Clinical trial NCT04572997
Conditions: Palmoplantar Pustulosis
Keywords: PPP Palmoplantar Pustulosis Apremilast Otezla
Sponsor: Kristian Reich
Start date: 2018-11-29; Completion date: 2019-08-29
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Multicenter, open-label, single-arm, phase II, pilot study. The screening period was up to 4 weeks and treatment took place over 20 weeks per patient. Five visits per patient were performed including: Visit 1 at week -4 to -1 (screening), Visit 2 at week 0 (baseline), Visit 3 at week 4, Visit 4 at week 12, and Visit 5 at week 20 (end of study). There was no follow-up period.

Detailed description:
This was a multicenter, open-label, single-arm, phase II, pilot study to evaluate the efficacy and safety of apremilast involving 21 patients with PPP. The screening period was up to 4 weeks and treatment took place over 20 weeks per patient. No follow up period took place. No extension was done.

Recruitment period was 4 months; hence study duration from first patient in to last patient out was approximately 9 months. About 4-6 patients per center were recruited, assuming enrolment of both genders with distribution according to prevalence of condition.

Patient recruitment took place at 5 centers in Germany. The investigators had relevant expertise in diagnosing and treating PPP or were specialized in dermatology. Patients were enrolled until approximately 20 patients were included into the study. One drop-out was replaced during the recruitment phase.

Five visits per patient were performed including:

* Visit 1 at week -4 to -1 (screening)
* Visit 2 at week 0 (baseline)
* Visit 3 at week 4
* Visit 4 at week 12
* Visit 5 at week 20 (end of study)

After the end of study participation the investigator ensured that the patient received a suitable therapy appropriate to patient's condition.

Arms: arm 1: The full analysis set (FAS) consisted of all patients who received at least one dose of study drug.
Interventions: intervention 1: Apremilast
Intervention descriptions: intervention 1: Apremilast was taken orally twice daily (except Day 1). Patients received tablets in blister/bottles sufficient for one month. To mitigate potential gastrointestinal side effects (primarily mild-to-moderate nausea and diarrhoea), dose titration was implemented in this study in accordance with the Summary of Product Characteristics (SmPC). A titration pack included tablets of 10, 20 and 30 mg for a period of one month. During the first 5 days, the dosage was up-titrated. The initial dose on day 1 was 10 mg in the morning; this was increased to 10 mg in the morning and evening on day 2. The evening dose was further increased by 10 mg (to 20 mg) on day 3. On day 4, the morning dose was increased to 20 mg, so that 20 mg was taken twice daily, and on day 5 the evening dose was increased to 30 mg. From Day 6 onwards, patients received the 30 mg dose twice a day. Subsequent packs included only tablets of 30 mg strength.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
A multicenter, open label, single-arm pilot study to evaluate the 
efficacy and safety of oral apremilast in patients with moderate to 
severe palmoplantar pustulosis (PPP) (APLANTUS) 
 
 
Document: 
Clinical Study Protocol 
Version/ Date: 
Final 3.0, 07. June 2018 
 
 
Protocol Number: 
069-008 
Internal Study Code: 
AP-CL-PSOR-PI-006639 
EudraCT No.: 
2016-005122-11 
Study Phase: 
Phase II 
 
 
Sponsor: 
Prof. Dr. Kristian Reich 
TFS Trial Form Support GmbH (formerly SCIderm GmbH) 
Drehbahn 1-3 
20354 Hamburg 
Deutschland 
 
 
Prepared by: 
TFS Trial Form Support GmbH 
 
Drehbahn 1-3 
20354 Hamburg 
Germany 
Author(s): 
Dr. Wiebke Griemberg 
Anne Rousseau 
 
 
 
 
Confidential 
May not be used, published, or otherwise disclosed  
without the consent of Prof. Dr. Kristian Reich. 
No information may be disclosed to any third party without prior  
written consent of Prof. Dr. Kristian Reich. 
 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 2 of 75 
 
