Conditions: Psoriasis Skin Diseases
Keywords: Psoriasis Orismilast
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 202
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 plaque-type psoriasis. The purpose of the study is to assess the effect of orismilast modified release in moderate-to-severe plaque-type psoriasis 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 for 16 weeks arm 2: Oral, twice daily morning and evening for 16 weeks arm 3: Oral, twice daily morning and evening for 16 weeks arm 4: Oral, twice daily morning and evening for 16 weeks

Interventions: intervention 1: Orismilast modified release tablets intervention 2: Placebo
Intervention descriptions: intervention 1: Orismilast modified release is a next generation phosphodiesterase-4 (PDE4) inhibitor with high selectivity for the PDE4 subtypes linked to inflammation. intervention 2: Matching placebo tablets

Protocol document:
Prot_000.pdf: 
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1. FINAL CLINICAL STUDY PROTOCOL AMENDMENT 2 
 
 
 
 
UNION therapeutics A/S 
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 Plaque-Type Psoriasis 
Protocol Number: UNI50001-203 
 
IND Number: 
129386 
EudraCT Number: 
2021-003209-22 
Name of Investigational Product: 
Orismilast 
Phase of Development: 
2b 
Indication: 
Treatment of moderate-to-severe plaque-type psoriasis 
Sponsor Representative(s): 
Dermatology 
Tel: 
Email: 
Sponsor: 
UNION therapeutics A/S 
Tuborg Havnevej 18 
DK-2900 Hellerup, Denmark 
Tel: +45 61 77 74 35 
Protocol Version: 
3.0 
Protocol Date: 
20 May 2022 
 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to UNION therapeutics A/S. Any 
unauthorized copying or use of this document is prohibited. 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL APPROVAL SIGNATURES 
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 Plaque-Type 
Psoriasis 
Protocol Number:    UNI50001-203 
 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice (GCP) and applicable regulatory requirements. 
Sponsor Signatory 
 
Consultant, 
Dermatology 
 
 
Signature 
 
 
 
Date (DD-Mmm-YYYY) 
 
Coordinating Investigator 
 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
Biostatistician 
 
 
 
 
UNION therapeutics A/S 
Signature 
 
 
Date (DD-Mmm-YYYY) 
Consultant Dermatologist, 
 


Coordinating lnvestigator 
 
 
UNION thcrapeutics AIS 
Orismilast 
 
PROTOCOL APPROVAL SIGNATURES 
UNl50001-203 
Version 3.0 
Protocol Tille: 
 
 
 
Protocol Number: 
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 Plaque-Type 
Psoriasis 
UNIS0001-203 
 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), lntemational Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice (GCP) and applicable regulatory re uirements. 
Sponsor Signatory 
      Signature 
 
Date (DD-Mmm-YYYY) 
 
Biostatistician 
           Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document is confidcntial. 
Page 2 of92 


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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 Plaque-Type Psoriasis 
Protocol Number:   UNI50001-203 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
• I, the undersigned, have reviewed this protocol (and any amendments), including 
appendices, 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. 
Name: 
 
Title: 
Investigator Signature 
Institution: 
 
Date (DD-Mmm-YYYY) 


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2. 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 Plaque-Type Psoriasis 
Protocol Number: 
UNI50001-203 
Investigators/Study Sites: 
Approximately 40 centers in Europe and North America 
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 plaque-type psoriasis. 
Secondary objectives: 
• 
Evaluate the dose response of orismilast and identify the dose with the 
best benefit/risk ratio to be evaluated in a Phase 3 program. 
Exploratory objectives: 
• 
• 
Evaluate the change in cardiovascular risk factors under orismilast 
treatment. 
• 
• 
Evaluate the change in skin psoriasis at “difficult to treat” anatomical 
areas such as the scalp. 
• 
Evaluate the change in psoriasis at “difficult to treat” anatomical areas 
such as nails. 
Study Endpoints: 
Primary endpoint: 
• 
The primary endpoint in this study is the percentage change in 
Psoriasis Activity and Severity Index (PASI) score from Baseline at 
Week 16. 
Key secondary endpoints: 
• 
Patients achieving 75% reduction in PASI (PASI75) response at 
Week 16. 
• 
Patients achieving a score of Clear (0) or Almost Clear (1) and an at 
least 2-point improvement in Investigator Global Assessment (IGA) at 
Week 16. 
Other secondary endpoints: 
• 
Patients achieving a score of Clear (0) or Almost Clear (1) and an at 
least 2-point improvement in IGA at Weeks 4, 8, 12, and 20. 
• 
Patients achieving PASI75 response at Weeks 4, 8, 12, and 20. 
• 
Patients achieving 50% reduction in PASI (PASI50) and 90% 
reduction in PASI (PASI90) response at Weeks 4, 8, 12, 16, and 20. 
• 
Change from Baseline in PASI at Weeks 4, 8, 12, and 20. 
• 
Change from Baseline in total Psoriasis Symptoms Scale (PSS) score 
at Weeks 4, 8, 12, 16, and 20. 


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• 
Change from Baseline in each individual item of the PSS at Weeks 4, 
8, 12, 16, and 20. 
• 
Change from Baseline in the affected body surface area (BSA) at 
Weeks 4, 8, 12, 16, and 20. 
• 
Change from Baseline in Dermatology Life Quality Index (DLQI) 
score at Weeks 16 and 20. 
• 
Patients experiencing psoriasis rebound by Week 20, defined as 
PASI ≥125% of Baseline or new generalized pustular, erythrodermic, 
or more inflammatory psoriasis. 
Safety endpoints: 
• 
The occurrence, severity, and seriousness of treatment-emergent 
adverse events (TEAEs) reported over the 16-week Treatment Period 
and the 4-week Follow-up Period. 
• 
Changes from Baseline in physical examination; vital sign 
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. 
• 
Changes from Baseline in electrocardiogram (ECG) findings over the 
16-week Treatment Period and the 4-week Follow-up Period. 
• 
Changes from Baseline in safety laboratory values (hematology, 
serum chemistry, and urinalysis) over the 16-week Treatment Period 
and the 4-week Follow-up Period. 
• 
Hospital Anxiety and Depression Scale at each visit except Week 2. 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) at each visit except 
Weeks 1 and 2. 
Exploratory endpoints: 
• 
Change from Baseline in Physician's Global Assessment of 
Fingernails (PGA-F) at Week 16. 
• 
Change in Scalp-Specific Investigator Global Assessment (ss-IGA) 
from Baseline at Week 16 in the subgroup of patients with Baseline 
score of at least 2 (mild scalp psoriasis). 
• 
Change from Baseline of scalp itch Numeric Rating Scale (NRS) at 
Week 16 in the subgroup of patients with Baseline score of at 
least 4 on the 11-point NRS. 
• 
• 
Change in cardiovascular risk factors at Week 16. The following 
parameters will be collected: weight, body mass index, waist and hip 
circumferences, blood pressure, fasting serum glucose, triglycerides, 
cholesterol (total and high-density lipoprotein / low-density 
lipoprotein fractions), and C-reactive protein. 
• 
• 
Plasma levels of the drug and its metabolites at scheduled visits. 
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 adult 
patients with moderate-to-severe plaque-type psoriasis. Efficacy and safety 
outcomes will be evaluated to select an appropriate orismilast dose for 
subsequent Phase 3 studies. 


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After a Screening visit up to 28 days before Baseline, approximately 200 
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. The maximum duration of study 
participation is approximately 24 weeks. 
Patients will be seen at the site on 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). Visits at Weeks 1 and 2 
could be conducted via a telemedicine procedure at Investigator’s 
discretion. 
At Baseline and each visit from Week 4 onwards, PASI, BSA, IGA, and 
PSS will be assessed. Quality of life will be assessed by administration of 
DLQI at Baseline and at Weeks 16 and 20 visits. Additional efficacy 
parameters include: an ss-IGA, a Physician Global Assessment of 
fingernail psoriasis (PGA-F), and 
. These parameters will be assessed at Baseline and Weeks 
16 and 20. Safety evaluations include adverse events (AEs), laboratory and 
vital sign assessments, physical examinations, as well as mood change 
evaluation by patient (Hospital Anxiety and Depression Scale) and suicidal 
ideation evaluation by Investigator (C-SSRS). A panel of cardiovascular 
risk factors will be assessed at Baseline and Week 16. 
Before administration of the study drug at Baseline and on Weeks 4, 8, 
and 16, blood will be collected for orismilast concentration determination. 
Selection of Patients: 
Main Inclusion Criteria: 
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 ≥18 years of age at the time of signing the 
ICF. 
3. Body weight of >40 kg at the time of signing the ICF. 
4. Diagnosis of chronic, stable plaque-type psoriasis at least 2 months 
before the Screening visit. If the patient is diagnosed with psoriasis 
arthritis, the arthritis should be stable. 
5. Moderate-to-severe plaque-type psoriasis as defined by PASI ≥12, 
BSA ≥10%, and IGA ≥3 at the screening and baseline visits. 
6. Candidate for systemic antipsoriatic treatment or phototherapy. 
7. Women of childbearing potential (WOCBP) must have a negative 
serum pregnancy test at the Screening visit and a negative urine 
pregnancy test at the Baseline visit. In addition, sexually active 
WOCBP must agree to use a highly effective method of contraception 
until at least 4 weeks after the end of study treatment. Highly effective 
methods of contraception are those that have a failure rate of <1% 
(when implemented consistently and correctly) 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 


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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 entire 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 months without an alternative 
medical cause and a confirmatory follicle-stimulating hormone (FSH) 
test or as cessation of menses for at least 24 months without an 
alternative medical cause. 
Main Exclusion Criteria: 
1. Therapy-resistant psoriasis defined as ≥2 treatment failures due to 
inadequate efficacy within the past 5 years of any biologic therapies 
(including but not limited to etanercept, adalimumab, infliximab, 
certolizumab pegol, guselkumab, secukinumab, risankizumab, 
ixekizumab, tildrakizumab, or ustekinumab) administered in 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 psoriasis or PsA with acute deterioration within 4 weeks of 
the Screening visit. 
3. History of allergy or hypersensitivity to any component of the study 
treatment. 
4. Active infection (eg, bacteria, viral, fungal) requiring treatment with 
systemic antibiotics within 4 weeks of the Screening visit. 
5. Malignancy or history of malignancy except for treated (ie, cured) 
basal cell skin carcinomas. 
6. Current diagnosis of predominant guttate, erythrodermic, exfoliative, 
or pustular psoriasis, or of drug-induced psoriasis, or other skin 
conditions that might confound the evaluation of psoriasis vulgaris, as 
judged by the Investigator (eg, atopic dermatitis, lupus). 
7. Any 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 at Baseline, schizophrenia, suicidal behavior, 
psychiatric hospitalization within the prior year) which, 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 for receiving the investigational 
therapy. 
9. Any therapies and systemic treatments as described in Table 3 which 
do not comply with the indicated washout interval. 
10. Any previous treatment with orismilast or failure of treatment with 
apremilast or any other systemic phosphodiesterase-4 inhibitor as 
described in Table 3. 
11. 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. 
12. Severe hepatic impairment based upon medical history and laboratory 
abnormalities (eg, low albumin and abnormal bilirubin). 
13. Any of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study-specific laboratory and confirmed 
by a single repeat, if deemed necessary: 
a. 
Absolute neutrophil count of <3.0 × 109/L (<3000/mm3) 


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b. Hemoglobin of <10.0 g/dL or hematocrit <30% 
c. 
Platelet count of <100 × 103 cells/mm3 (SI: <100 × 109 
cells/L). 
d. Absolute lymphocyte count of <1.0 × 109/L (<1000/mm3) 
e. 
Total bilirubin >1.5 × the upper limit of normal (ULN); 
patients with a history of Gilbert's syndrome may have a 
direct bilirubin measured and would be eligible for this 
study provided the direct bilirubin is ≤ULN; 
f. 
Alanine aminotransferase or aspartate aminotransferase 
>2.5 × the ULN; 
g. Serum creatinine ≥1.5 mg/dL. For a patient with a value 
of ≥1.5 mg/dL, a creatinine clearance of ≥60 mL/min 
(calculated using the CKD-EPI Creatinine Equation) is 
allowed. 
14. History or evidence of hepatitis B virus (HBV) infection at Screening. 
Patients with positive hepatitis B surface antigen (HBsAg) are 
excluded. For patients with isolated positive antihepatitis B core 
antibody (HBcAb), hepatitis B surface antibody (HBsAb) result must 
also be positive to be considered for this study. 
15. 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. 
16. History of positive HIV, or have 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. 
17. 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 the C-SSRS completed at the Baseline visit. 
18. Pregnant or breastfeeding. 
19. History of alcohol or substance abuse within 6 months before Baseline 
that, in the opinion of the Investigator, will preclude participation in 
the study. 
20. Institutionalized by court order or by local authority. 
Planned Sample Size: 
Approximately 200 patients will be enrolled to ensure approximately 
50 patients per arm. This sample size is based on assumptions that the 
percentage change from Baseline in PASI is -32.2% and -50.9% for placebo 
and each orismilast dose group, respectively, and the standard deviation is 
33%. Using a 2-sided 2-sample t-test, 50 patients in each treatment arm can 
achieve a power of 80% at the significance level of 5%. 
Investigational Therapy: 
Name: orismilast 
Unit doses strength and dose formulation: 20 mg (2 × 10 mg tablets), 30 mg 
(1 × 30 mg tablet), and 40 mg (1 × 10 mg tablet and 1 × 30 mg tablet) 
Route and frequency of administration: oral, twice daily 
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 


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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 
The plasma levels of the drug and its metabolites will be summarized 
descriptively by visit in this study. 
Patients will be offered optional participation in specific blood sampling for 
calculation of pharmacokinetic profiles. 
Statistical Methods and 
Planned Analyses: 
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 
Intention-to-Treat (ITT) Analysis Population. Missing data for primary and 
key secondary endpoints will be handled with multiple imputation method. 
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. Analyses will be repeated 
on the Per-Protocol Population for primary and secondary endpoints. 
When appropriate, the raw parameter, its change from Baseline, and 
percentage change from Baseline will be summarized. 
The primary endpoint, percentage change from Baseline to Week 16 in 
PASI, will be analyzed using analysis of covariance with treatment group as 
factor and Baseline PASI as covariate. The mixed model for repeated 
measures (MMRM) will 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% 
confidence interval of the difference between each active treatment and 
placebo will be calculated. The primary analysis set will be the ITT 
Analysis Population with multiple imputation approach to handle missing 
values. The same analyses will be repeated for Weeks 20, 12, 8 and 4. 
The key secondary and other binary endpoints (IGA success, PASI50, 
PASI75, PASI90) will be analyzed using the Mantel-Haenszel (MH) test, 
comparing each active treatment group to placebo in the ITT Analysis set. 
For categorical variables, 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 scores/full scale will be analyzed 
using the MH test and the row mean score statistics and the ridit 
transformation. 
The other continuous secondary endpoints will be analyzed using MMRM. 
The above endpoints (PASI changes and percentage changes, IGA success, 
PASI50, PASI75, PASI90) 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 
distribution. The PASI percentage changes from Baseline will be plotted to 
identify where the best separation between treatments occurs. 
All safety analyses will be conducted using the Safety Analysis Population. 
AE data will be presented and tabulated according to Medical Dictionary 
for Regulatory Activities (MedDRA) classification. Reported AEs will be 
summarized by the number of patients reporting the events, as well as by 


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System Organ Class (SOC) and Preferred Term (PT), SOC, PT, and 
severity, and SOC, PT, and relationship to study product. 
Laboratory (chemistry and hematology) parameters 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. 
No interim analysis is planned in this study. 


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3. TABLE OF CONTENTS 
1. 
FINAL CLINICAL STUDY PROTOCOL AMENDMENT 2 .......................................... 1 
2. 
SYNOPSIS......................................................................................................................... 4 
3. 
TABLE OF CONTENTS ................................................................................................. 11 
3.1. 
List of In-text Tables .................................................................................................. 15 
3.2. 
List of In-text Figures ................................................................................................. 16 
4. 
LIST OF ABBREVIATIONS .......................................................................................... 17 
5. 
INTRODUCTION ........................................................................................................... 19 
5.1. 
Background on Plaque-Type Psoriasis ....................................................................... 19 
5.2. 
Background on Orismilast .......................................................................................... 20 
5.2.1. 
Nonclinical Studies............................................................................................. 20 
5.2.2. 
Clinical Studies .................................................................................................. 21 
5.2.2.1. 
Clinical Pharmacology .................................................................................. 21 
5.2.2.2. 
Efficacy ......................................................................................................... 22 
5.2.2.3. 
Safety ............................................................................................................ 23 
5.3. 
Clinical Risks/Benefits ................................................................................................ 24 
5.4. 
Study Rationale ........................................................................................................... 24 
5.4.1. 
Dose Rationale ................................................................................................... 25 
6. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 27 
6.1. 
Study Objectives ......................................................................................................... 27 
6.1.1. 
Primary Objective ............................................................................................... 27 
6.1.2. 
Secondary Objectives ......................................................................................... 27 
6.1.3. 
Exploratory Objectives ....................................................................................... 27 
6.2. 
Study Endpoints .......................................................................................................... 27 
6.2.1. 
Primary Endpoint ............................................................................................... 27 
6.2.2. 
Secondary Endpoints .......................................................................................... 27 
6.2.2.1. 
Key Secondary Endpoints............................................................................. 27 
6.2.2.2. 
Other Secondary Endpoints .......................................................................... 27 
6.2.2.3. 
Safety Endpoints ........................................................................................... 28 
6.2.3. 
Exploratory Endpoints ........................................................................................ 28 
7. 
INVESTIGATIONAL PLAN .......................................................................................... 30 
7.1. 
Description of Overall Study Design and Plan ........................................................... 30 
7.2. 
Discussion of Study Design ........................................................................................ 31 
7.3. 
End of Study ............................................................................................................... 32 


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8. 
SELECTION OF STUDY POPULATION ..................................................................... 33 
8.1. 
Inclusion Criteria ........................................................................................................ 33 
8.2. 
Exclusion Criteria ....................................................................................................... 33 
8.3. 
Rescreening ................................................................................................................. 35 
8.4. 
Study Withdrawal, Removal, and Replacement of Patients ....................................... 35 
8.5. 
Suspension or Premature Termination of the Clinical Investigation .......................... 36 
9. 
TREATMENTS ............................................................................................................... 38 
9.1. 
Details of Study Treatments and Dosage Schedule .................................................... 38 
9.2. 
Measures to Minimize Bias: Study Treatments .......................................................... 38 
9.2.1. 
Method of Study Treatment Assignment ........................................................... 38 
9.2.2. 
Blinding39 
9.3. 
Dosage Modification ................................................................................................... 40 
9.3.1. 
Titration40 
9.4. 
Treatment Accountability and Compliance ................................................................ 41 
9.5. 
Prior and Concomitant Therapy .................................................................................. 41 
9.5.1. 
Allowed Treatments and Rescue Medications ................................................... 42 
9.5.2. 
Prior and Concomitant Medications ................................................................... 42 
9.5.3. 
Drug-Drug Interactions ...................................................................................... 43 
10. STUDY PROCEDURES ................................................................................................. 45 
10.1. Informed Consent ....................................................................................................... 49 
10.2. Study Procedures ........................................................................................................ 49 
11. EFFICACY ASSESSMENTS ......................................................................................... 50 
11.1. Investigator Assessments ............................................................................................ 50 
11.1.1. 
Psoriasis Area and Severity Index ...................................................................... 50 
11.1.2. 
Investigator Global Assessment ......................................................................... 50 
11.1.3. 
Scalp-specific Investigator Global Assessment .................................................. 50 
11.1.4. 
Physician’s Global Assessment of Fingernail Psoriasis ..................................... 50 
11.1.5. 
Body Surface Area ............................................................................................. 51 
11.2. Patient-Reported Outcomes ........................................................................................ 51 
11.2.1. 
Psoriasis Symptom Scale.................................................................................... 51 
11.2.2. 
Scalp Itch ............................................................................................................ 51 
11.2.4. 
Dermatology Life Quality Index ........................................................................ 51 
12. SAFETY ASSESSMENTS .............................................................................................. 52 


