with the indicated washout interval.
11. Any previous treatment with orismilast or failure of treatment for AD with apremilast or any other 
systemic PDE4 inhibitor.


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12. Any condition, including laboratory or ECG abnormalities, that places the patient at unacceptable 
risk to participate in the study or confounds the ability to interpret data from the study.
13. Severe hepatic impairment based upon medical history and laboratory abnormalities (eg, low 
albumin and abnormal bilirubin levels).
14. Any of the following abnormalities in clinical laboratory test results at Screening, as assessed by 
the study-specific laboratory and confirmed by a single repeat test, if deemed necessary:
a)
Absolute neutrophil count of less than 3.0 × 109/L (less than 3000/mm3).
b)
Hemoglobin of less than 10.0 g/dL or hematocrit less than 30%.
c)
Platelet count of less than 100,000 mm3.
d)
Absolute lymphocyte count of less than 1.0 × 109/L (less than 1000/mm3).
e)
Total bilirubin greater than 1.5 × the upper limit of normal (ULN); patients with a history of 
Gilbert’s syndrome may have direct bilirubin measured and would be eligible for this 
study provided the direct bilirubin result is less than or equal to the ULN.
f)
Alanine aminotransferase or aspartate aminotransferase greater than 2.5 × the ULN.
g)
Serum creatinine greater than or equal to 1.5 mg/dL. For patients with a value of greater 
than or equal to 1.5 mg/dL, if their creatinine clearance is at least 60 mL/min (calculated 
using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation), 
enrollment may be allowed.
15. History or evidence of hepatitis B virus infection at Screening. Patients with a positive hepatitis B 
surface antigen result are excluded. For patients with an isolated positive antihepatitis B core 
antibody result, the hepatitis B surface antibody result must also be positive to be eligible for this 
study.
16. History or positive test result for hepatitis C virus (HCV) antibody, indicating ongoing infection, at 
Screening. Confirmatory testing for HCV RNA will be conducted for patients who have a positive 
test result. Patients who have a negative result for HCV RNA will be eligible to participate in the 
study.
17. History of positive HIV test result or congenital or acquired immunodeficiency (eg, common 
variable immunodeficiency disease). Patients who are positive for HIV antibodies (HIV-1 or HIV-
2) at Screening are excluded from the study.
18. Suicidal ideation or behavior in the past 12 months as indicated by a positive response (yes) to 
question 4 or 5 on the C-SSRS completed at the Screening visit or at Baseline.
19. Pregnant or breastfeeding.
20. History of alcohol or substance abuse within 6 months before Baseline that, in the opinion of the 
Investigator, will preclude participation in the study.
21. Institutionalized by court order or by local authority.
22. Regular use (more than 2 visits per week) of a tanning booth/parlor.
Determination of Sample Size
Approximately 210 patients will be randomly assigned to receive orismilast 20 mg, 30 mg, or 40 mg BID 
or placebo for 16 weeks.
This sample size is based on assumptions that there is a difference of 25.0% in the percent change from 
baseline in EASI scores between each orismilast dose group with placebo, respectively, and that the 
common standard deviation in the percent change from baseline in EASI score is 43%. Using a 2-sided 2-
sample t-test, 47 patients in each treatment group (188 in total) will achieve a power of 80% at the 
significance level of 5%. To account for an early dropout rate of approximately 10%, an additional 22 
patients will be randomized.


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Treatment Assignment and Blinding
Randomization will occur before the first study treatment administration, at the Baseline visit. Patients will 
be assigned randomly in a 1:1:1:1 ratio to 1 of 3 orismilast dose groups (20 mg, 30 mg, or 40 mg) or 
placebo. The randomization is stratified by site. All patients will be assigned to randomized study 
treatment using an Interactive Web Response System (IWRS).
A randomization list will be used to assign the treatments to each patient. The randomization list will be 
kept secured with access restricted to only the designated personnel directly responsible for labeling and 
handling the study drug until the study blind is broken at the end of study (database lock). 
To facilitate the double blinding, the tablets will be packaged in the same type of blister, and the active 
and placebo tablets will have the same appearance (in terms of size, form, weight, and color). One dose 
consists of 2 identical tablets (a 10 mg or 30 mg orismilast tablet or a matching placebo tablet).
Blinding codes should only be broken in emergency situations for reasons of patient safety. The patient 
for whom the blind has been broken will be discontinued from the study and undergo the early termination 
procedures. The primary reason for discontinuation (the event or condition which led to the unblinding) 
will be recorded.
The Sponsor’s safety staff may unblind the study drug assignment for any patient with an SAE. If the SAE 
requires that an expedited regulatory report be sent to 1 or more regulatory agencies, a copy of the report 
identifying the patient’s study drug assignment may be sent to investigators in accordance with local 
regulations and/or Sponsor policy. 
Administration of Study Medication
The patients will receive the study drug at the site directly from the Investigator or designee. The date of 
the first dose should be recorded in the source documents and recorded in the eCRF. At all site visits 
beginning with the Week 2 visit, patients will return all study drug, including packaging, dispensed at the 
previous visit, and it will be documented using the IWRS.
The patients will self-administer the study drug at home, and compliance with the protocol will be 
assessed at each visit beginning with the Week 2 visit. Compliance will be assessed by direct questioning 
and counting returned tablets during the site visits and documented in the source documents and relevant 
form. Deviation from the prescribed dosage regimen should be recorded.
A record of the quantity of study drug dispensed to and administered by each patient must be maintained 
and reconciled with study drug and compliance records. Study drug administration dates, including dates 
for administration delays and/or dose reductions, will also be recorded. Discontinuation for 
noncompliance is at the investigator’s discretion and is to be noted on the eCRF.
Study Procedures and Flowchart
The Schedule of assessments is in Protocol Section 9. 