1 
Study Synopsis 
Study Title 
A multicenter, open label, single-arm pilot study to evaluate the 
efficacy and safety of oral apremilast in patients with moderate to 
severe palmoplantar pustulosis (PPP) (APLANTUS) 
Short Title 
APLANTUS 
Protocol No. 
069-008 
Internal Study Code 
AP-CL-PSOR-PI-006639 
EudraCT No. 
2016-005122-11 
Clinical Phase 
Phase II 
Study Design  
Multicenter, open label, single-arm pilot study 
Study Objective(s) 
The primary objective of this study is: 
 To demonstrate a significant improvement of Palmoplantar 
Pustulosis Psoriasis Area and Severity Index (PPPASI) at week 
20 compared with baseline in moderate to severe chronic 
palmoplantar pustulosis under apremilast therapy. 
The secondary objectives of the study are: 
 To evaluate an improvement of PPPASI at all assessment times 
compared with baseline in moderate to severe chronic 
palmoplantar pustulosis under apremilast therapy. 
 To evaluate differences during the treatment with apremilast in 
life quality assessment measures: Dermatology Life Quality 
Index (DLQI) at all assessment times compared with baseline 
 To evaluate safety of apremilast in patients with moderate to 
severe palmoplantar pustulosis 
Exploratory objectives are: 
 Time course of Hand and Feet Physician Global Assessment 
(H&F PGA) at all assessment times. 
 Pustules count 50 response and Pustules count 75 response, 
defined as a 50% and 75% decrease in Pustules count from 
baseline, during the 20 weeks treatment period 
 To evaluate differences in the mean change from baseline at all 
assessment times of Visual Analogue Scale (VAS) discomfort / 
pain, VAS pruritus / itch at all assessment times relatively to day 
0 (baseline)  
 To evaluate changes in Psoriasis Area Severity Index (PASI), 
Physician Global Assessment (PGA) and dynamic PGA if 
plaque psoriasis is present between baseline and all 
assessment times 
 To explore the effect of apremilast on serum / plasma 
immunological markers  
 To explore the effect of apremilast on immunological markers in 
skin biopsy samples (sub-study) 
Approximate 
Duration of Study 
The study is estimated to have duration of approximately 11 
months from first patient in (FPI) to last patient out (LPO). 
Enrolment will cease if the target number of patients is reached. 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 3 of 75 
 
Duration of Patient 
Participation 
Up to 4 weeks screening period, 20 weeks treatment period 
Number of Visits 
5 
Approx. Number of 
Sites 
5 in Germany 
Number of Patients 
20 
Target Disease 
Palmoplantar pustulosis (PPP) 
Criteria for Inclusion 
 Male and female patients aged 18 years or more at screening 
visit. 
 Patients with chronic PPP (disease history of at least 6 months 
of diagnosis), who are eligible for treatment with systemic 
therapy defined as having PPP inadequately controlled by 
topical treatment and / or phototherapy and / or previous 
systemic therapy 
 Patients with chronic moderate to severe PPP defined as 
patients with a PPPASI ≥ 12 with or without concomitant plaque-
type psoriasis 
 Negative result of a urine pregnancy test taken at screening and 
at baseline for all women, except those who are surgically sterile 
or at least 1 year postmenopausal (i.e. at least 12 consecutive 
months with amenorrhea without other known or suspected 
medical cause) 
 Willingness and capability of using a highly effective 
contraceptive measure from Screening visit until the end of at 
least one menstrual cycle (but not less than 28 days) following 
discontinuation of apremilast as defined below: 
o Female patient of childbearing potential (fertile, following 
menarche and until becoming post-menopausal unless 
permanently sterile) using a highly effective method of 
contraception OR female patients of non-childbearing 
potential (surgically sterilized [e.g. hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy] or post-
menopausal) 
o Male patient, and his female partner of childbearing 
potential, using a highly effective method of contraception  
o Adequate contraceptive method defined as: 
 A method with less than 1% failure rate (e.g. permanent 
sterilization, hormone implants, hormone injections, some 
intrauterine devices, or vasectomized partner)  
OR 
 The use of two methods of contraception (e.g. one barrier 
method [condom, diaphragm or cervical/vault caps] with 
spermicide and one hormonal contraceptive [e.g. 
combined oral contraceptives, patch, vaginal ring, 
injectables and implants]) 
 Patient is capable of understanding and giving written, voluntary 
informed consent before study screening. 
 Willingness and capability of complying with all study 
procedure requirements, as per the Investigator’s judgment 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 4 of 75 
 
(e.g. patient able to swallow the apremilast tablets, blood 
sampling). 
 