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12.1. Medical History .......................................................................................................... 52 
12.2. Vital Signs .................................................................................................................. 52 
12.3. Physical Examination .................................................................................................. 53 
12.4. Electrocardiogram ....................................................................................................... 53 
12.5. Waist and Hip Circumferences ................................................................................... 53 
12.6. Laboratory Assessments ............................................................................................. 53 
12.7. The Hospital Anxiety and Depression Scale .............................................................. 55 
12.8. The Columbia-Suicide Severity Rating Scale ............................................................. 55 
12.9. Adverse Events ........................................................................................................... 55 
12.9.1. 
Adverse Events ................................................................................................... 56 
12.9.2. 
Adverse Events of Special Interest ..................................................................... 57 
12.9.3. 
Serious Adverse Events ...................................................................................... 58 
12.9.4. 
Serious Adverse Event Reporting ...................................................................... 58 
12.9.5. 
Suspected Unexpected Serious Adverse Reactions ............................................ 59 
12.9.6. 
Pregnancy ........................................................................................................... 60 
12.9.7. 
Overdose ............................................................................................................. 61 
13. PHARMACOKINETICS ................................................................................................. 62 
13.1. Pharmacokinetic Sampling ......................................................................................... 62 
13.1.1. 
Blood Samples .................................................................................................... 62 
13.2. Pharmacokinetic Analytical Methodology.................................................................. 63 
14. PHARMACODYNAMICS .............................................................................................. 64 
15. STATISTICAL ANALYSIS ........................................................................................... 65 
15.1. Determination of Sample Size .................................................................................... 65 
15.2. Analysis Populations ................................................................................................... 65 
15.3. Efficacy Analysis ........................................................................................................ 66 
15.3.1. 
Analysis of Primary Efficacy Endpoint .............................................................. 66 
15.3.2. 
Analysis of Secondary Efficacy Endpoints ........................................................ 66 
15.3.3. 
Analysis of Exploratory Endpoints .................................................................... 67 
15.4. Safety Analysis ........................................................................................................... 67 
15.5. Pharmacokinetic Analysis ........................................................................................... 67 
15.6. Interim Analysis .......................................................................................................... 67 
16. STUDY MANAGEMENT .............................................................................................. 68 
16.1. Approval and Consent ................................................................................................ 68 
16.1.1. 
Regulatory Guidelines and Ethical Considerations ............................................ 68 


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16.1.2. 
Informed Consent ............................................................................................... 68 
16.2. Data Protection............................................................................................................ 69 
16.3. Dissemination of Clinical Study Data ......................................................................... 69 
16.4. Data Quality Assurance .............................................................................................. 70 
16.5. Source Documents ...................................................................................................... 70 
16.6. Protocol Amendment and Protocol Deviation ............................................................ 71 
16.6.1. 
Protocol Amendment .......................................................................................... 71 
16.6.2. 
Protocol Deviations ............................................................................................ 71 
16.7. Financing and Insurance ............................................................................................. 71 
16.8. Publication Policy/Disclosure of Data ........................................................................ 72 
17. REFERENCES ................................................................................................................ 73 
18. APPENDICES ................................................................................................................. 74 
Appendix 1. Protocol Amendment 1 Summary of Changes .................................................... 75 
Appendix 2. Psoriasis Area and Severity Index (PASI) ........................................................... 79 
Appendix 3. Investigator Global Assessment (IGA)................................................................ 80 
Appendix 4. Scalp-specific Investigator Global Assessment (ss-IGA) ................................... 81 
Appendix 5. Physician Global Assessment of Fingernail Psoriasis (PGA-F) .......................... 82 
Appendix 6. Body Surface Area (BSA) ................................................................................... 83 
Appendix 7. Psoriasis Symptom Scale (PSS) .......................................................................... 84 
Appendix 8. Dermatology Life Quality Index (DLQI) ............................................................ 85 
Appendix 9. The Hospital Anxiety and Depression Scale (HADS)......................................... 87 
Appendix 10. The Columbia-Suicide Severity Rating Scale (C-SSRS) .................................. 88 


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3.1. List of In-text Tables 
 
Table 1. Study Treatment and Dosage Schedule ................................................................... 38 
Table 2. Dose Titration Schedule .......................................................................................... 41 
Table 3. Disallowed therapies and treatments ....................................................................... 42 
Table 4. Schedule of Assessments .........................................................................................46 
Table 5. Laboratory Assessments ..........................................................................................54 
Table 6. National Cancer Institute Common Terminology Criteria for Adverse Events ...... 57 
Table 7. Classification of Adverse Events by Relationship to Study Drug ...........................57 


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3.2. List of In-text Figures 
Figure 1. Study Design ........................................................................................................... 31 
Figure 2 Pharmacokinetic Blood Sample Collection ............................................................. 62 


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4. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AD 
atopic dermatitis 
ADL 
Activities of Daily Living 
AE 
adverse event 
AESI 
Adverse Event of Special Interest 
AUC 
area under the curve 
AUC0-∞ 
area under the curve from time 0 to infinity 
AUC0-t 
area under the curve from time 0 to the last measurable concentration 
BID 
twice daily 
BMI 
body mass index 
BSA 
body surface area 
cAMP 
cyclic adenosine monophosphate 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
cGMP 
cyclic guanosine monophosphate 
COPD 
chronic obstructive pulmonary disease 
Cmax 
maximum plasma concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLQI 
Dermatology Life Quality Index 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
EOT 
End of Treatment 
GCP 
good clinical practice 
GI 
gastrointestinal 
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 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IFN-γ 
interferon gamma 
IGA 
Investigator Global Assessment 
IL 
interleukin 
IND 
Investigational New Drug 


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Abbreviation 
Definition 
IRB 
institutional review board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
MH 
Mantel-Haenszel 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MIP-1α 
macrophage inflammatory protein-1 alpha 
MMRM 
mixed model for repeated measure 
NRS 
Numeric Rating Scale 
PASI 
Psoriasis Activity and Severity Index 
PASI50 
50% reduction in PASI 
PASI75 
75% reduction in PASI 
PASI90 
90% reduction in PASI 
PD 
pharmacodynamics 
PDE 
phosphodiesterase 
PGA 
Physician’s Global Assessment of disease severity 
PGA-F 
Physician Global Assessment of Fingernail/ Physician Global Assessment of 
Fingernail psoriasis 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PRO 
patient-reported outcome 
PsA 
psoriatic arthritis 
PSS 
Psoriasis Symptoms Scale 
PT 
preferred term 
QoL 
quality of life 
SAE 
serious adverse event 
SOC 
system organ class 
ss-IGA 
scalp-specific Investigator Global Assessment 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum plasma concentration 
TNF-α 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
women of childbearing potential 


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5. INTRODUCTION 
 
5.1. Background on Plaque-Type Psoriasis 
 
Psoriasis is a multisystem disease with predominantly skin and joint manifestations characterized 
by well-demarcated, erythematous, scaly plaques which are often itchy. Psoriasis is considered a 
systemic disease; it is associated with psychological, metabolic, arthritic, and cardiovascular 
comorbidities. Epidemiological data on the incidence of psoriasis are limited, with studies 
conducted mainly in Europe and North America (Parisi 2020). Reported prevalence of psoriasis 
in adults varies from about 1.4% in the United States (US) to 2.5% in Western or Eastern Europe 
(https://www.globalpsoriasisatlas.org/statistics/statistics). 
The most common clinical type of psoriasis, affecting 80% to 90% of patients, is psoriasis 
vulgaris (plaque-type psoriasis). For patients with moderate-to-severe plaque-type psoriasis who 
comprise about one-third of all psoriasis patients, systemic agents (biological or nonbiological) 
or phototherapy is the regimen of choice (Menter 2009, 2010). However, the long-term treatment 
of psoriasis with biological therapies may be limited by safety and tolerability issues, reduced 
efficacy over time, and poor adherence due to an inconvenient route of administration (eg, 
injection) (Ravindran 2008). Therefore, despite a large number of biologic agents being 
available, there is still an unmet need for safe, effective, and convenient long-term oral 
treatments for patients with moderate-to-severe psoriasis. 
The involvement of inflammatory cells, such as T cells and myeloid dendritic cells, and 
proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-12 
and IL- 17 in the pathogenesis of psoriasis is well established (Quaglino 2011). 
Phosphodiesterases (PDEs) constitute a superfamily of enzymes catalyzing the hydrolysis of the 
intracellular second messengers cyclic adenosine monophosphate (cAMP) and/or cyclic 
guanosine monophosphate (cGMP) that play key roles in mediating biological responses 
generated by a variety of extracellular signals. PDE4 is a cAMP-specific PDE expressed by 
immune and inflammatory cells, including neutrophils, T-lymphocytes, macrophages, and 
eosinophils. High cAMP levels decrease proliferation and cytokine production whereas low 
concentrations have the opposite effect. Specific inhibition of PDE4 thus has the potential to 
have beneficial effects in a wide variety of inflammatory disorders including rheumatoid 
arthritis, ankylosing spondylitis, inflammatory bowel disease, airway disease, skin disease, and 
neuro inflammation. 
Currently marketed PDE4 inhibitors include roflumilast approved for chronic obstructive 
pulmonary disease (COPD), crisaborole for atopic dermatitis, and apremilast approved for 
psoriasis, psoriatic arthritis (PsA), and oral ulcers associated with Behcet’s disease. 
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 for COPD, and apremilast for psoriasis and PsA some years 
later. Both therapies had tolerability issues affecting, primarily, but not exclusively, the 


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gastrointestinal (GI) tract, characterized by nausea, vomiting, and diarrhea/loose stools. 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 1 month) to reduce side effects. 
 
5.2. 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 
atopic dermatitis. During initial development Phase 1/2a, different oral formulations have been 
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 selected for further development. This 
new formulation was shown to improve the GI tolerability without a significant loss in systemic 
exposure. 
 
5.2.1. 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 
atopic dermatitis (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 hERG ion channel current amplitudes at 10 μM. 
The pharmacokinetics (PK) of orismilast has been investigated in mice, rats, rabbits and minipigs 
after administration by oral gavage. In rats, area under the curve (AUC) and maximum plasma 
concentration (Cmax) generally increased in proportion to dose in the tested range (0.5–1.75 
mg/kg), with female rats having AUC and Cmax values 1.5 to 3 times higher than male rats. In 
mice, rabbits, and minipigs, AUC and Cmax increased less than, or proportional to, the 
investigated doses (5–500 mg/kg, twice daily dosing, and 1.0–30 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 (1.0–10 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 faces in rats and minipigs. 
The in vitro plasma protein binding of orismilast was low to moderate (35–67%) 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 hERG tail current 
recorded from human embryonic kidney (HEK-293) cells gave an IC50 value of 11.4 μM. In 


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conscious telemetered minipigs, oral administration of orismilast produced no treatment- related 
effects on heart rate, body temperature, 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. 
Orismilast was not genotoxic when tested in the standard International Council for 
Harmonisation (ICH) battery of 2 in vitro and 1 in vivo genotoxicity tests. 
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 
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 
twice daily (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. 
 
5.2.2. Clinical Studies 
 
As of 01 Dec 2020, the orismilast clinical development program in psoriasis consists of 
8 completed trials including 7 Phase 1 trials in healthy subjects and 1 Phase 2a trial in subjects 
with moderate-to-severe psoriasis vulgaris. 
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; LP0058- 1362), 
a PK trial evaluating the PK and safety/tolerability profiles of several new formulations 
(LP0058-1442), 2 drug-drug interaction trials using a orismilast immediate-release tablet 
formulation and midazolam (trial LP0058-1267 and LP0058-1324), and a proof of concept Phase 
2a trial using an immediate-release tablet formulation (trial LP0058-1072). 
5.2.2.1. 
Clinical Pharmacology 
After single and multiple dosing of up to 60 mg twice daily of the initial capsule formulation, in 
the fasted state or after a standard breakfast, orismilast was steadily absorbed with a median time 
to maximum plasma concentration (tmax) of 2–4 hours. Systemic exposure to orismilast increased 
in an approximately dose proportional manner. Estimates of elimination half-lives varied across 


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studies, from 4–6 hours (for dose levels up to 30 mg 3 times a day) and up to 10 hours (for 60 
mg twice daily 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 area under the curve from time 0 to infinity (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 
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 53–75% lower than to orismilast. 
PDE4 enzymatic activity was measured in a scintillation proximity assay using purified human 
recombinant PDE4D protein. Orismilast is a potent inhibitor of PDE4D activity. LEO 40815 was 
approximately 100 times less potent than 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, there has not been identified any differences in the PK 
profile of orismilast between races (LP0058-1362) or gender (LP0058-1114). 
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 twice daily compared with midazolam alone (geometric means of 132% for area under 
the curve from time 0 to the last measurable concentration [AUC0-t] and 137% for Cmax). These 
results classify orismilast as a weak inhibitor of CYP3A4. 
Pharmacodynamic evaluation from trial LP0058-S01 using an ex vivo cytokine release assay 
indicated that orismilast inhibited the secretion of TNF-α and interferon gamma (IFN-γ). 
Maximum inhibition generally occurred between 4–6 hours postdose. 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 67–70% for TNF-α and 52–77% for INF-γ levels 
across dose groups receiving 10, 20 and 30 mg 3 times a day orismilast. In accordance, reduced 
levels of TNF-α, IFN-γ, macrophage inflammatory protein-1 alpha (MIP-1α), and MIP-1β were 
observed in lipopolysaccharide- stimulated blood from subjects treated with orismilast in the 
LP0058-1072 trial, suggesting that pharmacologically relevant levels of orismilast were present. 
5.2.2.2. 
Efficacy 
So far one efficacy trial (LP0058-1072) with orismilast immediate-release tablets has been 
completed. A total of 36 subjects with moderate-to-severe psoriasis vulgaris were randomized in 
the trial in a 1:1 ratio to treatment with either 30 mg orismilast or placebo, administered orally as 
3 tablets twice daily for 16 weeks (1-week dose escalation followed by 15-week full dose 
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After 16 weeks of treatment, the mean psoriasis area and severity index (PASI) score (primary 
endpoint) was statistically significantly lower in subjects treated with orismilast tablets (least 
squares mean: 7.1) compared with subjects in the placebo group (least squares mean: 13.1). 
Mean PASI at entry was 14.9. A higher proportion of patients achieved a 75% improvement in 
PASI (PASI75) in the orismilast group (44.4%) vs placebo (5.6%; P =.019). In addition, 
treatment success (defined as clear or almost clear) according to Physician’s Global Assessment 
of disease severity (PGA) at Week 16 was higher in the orismilast group (7 of 18 subjects, 
38.9%) than in the placebo group (1 of 18 subjects, 5.6%). The estimated itch score was 
numerically lower at Week 16 in the orismilast group (least squares mean: 3.4) compared with 
the placebo group (least squares mean: 5.7). 
Approximately half of the subjects 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 impact on the 
estimated efficacy, it was not considered to disqualify the clear difference observed between the 
2 treatments. 
5.2.2.3. 
Safety 
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. Orismilast was 
moderately well tolerated in multiple doses up to 50 mg twice daily, after gradual up-titration to 
the 50 mg twice daily level over 8 days. Poor tolerability at the 60 mg dose level was due to an 
increased incidence and severity of GI adverse events (AEs). This was most likely 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 
twice daily level but was poorly tolerated when up-titrated to the 40 and 50 mg twice daily levels 
in trial LP0058-1267. Six subjects were withdrawn from the trial by the Investigator because of 
AEs. Likewise, in the LP0058-1072 trial, orismilast tablets (30 mg twice daily) were poorly 
tolerated in subjects with moderate-to-severe psoriasis vulgaris. AEs leading to withdrawal from 
the trial were reported for 50% of the subjects 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 adverse events (SAEs) were reported across all trials; 3 SAEs in 3 subjects in 
the LP0058-1072 trial in subjects with moderate-to-severe psoriasis vulgaris and 2 SAEs in 1 
subject in the LP0058-1324 trial. In the LP0058-1072 trial, 2 subjects 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 subject in the placebo group had 1 SAE 
(‘condition aggravated’, relating to preexisting Scheuermann's disease and considered not related 
to the treatment). In the LP0058-1324 trial, 1 subject reported SAEs (abdominal pain and 
abdominal cramps, considered possibly related to the treatment). 


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The majority of 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 dose 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). 
 
5.3. Clinical Risks/Benefits 
 
Despite the positive and encouraging efficacy results of the Phase 2a study of the immediate- 
release tablets of orismilast, this formulation presented an undesirable safety profile with 50% of 
patients prematurely discontinuing because of GI effects. To improve the GI tolerance, several 
formulations were tested in an extensive Phase 1 clinical program, leading to the selection of a 
modified-release formulation with notably better GI tolerance in healthy volunteers. The 
modified-release formula is expected to mitigate potential GI effects previously observed in 
psoriasis patients with the immediate-release tablets while maintaining the efficacy previously 
observed. The titration dosing schedule at the initiation of study treatment will help to reduce the 
incidence and severity of GI side effects that tend to occur primarily when starting therapy. The 
improved safety profile of the modified-release formulation is expected to make the therapeutic 
window of orismilast wider this allowing to achieve dosing levels with adequate efficacy and 
good tolerability. 
Occurrence and severity of GI disorders will be promptly identified by monitoring the subjects 
for any signs of abdominal discomfort, abdominal distension, abdominal pain, nausea, vomiting, 
loss of appetite, and diarrhea. Depending on their severity, these AEs may qualify as an adverse 
event of special interest (AESI). Based on the occurrence of GI or other AEs considered having 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. Besides the above, all 
subjects will be monitored for any cardiovascular manifestations using vital signs and 12-lead 
ECG at each visit. Drug class potential effects such as weight loss and major depression will be 
monitored during the study. Subjects 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 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. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of orismilast may be found in the Investigator’s Brochure. 
 
5.4. Study Rationale 
 
PDE4 inhibitors have demonstrated efficacy in psoriasis and AD with 2 drugs having reached the 
market: apremilast, an oral agent for the treatment of plaque-type psoriasis and crisaborole, a 


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topical agent, for the treatment of AD. Orismilast is a novel PDE4 inhibitor being developed for 
the oral treatment of psoriasis. After an extensive Phase I program in healthy subjects and a 
Phase 2a study in patients with moderate-to-severe psoriasis, the clinical development program is 
progressing into a Phase 2b dose-finding clinical study using a modified-release oral formulation 
that is expected to present a more favorable safety profile. 
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 administered orally BID over a period of 16 weeks in patients with 
moderate-to-severe plaque psoriasis. Efficacy and patient’s outcome will be assessed through a 
set of validated measures for psoriasis. In addition, PK and pharmacodynamic (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. 
 
5.4.1. 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 
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. 


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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 patients 
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 
patients 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 
target dose for further development. 