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Endpoints  
Primary Efficacy Endpoint
x
Percentage change in EASI score from Baseline at Week 16.
Secondary Efficacy Endpoints
Key Secondary Efficacy Endpoints:
x
Patients achieving 75% reduction in EASI (EASI75) response at Week 16.
x
Patients achieving a score of clear (0) or almost clear (1) and at least a 2-point improvement in IGA-
AD at Week 16.
Other Secondary Efficacy Endpoints:
x
Patients achieving a score of clear (0) or almost clear (1) and at least a 2-point improvement in IGA-
AD at Weeks 2, 4, 8, 12, and 20.
x
Patients achieving EASI75 at Weeks 2, 4, 8, 12, and 20.
x
Patients achieving 50% reduction in EASI (EASI50) and 90% reduction in EASI (EASI90) response at 
Weeks 2, 4, 8, 12, 16, and 20.
x
Percent change from Baseline in EASI at Weeks 2, 4, 8, 12, and 20.
x
Change from Baseline in the peak pruritus NRS score at Weeks 1, 2, 4, 8, 12, 16, and 20.
x
Patients achieving at least a 4-point improvement in the peak pruritus NRS from baseline at Weeks 1, 
2, 4, 8, 12, 16, and 20 among patients with a baseline score ≥4.
x
Change from Baseline in affected BSA at Weeks 2, 4, 8, 12, 16, and 20.
x
Change from Baseline in DLQI score at Weeks 8, 16, and 20.
x
Change from Baseline in POEM score at Weeks 2, 4, 8, 12, 16, and 20.
x
Change from Baseline in PGIS score at Weeks 2, 4, 8, 12, 16, and 20.
x
PGIC score at Weeks 2, 4, 8, 12, 16, and 20.
x
Change from Baseline in sleep disturbance NRS score at Weeks 1, 2, 4, 8, 12, 16, and 20.
x
Change from Baseline in skin pain NRS score at Weeks 1, 2, 4, 8, 12, 16, and 20.
Exploratory Endpoints
x
Patients achieving at least a 2-point improvement in the peak pruritus NRS from baseline at Weeks 1, 
2, 4, 8, 12, 16, and 20 among patients with a baseline score ≥4.
x
Change from Baseline in pulmonary status NRS in patients with asthma at Weeks 4, 8, 12, 16, and 
20.
x
Patients achieving 100% reduction in EASI (EASI100) response at Weeks 2, 4, 8, 12, 16, and 20.
Pharmacokinetic Endpoint
x
Plasma levels of the drug and its metabolites at Weeks 4, 8, and 16.
Safety Endpoints
x
The occurrence, severity, and seriousness of treatment-emergent AEs (TEAEs) reported over the 16-
week Treatment Period and the 4-week Follow-up Period.


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x
Changes from Baseline in physical examination findings; vital signs measurements (body 
temperature, respiration rate, heart rate, and systolic and diastolic blood pressure measurements); 
and body weight over the 16-week Treatment Period and the 4-Week Follow-up Period.
x
Clinically significant abnormal changes in ECG findings over the 16-week Treatment Period.
x
Changes from Baseline in safety laboratory values (hematology, serum chemistry, and urinalysis) 
over the 16-week Treatment Period.
x
Change from Baseline in HADS score at each visit except Week 1.
x
C-SSRS score at each visit except Week 1.
Pharmacodynamic Endpoint
x
Change from Baseline in skin biomarkers at Week 16 collected via tape stripping and analyzed using 
proteomic methods.


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Analysis Populations
Randomized Population
The randomized population will include all patients randomized. Unless specified otherwise, this 
population will be used for patient listings and for summaries of patient disposition.
Safety Population
The safety population will include all randomized patients who receive at least 1 dose of study drug. The 
treatment group assignment in this population will be defined by the treatment actually received. This 
population will be used for the analysis of safety.
Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all randomized patients who receive at least 1 dose of 
study drug. The treatment group assignment will be designated according to initial randomization. The 
ITT population will serve as the basis for the analysis of efficacy.
Per-Protocol Population
The per-protocol (PP) population includes all randomized patients who receive at least 1 dose of study 
drug, have at least 1 post-Baseline EASI assessment, and who do not have any major protocol deviations 
affecting efficacy analysis. The treatment group assignment in this population will be designated 
according to initial randomization. Efficacy analysis for primary and key secondary endpoints will be 
repeated on the PP Population.
Protocol Deviations
Protocol deviation management at Syneos Health is detailed in Protocol Deviation and Non-compliance 
Management (3101.W02). For details on the process for defining analysis datasets refer to (Blind) Data 
Review and Definition of Analysis Sets SOP (3911). The Protocol deviation criteria are graded as minor 
and major.
Patients with a major protocol deviation affecting efficacy analysis will be excluded from the PP population. 
The list of major protocol deviations potentially leading to PP population exclusion includes at least the 
following deviations:
x
Violations of inclusion or exclusion criteria.
x
Use of disallowed medication (that may influence the interpretation of efficacy results).
x
Non-compliance with study medication intake: less than 80% of total number of tablets during entire 
treatment period or during the last 4 weeks.
x
Major deviation from study specific instructions/procedures.
The final list of patients who are to be included in the PP population will be determined at the Blinded 
Data Review Meeting (BDRM). The BDRM will occur when all or nearly all queries have been resolved 
and the database is near to final. For the BDRM meeting, a BDRM Preparation Plan will be prepared. 
This plan will detail further the types of protocol deviation criteria and will include, as a minimum: 1) the 
exact criteria which will be used to determine if a patient will be excluded from the PP population; 2) the 
listings which will be prepared for sponsor review in order to determine which patients to exclude from the 
PP population. Details of patient specific exclusions from the PP population will be detailed in the BDRM 
Report.


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General Aspects for Statistical Analysis
General Methods
x
All statistical analyses will be conducted using SAS® for Windows® Version 9.4 or higher.
x
All data will be listed, and summary tables will be provided. 
x
In general, unscheduled visit data will be listed, but not included in the summary tables by visit. 
Unscheduled data will be included to identify the worst-case post-baseline for safety shift tables. 
Unscheduled data will be used in the statistical analysis to avoid missing data.
x
Summary statistics will be presented by treatment group. For continuous variables, data will be 
summarized with the number of patients (N), mean, standard deviation, median, Q1, Q3, minimum, 
and maximum by treatment group. For categorical variables, data will be tabulated with the number 
and proportion of patients for each category by treatment group.
x
There will be no adjustment for multiplicity, thus all p-values reported will be nominal.
x
The randomized population will be used for patient data listings. 
x
Unless otherwise specified, listings will be sorted by randomized treatment, subject number and
chronologically by assessment date and time.
x
Missing records will be omitted from the listings, and missing data within a record will be left blank.
x
Unless otherwise specified, baseline summaries will be presented for each treatment (Placebo, 
Orismilast 20 mg BID, Orismilast 30 mg BID, Orismilast 40 mg BID) and for Overall. Safety 
summaries will be presented for each treatment (Placebo, Orismilast 20 mg BID, Orismilast 30 mg 
BID, Orismilast 40 mg BID) and for Orismilast Total. Efficacy summaries will be presented for each 
treatment (Placebo, Orismilast 20 mg BID, Orismilast 30 mg BID, Orismilast 40 mg BID).
Key Definitions
Treatment period
The Treatment Period for this study is 16 weeks, from Day 1 to Week 16 (112 ± 3 days).
Study day
If the event date ≥ date of first dose of IP, study day = event date – date of first dose of IP + 1.
If the event date < date of first dose of IP, study day = event date – date of first dose of IP.
Baseline Value
Baseline value will be defined as the last non-missing value recorded prior to the first intake of study 
treatment.
Change from Baseline (CFB)
CFB = Post-baseline value – Value at baseline
Percentage change from baseline (PCFB)
PCFB = ((Post-baseline value – Value at baseline) / Value at baseline)*100%.