Criteria for 
Exclusion 
General 
 Pregnant or breast-feeding women 
 Current or history of psychiatric disease that would interfere with 
the ability to comply with the study protocol or give informed 
consent 
 Patients known to have had a substance abuse (drug or alcohol) 
problem within the previous 12 months 
 Individuals who are involved in the organization of the study 
 Patients who are in any way dependent on the investigator 
 Patients who are participating in a clinical study 
 Relatives, partner or staff of any clinical site personnel 
Disease-related 
 Evidence of skin conditions (e.g. eczema) other than PPP / 
psoriasis that would interfere with evaluations of the effect of 
study medication on PPP or psoriasis. 
 Laboratory values available from routine blood test taken within 
8 weeks prior to screening with any of the following: 
o 
Serum creatinine >1.4 x upper limit of normal (ULN) for age 
and gender  
o 
Estimated Glomerular Filtration Rate (eGFR) < 30 
mL/min/1.73 m2 according to the CKD-EPI equation  
 Pustular psoriasis lesions on the part of body other than hands 
or feet 
 Significant concurrent medical conditions at the time of 
screening, including: 
o 
Risk factors for renal toxicity (renal inflammation) 
o 
Severe hepatic dysfunction 
o 
Unstable angina pectoris 
o 
Uncompensated congestive heart failure 
o 
Severe pulmonary disease requiring hospitalization or 
supplemental oxygen therapy 
o 
Immunodeficiency disorders: primary or secondary 
o 
Known positive HIV test result, hepatitis B surface (HBS) 
antigen or hepatitis C (HCV) test result  
o 
Uncontrolled Insulin-dependent diabetes mellitus 
o 
Cancer or history of cancer (except for resected cutaneous 
basal cell or squamous cell carcinoma) in the last 5 years 
o 
Open cutaneous ulcers 
 Any condition that, in the judgment of the investigator, might 
cause this study to be detrimental to the patient. 
Medication-related 
 Ultraviolet B (UVB) therapy, topical steroids, topical calcineurin 
inhibitors, topical Vitamin A or D analog preparations, or 
anthralin within 14 days of baseline 
 Exceptions: low potency topical corticosteroids (class I and II, 
according to European classification for potency of topical 
corticosteroids) will be allowed as therapy for the face, groin, 
axillae in accordance with the manufacturer’s suggested usage 
dose 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 5 of 75 
 
 Psoralen plus ultraviolet A radiation (PUVA), ciclosporin, 
acitretin, alitretinoin, alefacept (Amevive®), anakinra (Kineret®), 
systemic corticosteroids, methotrexate, fumaric acids or any 
other systemic anti-psoriasis therapy within 28 days of baseline 
 Prior (within the last 2 years) or concomitant use of antipsoriatic 
biologic therapy with Tumor Necrosis Factor (TNF)-α blocker 
and / or ustekinumab and / or ixekizumab and / or secukinumab 
and / or brodalumab and / or guselkumab 
 Concomitant use of strong cytochrome P450 3A4 (CYP3A4) 
enzyme 
inductors 
(e.g. 
rifampicin, 
phenobarbital, 
carbamazepin, phenytoin and St. John`s wort) 
 Use of an investigational drug within 4 weeks prior to baseline 
or 5 pharmacokinetic / pharmacodynamics half-lives (whichever 
is longer) 
 Prior treatment with apremilast / Otezla® 
 Receipt of any live (attenuated) vaccine within 28 days prior to 
baseline. 
 Concomitant use of any other phosphodiesterase 4 inhibitor 
 Patients with hereditary problems of galactose intolerance, lapp 
lactase deficiency or glucose-galactose malabsorption 
 For patients with skin biopsy samples taken: patients with 
clinically relevant coagulation disorders or medication or known 
hypersensitivity against local anesthetics 
Investigational 
Medicinal Product 
(Including Placebo 
and Active 
Comparator, If Any) 
Apremilast (Otezla®) 
Dosage and 
Administration 
Apremilast BID, orally 
Day 1: 10 mg in morning 
Day 2: 10 mg in morning and 10 mg in evening 
Day 3: 10 mg in morning and 20 mg in evening 
Day 4: 20 mg in morning and 20 mg in evening 
Day 5: 20 mg in morning and 30 mg in evening 
Day 6 and thereafter: 30 mg twice daily 
Concomitant 
Treatment 
Required concomitant medication (except those listed under 
exclusion criteria) for the treatment of concomitant diseases and 
not known to interfere with the study drug or to mask the effect of 
the study drug, is unrestricted and may be continued during the 
study. 
Low potency topical corticosteroids (class I and II, according to 
European classification for potency of topical corticosteroids) will 
be allowed as background therapy for the treatment of the face, 
axillae, and groin in accordance with the manufacturer’s suggested 
usage during the course of the study except for lesions selected for 
clinical evaluations. 
An unmedicated skin moisturizer (without urea) is permitted for 
body lesions only. Patients should not use the unmedicated skin 
moisturizer within 12 hours prior to the clinic visit on lesions 
selected for clinical evaluations. 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 6 of 75 
 