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6. STUDY OBJECTIVES AND ENDPOINTS 
 
6.1. Study Objectives 
 
6.1.1. 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 plaque-type psoriasis. 
 
6.1.2. Secondary Objectives 
 
Evaluate the dose response of orismilast and identify the dose with the best benefit/risk ratio to 
be evaluated in a Phase 3 program. 
 
6.1.3. Exploratory Objectives 
The exploratory objectives are to: 
• 
• Evaluate the change in cardiovascular risk factors under orismilast treatment. 
• 
 
• Evaluate the change in skin psoriasis at “difficult to treat” anatomical areas such as the 
scalp. 
• Evaluate the change in psoriasis at “difficult to treat” anatomical areas such as nails. 
 
6.2. Study Endpoints 
 
6.2.1. Primary Endpoint 
 
The primary endpoint in this study is the percentage change in Psoriasis Activity and Severity 
Index (PASI) score from Baseline at Week 16. 
 
6.2.2. Secondary Endpoints 
 
6.2.2.1. 
Key Secondary Endpoints 
• Patients achieving 75% reduction in PASI (PASI75) response at Week 16. 
• Patients achieving a score of Clear (0) or Almost Clear (1) and an at least 2-point 
improvement in Investigator Global Assessment (IGA) at Week 16. 
6.2.2.2. 
Other Secondary Endpoints 
• Patients achieving a score of Clear (0) or Almost Clear (1) and an at least 2-point 
improvement in IGA at Weeks 4, 8, 12, and 20. 


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• Patients achieving PASI75 response at Weeks 4, 8, 12, and 20. 
• Patients achieving 50% reduction in PASI (PASI50) and 90% reduction in PASI 
(PASI90) response at Weeks 4, 8, 12, 16, and 20. 
• Change from Baseline in PASI at Weeks 4, 8, 12, and 20. 
• Change from Baseline in total Psoriasis Symptoms Scale (PSS) score at Weeks 4, 8, 12, 
16, and 20. 
• Change from Baseline in each individual item of the PSS at Weeks 4, 8, 12, 16, and 20. 
• Change from Baseline in the affected body surface area (BSA) at Weeks 4, 8, 12, 16, and 
20. 
• Change from Baseline in Dermatology Life Quality Index (DLQI) score at Weeks 16 and 
20. 
• Patients experiencing psoriasis rebound by Week 20, defined as PASI ≥125% of Baseline 
or new generalized pustular, erythrodermic, or more inflammatory psoriasis. 
6.2.2.3. 
Safety Endpoints 
• The occurrence, severity, and seriousness of treatment-emergent adverse events (TEAEs) 
reported over the 16-week Treatment Period and the 4-week Follow-up Period. 
• Changes from Baseline in physical examination; vital sign 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. 
• Changes from Baseline in ECG findings over the 16-week Treatment Period and the 4- 
week Follow-up Period. 
• Changes from Baseline in safety laboratory values (hematology, serum chemistry, and 
urinalysis) over the 16-week Treatment Period and the 4-week Follow-up Period. 
• HADS at each visit except Screening, Week 1 and Week 2. 
• C-SSRS at each visit except Weeks 1 and 2. 
 
6.2.3. Exploratory Endpoints 
 
• Change from Baseline in Physician's Global Assessment of Fingernails (PGA-F) at 
Week 16. 
• Change in scalp-specific Investigator Global Assessment (ss-IGA) from Baseline at 
Week 16 in the subgroup of patients with Baseline score of at least 2 (mild scalp 
psoriasis). 


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• Change from Baseline of scalp itch Numeric Rating Scale (NRS) at Week 16 in the 
subgroup of patients with Baseline score of at least 4 on the 11-point NRS. 
• 
 
• Change in cardiovascular risk factors at Week 16. The following parameters will be 
collected: weight, body mass index (BMI), waist and hip circumferences, blood pressure, 
fasting serum glucose, triglycerides, cholesterol (total and high-density lipoprotein / low- 
density lipoprotein fractions), and C-reactive protein. 
• 
 
• Plasma levels of the drug and its metabolites at scheduled visits. 


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7. INVESTIGATIONAL PLAN 
 
7.1. 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 adult patients with moderate-to-severe plaque-type psoriasis. Efficacy 
and safety outcomes will be evaluated to select an appropriate orismilast dose for subsequent 
Phase 3 studies. The study will be conducted in approximately 40 centers in Europe and North 
America. 
After a Screening visit up to 28 days before Baseline, approximately 200 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. The maximum duration of study participation 
is approximately 24 weeks. 
Patients will be seen at the site on Screening, Baseline (Day 1), and Weeks 1, 2, 4, 8, 12, 16 
(End-of-Treatment [EOT] visit), and 20 (Follow-up visit, 4 weeks after treatment completion or 
discontinuation). Visits at Weeks 1 and 2 could be conducted via a telemedicine procedure at 
Investigator’s discretion. 
At Baseline and each visit from Week 4 onwards, PASI, BSA, IGA, and PSS will be assessed. 
Quality of life (QoL) will be assessed by administration of DLQI at Baseline and at Weeks 16 
and 20 visits. Additional efficacy parameters include: an ss-IGA, a PGA of fingernail psoriasis 
(PGA-F), and 
. These parameters will 
be assessed at Baseline and Weeks 16 and 20. Safety evaluations include AEs, laboratory and 
vital sign assessments, physical examinations as well as mood change evaluation by patient 
(HADS) and suicidal ideation evaluation by Investigator (C-SSRS). A panel of cardiovascular 
risk factors will be assessed at Baseline and Week 16. 
Before administration of the study drug at Baseline and on Weeks 4, 8, and 16, blood will be 
collected for orismilast concentration determination. 
 
See Figure 1 for the study design. 


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Figure 1. 
Study Design 
 
 
Abbreviation: BID, twice a day 
 
7.2. Discussion of Study Design 
 
A double-blind, randomized, placebo-controlled study is considered a gold-standard for 
conducting any interventional and dose-finding study. A sample size of 50 patients per treatment 
arm is also adequate to get robust outcome data for a comparison among doses and with placebo. 
Psoriasis is a chronic condition requiring long-term therapy. Primary efficacy assessments of 
psoriasis clinical trials are usually performed at 12 or 16 weeks after initiation of study treatment. 
Because of the initial titration period of up to 2 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. Primary evaluations of apremilast, the only PDE4 inhibitor 
currently approved for psoriasis treatment, were also conducted at Week 16. A 16-week 
Treatment Period was also deemed acceptable for the placebo arm because psoriasis is not a life- 
threatening disease warranting immediate treatment. 
Besides the usual psoriasis assessments including the PASI, the IGA, and the BSA, the effects of 
study treatment on nail and scalp psoriasis that represent location of disease more refractory to 
treatment will be explored. In patients with PsA, any potential effect on 
will be also 
assessed. A number of patient-reported outcome (PROs) will be administered to explore the 
patient’s perception of his or her condition and the related QoL, as recommended by regulatory 
agencies. This comprehensive evaluation of the psoriatic condition of patients will contribute to 
the selection of the most suitable dose(s) for the Phase 3 clinical program. 


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7.3. End of Study 
 
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). 
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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8. SELECTION OF STUDY POPULATION 
 
8.1. Inclusion Criteria 
 
Patients are eligible to be included in the study only if all of the following criteria apply: 
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 ≥18 years of age at the time of signing the ICF. 
3. Body weight of >40 kg at the time of signing the ICF. 
4. Diagnosis of chronic, stable plaque-type psoriasis at least 2 months before the Screening 
visit. If the patient is diagnosed with psoriasis arthritis, the arthritis should be stable. 
5. Moderate-to-severe plaque-type psoriasis as defined by PASI ≥12, BSA ≥10%, and 
IGA ≥3 at the screening and baseline visits. 
6. Candidate for systemic antipsoriatic treatment or phototherapy. 
7. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
at the Screening visit and a negative urine pregnancy test at the Baseline visit. In 
addition, sexually active WOCBP must agree to use a highly effective method of 
contraception until at least 4 weeks after the end of study treatment. Highly effective 
methods of contraception are those that have a failure rate of <1% (when implemented 
consistently and correctly) 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 entire 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 months without an 
alternative medical cause and a confirmatory follicle-stimulating hormone (FSH) test or 
as cessation of menses for at least 24 months without an alternative medical cause. 
 
8.2. Exclusion Criteria 
 
Patients are excluded from the study if any of the following criteria apply: 
1. Therapy-resistant psoriasis defined as ≥2 treatment failures due to inadequate efficacy 
within the past 5 years of any biologic therapies (including but not limited to etanercept, 


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adalimumab, infliximab, certolizumab pegol, guselkumab, secukinumab, risankizumab, 
ixekizumab, tildrakizumab, or ustekinumab) administered in 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 psoriasis or PsA with acute deterioration within 4 weeks of the Screening visit. 
3. History of allergy or hypersensitivity to any component of the study treatment. 
4. Active infection (eg, bacteria, viral, fungal) requiring treatment with systemic antibiotics 
within 4 weeks of the Screening visit. 
5. Malignancy or history of malignancy except for treated (ie, cured) basal cell skin 
carcinomas. 
6. Current diagnosis of predominant guttate, erythrodermic, exfoliative, or pustular 
psoriasis, or of drug-induced psoriasis, or other skin conditions that might confound the 
evaluation of psoriasis vulgaris, as judged by the Investigator (eg, AD, lupus). 
7. Any 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) which, 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 for receiving the 
investigational therapy. 
9. Any therapies and systemic treatments as described in Table 3 which do not comply with 
the indicated washout interval. 
10. Any previous treatment with orismilast or failure of treatment with apremilast or any 
other systemic PDE4 inhibitor as described in Table 3. 
11. 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. 
12. Severe hepatic impairment based upon medical history and laboratory abnormalities (eg, 
low albumin and abnormal bilirubin). 
13. Any of the following abnormalities in clinical laboratory tests at Screening, as assessed 
by the study-specific laboratory and confirmed by a single repeat, if deemed necessary: 
a. Absolute neutrophil count of <3.0 × 109/L (<3000/mm3) 
b. Hemoglobin of <10.0 g /dL or hematocrit <30% 
c. Platelet count of <100 × 103 cells/mm3 (SI: <100 × 109 cells/L). 
d. Absolute lymphocyte count of <1.0 × 109/L (<1000/mm3) 


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e. Total bilirubin >1.5 × the upper limit of normal (ULN); patients with a history of 
Gilbert's syndrome may have a direct bilirubin measured and would be eligible for 
this study provided the direct bilirubin is ≤ULN 
f. Alanine aminotransferase or aspartate aminotransferase >2.5 × the ULN. 
g. Serum creatinine ≥1.5 mg/dL. For a patient with a value of ≥1.5 mg/dL, a 
creatinine clearance of ≥60 mL/min (calculated using the CKD-EPI Creatinine 
Equation) is allowed. 
14. History or evidence of hepatitis B virus (HBV) infection at Screening. Patients with 
positive hepatitis B surface antigen (HBsAg) are excluded. For patients with isolated 
positive antihepatitis B core antibody (HBcAb), hepatitis B surface antibody (HBsAb) 
result must also be positive to be considered for this study. 
15. 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. 
16. History of positive HIV, or have 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. 
17. 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 the C-SSRS 
completed at the Baseline visit. 
18. Pregnant or breastfeeding. 
19. History of alcohol or substance abuse within 6 months before Baseline that, in the 
opinion of the Investigator, will preclude participation in the study. 
20. Institutionalized by court order or by local authority. 
 
8.3. 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 time. 
 
8.4. Study Withdrawal, Removal, and Replacement of Patients 
 
If a patient discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Patients who 
complete or discontinue early from the study will be asked to return to the study site within 
4 weeks of the last administration of study drug to complete EOT assessments as indicated in the 


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Schedule of Assessments (Table 4). If the study treatment is permanently discontinued, the 
patient will remain in the study to be evaluated for safety. 
In the event that a patient discontinues prematurely from the study because of a TEAE or serious 
TEAE assessed as ≥Grade 3 (≥Grade 2 for the system organ class [SOC] of cardiac disorders) 
according to Common Terminology Criteria for Adverse Events version 5 (CTCAE v 5), the 
TEAE or serious TEAE 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. 
Once a patient is withdrawn from the study, the patient cannot reenter 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: 
• unacceptable toxicity or AE 
• patient’s 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. 
• 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 patient’s 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 12.9.6. 
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. 
 
8.5. Suspension or Premature Termination of the Clinical Investigation 
 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 


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The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further development of the study drug 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
institutional review board (IRB)/independent ethics committee (IEC) or local health 
authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients by 
the Investigator. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow up. 


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9. TREATMENTS 
 
9.1. Details of Study Treatments and Dosage Schedule 
 
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. Pharmacokinetic (PK) studies have shown no difference 
whether the product is taken under fasted condition or during a low-fat meal. Intake during a 
high-fat meal leads to higher blood concentrations, and possibly higher incidence of GI side 
effects and must, 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 
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 x 
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. 
 
9.2. Measures to Minimize Bias: Study Treatments 
 
9.2.1. 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 based on chronological order of Screening dates (eg, 01-010 for the 10th 
patient screened at the Site #01). 
Randomization will occur prior to 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. 


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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). Further guidance and information can be obtained in the study manual. 
 
9.2.2. Blinding 
 
To facilitate the double blind, 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). 
Blinding codes should only be broken in emergency situations for reasons of patient safety. 
When the blind for a patient has been broken, the reason must be fully documented in the source 
document and eCRF. Whenever possible, the Investigator should contact the sponsor or its 
designee before breaking the blind. If the blind is broken, the Investigator should promptly 
inform the medical monitor. Documentation of breaking the blind should be recorded 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 early termination procedures. The primary reason for discontinuation (the event or condition 
which led to the unblinding) will be recorded. 
The Interactive Web Response System (IWRS) will be programmed with blind-breaking 
instructions. In case of an emergency, the Investigator has the sole responsibility for determining 
if unblinding of a patients’ 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 prior to unblinding a 
patient’s treatment assignment unless this could delay emergency treatment of the patient. If a 
patient’s treatment assignment is unblinded, the sponsor must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable. 
All patients will be centrally assigned to randomized study treatment using an IWRS. Before the 
study is initiated, the telephone number and call-in directions for the log in information and 
directions for the IWRS will be provided to each site. 
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. 
Sponsor 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 one 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. 


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9.3. Dosage Modification 
 
If a patient experiences a TEAE assessed as ≥Grade 3 (≥Grade 2 for the SOC of Cardiac 
Disorders) according to CTCAE v 5, the patient should be permanently discontinued from the 
study drug and not receive additional doses. As a reminder Grade 3 is defined as “Severe or 
medically significant but not immediately life threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care activities of daily living (ADL)”. 
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 during the treatment up- 
titration and/or during maintenance period, the Investigator might consider decreasing the 
regimen as described in Section 9.3.1. 
If the study drug is permanently discontinued, the patient will remain in the study to be evaluated 
for safety. 
 
9.3.1. Titration 
 
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 less 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 (see Table 2). 
If tolerability issues arise during the treatment up-titration and/or during maintenance period, the 
following treatment pauses are allowed only if instructed by the Investigator: 
• First day: The Investigator is informed of the tolerability issue; thus, the evening dose can 
be skipped. 
• Second day: Morning dose can be skipped. The patient must take the evening dose. 
• Third day: Similar to Day 2, morning dose can be skipped. The patient must take the 
evening dose. 
• Fourth day: BID daily dosing regimen is reintroduced. 
The aforementioned treatment pauses do not impact calculation of dosing days and duration of 
titration is not prolonged. Treatment pauses will be captured in the eCRFs. This titration will not 
break the blind as all patients will receive 2 of indistinguishable orismilast or placebo tablets 
BID. 


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Table 2. 
Dose Titration Schedule 
 
Abbreviation: BID, twice daily 
 
9.4. Treatment Accountability and Compliance 
 
The patients will receive the study drug at the site 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 in eCRF and patient’s source document. 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 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. 
 
9.5. Prior and Concomitant Therapy 
 
Any concomitant medication, supplement, or procedure within 6 months prior to Baseline or 
receives 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. 


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9.5.1. Allowed Treatments and Rescue Medications 
 
All medications (prescription and nonprescription), treatments and therapies taken from 
Screening throughout their entire participation in the study, including those initiated prior to the 
start of the study, must be recorded on the patient’s source document and on the appropriate page 
of the eCRF. The dose, unit, frequency, route, indication, date the medication was started and the 
date the medication was stopped (if not ongoing) must be recorded. The recording of any 
permitted topical medications taken for psoriasis should also include the area of the body to 
which they are applied and the frequency of application. 
The following topical therapies will be permitted during the study: 
• For psoriasis body lesions: nonmedicated emollients or low potency corticosteroids used 
only for treatment of the face, axillae, and groin 
Examples of low potency corticosteroids (Groups VI and VII): 
o Betamethasone valerate lotion 0.05% 
o Desonide cream 0.05% 
o Fluocinolone acetonide solution 0.01% 
o Dexamethasone sodium phosphate cream 0.1% 
o Hydrocortisone lotion, cream, or ointment 2.5% 
o Hydrocortisone acetate cream 1% 
o Methylprednisolone acetate cream 0.25% 
• For scalp psoriasis lesions: coal tar shampoos and/or salicylic acid scalp preparations but 
only if on a stable use since Screening 
Topical preparations should not be applied within 24 hours of the clinic visit. 
 
9.5.2. Prior and Concomitant Medications 
 
Restricted prior therapies are provided in Table 3. In addition, patients with any prior treatment 
with orismilast or failure of treatment with apremilast or any other systemic PDE4 inhibitor are 
ineligible. 
Table 3.    Disallowed therapies and treatments 
 
Compound 
Washout 
Topical medications/treatments that could affect psoriasis 
or study evaluations (eg, corticosteroids, anthralin, 
calcipotriene, vitamin D derivatives, retinoids, tazarotene, 
pimecrolimus, tacrolimus, or PDE4 inhibitor) 
Within 2 weeks prior to Baseline 
and throughout the study 
Systemic treatment with therapies other than biologics 
with a possible effect on psoriasis like apremilast, 
corticosteroids, retinoids, systemic immunosuppressants 
(eg, methotrexate, azathioprine, cyclosporine), protein 
Within 4 weeks prior to Baseline 
or 5 half-lives (whichever is 
longer) and throughout the study 


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Compound 
Washout 
kinase inhibitors (eg, tofacitinib, baricitinib, or 
upadacitinib) or fumaric acid 
Investigational drugs other than the study drug 
Within 4 weeks of 
randomization, or 5 half-lives, if 
known (whichever is longer) and 
throughout the study 
Initiation of or changes of doses to concomitant 
medication that could exacerbate psoriasis (for example, 
beta blockers, angiotensin-converting enzyme inhibitors, 
antimalarial drugs, lithium) 
Within 4 weeks prior to Baseline 
and throughout the study 
Use of phototherapy or prolonged sun exposure or use of 
tanning booths or other ultraviolet light sources (ie, UVB, 
psoralens and long-wave ultraviolet radiation) 
Within 4 weeks of Baseline and 
throughout the study 
Etanercept 
Within 8 weeks prior to Baseline 
and throughout the study 
TNF inhibitors like adalimumab, certolizumab pegol, or 
infliximab 
Within 12 weeks prior to 
Baseline and throughout the 
study 
Any biologic agents targeting IL-12, IL-17, or IL-23 like 
ustekinumab, secukinumab, brodalumab, guselkumab, 
ixekizumab, risankizumab, or tildrakizumab 
Within 16 weeks prior to 
Baseline and throughout the 
study 
Rituximab and any B-cell depleting agent 
Within 24 weeks prior to 
Baseline and throughout the 
study 
Concomitant medication mainly metabolized via 
cytochrome 2D6 isozyme and with narrow therapeutic 
window such as tricyclic antidepressants (e.g., 
nortriptyline, amitriptyline, imipramine, desipramine) or 
Type 1C antiarrhythmics (propafenone, flecainide and 
encainide) or via cytochrome 3A4 with a narrow 
therapeutic index 
4 weeks prior to Baseline and 
throughout the study 
Abbreviations: IL, interleukin; PDE4, phosphodiesterase-4; TNF, tumor necrosis factor alpha 
Concomitant medication mainly metabolized via cytochrome 3A4 and with 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. 
 