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Missing Data
Missing data will be treated as missing, except in the following cases.
Efficacy
To ensure that we evaluate the effect of study treatment (and not the effect of study treatment + 
disallowed medications (e.g. topical medications)), patients efficacy data collected after date of first 
disallowed medication (which may influence efficacy assessments e.g. any medication given to control 
unacceptable atopic dermatitis symptoms) will be ‘set to missing’ / ‘treated as missing’ in the primary 
statistical analysis . If disallowed medication is introduced the same day as an efficacy assessment, the 
efficacy assessment will be used as is.
Missing data and data 'treated as missing’ for the primary analysis of primary and secondary binary 
endpoints will be handled with the multiple imputation method, assuming Missing At Random (MAR) 
within arm. 
For categorical efficacy endpoint based on a continuous variable, the multiple imputation will be first done 
for the continuous variable, then determine the category using the imputed values.
Secondary continuous endpoints will be analyzed based on observed data using an MMRM, thus using a 
modelling approach assuming MAR for missing data.
For a supportive analysis of key secondary efficacy endpoints missing data will be handled as non-
response.
Safety
• Missing AE relationship will be imputed by ‘definitely’.
• Missing AE severity will be imputed by ‘Grade 3’.
• Missing or incomplete dates in safety data:
In all listings, missing or incomplete dates will be left as they have been recorded. However, for
calculation / sorting / assignation based on dates, the following methods will be used:
I.
The most conservative approach will be systematically considered (i.e. if the onset date of an
AE/concomitant medication is missing or incomplete, it is assumed to have occurred during the 
treatment period (i.e. a TEAE for AEs) except if the partial onset date indicates differently).
II.
A missing/incomplete date of medical history or disease diagnosis will be assumed to have
occurred before any study treatment.
Visit Windows
If there are multiple planned assessments for any study procedure at a given time point, the latest non-
missing value will be used for summarization. Unscheduled assessments will be listed and will be used to 
flag baseline visit if this is the last non-missing assessment before the first dose of study drug, but 
unscheduled assessments will not be included in the summarization, unless to be used to avoid missing 
data at Week 16.
Pooling of Centers
Not applicable since no adjustment for center or by center analyses are planned.
Subgroups
Subgroup analyses only apply to some of the exploratory endpoints and are described in section 9.2.3.


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Demographic, Other Baseline Characteristics and Medication
Patient Disposition and Withdrawals
The following frequencies (number and percent) will be displayed for all patients screened, patients 
randomized, screen failures, and reasons for screen failure.”. 
The analysis populations will be summarized with counts and percentages by treatment group. This table 
will include the following: number of patients screened, patients randomized, patients in safety population, 
reasons for exclusion from the safety population, patients in ITT population, reasons for exclusion from 
the ITT population, patients in PP population, and reasons for exclusion from the PP population.
The following frequencies (number and percent) will be displayed for all patients in the randomized
population: patients in the safety population, patients in ITT population, patients in PP population, patients 
who completed the study (including follow-up), patients who discontinued early, study duration in days,
patients who completed study treatment, patients who discontinued study treatment early also presented 
by reason for early discontinuation. The denominators will be the number of randomized patients. 
A Kaplan-Meier plot of time to discontinuation of study treatment will be presented by treatment for the 
ITT population. Cumulative proportion of patients with discontinuation of study treatment by treatment 
group as a function of time since randomization will be presented for the ITT Population. Cumulative 
proportion of patients with discontinuation of study treatment by treatment group and reason for 
discontinuation as a function of time since randomization will be presented for the ITT population.
Listings of treatment assignments, including the subject’s identification, date and time of randomization, 
and assignment to treatment, will be presented. 
Patient disposition, COVID-19 visit impact, inclusion/exclusion criteria violations and exclusions from 
analysis populations will be listed by patient. 
Protocol Deviations
All protocol deviations (minor and major) observed during the conduct of the study will be listed. Major 
protocol deviations (patients with at least one major PD overall and split by PD category), and minor 
deviations (patients with at least one minor PD overall and split by PD category) will be summarized by 
treatment group for all randomized patients.
Demographic and Baseline Characteristics
Demographic and baseline characteristics, including age, sex, child-bearing potential, race, ethnicity, 
asthma diagnosis, disease duration, height, body weight, and body mass index (BMI) will be summarized 
for the ITT population using standard descriptive statistics. This table will be repeated for the PP 
population. 
Baseline efficacy assessments: EASI, IGA-AD, BSA, DLQI score, POEM, PGIS, skin pain NRS, sleep 
disturbance NRS, peak pruritus NRS, and pulmonary status NRS will be summarized for the ITT
population. No formal statistical comparisons between populations will be performed. This table will be 
repeated for the PP population. Demographics will be listed for all patients in the randomized population.


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Smoking and Alcohol History 
Smoking and alcohol history will be summarized for the ITT population using standard descriptive 
statistics and listed for all patients in the randomized population.
Medical History
Medical history, including surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) 24.0. Medical history and ongoing conditions will be summarized in separate tables for the ITT
population presenting the number and percentages of patients within each preferred term (PT) grouped 
by the system organ class (SOC). A patient with multiple occurrences of an event in a PT is counted only 
once. Medical history will be listed for all patients in the randomized population. 
Medication
The WHO Drug, March 2021, B3 will be used to classify prior and concomitant medications by therapeutic 
class and drug name. 
Prior medication is defined as any medication taken before the date of the first dose of study treatment. 
Concomitant medication is defined as any medication taken on or after the date of the first dose of study 
treatment. 
The use of prior medications, concomitant medications, and concomitant disallowed medications will be 
summarized by the number and percentage of patients for the ITT population. If a patient takes a specific 
medication multiple times or takes multiple medications within a specific therapeutic class, that patient
would be counted only once for the coded drug name or therapeutic class. 
A table will be provided showing patients receiving disallowed medications that may influence efficacy 
assessments at any time during the initial 16-weeks (e.g. topical treatments, systemic treatments, 
biologics or phototherapy) 
A figure will be provided with the cumulative proportion of patients over time receiving disallowed 
medication that may influence efficacy assessments. Patients will count as receiving disallowed 
medication that may influence efficacy from first initiation.
Prior medications, concomitant medications, and concomitant disallowed medications will be listed for all 
patients in the randomized population.
A summary table will be provided for previous treatments for atopic dermatitis (e.g. prior systemics, 
biologics). Previous treatments for atopic dermatitis and reasons for stopping previous treatments for 
atopic dermatitis will be summarized for the ITT population. Previous treatments for atopic dermatitis will 
be listed for all patients in the randomized population.
Extent of Exposure
Study drug administration data, study drug accountability data, and study drug compliance check data will 
be listed for all patients in the ITT population.