Efficacy Evaluation 
Efficacy will be assessed by evaluating PASI, PPPASI, PGA, 
dynamic PGA, H&F PGA, pustules count, VAS for pruritus / itch 
and discomfort / pain on hands and feet, DLQI, and immunological 
markers. 
Safety and 
Tolerability 
Evaluation 
Safety will be assessed by evaluating Adverse Events (AEs), vital 
signs and physical examination. 
Primary Endpoint 
Percentage change from baseline in PPPASI after 20 weeks of 
treatment with apremilast 
Secondary 
Endpoints 
 
Absolute and percent change from baseline in PPPASI during 
the 20 weeks treatment period 
 
PPPASI 50 response and PPPASI 75 response, defined as a 
50% and 75% decrease in PPPASI from baseline, during the 
20 weeks treatment period 
 
DLQI bands (0-1 no effect, 2-5 small effect, 6-10 moderate 
effect, 11-20 very large effect, 21-30 extremely large effect on 
the disease related quality of life) during the 20 weeks treatment 
period 
 
Absolute and percent change from baseline in DLQI during the 
20 weeks treatment period 
 
Safety as assessed by AEs, vital signs and physical 
examination 
Exploratory 
Endpoints 
 
Absolute and percentage change from baseline in level of 
immunological markers in plasma / serum during the 20 weeks 
treatment period with apremilast  
 
Percentage change from baseline in level of immunological 
markers in skin biopsy samples after 20 weeks of treatment with 
apremilast (sub-study) 
Data Analysis / 
Statistical Methods 
This is a pilot study intended to gain first information on the possible 
clinical and mechanistical effects of apremilast on PPP; therefore 
the sample size is not based on statistical considerations. 
The Full Analysis Set (FAS) is defined as all patients who received 
at least one dose of study drug and the Per Protocol Set (PP) is 
defined as all patients who received at least one dose of study drug 
who completed the study with no major protocol violations. These 
two analysis sets will be used for analyses of efficacy endpoints. 
The definition of the PP set will be finalized in the data review 
meeting prior to database closure. 
In general, categorical variables will be summarized using 
frequencies and percentages and continuous variables will be 
summarized using number of observations, mean, standard 
deviation, median, minimum, first quartile, third quartile, and 
maximum. 
The primary endpoint percent change from baseline in PPPASI 
after 20 weeks of treatment will be summarized as continuous 
variable 
together 
with 
95%-confidence 
limits. 
Statistical 
comparison between post- versus pre-treatment values will be 
done based on the Wilcoxon signed-rank test with two-sided p-
value <0.05 indicating significance. Missing values will be replaced 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 7 of 75 
 
using last-observation-carried-forward (LOCF) method for the 
analysis of the primary endpoint based on the FAS. 
Exploratory endpoints (plasma / serum immunological marker 
analysis and the skin biopsy immunological marker (sub-study)) will 
be analyzed outside of the study setting by a research laboratory 
(Psoriasis Research and Treatment Center, University Hospital 
Charité, Berlin, Germany). Statistical comparison between post- 
versus pre-treatment values will be done based on the Wilcoxon 
signed-rank test with two-sided p-value <0.05 indicating 
significance. 
Ethical 
Considerations 
This study will be conducted in accordance with applicable laws 
and regulations including, but not limited to, the ICH E6 guideline 
and the ethics principles that have their origins in the Declaration 
of Helsinki. The independent ethics committee and the competent 
authority must review and approve the study before any patients 
are enrolled. Consent must be obtained from the patient using the 
approved informed consent form (ICF) before any procedures 
specified in the protocol are performed. 
The data acquisition meets all requirements of data protection for 
each individual patient, since all patient-related documentation can 
only be identified by a patient identification number. All personal 
information of the patient is accessible only to the treating 
physician. 
 