9.5.3. Drug-Drug Interactions 
 
From clinical studies, orismilast can be considered a mild inhibitor of CYP3A4/5, and systemic 
exposure to medicinal products metabolized by CYP3A4 may be increased when co- 
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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 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. Co-administration of drugs with a narrow therapeutic index 
such as tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine, desipramine) or 
Type 1C antiarrhythmics (propafenone, flecainide and encainide) is prohibited (see Table 3). 


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10. STUDY PROCEDURES 
 
Table 4 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.5 specifies laboratory assessment samples to be obtained. See Sections 11 and 12 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 -1 
Day 1 
(Baseline) 
W1 
(±1d) 
W2 
(±1d) 
W4 
(±2d) 
W8 
(±3d) 
W12 
(±3d) 
W16 
(EOT/ET; 
±3d) 
W20 
(±3d) 
Informed consent (before any study procedures) 
X 
Demography 
X 
Medical history, including medication, alcohol, and smoking 
history (last 6 months) 
X 
Concurrent medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion and exclusion criteria 
X 
X 
Physical examinationa 
X 
X 
X 
X 
12-lead ECG (single measurement) 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
Weightc 
X 
X 
X 
X 
X 
X 
X 
Heightc 
X 
BMIc 
X 
X 
X 
X 
Waist and hip circumferencesc 
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, and HBsAb) 
X 
Safety laboratory assessments (hematology, serum chemistry, 
urinalysis) 
X 
X 
X 
X 
X 
Cardiovascular risk factor laboratory assessmentsc,d 
X 
X 
Pregnancy teste 
X 
X 
X 
X 
X 
X 
Blood samples for drug and metabolite PK analysis: trough levels 
(before study drug administration) 
X 
X 
X 
X 
Blood samples for drug PK profile (optional) 
X 
X 
 
X 
X 


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Screening 
Treatment Period 
Follow up 
Procedure 
Between Day 
-28 and -1 
Day 1 
(Baseline) 
W1 
(±1d) 
W2 
(±1d) 
W4 
(±2d) 
W8 
(±3d) 
W12 
(±3d) 
W16 
(EOT/ET; 
±3d) 
W20 
(±3d) 
IGA, BSA, and PASI 
X 
X 
X 
X 
X 
X 
X 
PGA-F 
X 
X 
X 
Scalp Psoriasis ss-IGA 
X 
X 
X 
Scalp itch NRS 
X 
X 
X 
X 
X 
PSS 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
DLQI 
X 
X 
X 
HADS 
X 
X 
X 
X 
X 
X 
Dispense study drug 
X 
Xh 
Xh 
X 
X 
X 
Collect study drug including packaging 
Xh 
Xh 
X 
X 
X 
X 
Compliance check 
X 
X 
X 
X 
X 
X 
Abbreviations: BMI, body mass index; BSA, body surface area; CRP, c-reactive protein; C-SSR, Columbia-Suicide Severity Rating Scale; d, day; 
DLQI, Dermatology Life Quality Index; ECG, electrocardiogram; EOT, end of trial; 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; hCG, human chorionic 
gonadotropin; HDL, high-density lipoprotein; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IGA, Investigator Global Assessment; LDL, 
low-density lipoprotein; NRS, Numerical Rating Scale; PASI, Psoriasis Area and Severity Index; PGA-F, Physician Global Assessment of Fingernail 
Psoriasis; PK, pharmacokinetic; PSS, Psoriasis Symptoms Scale; ss-IGA, scalp-specific Investigator Global Assessment; W, week. 
a. 
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 
Week 20. 
b. 
All vital signs will be measured after the patient has been resting in a sitting position for at least 5 minutes. 
c. 
Cardiovascular risk assessments include: height, weight, BMI, waist and hip circumferences, blood pressure, fasting serum glucose, triglycerides, 
cholesterol (total and HDL/LDL fractions), and C-reactive protein. 
d. 
Cardiovascular risk factor laboratory assessments include CRP, glucose, total cholesterol, HDL, LDL, and triglycerides. Patients should be in fasting 
condition (no food or fluids other than water for 8 hours) before sample collection at Baseline and Week 16. 
e. 
Serum Beta-hCG and urine pregnancy test at Screening. Urine pregnancy test 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. 
f. 
 
g. 
h. 
Only applicable if the visit is conducted in person. 
 


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10.1. 
Informed Consent 
 
Before performing any study-related procedures, the Investigator (or designee) will obtain 
written ICF 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. 
 
10.2. 
Study Procedures 
 
Assessments and their timing are to be performed as outlined in the Schedule of Assessments 
(Table 4). Section 12.5 specifies laboratory assessment samples to be obtained. 
All PROs should be administered prior to any other visit procedure. Furthermore, vital signs, 
weight measurement, and ECG must be done prior to blood sampling. The study drug is 
administered after completion of all other procedures. 
Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of treatment. 
Efficacy assessments are described in Section 11 and include PASI, IGA, BSA, ss-IGA, IGA-F, 
PSS, 
, scalp itch, and DLQI. 
Safety assessments are described in Section 12 and include vital signs, physical examinations, 
ECGs, laboratory assessments, HADS, C-SSRS, and AEs. 
PK assessments are described in Section 13 and PD assessments are described in Section 14. 


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11. 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 
Physician’s assessments. The same assessor should perform all evaluations within the same 
patient throughout their study participation. 
 
11.1. 
Investigator Assessments 
 
11.1.1. Psoriasis Area and Severity Index 
 
The PASI is a measure of psoriatic disease severity, taking into account qualitative lesion 
characteristics (erythema, induration, and desquamation) and percentage of affected skin surface 
area on defined anatomical regions. The PASI is a validated instrument that is the most widely 
used tool for measurement of severity of psoriasis. 
Psoriasis Area Severity Index scores range from 0 to 72, with higher scores reflecting greater 
disease severity (Fredriksson 1978). Erythema, induration/thickness, and scaling are scored on a 
scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, 
and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 
0 (no involvement) to 6 (90% to 100% involvement). The total qualitative score (sum of 
erythema, thickness, and scaling scores) is multiplied by the degree of involvement for each 
anatomic region and then multiplied by a constant. The scores for each anatomic region are 
combined to yield the final PASI. 
 
11.1.2. Investigator Global Assessment 
 
The IGA is a measure used by physicians to determine the patient’s overall severity of disease. 
The static version (Langley 2015) is used in this trial for measurement at a single point in time as 
indicated in the schedule of assessments. The Investigator will rate the severity of patient’s 
psoriasis on a 5-point scale ranging from 0 (clear) to 4 (severe). 
 
11.1.3. Scalp-specific Investigator Global Assessment 
 
The ss-IGA assesses lesions on the scalp for degree of redness, thickness, and scaling on a 5- 
point scale, with 0 indicating absence of disease and 4 indicating severe disease. 
 
11.1.4. Physician’s Global Assessment of Fingernail Psoriasis 
 
The PGA-F is used in this trial to evaluate abnormalities in the fingernails, and the severity of 
these, in patients with nail psoriasis. It is a simple and reliable clinician-rated scale, which is easy 
to use in clinical practice and research. The scale rates the overall condition of the fingernails 
and is based on a 5-point scale, with 0 indicating clear and 4 indicating severe. 


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11.1.5. Body Surface Area 
 
The BSA assessment estimates the extent of disease or skin affected by psoriasis and is 
expressed as a percentage of total body surface. BSA will be determined by the Investigator or 
designee using the patient palm = 1% BSA rule. 
 
11.2. 
Patient-Reported Outcomes 
 
11.2.1. Psoriasis Symptom Scale 
 
The PSS is a 4-item patient-completed questionnaire (Rentz et al 2017). It is patient relevant, its 
domains are reliable and valid, and it takes few minutes to complete. The PSS assesses severity 
of pain, itching, redness, and burning during the past 24 hours using a 5-point severity scale from 
0 = none to 4 = very severe. 
 
11.2.2. Scalp Itch 
 
Scalp itch will be assessed by requesting the patients to grade their worst scalp itch over the past 
24 hours on a 11-point with an NRS with 0 corresponding to No itch and 10 to Worst imaginable 
itch. 
 
 
 
 
 
11.2.4. Dermatology Life Quality Index 
 
The DLQI is a 10-item validated questionnaire completed by the patient used to assess the 
impact of skin disease on the patient’s QoL during the previous week. The 10 questions cover 
the following topics: symptoms, embarrassment, shopping and home care, clothes, social and 
leisure, sport, work or study, close relationships, 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 QoL. DLQI responses will be captured 
as outlined in the SoA. 


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12. SAFETY ASSESSMENTS 
 
Safety assessments (vital signs, physical examinations, ECG recording, AEs, HADS, C-SSRS, 
clinical laboratory results [routine hematology and biochemistry]) are to be performed at 
protocol-specified visits, as specified in the Schedule of Assessments (Table 4). 
 
12.1. 
Medical History 
 
Medical history will be recorded at Screening. Investigators should document the occurrence, 
signs, and symptoms of the patient’s preexisting conditions, including all prior significant 
illnesses. Additional preexisting conditions present at the time when informed consent is given, 
and up to the time of first dosing, are to be regarded as concomitant. Medical history will include 
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 12.7. 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. 
 
12.2. 
Vital Signs 
 
Vital signs (body temperature, 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). Using of tympanic/ear thermometer is recommended for body temperature. 
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 at 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. 


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12.3. 
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 Week 20 to verify continued patient eligibility and to Follow up 
regarding any change in medical history. Physical examinations will be performed by a 
physician. 
Symptom-driven, limited physical examinations will be performed as clinically indicated at any 
study visit. Additionally, patients’ BMI, height, weight, as well as waist and hip circumference 
will be measured at the visits indicated in the Schedule of Assessments (Table 4). 
 
12.4. 
Electrocardiogram 
 
A 12-lead, resting ECG will be obtained 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 will be recorded; 
if the ECG is considered abnormal, the abnormality will be documented on the eCRF. ECGs will 
be repeated if clinically significant abnormalities are observed, or artifacts are present. 
 
12.5. 
Waist and Hip Circumferences 
 
The waist circumference should be measured at the top of the iliac crest, using a stretch‐ 
resistant tape. Hip circumference should be measured around the widest portion of the buttocks, 
with the tape parallel to the floor. 
The individual should stand with feet close together, arms at the side, and body weight evenly 
distributed, and he or she should wear little clothing. The subject should be relaxed, and the 
measurements should be taken at the end of a normal respiration. 
 
12.6. 
Laboratory Assessments 
 
Laboratory assessment samples (Table 5) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 4). Patients should be in fasting condition (no food or fluids 
other than water for 8 hours) before sample collection at Baseline and Week 16. 


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Table 5. 
Laboratory Assessments 
 
Hematology 
Serum Chemistry 
Urinanalysis (Dipstick) 
Full and differential blood count 
Albumin 
Appearance 
Hct 
ALT 
pH 
Hb 
ALP 
Protein 
MCH 
AST 
Glucose 
MCHC 
BUN or urea 
Ketone bodies 
MCV 
Creatinine 
Indicators of blood and WBCs 
Platelet count 
RBC count (% reticulocytes) 
WBC count with differential 
(neutrophils, lymphocytes, 
monocytes, eosinophils, and 
basophils) 
Electrolytes (sodium, potassium, 
chloride, calcium, phosphorus) 
GGT 
LDH 
Total bilirubin 
Direct bilirubin 
Specific gravity 
Urine hCG (premenopausal females 
only) 
Urobilinogen 
Cardiovascular Risk Factors (fasting 
condition and at Baseline and Week 16 only) 
Other Screening Tests 
CRP 
HIV antibody 
Glucose 
Total cholesterol 
HBV 
HCV 
HDL 
LDL 
Triglycerides 
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) 
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 as indicated in Table 4. 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
BUN, blood urea nitrogen; GGT, gamma-glutamyl transpeptidase; CRP, c-reactive protein; hCG, human 
chorionic gonadotropin; Hb, hemoglobin; Hct, hematocrit; HBcAb, hepatitis B core antibody; HBsAb, hepatitis 
B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDL, 
high-density lipoprotein; HIV, human immunodeficiency virus; LDL, low-density lipoprotein; LDH, lactate 
dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; 
MCV, mean corpuscular volume; RBC, red blood cell; WBC, white blood cell. 
Samples will be analyzed at a central laboratory facility. Urine samples will be analyzed by 
dipstick at site; if the results of the dipstick indicate abnormalities a urine sample will be 
collected for microscopic analysis to be performed at a central laboratory for further 
investigation. All laboratory reports must be reviewed, signed, and dated by the Investigator. A 
legible copy of all reports must be filed with both the patient’s 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. 


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12.7. 
The Hospital Anxiety and Depression Scale 
 
The HADS is a PRO and comprises of 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. The HADS is 
one of the National Institute for Health and Care Excellence recommended tools for diagnosis of 
depression and anxiety. 
Any patient with a score for depressive symptoms ≥15 at Baseline will not be eligible for 
randomization 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 0. 
 
12.8. 
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 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 items 4 or 5 in the past year, the patient 
will not be included in the study. 
Any subject with a positive response on the C-SSRS (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 0. 
 
12.9. 
Adverse Events 
 
AEs will be collected throughout the study as shown in the Schedule of Assessments (Table 4). 


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12.9.1. Adverse Events 
 
An AE is any untoward medical occurrence associated with the use of a drug in humans. An AE 
can, therefore, be any unfavorable and unintended sign, including a clinically significant 
abnormal laboratory finding, symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related causally to the investigational product 
(US Code of Federal Regulations [CFR] Title 21 Section 312.32[a]). Any abnormal finding that 
is deemed not clinically significant is not an AE. 
AEs include the onset of new illness and the exacerbation of preexisting conditions. Any medical 
condition that is present at the time when the patient is screened should be recorded on the 
medical history eCRF and not reported as an AE. However, if that condition deteriorates or 
severity changes at any time during the study, it should be recorded as an AE. 
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. 
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. 
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). 
Specific guidelines for classifying AEs by intensity and relationship to study drug are given in 
Table 6 and Abbreviations: ADL, Activities of Daily Living; AE, adverse event 
Table 7. 


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Table 6. 
National Cancer Institute Common Terminology Criteria for Adverse Events 
 
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 
Table 7. 
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 patient’s 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 patient’s 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 patient’s 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. 
Abbreviations: AE, adverse event 
 
12.9.2. Adverse Events of Special Interest 
 
An AESI (serious or non-serious) 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 12.9.4). Such an event might require 


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further investigation in order 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. 
In this trial, the following AEs are to be considered AESIs: 
• 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 
• Any weight loss >5% compared to Baseline, and/or 
• Any of the following GI TEAEs: vomiting, diarrhea with an increase of at least four 
stools per day over Baseline (Grade 2 CTCAE) for at least 3 days. 
 
12.9.3. 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 
• results from overdose 
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. 
 
12.9.4. 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 
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 immediately, and under no circumstances later than 


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24 hours after the Investigator has become aware of the event. Notification can be made using 
the dedicated fax line or email for 
Safety and Pharmacovigilance group: 
• 
Safety and Pharmacovigilance 
• 
Safety and Pharmacovigilance email address: 
 
If the Investigator contacts the 
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 
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. 
 
12.9.5. 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 or not an event is causally related to study treatment. 
will consider the Investigator’s assessment and determine whether or not 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 IEC/IRB (where 


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required) within 7 days after the 
/UNION therapeutics A/S has first knowledge of 
them, with a Follow-up report (when applicable) 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 
/UNION therapeutics A/S first has knowledge of them. 
The Sponsor 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 IRB/IEC of reportable events within the applicable 
timeframes. 
 
12.9.6. Pregnancy 
 
WOCBP must have a negative serum pregnancy test at Screening and are required to use one of 
the highly effective contraception methods (Inclusion Criterion 7). Women on hormone 
replacement therapy, and whose menopausal status is in doubt, will be required to use one 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 months without an 
alternative medical cause, and a confirmatory FSH test or as cessation of menses for at least 24 
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 
Safety and 
Pharmacovigilance within 24 hours of knowledge of the event. If any patient becomes pregnant 
during the study, they are to immediately discontinue any UNION-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 
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 
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 
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 


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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. 
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 
and Pharmacovigilance after delivery. 
 
12.9.7. Overdose 
 
In case of suspected overdose, please contact the Sponsor immediately. 


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13. PHARMACOKINETICS 
 
13.1. 
Pharmacokinetic Sampling 
 
13.1.1. Blood Samples 
 
Blood samples of approximately 
mL will be collected for measurement of concentrations of 
orismilast and its major metabolite (LEO 40815) as specified in the Schedule of Assessments 
(Table 4) before dose of the study drug. The actual date and time of each blood sample collection 
will be recorded. 
Blood sampling for measuring trough levels: The blood collection for PK analysis should 
preferably be conducted approximately 
hours after the last study drug administration. It is 
recommended to have date and time of patient’s last drug intake before PK sampling recorded in 
patient’s source and in the eCRF as well. 
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, 
additional blood samples will be collected during each visit at 
and 
 
. 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: 
(estimated Cmax),  
 
 
after 
intake of the study drug, as shown in Figure 2. An additional optional  
blood sample will 
be collected if possible for the patient. 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: Lab, laboratory; PK, pharmacokinetics 
Details of PK blood sample collection, processing, storage, and shipping procedures are provided 
in a separate laboratory manual. 


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13.2. 
Pharmacokinetic Analytical Methodology 
 
The concentration of study drug 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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14. PHARMACODYNAMICS 


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15. 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 compliment 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 treatment group. For continuous variables, data will be 
summarized with the number of patients (N), 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. 
 
15.1. 
Determination of Sample Size 
 
Approximately 200 patients will be enrolled to ensure approximately 50 patients per arm. This 
sample size is based on assumptions that the percentage change from Baseline in PASI is -32.2% 
and -50.9% for placebo and each orismilast dose group, respectively, and the standard deviation 
is 33%. Using a 2-sided 2-sample t-test, 50 patients in each treatment arm can achieve a power of 
80% at the significance level of 5%. 
 
15.2. 
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 (PP) population includes all randomized patients who receive at least 1 dose of 
study drug, have at least 1 post-Baseline PASI assessment, and without 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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15.3. 
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 Analysis Population. 
Missing data for primary and key secondary endpoints will be handled with the multiple 
imputation method. 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. Analyses will be repeated on the PP Population for primary and 
secondary endpoints. 
When appropriate, the raw parameter, its change from Baseline, and percentage change from 
Baseline will be summarized. 
 