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Treatment Compliance 
When patients receive the study drug at the site, they will receive it directly from the investigator or 
designee who will also give instruction for dose administration. The date of study drug dispensed to the 
patients will be recorded. At all site visits, patients will return all study drug, including packaging, 
dispensed at the previous visit.
The dose of study drug and study patient identification will be confirmed at the time of administration by a 
member of the study site staff other than the person administering the study drug.
When patients self-administer the study drug at home, compliance with the protocol will be assessed at 
each visit. Compliance will be assessed by direct questioning and counting returned tablets during the 
site visits. Deviation from the prescribed dosage regimen should be recorded.
A record of the quantity of study drug dispensed to and administered by each patient must be maintained 
and reconciled with study drug and compliance records. Study drug administration dates, including dates 
for administration delays and/or dose reductions will also be recorded.
Number of patients with missed doses, number of missed doses, reasons for dose interruption, duration 
of exposure, compliance rate and compliance rate until treatment discontinuation will be summarized 
overall by treatment group for the ITT population and separately for the titration period.


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Efficacy
For inferential analyses of primary and secondary efficacy endpoints, each active treatment group will be 
compared with the placebo group.
Patients who receive topical medications will be allowed to continue with study treatment while patients 
receiving systemic medication will be discontinued from study treatment.  This means that some patients 
(particularly in the less effective arms) will have efficacy assessments collected after receiving topical 
medicals which may influence efficacy assessments. 
To ensure that the primary analyses evaluate the effect of study treatment (and not the effect of study 
treatment + disallowed medications (e.g. topical medications) the following approach will be taken: 
Patients efficacy data collected after date of first disallowed medication (which may influence efficacy 
assessments e.g. any medication given to control unacceptable atopic dermatitis symptoms) will be first 
‘set to missing’ / ‘treated as missing’. If disallowed medication is introduced the same day as an efficacy 
assessment, the efficacy assessment will be used as is. Thereafter, the below described analyses should 
applied.
Primary and secondary efficacy endpoints are to be assessed in the ITT Population. Missing data and 
data 'treated as missing’ for the primary analysis of primary and secondary binary endpoints will be 
handled with the following multiple imputation method: Intermittent missing data will first be imputed using 
the MCMC method implemented with the SAS MI procedure, which is appropriate for non-monotonic 
missing data. Data missing (including ‘treated as missing’) will then be multiply imputed with the SAS MI 
procedure using a regression statement (number of imputations: 50, seed: 3628479. At each time point, 
missing data will be assumed to be MAR and to follow a distribution similar to scores for patients who are 
still in the study and randomized to the same treatment group.
For categorical efficacy endpoints based on a continuous variable, the multiple imputation will be first 
done for the continuous variable, then determine the category using the imputed values. Efficacy 
analyses will be repeated on the PP Population for primary and key secondary endpoints.
When appropriate, the raw parameter, its change from Baseline, and percentage change from Baseline 
will be summarized.
Primary Efficacy Endpoint and Analysis
The primary endpoint in this study is the percentage change in EASI score from Baseline at Week 16.
The primary endpoint (primary analysis) will be analyzed using analysis of covariance (ANCOVA) with 
treatment group as factor and Baseline EASI as covariate. Each active treatment dose will be compared 
with placebo. No adjustment for multiplicity will be made and the 0.05 level of significance will be used to 
claim efficacy compared with placebo. Least square means and the 95% confidence interval of the 
difference between each active treatment and placebo will be calculated. 
The primary analysis set will be the ITT population with multiple imputation approach to handle missing 
values. The same analyses will be repeated for Weeks 20, 12, 8, 4 and 2. These analyses will be 
repeated on the PP population.
LS Mean (+/-SE) percentage change of EASI score will be presented graphically over time from Baseline 
to Week 2, 4, 8, 12, 16, and 20.  


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Actual values, change from baseline values, and percentage change from baseline of EASI will be 
summarized by visit using descriptive statistics and presented graphically over time.
The mixed model for repeated measures (MMRM) will be used as a supportive analysis with data 
collected after date of first disallowed medication 'treated as missing'. If disallowed medication is 
introduced the same day as an efficacy assessment, the efficacy assessment will be used as is. Some 
patients may not have any post-baseline data collected before initiation of disallowed medication. To 
ensure that all patients are included in the analysis, the baseline value for these patients should be 
carried forward as the first post-baseline assessment, corresponding to imputing a change of 0 at the first 
post-baseline assessment. The MMRM model will be implemented using SAS PROC MIXED with 
treatment group, visit, and treatment-by-visit interaction as factors and baseline EASI score by-visit 
interaction as a covariate. A restricted maximum likelihood (REML) will be used. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom and adjust standard errors. 
Least Squares Means Estimates and 95% confidence intervals will be given for each treatment group and 
for the difference between treatment groups (here also p-values will be presented). As an additional 
supportive analysis, this MMRM analysis will be repeated, with all observed data included irrespectively of 
disallowed medication or discontinuation of study drug.
EASI (including change from baseline values, percentage change from baseline values, EASI50, EASI75, 
and EASI90) will be listed.
Secondary Efficacy Endpoints and Analyses
Continuous secondary efficacy endpoints will be analyzed based on observed data prior to first initiation 
of disallowed medication using MMRM, using a modelling approach assuming MAR for missing data.
If 
disallowed medication is introduced the same day as an efficacy assessment, the efficacy assessment 
will be used as is.
The binary secondary efficacy endpoints will be analyzed using difference in proportions, comparing each 
active treatment group to placebo in the ITT population with handling of missing data and data 'treated as 
missing’ as specified in Section 9. Response by treatment group and difference in response rate and p-
values compared to placebo will be presented. 
The secondary endpoints and the percentage change of BSA will be presented graphically over time from 
Baseline to Week 20. In addition, shift tables will be provided between Baseline and each visit for the 
IGA-AD distribution. The EASI percentage changes from Baseline will be plotted to identify where the 
best separation between treatments occur. These figures and tables are based on observed cases, thus 
purely descriptive.
Key Secondary Endpoints
•
Patients achieving 75% reduction in EASI (EASI75) response at Week 16.
•
Patients achieving a score of Clear (0) or Almost Clear (1) and an at least 2-point 
improvement in IGA-AD at Week 16.
In addition to absolute EASI scores, response to treatment is presented as a percentage response rate: 
EASI50, EASI75, and EASI90. EASI75 represents the percentage of patients who have achieved a 75% 
or more reduction in their EASI score from baseline.