 
 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 8 of 75 
 
Study Flow Chart 
Phase 
Screening 
Treatment Phase 
Visits 
V1 
V2 
Baseline 
V3 
V4 
V5  
End of Study 
Early 
Termi-
nation 
Week 
-4 - -1 
0  
4 
12 
20 
Day 
-28 - -1 
0 
28 ± 4  
84 ± 4  
140 ± 7  
In- / exclusion criteria 
x 
x 
- 
- 
- 
- 
Pregnancy test1 
x 
x 
x 
x 
x 
x 
Informed consent 
x 
- 
- 
- 
- 
- 
Demography, 
educational status 
x 
- 
- 
- 
- 
- 
Medical and psoriasis 
history, prior medication 
x 
- 
- 
- 
- 
- 
PsA, comorbidity 
x 
x 
- 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
Nicotine anamnesis 
x 
- 
- 
- 
x 
- 
Physical examination 
incl. weight and height2 
(BMI) 
x 
x 
- 
- 
x 
x 
Vital signs3 
x 
x 
x 
x 
x 
x 
Results of routine blood 
test / urinalysis 
available4 
x 
- 
- 
- 
- 
- 
Investigator assessments 
PASI 
- 
x 
x 
x 
x 
x 
PPPASI 
x5 
x 
x 
x 
x 
x 
PGA 
- 
x 
x 
x 
x 
x 
H&F PGA 
- 
x 
x 
x 
x 
x 
Dynamic H&F PGA 
- 
 
x 
x 
x 
x 
Pustules count 
- 
x 
x 
x 
x 
x 
Patient reported outcomes 
VAS (pruritus / itch 
and discomfort / 
pain) on hands and 
feet 
- 
x 
x 
x 
x 
x 
DLQI 
- 
x 
- 
x 
x 
- 
Photographs6 (optional) 
- 
x 
- 
- 
x 
- 
Serum and plasma  
- 
x 
x 
x 
x 
x 
Biopsies7 (optional sub-
study) 
- 
x 
- 
- 
x 
x 
Documentation for drug 
accountability and 
treatment compliance 
- 
x 
x 
x 
x 
x 
Medication dispensing8 
- 
x 
x 
x 
- 
- 
Return of study 
medication 
- 
- 
x 
x 
x 
x 
AEs / SAEs 
x 
x 
x 
x 
x 
x 
Reason for 
discontinuation 
 
 
 
 
 
x 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 9 of 75 
 
1. 
Urine pregnancy test for female patients of childbearing potential 
2. 
Only at V1: height 
3. 
Sitting blood pressure and pulse rate 
4. 
Within the ranges given in the exclusion criteria not older than 8 weeks prior to screening 
5. 
For inclusion PPPASI must be ≥ 12 
6. 
From both hands and feet (optional) 
7. 
Two lesional biopsies from feet or hands (optional) 
8. 
Including instructions for medication intake 
 
AE / SAE 
Adverse Event / Serious Adverse Event 
BMI 
 
Body Mass Index 
DLQI 
 
Dermatology Life Quality Index 
H&F PGA 
Hand and Feet Physician Global Assessment 
PASI 
 
Psoriasis Area and Severity Index 
PGA 
 
Physician’s Global Assessment 
PPPASI  
Palmoplantar Pustulosis Psoriasis Area and Severity Index 
PsA 
 