15.3.1. Analysis of Primary Efficacy Endpoint 
 
The primary endpoint, percentage change from Baseline to Week 16 in PASI, will be analyzed 
using analysis of covariance with treatment group as factor and Baseline PASI as covariate. As a 
supportive analysis, a mixed model for repeated measure (MMRM) will be performed with 
treatment group, visit and treatment-by-visit interaction as factors and Baseline PASI 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% confidence interval of the difference between each active 
treatment and placebo will be calculated. The primary analysis set will be the ITT Analysis 
Population with multiple imputation approach to handle missing values. The same analyses will 
be repeated for Weeks 20, 12, 8 and 4. 
 
15.3.2. Analysis of Secondary Efficacy Endpoints 
 
For continuous secondary efficacy endpoints including change from Baseline in PASI, total PSS, 
each individual item of the PSS, BSA and DLQI, a MMRM will be performed similar to the 
supportive MMRM for the primary endpoint. 
The key secondary efficacy endpoints and other binary secondary efficacy endpoints (IGA 
success, PASI50, PASI75, PASI90) will be analyzed using the Mantel-Haenszel (MH) test, 
comparing each active treatment group to placebo in the ITT Analysis set. 
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 scores/full scale 
will be analyzed using the MH test and the row mean score statistics and the ridit transformation. 


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The above endpoints (PASI changes and percentage changes, IGA success, PASI50, PASI75, 
PASI90) 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 distribution. The PASI percentage changes from Baseline will be plotted to identify 
where the best separation between treatments occur. 
 
15.3.3. Analysis of Exploratory Endpoints 
 
All exploratory endpoints including change from Baseline in PGA-F, ss-IGA, scalp itch NRS, 
, risk factors, and 
at Week 16 will be summarized 
descriptively in the ITT Population or a subgroup. 
 
15.4. 
Safety Analysis 
 
All safety analyses will be conducted using the Safety Analysis Population. AE data will be 
presented and tabulated according to Medical Dictionary for Regulatory Activities (MedDRA) 
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 and hematology) parameters 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. 
 
15.5. 
Pharmacokinetic Analysis 
 
The plasma levels of the drug and its metabolites will be summarized descriptively by visit in 
this study. 
 
15.6. 
Interim Analysis 
 
No interim analysis is planned in this study. 


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16. STUDY MANAGEMENT 
 
16.1. 
Approval and Consent 
 
16.1.1. Regulatory Guidelines and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and the following: 
• 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 Good Clinical Practice (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 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
patients. 
The Investigator will be responsible for the following: 
• 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 requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies 
(if applicable), and all other applicable local regulations 
 
16.1.2. 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 the nature of the study 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. 


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Patients must be informed that their participation is voluntary. 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 re-consented 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 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. 
 
16.2. 
Data Protection 
 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the 
informed consent 
The patient must be informed that medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
 
16.3. 
Dissemination of Clinical Study Data 
 
The Sponsor will list the study on a public database listing of clinical trials. Publication policy 
information is presented in Section 16.8. 


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16.4. 
Data Quality Assurance 
 
All patient data relating to the study will be recorded on printed 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 physically or electronically signing the 
CRF. Access to the electronic data capture system will be restricted and user 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 prior to the study being initiated and 
any data being entered into the eCRF. 
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. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Protocol deviations from inclusion/exclusion criteria, concomitant medication restrictions and 
from any other protocol requirements that could result in significant risk to the patient and/or 
affect the outcome of the study will be collected. Additionally, nonadherence to the study 
procedures or schedule as defined by the protocol such as a missed procedure or an out-of- 
window study visit will be documented as protocol deviations. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data prior to data base closure. 
The sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator according to ICH guidelines, local regulations, or as specified in the 
Clinical Trial Agreement, whichever retention period is longer. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
 
16.5. 
Source Documents 
 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 


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Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
 
16.6. 
Protocol Amendment and Protocol Deviation 
 
16.6.1. 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 
acknowledgement 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. 
 
16.6.2. 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. 
 
16.7. 
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). 
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. 


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16.8. 
Publication Policy/Disclosure of Data 
 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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17. REFERENCES 
 
1. Fredriksson T, Pettersson U. Severe psoriasis - oral therapy with a new retinoid. 
Dermatologica. 1978; 157(4):238-244. doi: 10.1159/000250839. 
2. Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. The 5-point 
Investigator's Global Assessment (IGA) Scale: A modified tool for evaluating plaque 
psoriasis severity in clinical trials. J Dermatolog Treat. 2015 Feb;26(1):23-31. doi: 
10.3109/09546634.2013.865009. 
3. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al. Guidelines 
of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelines of care 
for the management and treatment of psoriasis with traditional systemic agents. J Am Acad 
Dermatol. 2009 Sep;61(3):451–85. 
4. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al. Guidelines 
of care for the management of psoriasis and psoriatic arthritis: Section 5. Guidelines of care 
for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad 
Dermatol. 2010 Jan;62(1):114–35. 
5. Parisi R, Iskandar IYK, Kontopantelis E, Augustin M, Griffiths CEM, Ashcrof DM. 
National, regional, and worldwide epidemiology of psoriasis: systematic analysis and 
modelling study. BMJ. 2020 May 28;369:m1590. doi: 10.1136/bmj.m1590. 
6. Ravindran V, Scott DL, Choy EH. A systematic review and meta-analysis of efficacy and 
toxicity of disease modifying anti-rheumatic drugs and biological agents for psoriatic 
arthritis. Ann Rheum Dis. 2008 Jun;67(6):855–9. 
7. Quaglino P, Bergallo M, Ponti R, Barberio E, Cicchelli S, Buffa E, et al. Th1, Th2, Th17 and 
regulatory T cell pattern in psoriatic patients: modulation of cytokines and gene targets 
induced by etanercept treatment and correlation with clinical response. Dermatol Basel 
Switz. 2011;223(1):57–67. 
8. Zerilli T, Ocheretyaner E. Apremilast (Otezla): a new oral treatment for adults with psoriasis 
and psoriatic arthritis. P T. 2015 Aug;40(8):495-500. 
9. [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed 04 June 2021. 


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18. APPENDICES 
 
The assessments and scales included in the appendices are samples of what may be used during 
the study. The study-specific assessments and scales may be different. 
Appendix 1. Protocol Amendment 1 and 2 Summary of Changes 
Appendix 2. Psoriasis Area and Severity Index (PASI) 
Appendix 3. Investigator Global Assessment (IGA) 
Appendix 4. Scalp-specific Investigator Global Assessment (ss-IGA) 
Appendix 5. Physician Global Assessment of Fingernail Psoriasis (PGA-F) 
Appendix 6. Body Surface Area (BSA) 
Appendix 7. Psoriasis Symptom Scale (PSS) 
Appendix 8. Dermatology Life Quality Index (DLQI) 
Appendix 9. The Hospital Anxiety and Depression Scale (HADS) 
Appendix 10. The Columbia-Suicide Severity Rating Scale (C-SSRS) 


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Appendix 1. Protocol Amendment 1 Summary of Changes 
 
Protocol version 1.0 dated 02 Oct 2020 is being amended to create Protocol Amendment version 
2.0 dated 14 July 2021; the amended version of the protocol supersedes version 1.0. The purpose 
of this amendment is to update the protocol to provide further details about the study design, 
study objectives and endpoints, subject selection criteria, as well as data collection and analyses. 
• Protocol structure was revised for better flow of information in a new template. 
• Information regarding clinical studies revised as per the revised Investigator’s Brochure. 
• Safety added as a primary objective. 
• 
 
• Change in psoriasis at “difficult to treat” anatomical areas were divided into 2 separate 
exploratory objectives for scalp and nails. 
•  Secondary endpoints were divided into “key secondary endpoints” and “other secondary 
endpoints”. 
• Timing of assessments were revised. 
• A study schematic was added. 
• Body weight of >40 kg at the time of signing the informed consent form was added as an 
inclusion criteria. 
• Clarifying language was added regarding contraception requirements. 
• History and evidence of severe hepatic impairment added as exclusionary criteria 
• History and evidence of hepatitis B virus and hepatitis C virus added as exclusionary 
criteria. 
• Blood pressure removed as an exclusionary criterion. 
• A section of study withdrawal, removal, and replacement of patients was added. 
• Further details on study treatments and dosage schedule were added. 
• Clarification regarding blinding was provided. 
• More information regarding prior and concomitant therapy was included. 
• Proper order for assessments and procedures was specified. 
• More details were added to the definition of assessments and patient-reported outcomes 
(PROs). 
• The name of assessments and PROs used in trial was updated for consistency throughout 
the document. 
• Details about particular tests as well as sample collection and analysis for laboratory 
assessments were added. 
• Further information about adverse event and serious adverse event collection and 
reporting was included. 
• PK assessment information was revised for clarity. 
• 


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• Statistical methods and planned analyses revised to provide further clarification on 
analyses populations and the overall data collection and analyses. 
• Assessments and PROs used in this study added as appendices. 


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Protocol Amendment 2 Summary of Changes 
 
Protocol Amendment version 2.0 dated 14 July 2021 is being amended to create Protocol 
Amendment version 3.0 dated 20 May 2022; the amended version of the protocol supersedes 
version 2.0. The main purpose of this amendment is to add PK sampling to enable meaningful 
PK data from the trial. Updates to the study design, study endpoint, subject selection criteria, as 
well as data collection and analyses were also made. 
• Name of biostatistician was updated. 
• “Patient” updated to “Participant” throughout the protocol. 
• 
 
• Section 5.2.1: Addition of detailed information regarding nonclinical studies and to note 
that results from genotoxicity and reproductive toxicity studies did not raise any 
concerns. 
• Addition of a new section, Section 5.4.1 Dose Rationale, to explain the rationale for 
choosing the doses of modified-release orismilast for this study. 
• Synopsis and Section 8.1: Inclusion criterion 7 updated to remove male participants. “7. 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
at the Screening visit and a negative urine pregnancy test at the Baseline visit. In 
addition, sexually active WOCBP and male participants (including partners of male 
participants who are WOCBP) must agree to use a highly effective method of 
contraception until at least 4 weeks after the end of study treatment.” 
• Inclusion Criteria#5 was elaborated (assessed at both Screening and Baseline). 
• Example for psychiatric condition was updated in Exclusion Criteria#8 and actions to be 
taken in case of severe depression/suicidal thoughts were added. 
• Unit was added in Exclusion Criteria#13c (platelet count). 
• 
• HBsAg was corrected to HBsAb. 
• Optional PK sampling was added; and PK-related text was updated. 
• Statistical analysis section was updated based on the input provided for the Statistical 
Analysis Plan. 
• General comments from the Food and Drug Administration on the Atopic Dermatitis 
(AD) protocol (UNI50001-202) were incorporated in this protocol amendment (Adverse 
Event of Special Interest definition and related text). 
• Information was added to clarify which TEAEs would require follow-up after a patient 
discontinues prematurely from the study because of a TEAE. 
• The full form of HADS was corrected from Hamilton Anxiety and Depression Scale to 
Hospital Anxiety and Depression Scale at few instances. Timepoints for HADS were 
corrected and description for HADS was updated. 
• Timepoint for height (without shoes) was corrected from Screening to Baseline. 


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• Clarification for urine sampling was added. 
• Initial titration period was corrected from up to 3 weeks to 2 weeks duration. 
• Update made to reflect that dose administration in the clinic is not required. 
• Examples of low potency corticosteroids was added. 
• Description for the Columbia-Suicide Severity Rating Scale was updated. 
• Appendix 10. The Columbia-Suicide Severity Rating Scale (C-SSRS) was updated. 
• Appendix 11. QoL Questionnaire related to Nail Psoriasis was removed. 


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Appendix 2. Psoriasis Area and Severity Index (PASI) 
 
The PASI was developed in 1978 by Fredriksson and Pettersson to assess the effects of retinoids 
in psoriasis. The PASI combines assessments of 4 body areas: the head and neck (H), the upper 
limbs (UL), the trunk (T) and the lower limbs (LL). The percentage of skin affected by psoriasis 
in each area is given a numerical score (A) representing the proportion involved: 1 (0–9%), 2 
(10–29%), 3 (30–49%), 4 (50–69%), 5 (70–89%) or 6 (90–100%). Within each area (H, UL, T, 
LL) the severity of 3 plaque signs – erythema (E), thickness/induration (I) and 
desquamation/scaling (D) – is assessed on a 5-point scale: 0 (none), 1 (mild), 2 (moderate), 3 
(severe) or 4 (very severe). The final PASI score ranges from 0 to 72, and is calculated using the 
following formula: PASI = 0.1 (EH+IH+HH) AH + 0.2 (EUL+IUL+HUL) AUL + + 0.3 (ET+IT+HT) AT 
+ 0.4 (ELL+ILL+HLL) ALL 


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Appendix 3. Investigator Global Assessment (IGA) 
 
Score 
Definition 
0=clear 
• No signs of psoriasis (postinflammatory hyperpigmentation may 
be present) 
1=almost Clear 
• Normal to pink coloration of lesions 
• No thickening 
• No to minimal focal scaling 
2=mild disease 
• Pink to light red coloration 
• Just detectable to mild thickening 
• Predominantly fine scaling 
3=moderate disease 
• Dull to bright red, clearly distinguishable erythema 
• Clearly distinguishable to moderate thickening 
• Moderate scaling 
4=severe disease 
• Bright to deep dark red coloration 
• Severe thickening with hard edges 
• Severe/coarse scaling covering almost all of all lesions 


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Appendix 4. Scalp-specific Investigator Global Assessment (ss-IGA) 
 
 
 
Foley P, Gordon K, Griffiths CEM, et al. Efficacy of Guselkumab Compared With Adalimumab and 
Placebo for Psoriasis in Specific Body Regions: A Secondary Analysis of 2 Randomized Clinical Trials. 
JAMA Dermatol. 2018;154(6):676–683. 


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Appendix 5. Physician Global Assessment of Fingernail Psoriasis (PGA-F) 
 
 
Foley P, Gordon K, Griffiths CEM, et al. Efficacy of Guselkumab Compared With Adalimumab 
and Placebo for Psoriasis in Specific Body Regions: A Secondary Analysis of 2 Randomized 
Clinical Trials. JAMA Dermatol. 2018;154(6):676–683. 


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Appendix 6. Body Surface Area (BSA) 
 
The body surface area (BSA) assessment estimates the extent of disease or skin involvement 
with respect to atopic dermatitis (AD) and is expressed as a percentage of total body surface. 
Determine BSA using the patient’s palm = 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 affected AD area. 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 one patient 
palm. 
2. Only include the edge of current lesions, not areas that have cleared. 
3. Double check to see if area derived matches eyeball method. 


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Appendix 7. Psoriasis Symptom Scale (PSS) 
 
1. How severe was your pain from your psoriasis during the past 24 hours? 
• None 
• Mild 
• Moderate 
• Severe 
• Very severe 
2. How severe was the redness from your psoriasis during the past 24 hours? 
• None 
• Mild 
• Moderate 
• Severe 
• Very severe 
3. How severe was your itching from your psoriasis during the past 24 hours? 
• None 
• Mild 
• Moderate 
• Severe 
• Very severe 
4. How severe was your burning from your psoriasis during the past 24 hours? 
• None 
• Mild 
• Moderate 
• Severe 
• Very severe 


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Appendix 8. Dermatology Life Quality Index (DLQI) 
 
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 
Very much □ 
stinging has your skin been? 
A lot 
□ 
A little 
□ 
Not at all 
□ 
2.  Over the last week, how embarrassed or self- 
Very much □ 
conscious have you been because of your skin? 
A lot 
□ 
A little 
□ 
Not at all 
□ 
Not relevant 
□ 
3.  Over the last week, how much has your skin 
Very much □ 
interfered with you going shopping or looking 
A lot 
□ 
after your home or garden? 
A little 
□ 
Not at all 
□ 
Not relevant 
□ 
4.  Over the last week, how much has your skin 
Very much □ 
influenced the clothes you wear? 
A lot 
□ 
A little 
□ 
Not at all 
□ 
Not relevant 
□ 
5.  Over the last week, how much has your skin 
Very much □ 
affected any social or leisure activities? 
A lot 
□ 
A little 
□ 
Not at all 
□ 
Not relevant 
□ 
6.  Over the last week, how much has your skin 
Very much □ 
made it difficult for you to do any sport? 
A lot 
□ 
A little 
□ 
Not at all 
□ 
Not relevant 
□ 
7. Over the last week, has your skin prevented you 
from working or studying? 
Yes 
□ 
No 
□ 
If “No”, over the last week how much has your 
skin been a problem at work or studying? 
A lot 
□ 
A little 
□ 
Not at all 
□ 
8.  Over the last week, how much has your skin 
Very much □ 
created problems with your partner or any of 
A lot 
□ 
your close friends or relatives? 
A little 
□ 
Not at all 
□ 
Not relevant 
□ 
9.  Over the last week, how much has your skin 
Very much □ 
caused any sexual difficulties? 
A lot 
□ 
A little 
□ 
Not at all 
□ 
Not relevant 
□ 


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10. Over the last week, how much of a problem has 
Very much □ 
the treatment for your skin been, for example by 
A lot 
□ 
making your home messy, or taking up time? 
A little 
□ 
Not at all 
□ 
Not relevant 
□ 
□ Please check you have answered EVERY question. Thank you. 


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Appendix 9. The Hospital Anxiety and Depression Scale (HADS) 
 


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Appendix 10. The Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
For Screening 
 
Past Year 
Ask questions that are bolded and underlined. 
YES 
NO 
Ask Questions 1 and 2 
1) Have you wished you were dead or wished you could go to sleep and not wake up? 
2) Have you actually had any thoughts of killing yourself? 
If YES to 2, ask questions 3, 4, 5, and 6. If NO to 2, go directly to question 6. 
3) Have you been thinking about how you might do this? 
E.g., “I thought about taking an overdose, but I never made a specific plan as to when 
where or how I would actually do it….and I would never go through with it.” 
4) Have you had these thoughts and had some intention of acting on them? 
As opposed to “I have the thoughts, but I definitely will not do anything about them.” 
5) Have you started to work out or worked out the details of how to kill yourself? Did you 
intend to carry out this plan? 
6) Have you ever done anything, started to do anything, or prepared to do anything to end 
your life? 
Examples: Collected pills, obtained a gun, gave away valuables, wrote a will or suicide 
note, took out pills but did not swallow any, held a gun but changed your mind or it was 
grabbed from your hand, went to the roof but did not jump; or actually took pills, tried to 
shoot yourself, cut yourself, tried to hang yourself, etc. 
If YES, ask: Was this within the past 3 months? 
 
For Study 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If 
the answer to question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 
and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
Since Last Visit 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore or wish to fall 
asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe: 
Yes □ No □ 
2. Nonspecific Active Suicidal Thoughts 
General nonspecific thoughts of wanting to end one’s life/die by suicide (e.g., “I’ve 
thought about killing myself”) without thoughts of ways to kill oneself/associated 
methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
Yes □ No □ 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the 
assessment period. This is different than a specific plan with time, place or method details 
worked out (e.g., thought of method to kill self but not a specific plan). Includes person 
Yes □ No □ 


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who would say, “I thought about taking an overdose, but I never made a specific plan as to 
when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on 
such thoughts, as opposed to “I have the thoughts, but I definitely will not do anything 
about them.” 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
Yes □ No □ 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject 
has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Did you 
intend to carry out this plan? 
If yes, describe: 
Yes □ No □ 
INTENSITY OF IDEATION 
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 
Recent - Most Severe Ideation:  
Type # (1-5) 
 
Description of Ideation 
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? 
 