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The key secondary endpoints (primary analysis) will be analyzed using difference in proportions,
comparing each active treatment group to placebo in the ITT population. Response by treatment group 
and difference in response rate and p-values compared to placebo will be presented. These analyses will 
be repeated on the PP population. As supportive analysis, this analysis will be repeated, with handling of 
missing data and data 'treated as missing’ as non-response. As an additional supportive analysis, for both 
key secondary endpoints, this analysis will be repeated with all observed data included irrespectively of 
disallowed medication or discontinuation of study treatment. Any other missing data should be imputed as 
non-response. In case of imbalance in baseline disease severity between treatment groups an additional 
supportive analysis stratifying for baseline IGA using a Cochran-Mantel-Haenszel (CMH) test will be 
performed. As an additional supportive analysis, for both key secondary endpoints, this analysis will be 
repeated (in a descriptive table and a table using non-response imputation if a score is missing or ‘treated 
as missing’)) by subgroups: baseline IGA (moderate / severe), body weight at baseline( <80, 80-100, 
≥100 kg) and region (US vs non-US).    
Actual values of IGA-AD will be summarized by visit using descriptive statistics and presented graphically 
over time.The percentage of patients with EASI75 and the percentage of patients achieving clear (0) or 
almost clear(1) will be presented graphically over time. These figures are based on observed cases, thus 
purely descriptive.
Other Secondary Endpoints
x
Patients achieving a score of clear (0) or almost clear (1) and at least a 2-point improvement in 
IGA-AD at Weeks 2, 4, 8, 12, and 20.
x
Patients achieving EASI75 at Weeks 2, 4, 8, 12, and 20.
x
Patients achieving EASI50 and EASI90 response at Weeks 2, 4, 8, 12, 16, and 20.
x
Percent change from Baseline in EASI at Weeks 2, 4, 8, 12, and 20.
x
Change from Baseline in the peak pruritus NRS score at Weeks 1, 2, 4, 8, 12, 16, and 20.
x
Patients achieving at least a 4-point improvement in the peak pruritus NRS from baseline at 
Weeks 1, 2, 4, 8, 12, 16, and 20 among patients with a baseline score ≥4.
x
Change from Baseline in affected BSA at Weeks 2, 4, 8, 12, 16, and 20.
x
Change from Baseline in DLQI score at Weeks 8, 16, and 20.
x
Change from Baseline in POEM score at Weeks 2, 4, 8, 12, 16, and 20.
x
Change from Baseline in PGIS score at Weeks 2, 4, 8, 12, 16, and 20.
x
PGIC score at Weeks 2, 4, 8, 12, 16, and 20.
x
Change from Baseline in sleep disturbance NRS score at Weeks 1, 2, 4, 8, 12, 16, and 20.
x
Change from Baseline in skin pain NRS score at Weeks 1, 2, 4, 8, 12, 16, and 20.
EASI50 represents the percentage of patients who have achieved a 50% or more reduction in their EASI
score from baseline. EASI90 represents the percentage of patients who have achieved a 90% or more 
reduction in their EASI score from baseline.
Continuous secondary efficacy endpoints will be analyzed using MMRM, similar to the supportive MMRM 
for the primary endpoint, i.e. based on observed data prior to first initiation of disallowed medication. 
The analysis on categorical secondary efficacy endpoints will be performed using difference in 
proprotions, comparing each active treatment group to placebo in the ITT population with handling of 
missing data and data 'treated as missing’ as specified in Section 9. Response by treatment group and 
difference in response rate and p-values compared to placebo will be presented.


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Actual values and change from baseline values of POEM, PGIS, sleep disturbance NRS and skin pain 
NRS will be summarized by visit using descriptive statistics and presented graphically over time. Actual 
values of PGIC will be summarized by visit using descriptive statistics and presented graphically over 
time. Actual values, change from baseline values and percentage change from baseline of BSA and DLQI 
will be summarized by visit using descriptive statistics and presented graphically over time. The 
percentage of patients with EASI50 and EASI90 will be presented graphically over time. These tables and 
figures are based on observed cases, thus purely descriptive. In addition a summary table presenting 
patients achieving reduction of DLQI score of ≥4 points at week 16 from baseline in patients in the ITT 
population with a baseline score ≥4 wil be provided.
POEM, PGIS, peak pruritis NRS, sleep disturbance NRS and skin pain NRS (including change from 
baseline values) will be listed. PGIC will be listed. BSA and DLQI (including change from baseline and 
percentage change from baseline values) will be listed.
Exploratory Endpoints
•
Patients achieving at least a 2-point improvement in the peak pruritus NRS from baseline at 
Weeks 1, 2, 4, 8, 12, 16, and 20 among patients with a baseline score ≥4.
•
Change from Baseline in pulmonary status NRS in patients with asthma at Weeks 4, 8, 12, 
16, and 20. 
•
Patients achieving 100% reduction in EASI (EASI100) response at Weeks 2, 4, 8, 12, 16, and 
20
All exploratory endpoints will be summarized descriptively in the ITT Population. A summary table of 
patients achieving EASI50, EASI75, EASI90, EASI100 and IGA 0/1 response at weeks 2, 4, 8, 12, 16 and 
20 will be provided. Peak pruritus NRS, pulmonary status NRS will be listed.


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Pharmacokinetics
Exploratory endpoint: Plasma levels of the drug and its metabolites at Weeks 4, 8, and 16.
Blood samples will be collected for measurement of concentrations of orismilast and its major metabolites
(LEO 40815 and LEO 32728) as specified in the SoA in Protocol Section 9 before the morning dose of 
the study drug. The concentration of study drug will be determined from the plasma samples using a 
validated analytical method. 
Blood sampling for measuring plasma levels: The patients will be instructed to self-administer the study 
drug approximately 12 hours prior to the planned blood collection for PK analysis. The date and time of 
the dose taken prior to the PK blood sampling will be collected and registered.
Blood sampling for calculation of PK profiles: In addition to the sample collected for measuring trough 
levels, patients will be offered optional participation in specific blood sampling for calculation of PK 
profiles. This additional procedure is voluntary for patients and patient’s consent will be obtained before 
collection of the blood samples. For PK profiling, 4 or 5 additional blood samples will be collected during 
each visit at Week 4 and Week 16. The patient will be instructed to take the next dose of the study drug in 
the clinic and blood samples will be taken at the following timepoints: 45 min, 2.5 hours (estimated Cmax), 
4 hours and 6 hours after intake of the study drug, as shown in the figure below. An additional optional 8-
hour blood sample will be collected if the patient agrees. The actual date and time of the study drug 
administration in the clinic and each blood sample collection will be recorded. 
Figure 2 Pharmacokinetic Blood Sample Collection
Abbreviations: H, hour; Lab, laboratory; PK, pharmacokinetic
The plasma levels of the drug and its metabolites will be summarized descriptively by visit and time 
categories: ‘before 12 hours’, ‘at 12 hours (+/- 15%), ‘after 12 hours’.
A listing of PK levels will be presented by treatment group, subject number, and collection date and time.