Psoriasis Arthritis 
V 
 
Visit 
VAS 
 
Visual Analogue Scale 
 
 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 10 of 75 
 
2 
Table of Contents 
1 
STUDY SYNOPSIS .................................................................................................... 2 
2 
TABLE OF CONTENTS .............................................................................................. 10 
3 
CONTACTS ................................................................................................................ 13 
4 
SIGNATURE PAGE .................................................................................................... 15 
5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................ 17 
6 
INTRODUCTION ........................................................................................................ 21 
6.1 
Background and Rationale ................................................................................ 21 
6.2 
Potential Risks and Benefits .............................................................................. 23 
7 
STUDY OBJECTIVES AND PURPOSE ..................................................................... 24 
7.1 
Primary Objective .............................................................................................. 24 
7.2 
Secondary Objective(s) ..................................................................................... 24 
8 
STUDY DESIGN......................................................................................................... 25 
8.1 
Description of the Study Design ........................................................................ 25 
8.2 
Study Endpoints ................................................................................................ 25 
8.2.1 Primary Endpoint(s) .................................................................................. 25 
8.2.2 Secondary Endpoint(s) ............................................................................. 25 
8.2.3 Exploratory Endpoints .............................................................................. 26 
8.3 
Patient Identification .......................................................................................... 26 
8.4 
Withdrawal of Patients ....................................................................................... 26 
8.5 
Discontinuation of Entire Study .......................................................................... 27 
9 
SELECTION OF PATIENTS ....................................................................................... 29 
9.1 
Inclusion / Exclusion Criteria .............................................................................. 29 
9.1.1 Inclusion Criteria....................................................................................... 29 
9.1.2 Exclusion Criteria ..................................................................................... 30 
10 STUDY MEDICATION ................................................................................................ 32 
10.1 Investigational and Control Drugs ...................................................................... 32 
10.2 Route of Administration, Dosage, Dosage Regimen and Treatment Period ....... 32 
10.3 Packaging and Labelling ................................................................................... 33 
10.4 Storage of Study Medication .............................................................................. 33 
10.5 Study Medication Supply and Re-supply, Accountability Procedures ................. 33 
10.6 Instructions for Supplying and Taking the Study Medication .............................. 34 
10.6.1 Treatment after End of Study ............................................................... 34 
10.7 Permitted Study Medication Dose Adjustments and Interruptions ...................... 34 
10.8 Prior and Concomitant Treatment ...................................................................... 35 
10.8.1 Permitted Treatments ........................................................................... 35 
10.8.2 Prohibited Treatments .......................................................................... 35 
10.9 Procedures for Monitoring Compliance .............................................................. 35 
11 STUDY SCHEDULE ................................................................................................... 37 
11.1 Study Flow Chart ............................................................................................... 37 
11.2 Study Visit Description ....................................................................................... 37 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 11 of 75 
 
11.2.1 Visit 1 - (Screening / Day -28 - -1) ........................................................ 37 
11.2.2 Visit 2 - (Baseline / Day 0) .................................................................... 37 
11.2.3 Visit 3 - (Week 4, Day 28 ±4)................................................................ 38 
11.2.4 Visit 4 - (Week 12, Day 84 ±4) .............................................................. 38 
11.2.5 Visit 5 - (Week 20, Day 140 ±7) ............................................................ 39 
11.2.6 Early Termination Visit ......................................................................... 39 
11.2.7 Unscheduled Visits ............................................................................... 40 
12 ASSESSMENTS......................................................................................................... 41 
12.1 Efficacy Assessments ........................................................................................ 41 
12.1.1 Dermatology Life Quality Index (DLQI) ................................................. 41 
12.1.2 Psoriasis Area and Severity Index (PASI) ............................................ 41 
12.1.3 Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) . 41 
12.1.4 Physician’s Global Assessment (PGA) ................................................. 41 
12.1.5 Dynamic Hand and Feet (H&F) Physician’s Global Assessment .......... 42 
12.1.6 Hand and Feet (H&F) Physician’s Global Assessment ......................... 42 
12.1.7 Pustules Count ..................................................................................... 42 
12.1.8 Visual Analogue Scale (VAS) ............................................................... 42 
12.1.9 Photo Documentation ........................................................................... 42 
12.1.10 Exploratory assessments ................................................................... 43 
12.2 Safety Assessments .......................................................................................... 44 
12.2.1 Adverse Events (AE) ............................................................................ 44 
12.2.2 Pregnancy Test .................................................................................... 44 
12.2.3 Physical Examination and Vital Signs................................................... 44 
12.3 Demographics and Baseline Characteristics ..................................................... 45 
12.3.1 Patient Demography ............................................................................ 45 
12.3.2 Medical History .................................................................................... 45 
12.3.3 Psoriasis History .................................................................................. 45 
12.3.4 Nicotine Anamnesis ............................................................................. 46 
13 ADVERSE EVENT REPORTING ............................................................................... 47 
13.1 Definitions ......................................................................................................... 47 
13.2 Record of Adverse Events ................................................................................. 48 
13.3 Procedures for Reporting Serious Adverse Events ............................................ 49 
13.4 Pregnancy ......................................................................................................... 50 
14 STATISTICS ............................................................................................................... 51 
14.1 Protocol Deviations ........................................................................................... 51 
14.2 Analysis Populations ......................................................................................... 51 
14.3 Demographics and Baseline Characteristics ..................................................... 52 
14.4 Treatments ........................................................................................................ 52 
14.5 Analysis of Primary Endpoint ............................................................................. 52 
14.5.1 Primary Endpoint.................................................................................. 52 
14.5.2 Statistical Methods of Analysis ............................................................. 52 
14.6 Analysis of Secondary Efficacy Endpoints ......................................................... 53 
14.7 Analysis of Secondary Safety Endpoints ........................................................... 53 
14.8 Exploratory Analysis .......................................................................................... 53 
14.9 Handling of Missing Values ............................................................................... 54 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 12 of 75 
 