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(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 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last Visit 
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 
Yes No 
□ □ 
Total # of interrupted 


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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: 
 
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). 
Have you taken any steps towards making a suicide attempt or preparing to kill 
yourself (such as collecting pills, getting a gun, giving valuables away or writing a 
suicide note)? 
If yes, describe: 
Yes No 
□ □ 
Total # of preparatory 
acts 
Most Lethal Attempt Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches). 
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; 
sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, 
somewhat responsive; second-degree burns; bleeding of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive 
care required (eg, comatose with reflexes intact; third-degree burns less than 
20% of body; extensive blood loss but can recover; major fractures). 
4. Severe physical damage; medical hospitalization with intensive care required (eg, 
comatose without reflexes; third-degree burns over 20% of body; extensive blood 
loss with unstable vital signs; major damage to a vital area). 
5. Death 
Enter Code 
Potential Lethality: Only Answer if Actual Lethality = 0 
Likely lethality of actual attempt if no medical damage (the following examples, 
while having no actual medical damage, had potential for very serious lethality: put 
gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity 


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and internal consistency findings from 3 multisite studies with adolescents and adults. Am J 
Psychiatry. 2011 Dec;168(12):1266-77. 


 

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Statistical Analysis Plan for Interventional Studies 
 
 
SAP Version Number: 2.0 
SAP Date: 13-Dec-2022 
 
Sponsor Name: UNION therapeutics A/S 
 
Protocol Number: UNI50001-203 
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 
Plaque-Type Psoriasis 
 
Protocol Version and Date: (DD-Mmm-YYYY): 3.0, 10-May-2022 
 
 Project Code: 7025422  
 
Authors: 
, Senior Biostatistician 
 
 
 
 
 
 
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, 
 should be notified promptly. 
 
 
 
 
 
 
 


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Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.0 
09-Jun-2022  
 
Initial Release Version  
2.0 
13-Dec-2022 
 
Added carrying forward the baseline value to week 4 for 
those patients that don’t have any post-baseline data for 
the MMRM. 
Added reassignment of Week 16/EOT, Week 20/Follow-
up and unscheduled visits. 
Mantel-Haenszel test replaced with difference of 
proportions analyses. 


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I confirm that I have reviewed this document and agree with the content. 
Approvals 
 Approval 
, Senior Biostatistician 
 
Name, Title   
Lead Biostatistician  
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
, Biostatistics 
 
Name, Title 
Senior Reviewing Biostatistician 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
UNION therapeutics A/S Approval 
 Biometrics  
 
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 ......................................... 23 
 
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................................................................................................................ 53 
 
Index of Listings ............................................................................................................... 54 
 
Shells ............................................................................................................................... 56 
 
Appendices ...................................................................................................................... 57 
 


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Glossary of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Coviariance 
ATC 
Anatomical Therapeutic Chemical 
bpm 
beats per minute 
BDRM 
Blinded Data Review Meeting 
BID 
Twice a day 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CFB 
Change from Baseline 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DLQI 
Dermatology Life Quality Index 
ECG 
Electrocardiogram 
HADS 
Hospital Anxiety and Depression scale  
HBcAb 
Antihepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IGA 
Investigator Global Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 


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Abbreviation 
Description 
ITT 
Intent-To-Treat 
IEC 
Independent Ethics Committee 
MAR 
Missing At Random 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
MMRM 
Mixed Model for Repeated Measures 
N/A 
Not Applicable 
NCI 
National Cancer Institute 
NRS 
Numeric Rating Scale 
PASI 
Psoriasis Activity and Severity Index 
PASI50 
50% reduction in PASI 
PASI75 
75% reduction in PASI 
PASI90 
90% reduction in PASI 
PCFB 
Percentage Change from Baseline 
PD 
Pharmacodynamics 
PDE 
Phosphodiesterase 
pdf 
Portable document format 
PGA-F 
Nail Psoriasis Physician Global Assessment 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRO 
Patient-Reported Outcome 
PsA 
Psoriatic Arthritis 
PSS 
Psoriasis Symptoms Scale 
PT 
Preferred Term 
Q1 
First quartile, 25th percentile of the data 
Q3 
Third quartile, 75th percentile of the data 
QC 
Quality Control 
QoL 
Quality of Life 
QTc 
Corrected QT Interval 


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Abbreviation 
Description 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
ss-IGA 
Scalp-specific Investigator Global Assessment 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Table, Figure and Listing 
ULN 
Upper Limit of Normal 
US 
United States 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
 


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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 v3.0. 
 
Responsibilities 
 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 adults with moderate-to-severe plaque-type psoriasis.  
 
Secondary Objective 
Evaluate the dose response of orismilast and identify the dose with the best benefit/risk ratio to be 
evaluated in a Phase 3 program. 
 
Exploratory Objectives 
The exploratory objectives are to: 
• 
. 
• 
Evaluate the change in cardiovascular risk factors under orismilast treatment. 
• 
 
• 
Evaluate the change in skin psoriasis at “difficult to treat” anatomical areas such as the scalp. 
• 
Evaluate the change in psoriasis at “difficult to treat” anatomical areas such as nails. 
 
 
 
 
 
 
 
 
 
 


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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 adult patients with moderate-to-severe plaque-type psoriasis. Efficacy and safety endpoints will be 
evaluated to select an appropriate orismilast dose for subsequent Phase 3 studies. The study will be 
conducted in approximately 40 centers in Europe (Germany, Poland, UK) and US. 
After a Screening visit up to 28 days before Baseline, approximately 200 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 up to 14 days (for the orismilast arm only). The maximum duration of study 
participation is approximately 24 weeks. 
Patients will be seen at the site on Screening, Baseline (Day 1), and Weeks 1, 2, 4, 8, 12, 16 (End-of-
Treatment [EOT] visit), and 20 (Follow-up visit, 4 weeks after treatment completion or discontinuation). 
Visits at Weeks 1 and 2 could be conducted via a telemedicine procedure at Investigator’s discretion. 
At Baseline and each visit from Week 4 onwards, Psoriasis Activity and Severity Index (PASI), body 
surface area (BSA), Investigator Global Assessment (IGA), and Psoriasis Symptoms Scale (PSS) will be 
assessed. Quality of life will be assessed by administration of Dermatology Life Quality Index (DLQI) at 
Baseline and at Weeks 16 and 20 visits. Additional efficacy parameters include: a Scalp-specific 
Investigator Global Assessment (ss-IGA), a nail psoriasis Physician Global Assessment (PGA-F), and 
 
These parameters will be assessed at Baseline and Weeks 16 and 20. Safety evaluations include 
adverse events (AEs), laboratory and vital sign assessments, physical examinations as well as mood 
change evaluation by patient (Hospital Anxiety and Depression Scale [HADS]) and suicidal ideation 
evaluation by Investigator (Columbia-Suicide Severity Rating Scale[C-SSRS]). A panel of cardiovascular 
risk factors will be assessed at Baseline and Week 16. 
Before administration of the study drug at Baseline and on Weeks 4, 8, and 16, blood will be collected for 
orismilast concentration determination. In addition, 
 
 
 See  
 


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Figure 1 Study Design for the study design. 
 
 
 


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Figure 1 Study Design 
 
Abbreviation: BID, twice a day 
 
Patient Selection 
 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
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 ≥18 years of age at the time of signing the ICF. 
3. Body weight of >40 kg at the time of signing the ICF. 
4. Diagnosis of chronic, stable plaque-type psoriasis at least 2 months before the Screening visit. If 
the patient is diagnosed with psoriasis arthritis, the arthritis should be stable. 
5. Moderate-to-severe plaque-type psoriasis as defined by PASI ≥12, BSA ≥10%, and IGA ≥3 at the 
screening and baseline visits.. 
6. Candidate for systemic antipsoriatic treatment or phototherapy. 
7. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at the 
Screening visit and a negative urine pregnancy test at the Baseline visit. In addition, sexually 
active WOCBP must agree to use a highly effective method of contraception until at least 
4 weeks after the end of study treatment. Highly effective methods of contraception are those that 
have a failure rate of <1% (when implemented consistently and correctly) 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 entire duration of the study. Note: A woman of nonchildbearing potential is defined as a 


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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 months without an alternative medical cause and a confirmatory follicle-stimulating 
hormone (FSH) test or as cessation of menses for at least 24 months without an alternative 
medical cause. 
 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
1. Therapy-resistant psoriasis defined as ≥2 treatment failures due to inadequate efficacy within the 
past 5 years of any biologic therapies (including but not limited to etanercept, adalimumab, 
infliximab, certolizumab pegol, guselkumab, secukinumab, risankizumab, ixekizumab, 
tildrakizumab, or ustekinumab) administered in 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 psoriasis or PsA with acute deterioration within 4 weeks of the Screening visit. 
3. History of allergy or hypersensitivity to any component of the study treatment. 
4. Active infection (eg, bacteria, viral, fungal) requiring treatment with systemic antibiotics within 4 
weeks of the Screening visit. 
5. Malignancy or history of malignancy except for treated (ie, cured) basal cell skin carcinomas. 
6. Current diagnosis of predominant guttate, erythrodermic, exfoliative, or pustular psoriasis, or of 
drug-induced psoriasis, or other skin conditions that might confound the evaluation of psoriasis 
vulgaris, as judged by the Investigator (eg, atopic dermatitis, lupus). 
7. Any 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) which, 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 for receiving the investigational therapy. 
9. Any therapies and systemic treatments as described in Protocol Section 9.5.2 which do not 
comply with the indicated washout interval.
. 
10. Any previous treatment with orismilast or failure of treatment with apremilast or any other 
systemic PDE4 inhibitor as described in Protocol Section 9.5.2. 
11. Any condition, including laboratory or ECG abnormalities, that places the patient at an 
unacceptable risk to participate in the study or confounds the ability to interpret data from the 
study. 
12. Severe hepatic impairment based upon medical history and laboratory abnormalities (eg, low 
albumin and abnormal bilirubin). 
13. Any of the following abnormalities in clinical laboratory tests at Screening, as assessed by the 
study-specific laboratory and confirmed by a single repeat, if deemed necessary: 
a. Absolute neutrophil count of <3.0 × 109/L (<3000/mm3) 


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b. Hemoglobin of <10.0 g /dL or hematocrit <30% 
c. Platelet count of <100 × 103 cells/mm3 (SI: <100 × 109 cells/L). 
d. Absolute lymphocyte count of <1.0 × 109/L (<1000/mm3) 
e. Total bilirubin >1.5 × the upper limit of normal (ULN); patients with a history of Gilbert's 
syndrome may have a direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin is ≤ULN 
f. 
Alanine aminotransferase or aspartate aminotransferase >2.5 × the ULN; 
g. Serum creatinine ≥1.5 mg/dL. For a patient with a value of ≥1.5 mg/dL, a creatinine 
clearance of ≥60 mL/min (calculated using the CKD-EPI Creatinine Equation) is allowed. 
 
14. History or evidence of hepatitis B virus (HBV) infection at Screening. Patients with positive 
hepatitis B surface antigen (HBsAg) are excluded. For patients with isolated positive antihepatitis 
B core antibody (HBcAb),  hepatitis B surface antibody (HBsAb) result must also be positive to be 
considered for this study. 
15. 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. 
16. History of positive HIV, or have 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. 
17. 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 the C-SSRS completed at 
the Baseline visit. 
18. Pregnant or breastfeeding. 
19. History of alcohol or substance abuse within 6 months before Baseline that, in the opinion of the 
Investigator, will preclude participation in the study. 
20. Institutionalized by court order or by local authority. 
 
Determination of Sample Size 
Approximately 200 patients will be enrolled to ensure approximately 50 patients per arm. This sample 
size is based on assumptions that the percentage change from Baseline in PASI is -32.2% and -50.9% 
for placebo and each orismilast dose group, respectively, and the standard deviation is 33% (1, 2). Using 
a 2-sided 2-sample t-test, 50 patients in each treatment arm can achieve a power of 80% at the 
significance level of 5%. 
 
Treatment Assignment and Blinding 
Randomization will occur prior to 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.  
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 blind, 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). 


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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. 
All patients will be centrally assigned to randomized study treatment using an Interactive Web Response 
System (IWRS).  
Sponsor safety staff may unblind the study drug assignment for any patient with a serious adverse event 
(SAE). If the SAE requires that an expedited regulatory report be sent to one 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, who will also 
give instruction for dose administration. The date of study drug dispensed to the patientswill 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 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. 
 
 Study Procedures and Flowchart 
The Schedule of assessments is in Protocol Section 10.  


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 Endpoints   
 
Primary Efficacy Endpoint 
 
Percentage change in PASI score from Baseline to Week 16. 
 
Secondary Efficacy Endpoints 
Key Secondary Efficacy Endpoints: 
 
Patients achieving 75% reduction in PASI (PASI75) response at Week 16. 
 
Patients achieving a score of Clear (0) or Almost Clear (1) and an at least 2-point improvement in IGA 
at Week 16. 
Other Secondary Efficacy Endpoints: 
 
Patients achieving a score of Clear (0) or Almost Clear (1) and an at least 2-point improvement in IGA 
at Weeks 4, 8, 12, and 20. 
 
Patients achieving PASI75 response at Weeks 4, 8, 12, and 20. 
 
Patients achieving 50% reduction in PASI (PASI50) and 90% reduction in PASI (PASI90) response at 
Weeks 4, 8, 12, 16, and 20. 
 
Change from Baseline in PASI at Weeks 4, 8, 12, and 20. 
 
Change from Baseline in total PSS score at Weeks 4, 8, 12, 16, and 20. 
 
Change from Baseline in each individual item of the PSS at Weeks 4, 8, 12, 16, and 20. 
 
Change from Baseline in the affected BSA at Weeks 4, 8, 12, 16, and 20. 
 
Change from Baseline in DLQI score at Weeks 16 and 20. 
 
Patients experiencing psoriasis rebound by Week 20, defined as PASI ≥125% of Baseline or new 
generalized pustular, erythrodermic, or more inflammatory psoriasis. 
 
Exploratory Endpoints 
 
Change from Baseline in PGA-F at Week 16. 
 
Change in ss-IGA from Baseline at Week 16 in the subgroup of patients with Baseline score of at 
least 2 (mild scalp psoriasis). 
 
Change from Baseline of scalp itch NRS at Week 16 in the subgroup of patients with Baseline score 
of at least 4 on the 11-point NRS. 
 
 
 
 
Change in cardiovascular risk factors at Week 16. The following parameters will be collected: weight, 
body mass index, waist and hip circumferences, blood pressure, fasting serum glucose, triglycerides, 
cholesterol (total and HDL/LDL fractions), and C-reactive protein. 
 
Pharmacokinetic Endpoint 
 
Plasma levels of the drug and its metabolites 
 
Safety Endpoints 
 
The occurrence, severity, and seriousness of treatment-emergent adverse events (TEAEs) reported 
over the 16-week Treatment Period and the 4-week Follow-up Period. 


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 
Changes from Baseline in physical examination; vital sign 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. 
 
Changes from Baseline in electrocardiogram (ECG) findings over the 16-week Treatment Period and 
the 4-week Follow-up Period. 
 
Changes from Baseline in safety laboratory values (hematology, serum chemistry, and urinalysis) 
over the 16-week Treatment Period and the 4-week Follow-up Period. 
 
HADS at each visit except Week 2. 
 
C-SSRS at each visit except Weeks 1 and 2. 
 
Pharmacodynamic Endpoint 
 
 
 
 


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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 the 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 PASI assessment, and without major protocol deviations (PD) 
affecting efficacy analysis. The treatment group assignment in this population will be designated 
according to initial randomization. Efficacy analysis for primary and secondary endpoints will be repeated 
on the PP Population.  
 
Protocol Deviations 
Protocol deviation management at 
 Health is detailed in Protocol Deviation and Non-compliance 
Management 
. For details on the process for defining analysis datasets refer to 
 
. 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: 
 
Violations of inclusion or exclusion criteria. 
 
Use of disallowed medication (that may influence the interpretation of efficacy results). 
 
Non-compliance with study medication intake: less than 80% of total number of tablets during entire 
treatment period or during the last 4 weeks  
 
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 
 
All statistical analyses will be conducted using SAS® for Windows® Version 9.4 or higher. 
 
All data will be listed, and summary tables will be provided.  
 
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 to avoid missing data. 
 
 
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. 
 
There will be no adjustment for multiplicity, thus all p-values reported will be nominal. 
 
All relevant patient data will be included in listings. All patients entered into the database will be 
included in patient data listings. Screen failure data will be included at the end of the appropriate 
listings and labelled ‘Screen Failures’. 
 
 
Unless otherwise specified, listings will be sorted by randomized treatment, subject number and 
chronologically by assessment date and time. 
 
 
Missing records will be omitted from the listings, and missing data within a record will be left blank. 
 
 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 Total. 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 


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Percentage change from baseline (PCFB) 
PCFB = ((Post-baseline value – Value at baseline) / Value at baseline)*100%. 
 
Missing Data 
Missing data will be treated as missing, except in the following cases. 
 
Efficacy 
Missing data 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 4, 8, 12, 16 and 20. 
 
Visits in RAVE captured as ‘Week 16 / EoT and ‘Week 20 / Follow-up’ will be reassigned to either ‘Week 
16’ or another scheduled post-baseline visit or ‘EoT’ and ‘Week 20’ or ‘Follow-up’ as follows: If a patient 
completed the study treatment (based on the End-of-Treatment form information), data captured in RAVE 
as ‘Week 16 / EoT', will be presented as ‘Week 16’ irrespectively of violation of visit window.  If a patient 
discontinued the study treatment, provided that no data are available from a certain scheduled post-
baseline visit (Week 4, 8, 12, 16) for a subject, data captured on the ‘Week 16 / EoT’ visit have the 
potential to be assigned to a particular scheduled visit in data summaries and analyses, provided the data 
are collected between 13 days before and 14 days after the planned time point for the scheduled visit, as 
displayed in table below:  
  
 
 


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Visit  
(target day) 
Visit window  
(day is date of assessment minus date of first dose) 
Week 4 (day 28) 
Day 15 to 42  
Week 8 (day 56) 
Day 43 to 70  
Week 12 (day 84) 
Day 71 to 98 
Week 16 (day 112) 
Day 99 to Day 139 *    
* Week 16 uses a broader visit window.  
If the 'Week16/EoT' visit falls outside the visit schedule in the trial procedure it will be present as 'EoT'. 
If the subject completed study treatment, data captured in RAVE as ‘Week 20 / Follow-up’ will be 
presented as ‘Week 20’ irrespectively of violation of visit window. If the subject did not complete study 
treatment, data captured in RAVE as ‘Week 20 / Follow-up’ will be presented as ‘Follow-up’. 
 
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 
Listings of treatment assignments, including the subject’s identification, date of randomization, and 
assignment to treatment, will be presented. 
 
The following frequencies (number and percent) will be displayed for all patients in the screened 
population: patients screened, patients randomized, screen failures, and reasons for screen failure.  
 
The analysis populations will be summarized with counts and percentages by treatment. This table will 
include the following: number of patients in screened population, patients in safety population, reasons for 
exclusion from the safety population, patients in  Intent-to-Treat population, reasons for exclusion from 
the Intent-to-Treat population, patients in Per-Protocol population, and reasons for exclusion from the 
Per-Protocol population. 
 
The following frequencies (number and percent) will be displayed for all patients in the randomized 
population: randomized patients, patients in the safety population, patients in Intent-to-Treat population, 
patients in Per-Protocol population, patients who completed the study (including follow-up), patients who 
discontinued early, patients who completed study treatment, patients who discontinued study treatment 
early also presented by reason for early discontinuation and study duration in days. 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.   
 