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Pharmacodynamics
Exploratory endpoint: Change from Baseline in skin biomarkers at Week 16 collected via tape stripping and 
analyzed using proteomic methods.
Stratum corneum skin samples will be collected using the tape stripping method to evaluate biomarker 
expression levels. Tape stripping is a minimally invasive, nonscarring approach utilizing serial adhesive 
films to capture the stratum corneum and the upper part of the granular layer. At Baseline, before 
administration of study drug, 1 lesional and 1 nonlesional area will be identified, and 20 consecutive skin 
samples will be collected from each area. At Week 16, the same procedure will be repeated only from the 
same lesional area sampled at Baseline. Details of stratum corneum skin samples’ storage, and shipping 
procedures are provided in a separate laboratory manual. Change from Baseline in skin biomarkers will be 
summarized descriptively.
A listing of skin biomarker results will be presented by treatment group, subject number, and collection 
date and time.


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Safety
All safety analyses will be conducted using the safety population. 
Safety will be assessed based on adverse event (AE) reports, physical examination, vital signs, ECGs, 
clinical laboratory data, HADS, and C-SSRS using descriptive statistics. 
No inferential statistical analyses are planned on the safety parameters of this study. 
Adverse Events
AEs for all patients in the safety population will be included in the AE summaries. 
Adverse events will be summarized by system organ class (SOC) and preferred term (PT) for each 
treatment and Orismilast total, based on the MedDRA dictionary version 24.0. Severity of AEs will be 
graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.
Any AEs that occur before dosing on study Baseline will be categorized as pretreatment events. TEAEs 
will be defined as those AEs that occur or worsen in severity after initial dosing and up to 7 days after the 
last dose of study drug.
Duration will be calculated for AEs that resolve as the difference between the resolution date and onset 
date plus 1 and expressed in days.
The summary tables will include the number of patients and the number of events. Percentages will be 
based on the number of patients in the safety population. For summaries by SOC and PT, a patient will 
be counted once at the SOC level and once at each PT within the SOC level. 
For summaries by SOC, PT, and maximum severity, a patient will be counted once at the highest severity 
level for which the event occurred at the SOC level and the highest severity level for each unique PT 
within that SOC level. Therefore, patients may only contribute once to each PT and once to each SOC 
level. 
The summaries presenting frequency of AEs by SOC and PT will be ordered by Orismilast total
descending frequency of SOC and then, within a SOC, by Orismilast total descending frequency of PT. 
The following tables will be provided:
•
An overall summary of the number of events and number and percentage of patients reporting 
TEAEs, related TEAEs (TEAEs recorded as “Relationship to study drug” = “Possibly” or Probably” 
or “Definitely”), serious TEAEs (TESAEs), TEAEs resulting in death, TEAEs of special interest, 
TEAEs leading to study drug discontinuation, TESAEs leading to study drug discontinuation, 
TEAEs by relationship and TEAEs by toxicity grade (including exposure adjusted incidence rates 
[EAIR]);.A similar summary will be presented starting within the dose titration period (initial 3
weeks).” (without EAIR).
•
TEAEs overall by system organ class and preferred term (including EAIR);
•
TEAEs overall by system organ class and preferred term starting within the dose titration period 
(initial 3 weeks) 
•
TEAEs by maximum toxicity grade, overall and by system organ class and preferred term; 
•
TEAEs by toxicity grade, overall and by system organ class and preferred term;


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•
TEAEs by maximum relationship to study medication, overall and by system organ class and 
preferred term; 
•
TEAEs by relationship to study medication, overall and by system organ class and preferred term; 
•
TEAEs leading to study drug discontinuation, overall and by system organ class and preferred 
term; 
•
TEAEs leading to study drug discontinuation, overall and by body weight at baseline system 
organ class and preferred term; 
•
TEAEs leading to study drug discontinuation, overall and by region, system organ class and 
preferred term; TEAE coded by MedDRA preferred term as diarrhoea, nausea, headache, 
dizziness and vomiting by time of onset of event;
•
TEAEs of special interest, overall and by system organ class and preferred term;
•
AEs starting in the 4-week Follow-up period overall by system organ class and preferred term; 
•
SAEs starting in the 4-week Follow-up period overall and by system organ class and preferred 
term;
Only TEAEs will be included in the summary tables, however separate listings for treatment-emergent
AEs, non-treatment-emergent AEs, AEs starting within the dose titration period (initial 3 weeks), and AEs 
starting in the 4-week Follow-up period will be generated. Additional listings will be provided for deaths, 
AESIs, serious AEs, and AEs Leading to Study Drug Discontinuation.
Laboratory Evaluations
Safety laboratory samples for chemistry, hematology, and urinalysis will be collected at various visits. Refer 
to Section 9 of the Protocol for the schedule of activities indicating when the respective samples are taken.
The following parameters will be included:
Chemistry: Albumin, Alanine aminotransferase, Alkaline phosphatase, Aspartate aminotransferase, 
Blood urea nitrogen or urea, Creatinine, Electrolytes (sodium, potassium, chloride, calcium, phosphorus), 
Gamma glutamyltransferase, Lactate dehydrogenase, Total bilirubin, Direct bilirubin, and total 
Immunoglobulin E.
Hematology: Full and differential blood count, Hematocrit, Hemoglobin, Mean cell hemoglobin, Mean cell 
hemoglobin concentration, Mean cell volume, Platelet count, Red blood cell count (% reticulocytes), 
White blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils).
Urinalysis: Appearance, pH, Protein, Glucose, Ketone bodies, Indicators of blood and white blood cells, 
Specific gravity, Urine human chorionic gonadotropin (premenopausal females only), and Urobilinogen.
Serology: HIV antibody, Hepatitis B virus, Hepatitis C virus, Hepatitis C virus RNA, Hepatitis B surface 
antigen, Hepatitis B core antibody, Hepatitis B surface antibody, and Follicle-stimulating hormone
(confirmatory test for female patients in a postmenopausal status defined as cessation of menses for at 
least 12 months without an alternative medical cause).
Pregnancy test: A serum pregnancy test will be performed on all women of childbearing potential at 
Screening, and a urine pregnancy test will be performed at all other visits. Refer to Section 9 of the 
Protocol for the schedule of activities indicating when the respective pregnancy tests are performed.
All summaries will be based on results in SI (standard international system of units) units and will be 
output in the order listed above. 


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Actual values and changes from baseline in chemistry and hematology will be summarized by visit using 
descriptive statistics.
Shift tables, showing shifts from baseline to Week 16 relative to the normal ranges for chemistry and 
hematology will be provided. These summaries of normal range category changes illustrate the number 
and percentage of patients who fall into specified categories (Decrease to Low, Change to Normal or No 
Change, Increase to High) by comparing the baseline normal range category to the overall worst-case 
normal range category. The worst-case post-baseline row will be used to summarize the patients’ overall 
worst-case normal range category change. The determination of the worst-case takes into account both 
planned and unscheduled assessments. 
A liver safety analysis table summarizing values above the upper limit of normal for alanine 
aminotransferase, alkaline phosphatase, aspartate aminotransferase and bilirubin will be provided.
Patients with missing baseline value are to be assumed to have a normal baseline value. Worst-case can 
be either High or Low. If a patient has a Decrease to Low and an Increase to High during the same time 
interval, then the patient is counted in both the ‘Decrease to Low’ and ‘Increase to High’ categories. If a 
patient was high at baseline and decreases to Low during the time interval, then the patient is counted in 
the ‘Decrease to Low’ category. Likewise, if a patient was Low at baseline and increases to High during 
the time interval, then the patient is counted in the ‘Increase to High’ category. Patients are only counted 
in the ‘Change to Normal or No Change’ category if they are:
•
Normal at baseline and have no normal range High and no normal range Low values during the 
time interval.
•
High at baseline and do not change to Low during the time interval.
•
Low at baseline and do not change to High during the time interval.  
All laboratory results will be included in data listings. Abnormal results for chemistry, hematology, and 
urinalysis will be listed separately. Laboratory results for serology and pregnancy tests will be listed only.
Vital Signs 
Heart rate (beats per minute [bpm]), respiratory rate (breaths per minute), systolic and diastolic blood 
pressure (mmHg), BMI (kg/m2)_and body temperature (degree Celsius) will be measured at different 
visits as per the SoA in Protocol Section 9.
The conversion for temperature is as follows: Temperature (in °C) = 5/9 (Temperature [in °F]-32).
Actual values and changes from baseline in vital sign measurements will be summarized by visit using 
descriptive statistics.
All vital signs will be provided in data listings.
ECG
A 12-lead, resting ECG will be obtained at the visits indicated in the SoA in Protocol Section 9.


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Actual values and changes from baseline in ECG parameters (heart rate [bpm], PR Interval [msec], QRS 
Interval [msec], RR Interval [msec], QT Interval [msec], and QTc [msec]) will be summarized by visit using 
descriptive statistics. An outlier analysis will be performed that will summarize by treatment the frequency 
and percentage of participants who meet any of the following outlier criteria at each visit:
•
QTc interval > 450 msec.
•
QTc interval > 480 msec.
•
QTc interval > 500 msec.
•
QTc interval increases from baseline > 30 msec.
•
QTc interval increases from baseline > 60 msec.
This outlier analysis will be repeated summarizing frequency and percentage of participants by treatment 
who meet any of these outlier criteria at any time during the study.
All ECG parameters, including overall ECG evaluation, will be provided in data listings.
Physical Examination
A complete physical examination will be performed at Screening and Week 16. A limited physical 
examination will be conducted at Day 1 and Weeks 4, 8, 12, and 20.
A shift table to demonstrate changes in physical examination from baseline to all post-baseline visits by 
treatment will be generated.
Physical examination data will be listed.
The Hospital Anxiety and Depression Scale
The HADS is a patient reported outcome (PRO), comprises 7 questions for anxiety and 7 questions for 
depression, with each answer being graded from 0 to 3 with a higher score indicating a worse condition. 
For each group of questions, scores of less than 7 indicate noncases, whereas 8 to 10, 11 to 14, and 15 
to 21, indicate mild, moderate, or severe anxiety or depression, respectively. HADS will be collected at
different time points as per the SoA in Protocol Section 9.
Actual values and changes from baseline in HADS scores (depression, anxiety, and total) will be 
summarized by treatment group. A summary table presenting the frequency and percentage of 
participants by treatment group within categories (< 7, 8 – 10, 11 – 14 and 15 – 21) for anxiety and
depression at each visit will be generated. A shift table to demonstrate changes in anxiety total score and 
depression total score from baseline to all post-baseline visits by treatment will be generated.
HADS scores, questions, and answers will be provided in data listings.
The Columbia-Suicide Severity Rating Scale
The C-SSRS, investigator administered version, was designed to provide a prospective, standardized 
measure of suicidality. The scale allows clinicians and researchers alike to assess the severity and 
lethality of suicidal behaviors and ideations and can be used to monitor treatment outcomes and establish 
suicide risk in a variety of research and clinical settings. Requiring approximately 5 min for completion, 
the C-SSRS is administered in the form of a clinical interview. This C-SSRS is available in 3 versions:


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For this study we are using the following versions: For screening: Lifetime/Recent version and for the 
remaining part of the study: Since Last Visit version. 
C-SSRS will be collected at different time points as per the SoA in Protocol Section 9. 
The C-SSRS categories have been re-ordered from the actual scale to facilitate the definitions of the 
endpoints, and to enable clarity in the presentation of the results: Category 1 – Wish to be Dead, 
Category 2 – Non-specific Active Suicidal Thoughts, Category 3 – Active Suicidal Ideation with Any 
Methods (Not Plan) without Intent to Act, Category 4 – Active Suicidal Ideation with Some Intent to Act, 
without Specific Plan, Category 5 – Active Suicidal Ideation with Specific Plan and Intent, Category 6 – 
Preparatory Acts or Behavior, Category 7 – Aborted Attempt, Category 8 – Interrupted Attempt, Category 
9 – Actual Attempt (non-fatal), Category 10 – Completed Suicide. 
Suicidal ideation is defined as a “yes” answer at any time during treatment to any one of the five suicidal 
ideation questions (Categories 1-5) on the C-SSRS. Suicidal behavior is defined as a “yes” answer at any 
time during treatment to any one of the five suicidal behavior questions (Categories 6-10) on the C-SSRS. 
Suicidal ideation or behavior is defined as a “yes” answer at any time during treatment to any one of the 
ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
A summary table presenting number of patients with suicidal ideation, suicidal behavior, and self-injurious 
behavior without suicidal intent will be generated, as well as a shift table to demonstrate changes in 
C-SSRS suicidal ideation scores from baseline to all post-baseline visits by treatment. Patients with 
suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal intent based on the C-SSRS 
will be listed. 
 


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Interim Analyses
No interim analysis is planned in this study.


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Changes from Analysis Planned in Protocol
The randomized population is not specified in protocol, but this population is added for listings and 
disposition summaries.
Exploratory endpoint added: Patients achieving 100% reduction in EASI (EASI100) response at Weeks 2, 
4, 8, 12, 16, and 20.