Completion/discontinuation status, inclusion/exclusion criteria definitions and Inclusion/exclusion criteria 
violations 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, patients with at 
least one minor PD overall and split by PD categorywill 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, 
PsA, 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.  
A summary table will be provided for previous psoriasis treatments (e.g. prior systemics, biologics). 
Previous psoriasis treatments and reasons for stopping previous psoriaisis treatments will be summarized 
for the ITT population. Baseline efficacy assessments: PASI, IGA, PSS, BSA, DLQI score, PGA-F, ss-
IGA, scalp itch NRS and 
 will be summarized for the ITT population, No formal statistical 
comparisons between populations will be performed. Demographics will be listed for all patients in the 
randomized population.  
 
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.  


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Medical History 
Medical history, including surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) 24.0.Past 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.  
Prior and concomitant medications will be listed for all patients in the randomized population. 
 
Extent of Exposure 
Study drug administration data including dates for administration, dispensing and dose interruption details 
will be listed for all patients in the ITT population. 
 
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 
patientswill 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, days of dosing,  reasons doses were 
missed and compliance rate will be summarized overall by treatment 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. 
Primary and secondary efficacy endpoints are to be assessed in the ITT Population. Missing data 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 after 
patients discontinue treatment early will then be multiply imputed with the SAS MI procedure using a 
regression statement (number of imputations: 50, seed: 5863781). 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 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 PASI 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 PASI 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 and 4. These analyses will be repeated 
on the PP population. 
LSMean (+/-SE) percentage change of PASI score will be presented graphically over time from Baseline 
to Week 4, 8, 12, 16 and 20.   
Actual values, change from baseline values and percentage change from baseline of PASI 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. To ensure that 
all patients are included in the analysis, the baseline value for patients with no post-baseline data 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 PASI 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). 


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PASI (including change from baseline values, percentage change from baseline values, PASI50, PASI75, 
and PASI90) will be listed. 
 
Secondary Efficacy Endpoints and Analyses 
Continuous secondary efficacy endpoints will be analyzed based on observed data using MMRM, using a 
modelling approach assuming MAR for missing data. These analyses will be repeated on the PP 
population.  
The binary secondary efficacy endpoints will be analyzed using differences in proportions, comparing 
each active treatment group to placebo in the ITT population with handling of missing data 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 
distribution. The PASI 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 PASI (PASI75) response at Week 16. 
• 
Patients achieving a score of Clear (0) or Almost Clear (1) and an at least 2-point 
improvement in IGA at Week 16. 
In addition to absolute PASI scores, response to treatment is presented as a percentage response rate: 
PASI50, PASI75 and PASI90. PASI75 represents the percentage of patients who have achieved a 75% 
or more reduction in their PASI score from baseline. 
The key secondary endpoints (primary analysis) will be analyzed using differences 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.  As supportive 
analysis, this analysis will be repeated, with handling of missing data as non-response. In case of 
baseline imbalance in baseline disease severity between treatment groups an additional supportive 
analysis stratifying for baseline disease severity using a Cochran-Mantel-Haenszel (CMH) test will be 
performed.Actual values of IGA will be summarized by visit using descriptive statistics and presented 
graphically over time.The percentage of patients with PASI75 and the percentage of patients achieving 
clear (0) or almost clear(1) will be presented graphically over time. These tables and figures are based on 
observed cases, thus purely descriptive. 
 
 
Other Secondary Endpoints 
• 
Patients achieving a score of Clear (0) or Almost Clear (1) and an at least 2-point 
improvement in IGA at Weeks 4, 8, 12, and 20. 
• 
Patients achieving PASI75 response at Weeks 4, 8, 12, and 20. 


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• 
Patients achieving 50% reduction in PASI (PASI50) and 90% reduction in PASI (PASI90) 
response at Weeks 4, 8, 12, 16, and 20. 
• 
Change from Baseline in PASI at Weeks 4, 8, 12, and 20. 
• 
Change from Baseline in total Psoriasis Symptoms Scale (PSS) score at Weeks 4, 8, 12, 16, 
and 20. 
• 
Change from Baseline in each individual item of the PSS at Weeks 4, 8, 12, 16, and 20. 
• 
Change from Baseline in the affected body surface area (BSA) at Weeks 4, 8, 12, 16, and 20. 
• 
Change from Baseline in Dermatology Life Quality Index (DLQI) score at Weeks 16 and 20. 
• 
Patients experiencing psoriasis rebound by Week 20, defined as PASI ≥125% of Baseline or 
new generalized pustular, erythrodermic, or more inflammatory psoriasis. 
PASI50 represents the percentage of patients who have achieved a 50% or more reduction in their PASI 
score from baseline.PASI90 represents the percentage of patients who have achieved a 90% or more 
reduction in their PASI score from baseline. 
Continuous secondary efficacy endpoints will be analyzed using MMRM, similar to the supportive MMRM 
for the primary endpoint.The same analyses will be repeated on the PP population. 
The analysis on categorical secondary efficacy endpoints will be performed using differences in 
proportions, comparing each active treatment group to placebo in the ITT population with handling of 
missing data as specified in Section 9. Response by treatment group and difference in response rate and 
p-values compared to placebo will be presented.  
Actual values and change from baseline values of PSS 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 PASI50 and PASI90 will be 
presented graphically over time. These tables and figures are based on observed cases, thus purely 
descriptive. 
PSS (including change from baseline values) will be listed. BSA and DLQI (including change from 
baseline and percentage change from baseline values) will be listed. 
 
Exploratory Endpoints 
• 
Change from Baseline in PGA-F at Week 16. 
• 
Change in ss-IGA from Baseline at Week 16 in the subgroup of patients with Baseline score 
of at least 2 (mild scalp psoriasis). 
• 
Change from Baseline of scalp itch NRS at Week 16 in the subgroup of patients with a 
Baseline score of at least 4 on the 11-point NRS. 


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• 
 
 
• 
Change in cardiovascular risk factors at Week 16. The following parameters will be collected: 
weight, BMI, waist and hip circumferences, blood pressure, fasting serum glucose, 
triglycerides, cholesterol (total and HDL/LDL fractions), and C-reactive protein. 
The cardiovascular risk factors that will be collected are as follows: weight, body mass index, waist and 
hip circumferences, blood pressure, fasting serum glucose, triglycerides, cholesterol (total and HDL/LDL 
fractions), and C-reactive protein. 
All exploratory endpoints will be summarized descriptively in the ITT Population. 
PGA-F, ss-IGA, scalp itch NRS, 
, and cardiovascular risk factors (including change from 
baseline values) will be listed. 
 


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Pharmacokinetics 
Exploratory endpoint: Plasma levels of the drug and its metabolites at scheduled visits. 
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 10 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 trough levels: The patients will be instructed to self-administer the study 
drug approximately 
 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. It is recommended to have 
date and time of last subject’s drug intake before PK sampling recorded in subject’s source and in the 
eCRF as well. 
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, 
 additional blood samples will be collected during 
each visit at 
 and 
. 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: 
 (estimated Cmax), 
 after intake of the study drug, as shown in the figure below. An additional 
 
blood sample will be collected if the patient accepts. The actual date and time of the study drug 
administration in the clinic and each blood sample collection will be recorded.  
 
 
Abbreviations: Lab, laboratory; PK, pharmacokinetics 
The plasma levels of the drug and its metabolites will be summarized descriptively by visit and hour. 
A listing of PK levels will be presented by treatment group, subject number, and collection date and time. 


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Pharmacodynamics 
 
 


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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;  
• 
TEAEs overall by system organ class and preferred term;  
• 
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 starting within the dose titration period (initial 
3 weeks)  


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• 
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; 
• 
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;  
• 
TESAEs, overall and by system organ class and preferred term; 
• 
TESAEs by maximum toxicity grade, overall and by system organ class and preferred term;  
• 
TESAEs by toxicity grade, overall and by system organ class and preferred term; 
• 
TESAEs by maximum relationship to study medication, overall and by system organ class and 
preferred term;  
• 
TESAEs 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 death, overall and by system organ class and preferred term; 
• 
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 Adverse Events Leading to Study Drug Discontinuation. 
 
Laboratory Evaluations 
Safety laboratory samples for chemistry, hematology and urinalysis will be collected at various visits. Refer 
to Section 10 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. 
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), Urobilinogen. 
Cardiovascular risk factors (fasting condition and at Baseline and Week 16 only): C-reactive protein, 
Glucose, Total cholesterol, High-density lipoprotein, Low-density lipoprotein, Triglycerides. Patients 
should be in fasting condition (no food or fluids other than water for 8 hours) before sample collection at 
Baseline and Week 16. 


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Serology: HIV antibody, Hepatitis B virus, Hepatitis C virus, Hepatitis B surface antigen, Hepatitis B core 
antibody, Hepatitis B surface antibody, 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. 
All summaries will be based on results in SI (standard international system of units) units and will be 
output in the order listed above.  
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.  
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) and body temperature (degree Celsius) will be measured at different visits as per the 
SoA in Protocol Section 10. 
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. 


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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 10. 
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 at any time during the trial. 
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 Week 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 
conditionand. 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 10. 
Actual values and changes from baseline in HADS scores (depression, anxiety and total) will be 
summarized by treatment. A summary table presenting the frequency and percentage of participants by 
treatment within categories (< 7, 8 – 10, 11 – 14 and  15 – 20) 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 


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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 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. 
C-SSRS will be collected at different time points as per the SoA in Protocol Section 10. 
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. 
 
 
  
 


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Reference List 
1. 
K. Reich, M. Gooderham, L. Green, A. Bewley, Z. Zhang, I. Khanskaya, R.M. Day, J. 
Goncalves, K. Shah, V. Piguet,J. Soung. The efficacy and safety of apremilast, etanercept 
and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a 
phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol. 
2017,31, 507-517. doi: 10.1111/jdv.14015. 
2. 
C. Paul, J. Cather, M. Gooderham, Y. Poulin, U. Mrowietz, C. Ferrandiz, J. Crowley, C. Hu, 
R.M. Stevens, K. Shah, R.M. Day, G. Girolomoni and A.B. Gottlieb. Efficacy and safety of 
apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque 
psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2).Br J Dermatol 
2015; 173, 1387-1399. 
3. 
Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. The 5-point 
Investigator's Global Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis 
severity in clinical trials. J Dermatolog Treat. 2015 Feb;26(1):23-31. doi: 
10.3109/09546634.2013.865009. 


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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 
 
 
 
 
 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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Index of Tables 
Header 
Table Number 
Name 
Analysis Population 
14. 
 
TABLES AND FIGURES 
 
14.1 
 
Demographic Data 
 
14.1.1 
 
Patient Disposition 
 
 
14.1.1.1 
Screen Failure Reasons   
Screened Patients 
 
14.1.1.2.1 
Analysis Populations   
Screened Patients 
 
14.1.1.3.1 
Patient Disposition  
Randomized Population 
14.1.2 
 
Protocol Deviations 
 
 
14.1.2.1 
Protocol Deviations 
Randomized Population 
14.1.3 
 
Demographic and Baseline Characteristics 
 
14.1.3.1 
 
Patient Demographic and Baseline 
Characteristics 
 
 
14.1.3.1.1 
Demographic and Baseline Characteristics  
ITT  Population 
 
14.1.3.1.2 
Demographic and Baseline Characteristics  
PP Population 
 
14.1.3.1.3 
Previous Psoriasis Treatments 
ITT Population 
 
14.1.3.1.4.1 
Baseline Efficacy Assessments 
ITT Population 
 
14.1.3.1.4.2 
Baseline Efficacy Assessments 
PP Population 
14.1.3.2 
 
Baseline Disease Characteristics 
 
 
14.1.3.2 
Smoking and Alcohol History  
ITT Population 
14.1.3.3 
 
Medical History 
 
 
14.1.3.3.1 
Medical History  
ITT Population 
 
14.1.3.3.2 
Ongoing Conditions 
ITT Population 
14.1.4 
 
Medications 
 
 
14.1.4.1 
Prior Medication 
ITT Population 
 
14.1.4.2 
Concomitant Medication 
ITT Population 
 
14.1.4.3 
Concomitant Disallowed Medication 
ITT Population 
14.1.5 
 
Treatment Compliance 
 
 
14.1.5.1 
Compliance - Overall 
ITT Population 
 
14.1.5.2 
Compliance - During the Titration Period 
ITT Population 
14.2 
 
Efficacy Data 
 
14.2.1 
 
Primary Efficacy Parameters 
 
 
14.2.1.1.1 
Percentage Change in Psoriasis Activity and 
Severity Index (PASI) Score from Baseline at 
Week 16  
Primary Efficacy Analysis: ANCOVA - Multiple 
Imputation  
ITT Population 
 
14.2.1.1.2 
Percentage Change in Psoriasis Activity and 
Severity Index (PASI) Score from Baseline at 
Weeks 20, 12, 8 and 4  
Primary Efficacy Analysis: ANCOVA - Multiple 
Imputation 
ITT Population  
 
14.2.1.1.3 
Percentage Change in Psoriasis Activity and 
Severity Index (PASI) Score from Baseline at 
Week 16  
Primary Efficacy Analysis: ANCOVA – 
Multiple Imputation 
PP Population  
 
14.2.1.1.4 
Percentage Change in Psoriasis Activity and 
Severity Index (PASI) Score from Baseline at 
Weeks 20, 12, 8 and 4  
Primary Efficacy Analysis: ANCOVA – 
Multiple Imputation 
PP Population  


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Header 
Table Number 
Name 
Analysis Population 
 
14.2.1.1.5 
Actual Values, Change from Baseline and 
Percentage Change from Baseline in 
Psoriasis Activity and Severity Index (PASI) 
Score   
Primary Efficacy Analysis: Descriptive 
Statistics– Observed Cases  
ITT Population  
 
14.2.1.1.6 
Percentage Change in Psoriasis Activity and 
Severity Index (PASI) Score from Baseline at 
Weeks 4, 12, 16 and 20  
Primary Efficacy Analysis: Mixed Model for 
Repeated Measures  
ITT Population  
14.2.2 
 
Secondary Efficacy Parameters 
 
 
14.2.2.1.1 
Patients achieving 75% reduction in PASI 
(PASI75) response at Week 16  
Key Secondary Efficacy Analysis – Multiple 
Imputation  
ITT Population 
 
14.2.2.1.2 
Patients achieving 75% reduction in PASI 
(PASI75) response at Week 16  
Key Secondary Efficacy Analysis – Multiple 
Imputation 
PP Population 
 
14.2.2.2.1 
Patients achieving a score of Clear (0) or 
Almost Clear (1) and an at least 2-point 
improvement in Investigator Global 
Assessment (IGA) at Week 16.  
Key Secondary Efficacy Analysis – Multiple 
Imputation  
ITT Population 
 
14.2.2.2.2 
Patients achieving a score of Clear (0) or 
Almost Clear (1) and an at least 2-point 
improvement in Investigator Global 
Assessment (IGA) at Week 16.  
Key Secondary Efficacy Analysis – Multiple 
Imputation 
PP Population 
 
14.2.2.3.1 
Patients Achieving a Score of Clear (0) or 
Almost Clear (1) and an at least 2-point 
Improvement in IGA at Weeks 4, 8, 12, and 
20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
ITT Population 
 
14.2.2.3.2 
Patients Achieving a Score of Clear (0) or 
Almost Clear (1) and an at least 2-point 
Improvement in IGA at Weeks 4, 8, 12, and 
20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
PP Population 
 
14.2.2.3.3 
Patients Achieving a Score of Clear (0) or 
Almost Clear (1) and an at least 2-point 
Improvement in IGA at Weeks 4, 8, 12, 16 
and 20  
Other Secondary Efficacy Analysis – Non-
Response Imputation  
ITT Population 
 
14.2.2.3.4 
Shift in IGA Distribution between Baseline and 
each Visit Other Secondary Efficacy Analysis: 
Shift  - Observed Cases  
ITT Population 


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Header 
Table Number 
Name 
Analysis Population 
 
14.2.2.4.1 
Patients Achieving 75% reduction in PASI 
(PASI75) Response at Weeks 4, 8, 12, and 20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
ITT Population 
 
14.2.2.4.2 
Patients Achieving 75% reduction in PASI 
(PASI75) Response at Weeks 4, 8, 12, and 20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
PP Population 
 
14.2.2.4.4 
Patients Achieving PASI75 Response at 
Weeks 4, 8, 12, 16 and 20  
Other Secondary Efficacy Analysis – Non-
Response Imputation 
ITT Population 
 
14.2.2.5.1 
Patients achieving 50% reduction in PASI 
(PASI50) at Weeks 4, 8, 12, 16, and 20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
ITT Population 
 
14.2.2.5.2 
Patients achieving 50% reduction in PASI 
(PASI50) at Weeks 4, 8, 12, 16, and 20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
PP Population 
 
14.2.2.5.4 
Patients achieving 90% reduction in PASI 
(PASI90) response at Weeks 4, 8, 12, 16, and 
20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
ITT Population 
 
14.2.2.5.5 
Patients achieving 90% reduction in PASI 
(PASI90) response at Weeks 4, 8, 12, 16, and 
20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
PP Population 
 
14.2.2.6.1 
Change from Baseline and Percentage 
Change from Baseline in PASI at Weeks 4, 8, 
12, 16  and 20  
Other Secondary Efficacy Analysis: Mixed 
Model for Repeated Measures  
ITT Population 
 
14.2.2.6.2 
Change from Baseline and Percentage 
Change from Baseline in PASI at Weeks 4, 8, 
12, 16  and 20  
Other Secondary Efficacy Analysis: Mixed 
Model for Repeated Measures 
PP Population 
 
14.2.2.7.1 
Change from Baseline in Total Psoriasis 
Symptoms Scale (PSS) Score at Weeks 4, 8, 
12, 16, and 20 Other Secondary Efficacy 
Analysis: Mixed Model for Repeated 
Measures 
ITT Population 
 
14.2.2.7.2 
Change from Baseline in Total Psoriasis 
Symptoms Scale (PSS) Score at Weeks 4, 8, 
12, 16, and 20  
Other Secondary Efficacy Analysis: Mixed 
Model for Repeated Measures 
PP Population 


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Header 
Table Number 
Name 
Analysis Population 
 
14.2.2.7.3 
Actual Values, Change from Baseline in Total 
PSS Score  at Weeks 4, 8, 12, 16, and 20 
 
Other Secondary Efficacy Analysis: 
Descriptive Statistics– Observed Cases  
ITT Population 
 
14.2.2.7.4 
Actual Values, Change from Baseline in Total 
PSS Score  at Weeks 4, 8, 12, 16, and 20 
 
Other Secondary Efficacy Analysis: 
Descriptive Statistics– Observed Cases  
PP Population 
 
14.2.2.8.1 
Change from Baseline in Each Individual Item 
of the PSS at Weeks 4, 8, 12, 16, and 20  
Other Secondary Efficacy Analysis: Mixed 
Model for Repeated Measures 
ITT Population 
 
14.2.2.8.2 
Change from Baseline in Each Individual Item 
of the PSS at Weeks 4, 8, 12, 16, and 20  
Other Secondary Efficacy Analysis: Mixed 
Model for Repeated Measures 
PP Population 
 
14.2.2.8.3 
Actual Values, Change from Baseline in Each 
Individual Item of the PSS at Weeks 4, 8, 12, 
16, and 20  
Other Secondary Efficacy Analysis: 
Descriptive Statistics – Observed Cases   
ITT Population 
 