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Reference List


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Programming Considerations
Computer-generated TFL output will adhere to the following specifications. 
All TFLs, and statistical analyses will be generated using SAS for Windows, Release 9.4 (SAS Institute 
Inc., Cary, NC, USA). 
General Considerations
x
A separate SAS program will be created for each output
x
Each output will be stored in a separate file
x
Output files will be delivered in Word format and portable document format (pdf)
x
Numbering of TFLs will follow ICH E3 guidance 
Table, Figure, and Listing Format
General
x
All TFLs will be produced in landscape format on A4 paper size, unless otherwise specified
x
All TFLs will be produced using the Courier New font, size 8 which is the smallest acceptable point 
size for the Regulatory Authorities
x
The data displays for TFLs will have a minimum blank 1-inch margin on all 4 sides.
x
Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities
x
Legends will be used for all figures with more than one variable, group, or item displayed
x
TFLs will be in black and white (no color), unless otherwise specified
x
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below)
x
Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis
x
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate
Headers
x
All output will have the following header at the top left of each page: 
x
UNION therapeutics A/S Protocol UNI50001-202 (Syneos Health study number 7025424)


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x
Draft/Final Run <date>
x
All output will have Page n of N at the top or bottom right corner of each page. TFLs are internally 
paginated in relation to the total length (i.e., the page number will appear sequentially as page n of 
N, where N is the total number of pages in the table)
x
The date the output was generated will appear along with the program name as a footer on each 
page
Display Titles
x
Each TFL will be identified by the designation and a numeral. (i.e., Table 14.1.1). A decimal system 
(x.y and x.y.z) are used to identify TFLs with related contents. The title will be centered. The 
analysis population will be identified on the line immediately following the title and will be enclosed 
in parenthesis. The title and table designation will be single spaced. A solid line spanning the 
margins will separate the display titles from the Column headers. There will be one blank line 
between the last title and the solid line.
Table x.y.z
First Line of Title
Second Line of Title if Needed
(Safety population)
Column Headers
x
Column headings will be displayed immediately below the solid line described above in initial 
upper-case characters.
x
In the case of efficacy tables, the variable (or characteristic) column is on the far left followed by the 
treatment group columns and total column (if applicable). P-values may be presented under the 
total column or in separate p-value column (if applicable). Within-treatment comparisons may have 
p-values presented in a row beneath the summary statistics for that treatment
x
For numeric variables, include ‘unit’ in column or row heading when appropriate
x
Analysis population sizes will be presented for each treatment group in the column heading as 
(N=xx) (or in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive 
statistics representing the number of patients in the analysis population
x
The order of treatments in the tables and listings will be Placebo first.
Body of the Data Display
16.2.5.1.
General Conventions
Data in columns of a table or listing are formatted as follows:
x
Alphanumeric values will be left-justified;
x
Whole numbers (e.g., counts) will be right-justified; and


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x Numbers containing fractional portions will be decimal aligned. 
16.2.5.2. 
Table Conventions 
x Units will be included where available 
x For categorical parameters, all categories will be presented in the table, even if n=0 for all 
treatment groups in a given category. For example, the frequency distribution for symptom severity 
would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
x An Unknown or Missing category will be added to each parameter for which information is not 
available for 1 or more patients 
x Unless otherwise specified, the estimated mean and median for a set of values will be printed out 
to 1 more significant digit than the original values, and standard deviations will be printed out to 2 
more significant digits than the original values. The minimum and maximum will report the same 
significant digits as the original values. For example, systolic blood pressure will be presented as 
follows: 
n 
xxx 
Mean (SD) 
xx.x (x.xx) 
Median  
xx.x  
Min, Max 
Xx, xx 
x P-values will be output in the format: ‘0.xxx’, where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
x Percentage values will be printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise noted, for all percentages, the 
number of patients in the analysis population for the treatment group who have an observation will 
be the denominator. Percentages after zero counts will not be displayed and percentages equating 
to 100% will be presented as 100%, without decimal places  
x Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data will be presented by the body system, treatment class, or SOC with the 
highest occurrence in the active treatment group in decreasing order, assuming all terms are 
coded. Within the body system, drug class and SOC, medical history (by preferred term), drugs (by 
ATC3 level), and adverse events (by preferred term) will be displayed in decreasing order. If 
incidence for more than 1 term is identical, they will then be sorted alphabetically. Missing 
descriptive statistics or p-values which cannot be estimated will be reported as ‘-’ 


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x
The percentage of patients will normally be calculated as a proportion of the number of patients 
assessed in the relevant treatment group (or overall) for the analysis population presented. 
However, careful consideration is required in many instances due to the complicated nature of 
selecting the denominator, usually the appropriate number of patients exposed. Details will be 
described in footnotes or programming notes, as necessary
x
For categorical summaries (number and percentage of patients) where a patient can be included in 
more than one category, a footnote or programming note will be added describing whether the 
patient is included in the summary statistics for all relevant categories or just 1 category as well as
the selection criteria
x
Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by ‘(cont)’ at the top of each subsequent page. The 
overall summary statistics for the subheading should only be output on the first relevant page
16.2.5.3.
Listing Conventions
x
Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time
x
Missing data will be represented on patient listings as either a hyphen (‘-’) with a corresponding 
footnote (‘- = unknown or not evaluated’), or as ‘N/A’, with the footnote ‘N/A = not applicable’, 
whichever is appropriate
x
Dates will be printed in SAS DATE9.format (‘DD_MMM_YYYY’: 01JUL2000). Missing portions of 
dates will be represented on patient listings as dashes (--JUL2000). Dates that are missing 
because they are not applicable for the patient will be output as ‘N/A’, unless otherwise specified
x
All observed time values will be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study
x
Units will be included where available
16.2.5.4.
Figure Conventions
x
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis
Footnotes
x
A solid line spanning the margins will separate the body of the data display from the footnotes. 
x
All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display
x
Footnotes will always begin with ‘Note:’ if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote will start on a new line, where possible
x
Patient specific footnotes are avoided, where possible


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x Footnotes will be used sparingly and add value to the TFL. If more than six lines of footnotes are 
planned, then a cover page is strongly recommended to be used to display footnotes, and only 
those essential to comprehension of the data will be repeated on each page 
x The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, the date the program was run, and the listing source 
(i.e., ‘Program : myprogram.sas  Listing source: 16.x.y.z’) 
x Sources and/or cross-references in footnotes will use the keyword prefix (in singular form) for each 
reference and will be separated by a comma when multiple cross-references are displayed 
Example 
Listing source: Listing 16.2.4.1.1, Listing 16.2.4.1.2, Listing 16.2.4.2.1 


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Quality Control
SAS programs are developed to produce output such as analysis data populations, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Developing Statistical Programs SOP (3907).
Syneos Health Developing Statistical Programs SOP (3907), Conducting the Transfer of Biostatistical 
Deliverables SOP (3908), the Developing Statistical Programming and Validation Plan SOP (3920) End-
to-End Process of the Production of Study Data Tabulation Model (SDTM) SOP (3921), End-to-End 
Process of the Production of Analysis Datasets and Tables, Figures and Listings SOP (3922), describe 
the quality control procedures that are performed for all SAS programs and output. Quality control is 
defined here as the operational techniques and activities undertaken to verify that the SAS programs 
produce the output by checking for their logic, efficiency and commenting and by review of the produced 
output.




























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Shells
The TFL shells will be provided as a separate document. 


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Appendices
Not Applicable.