14.2.2.8.4 
Actual Values, Change from Baseline in Each 
Individual Item of the PSS at Weeks 4, 8, 12, 
16, and 20  
Other Secondary Efficacy Analysis: 
Descriptive Statistics – Observed Cases   
PP Population 
 
14.2.2.9.1 
Change from Baseline in the Affected Body 
Surface Area (BSA) at Weeks 4, 8, 12, 16, 
and 20  
Other Secondary Efficacy Analysis Mixed 
Model for Repeated Measures 
ITT Population 
 
14.2.2.9.2 
Change from Baseline in the Affected Body 
Surface Area (BSA) at Weeks 4, 8, 12, 16, 
and 20  
Other Secondary Efficacy Analysis: Mixed 
Model for Repeated Measures 
PP Population 
 
14.2.2.9.3 
Actual Values, Change from Baseline and 
Percentage Change from Baseline in Body 
Surface Area (BSA)  
Other Secondary Efficacy Analysis: 
Descriptive Statistics– Observed Cases  
ITT Population 
 
14.2.2.9.4 
Actual Values, Change from Baseline and 
Percentage Change from Baseline in Body 
Surface Area (BSA)  
Other Secondary Efficacy Analysis: 
Descriptive Statistics– Observed Cases  
PP Population 
 
14.2.2.10.1 
Change from Baseline in Dermatology Life 
Quality Index (DLQI) Score at Weeks 16 and 
20  
Other Secondary Efficacy Analysis: Mixed 
Model for Repeated Measures 
ITT Population 


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Header 
Table Number 
Name 
Analysis Population 
 
14.2.2.10.2 
Change from Baseline in Dermatology Life 
Quality Index (DLQI) Score at Weeks 16 and 
20  
Other Secondary Efficacy Analysis: Mixed 
Model for Repeated Measures 
PP Population 
 
14.2.2.10.3 
Actual Values, Change from Baseline and 
Percentage Change from Baseline in 
Dermatology Life Quality Index (DLQI) Score  
Other Secondary Efficacy Analysis: 
Descriptive Statistics– Observed Cases  
ITT Population 
 
14.2.2.10.4 
Actual Values, Change from Baseline and 
Percentage Change from Baseline in 
Dermatology Life Quality Index (DLQI) Score  
Other Secondary Efficacy Analysis: 
Descriptive Statistics– Observed Cases  
PP Population 
 
14.2.2.11.1 
Patients Experiencing Psoriasis Rebound by 
Week 20  
Other Secondary Efficacy Analysis – Multiple 
Imputation  
ITT Population 
 
14.2.2.11.2 
Patients Experiencing Psoriasis Rebound by 
Week 20  
Other Secondary Efficacy Analysis – Multiple 
Imputation 
PP Population 
 
14.2.2.12.1 
 Percentage of Patients with PASI50, PASI75, 
PASI90 and PASI100 Response over Time 
Other Secondary Efficacy Analysis: 
Descriptive Statistics - Observed cases 
ITT Population 
 
14.2.2.12.2 
Patients Achieving 90% reduction in PASI 
(PASI90) Response at Weeks 4, 8, 12, 16 and 
20 Other Secondary Efficacy Analysis - Non-
response Imputation 
ITT Population 
14.2.3 
 
Exploratory Parameters 
 
 
14.2.3.1 
Change from Baseline in Physician's Global 
Assessment of Finger Nails (PGA-F) at Week 
16  
Exploratory Analysis: Descriptive Statistics  
ITT Population 
 
14.2.3.2 
Change in Scalp-Specific Investigator Global 
Assessment (ss-IGA) from Baseline at Week 
16   
Exploratory Analysis: Descriptive Statistics  
ITT Population - 
Patients with Baseline 
Score of at least 2 (Mild 
Scalp Psoriasis) 
 
14.2.3.3 
Change from Baseline of Scalp Itch Numeric 
Rating Scale (NRS) at Week 16 Exploratory 
Analysis: Descriptive Statistics  
ITT Population - 
Patients with Baseline 
Score of at least 4 on 
the 11-point NRS 
 
14.2.3.4 
 
   
Exploratory Analysis: Descriptive Statistics  
ITT Population - 
 
 
 
 
 
14.2.3.5 
Change in Cardiovascular Risk Factors at 
Week 16   
Exploratory Analysis: Descriptive Statistics 
ITT Population 


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Header 
Table Number 
Name 
Analysis Population 
 
14.2.3.6.1 
Trough Levels of Orismilast and Metabolites  
Exploratory Analysis: Descriptive Statistics  
ITT Population 
 
14.2.3.6.2 
Plasma Levels of Orismilast and Metabolites  
Exploratory Analysis: Descriptive Statistics  
ITT Population - 
Patients Having 
Accepted The 
Additional Profiles 
 
14.2.3.6.3 
Trough Levels of Orismilast and Metabolites 
by Time Since Previous Dose 
Exploratory Analysis: Descriptive Statistics  
ITT Population 
 
14.2.3.7 
 
  
Exploratory Analysis: Descriptive Statistics  
ITT Population 
14.3 
 
Safety Data 
 
14.3.1 
 
Displays of Adverse Events 
 
 
14.3.1.1 
Overall Summary of Treatment Emergent 
Adverse Events (TEAEs) 
Safety Population 
 
14.3.1.2 
Treatment Emergent Adverse Events (TEAEs) 
by System Organ Class and Preferred Term 
Safety Population 
Safety Population 
 
14.3.1.3 
Treatment Emergent Adverse Events (TEAEs) 
by System Organ Class, Preferred Term and 
Maximum Toxicity Grade  
Safety Population 
 
14.3.1.4 
Treatment Emergent Adverse Events (TEAEs) 
by System Organ Class, Preferred Term and 
Toxicity Grade  
Safety Population 
 
14.3.1.5 
Treatment Emergent Adverse Events (TEAEs) 
by System Organ Class, Preferred Term and 
Maximum Relationship  
Safety Population 
 
14.3.1.6 
Treatment Emergent Adverse Events (TEAEs) 
by System Organ Class, Preferred Term and 
Relationship  
Safety Population 
 
14.3.1.7 
Treatment Emergent Serious Adverse Events 
(TESAEs) by System Organ Class and 
Preferred Term  
Safety Population 
 
14.3.1.8 
Overall Summary of Treatment Emergent 
Adverse Events (TEAEs) Starting Within the 
Dose Titration Period (initial 3 weeks) 
Safety Population 
 
14.3.1.9 
Treatment Emergent Adverse Events (TEAEs) 
by System Organ Class and Preferred Term 
Starting Within the Dose Titration Period 
(initial 3 weeks) 
Safety Population 
 
14.3.1.10 
Summary of Treatment Emergent Adverse 
Events (TEAEs) by System Organ Class, 
Preferred Term and Maximum Toxicity Grade  
Safety Population 
 
14.3.1.11 
Treatment Emergent Adverse Events (TEAEs) 
by System Organ Class, Preferred Term and 
Toxicity Grade  
Safety Population 
 
14.3.1.12 
Treatment Emergent Serious Adverse Events 
(TESAEs) by System Organ Class, Preferred 
Term and Maximum Relationship  
Safety Population 
 
14.3.1.13 
Treatment Emergent Serious Adverse Events 
(TESAEs) by System Organ Class, Preferred 
Term and Relationship  
Safety Population 


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Header 
Table Number 
Name 
Analysis Population 
 
14.3.1.14 
Treatment-Emergent Non-Serious Adverse 
Events by System Organ Class and Preferred 
Term  
Safety Population 
 
14.3.1.15 
Treatment-Emergent Adverse Events Leading 
to Study Drug Discontinuation by System 
Organ Class and Preferred Term  
Safety Population 
 
14.3.1.16 
Treatment-Emergent Adverse Events Leading 
to Death by System Organ Class and 
Preferred Term  
Safety Population 
 
14.3.1.17 
Treatment-Emergent Adverse Events of 
Special Interest by System Organ Class and 
Preferred Term  
Safety Population 
 
14.3.1.18 
Adverse Events Starting in the 4-week Follow-
up Period by System Organ Class and 
Preferred Term  
Safety Population 
 
14.3.1.19 
Serious Adverse Events Starting in the 4-
week Follow-up Period by System Organ 
Class and Preferred Term  
Safety Population 
14.3.2 
 
Listings of Deaths, Other Serious and Certain 
Other Significant Adverse Events 
 
 
14.3.2.1 
Listing of Deaths   
Safety Population 
 
14.3.2.2 
Listing of Adverse Events of Special Interest  
Safety Population 
 
14.3.2.3 
Listing of Serious Adverse Events  
Safety Population 
 
14.3.2.4 
Listing of Adverse Events Leading to Study 
Drug Discontinuation  
Safety Population 
14.3.3 
Not to be used 
for any Tables 
Narratives of Deaths, Other Serious and 
Certain Other Significant Adverse Events 
(NOTE: this section is for Medical Writing 
narratives only, normally not completed by 
 Biostatistics. No tables should 
go here. Nevertheless, the section is kept and 
a note should indicate the responsible party). 
 
14.3.4 
 
Laboratory, Vital Signs, and Physical 
Examination Changes  
 
14.3.4.1 
 
Clinical Laboratory Data 
 
14.3.4.1.1 
14.3.4.1.1 
Chemistry: Summary by Visit and Change 
from Baseline  
Safety Population 
 
14.3.4.1.2 
Chemistry: Maximum Shift From Baseline to 
Week 16 Relative to the Normal Range   
Safety Population 
 
14.3.4.1.3 
Listing of Chemistry Abnormal Results  
Safety Population 
 
14.3.4.2.1 
Hematology: Summary by Visit and Change 
from Baseline   
Safety Population 
 
14.3.4.2.2 
Hematology: Maximum Shift From Baseline to 
Week 16 Relative to the Normal Range   
Safety Population 
 
14.3.4.2.3 
Listing of Hematology Abnormal Results   
Safety Population 
 
14.3.4.3.1 
Urinalysis: Summary by Visit  
Safety Population 
 
14.3.4.3.2 
Urinalysis: Maximum Shift From Baseline to 
Week 16 Relative to the Normal Range    
Safety Population 
 
14.3.4.3.3 
Listing of Urinalysis Abnormal Results   
Safety Population 
 
 
Vital Signs 
 
 
14.3.4.4.1 
Vital Signs: Summary by Visit and Change 
from Baseline  
Safety Population 
 
 
ECG 
 


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Header 
Table Number 
Name 
Analysis Population 
 
14.3.4.4.2.1 
ECG Parameters: Summary by Visit and 
Change from Baseline  
Safety Population 
 
14.3.4.4.2.2 
ECG Outlier Analysis by Visit 
Safety Population 
 
14.3.4.4.2.3 
ECG Outlier Analysis at Any Time Post-
baseline 
Safety Population 
 
 
Physical Examination 
 
 
14.3.4.4.3 
Shift in Physical Examination between 
Baseline and each Visit   
Safety Population 
 
 
Other Safety 
 
 
14.3.4.4.4.1 
Hospital Anxiety and Depression Scale 
(HADS): Summary by Visit  and Change from 
Baseline 
Safety Population 
 
14.3.4.4.4.2 
Hospital Anxiety and Depression Scale 
(HADS): Summary by Category and Visit 
Safety Population 
 
14.3.4.4.4.3 
Hospital Anxiety and Depression Scale 
(HADS): Shift from Baseline 
Safety Population 
 
14.3.4.4.5 
Number of Patients with Suicidal Ideation, 
Suicidal Behavior, and Self-injurious Behavior 
without Suicidal Intent Based on the C-SSRS   
Safety Population 
 
14.3.4.4.6 
Shift in C-SSRS between Baseline and each 
Visit   
Safety Population 
 


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Index of Figures 
Header 
Figure Number 
Name 
Analysis 
Population 
14.1.1 
 
Patient Disposition 
 
 
14.1.1.3.2 
Time to Discontinuation of Study Treatment by Treatment 
Group 
ITT Population 
14.2.2 
 
Secondary Efficacy Parameters 
 
 
14.2.1.1.7 
LSMean (+/-SE) of Percentage Change in Psoriasis 
Activity and Severity Index (PASI) Score from Baseline at 
Weeks 4, 8, 12, 16 and 20 Primary Efficacy Analysis: 
Graphically Presented – Multiple Imputation 
ITT Population 
 
14.2.2.3.5 
Investigator Global Assessment (IGA) over Time  
ITT Population 
 
14.2.2.3.6 
Change from Baseline in Investigator Global Assessment 
(IGA) over Time  
ITT Population 
 
14.2.2.4.3 
Percentage of Patients with PASI75 Response over Time   ITT Population 
 
14.2.2.5.3 
Percentage of Patients with PASI50 Response over Time  ITT Population 
 
14.2.2.5.6 
Percentage of Patients with PASI90 Response over Time  ITT Population 
 
14.2.2.6.3 
Psoriasis Activity and Severity Index (PASI) over Time  
ITT Population 
 
14.2.2.6.4 
Change from Baseline in Psoriasis Activity and Severity 
Index (PASI) over Time  
ITT Population 
 
14.2.2.6.5 
Percentage Change from Baseline in Psoriasis Activity 
and Severity Index (PASI) over Time  
ITT Population 
 
14.2.2.7.5 
Total Psoriasis Symptoms Scale (PSS) Score over Time  
ITT Population 
 
14.2.2.7.6 
Change from Baseline in Total Psoriasis Symptoms 
Scale (PSS) Score over Time  
ITT Population 
 
14.2.2.8.5 
Each Individual Item of the PSS over Time  
ITT Population 
 
14.2.2.9.5 
Affected Body Surface Area (BSA) over Time  
ITT Population 
 
14.2.2.9.6 
Change from Baseline in the Affected Body Surface Area 
(BSA) over Time  
ITT Population 
 
14.2.2.9.7 
Percentage Change from Baseline in the Affected Body 
Surface Area (BSA) over Time  
ITT Population 
 
14.2.2.10.5 
Dermatology Life Quality Index (DLQI) Score over Time  
ITT Population 
 
14.2.2.10.6 
Change from Baseline in Dermatology Life Quality Index 
(DLQI) Score over Time  
ITT Population 
 
14.2.2.10.7 
Percentage Change from Baseline in Dermatology Life 
Quality Index (DLQI) Score over Time  
ITT Population 


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Index of Listings 
Header 
Listing 
Number 
Name 
Analysis Population 
 
16.1.7 
Listing of Randomization  
 Randomized 
Population 
16.2 
 
Patient Data Listings 
 
16.2.1 
 
Discontinued Patients 
 
 
16.2.1.1 
Analysis Population   
Randomized Population 
 
16.2.1.2 
Patient Disposition  
Randomized Population 
16.2.2 
 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations  
Randomized Population 
 
16.2.2.2 
COVID-19 Visit Impact 
Randomized Population 
16.2.3 
 
Patients Excluded from the Efficacy 
Analysis 
 
 
16.2.3.1 
Inclusion/Exclusion Criteria Violations  
Screened Population 
 
16.2.3.2 
Exclusions from Analysis Populations 
Randomized Population 
16.2.4 
 
Demographic Data 
 
 
16.2.4.1 
Demographics  
Randomized Population 
 
16.2.4.2 
Medical History 
Randomized Population 
 
16.2.4.3 
Smoking and Alcohol History  
Randomized Population 
 
16.2.4.4 
Prior and Concomitant Medications  
Randomized Population 
 
16.2.4.5 
Concomitant Disallowed Medications  
Randomized Population 
 
16.2.4.6 
Previous Psoriasis Treatments 
Randomized Population 
16.2.5 
 
Compliance and/or Drug Concentration 
Data  
 
 
16.2.5.1 
Study Drug Administration  
ITT Population 
 
16.2.5.2 
Study Drug Accountability  
ITT Population 
 
16.2.5.3 
Study Drug Compliance Check  
ITT Population 
16.2.6 
 
Individual Efficacy Response Data 
 
 
16.2.6.1.1 
Primary Efficacy Endpoint: Psoriasis 
Activity and Severity Index (PASI) – Total 
Score   
Randomized Population 
 
16.2.6.1.2 
Primary Efficacy Endpoint: Psoriasis 
Activity and Severity Index (PASI)  - 
Plaque Characteristics 
Randomized Population 
 
16.2.6.2.1 
Key Secondary Efficacy Endpoint: 
Investigator Global Assessment (IGA)   
Randomized Population 
 
16.2.6.2.2 
Other Secondary Efficacy Endpoint: 
Psoriasis Symptom Scale (PSS)  
Randomized Population 
 
16.2.6.2.3 
Other Secondary Efficacy Endpoint: 
Affected Body Surface Area (BSA)   
Randomized Population 
 
16.2.6.2.4 
Other Secondary Efficacy Endpoint: 
Dermatology Life Quality Index (DLQI) 
Score, incl.  Actual Values, Change from 
Baseline and Percentage Change from 
Baseline  
Randomized Population 
 
16.2.6.3.1 
Exploratory Endpoint: Physician's Global 
Assessment of Finger Nails (PGA-F)   
Randomized Population 
 
16.2.6.3.2 
Exploratory Endpoint: Scalp-Specific 
Investigator Global Assessment (ss-IGA)  
Randomized Population 
 
16.2.6.3.3 
Exploratory Endpoint: Scalp Itch Numeric 
Rating Scale (NRS)  
Randomized Population 


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Header 
Listing 
Number 
Name 
Analysis Population 
 
16.2.6.3.4 
 
  
Randomized Population 
 
16.2.6.3.5 
Exploratory Endpoint: Cardiovascular Risk 
Factors - Baseline and Week 16  
Randomized Population 
 
16.2.6.3.6 
Exploratory Endpoint: PK Levels of 
Orismilast and Metabolites  
Randomized Population 
 
16.2.6.3.7 
  
Randomized Population 
16.2.7 
 
Adverse Event Listings 
 
 
16.2.7.1 
Treatment-Emergent Adverse Events 
Randomized Population 
 
16.2.7.2 
Non-Treatment-Emergent Adverse Events 
Randomized Population 
 
16.2.7.3 
Adverse Events Starting Within the Dose 
Titration Period (initial 3 weeks) 
Randomized Population 
 
16.2.7.4 
Adverse Events Starting in the 4-week 
Follow-up Period 
Randomized Population 
16.2.8 
 
Listing of individual laboratory 
measurements by patient 
 
 
16.2.8.1 
Clinical Laboratory Data 
 
 
16.2.8.1.1 
Clinical Chemistry 
Randomized Population 
 
16.2.8.1.2 
Hematology 
Randomized Population 
 
16.2.8.1.3 
Urinalysis 
Randomized Population 
 
16.2.8.1.4 
Serology 
Randomized Population 
 
16.2.8.1.5 
Pregnancy Tests 
Randomized Population 
 
16.2.8.2 
Other Safety Data 
 
 
16.2.8.2.1 
Vital Signs 
Randomized Population 
 
16.2.8.2.2 
Electrocardiogram (ECG) 
Randomized Population 
 
16.2.8.2.3 
ECG Overall Evaluation 
Randomized Population 
 
16.2.8.2.4 
Physical Examination 
Randomized Population 
 
16.2.8.2.5 
Hospital Anxiety and Depression Scale 
(HADS)   
Randomized Population 
 
16.2.8.2.6 
Patients with Suicidal Ideation, Suicidal 
Behavior, or Self-Injurious Behavior 
without Suicidal Intent Based on the C-
SSRS  
Randomized Population 
 


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


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Appendices 
Not Applicable.