14.10 Examination of Subgroups................................................................................. 54 
14.11 Sample Size Calculation .................................................................................... 54 
14.12 Interim Analyses ................................................................................................ 54 
14.13 Multiple Comparison / Multiplicity ....................................................................... 54 
15 DATA HANDLING AND RECORD KEEPING ............................................................. 55 
15.1 Data Collection .................................................................................................. 55 
15.2 Source Documentation ...................................................................................... 55 
15.3 Archiving ........................................................................................................... 56 
16 QUALITY CONTROL AND QUALITY ASSURANCE .................................................. 57 
16.1 Personnel Training ............................................................................................ 57 
16.2 Clinical Monitoring ............................................................................................. 57 
16.3 Audits / Inspections ........................................................................................... 58 
17 ETHICS ...................................................................................................................... 59 
17.1 Regulatory and Ethics Compliance .................................................................... 59 
17.2 Informed Consent .............................................................................................. 59 
17.3 Amendments to the Protocol ............................................................................. 60 
17.4 Confidentiality .................................................................................................... 60 
18 FINANCING AND INSURANCE ................................................................................. 61 
18.1 Financing ........................................................................................................... 61 
18.2 Insurance .......................................................................................................... 61 
19 PUBLICATION POLICY .............................................................................................. 62 
20 REFERENCES ........................................................................................................... 64 
21 APPENDICES ............................................................................................................ 67 
21.1 Appendix I - Dermatology Life Quality Index (DLQI) .......................................... 67 
21.2 Appendix II - Psoriasis Area and Severity Index (PASI) ..................................... 69 
21.3 Appendix III: Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI)
 
 
 ................................................................................................................. 70 
21.4 Appendix IV - Physician’s Global Assessment (PGA) ........................................ 72 
21.5 Appendix V - Dynamic Hand and Feet (H&F) PGA ............................................ 73 
21.6 Appendix VI - Hand and Feet (H&F) PGA .......................................................... 74 
21.7 Appendix VII - Visual Analogue Scale (VAS) ..................................................... 75 
 
2.1 
List of Tables 
Table 1: Pharmaceutical information ....................................................................................32 
Table 2: Dosing information ..................................................................................................32 
 


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Clinical Study Protocol 
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Final 3.0, 07. June 2018 
 
 
 
 
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3 
Contacts 
Sponsor 
 
Prof. Dr. Kristian Reich 
TFS Trial Form Support GmbH (formerly 
SCIderm GmbH) 
Drehbahn 1-3 
20354 Hamburg, Germany 
Person(s) authorized to sign the protocol 
Prof. Dr. Kristian Reich 
CRO 
 
TFS Trial Form Support GmbH 
Drehbahn 1-3 
20354 Hamburg, Germany 
 
Monitoring (if other than the sponsor) 
Juliane Kukla 
Tel 
+49 40 55 44 01 113 
Fax 
+49 40 55 44 01 291 
Email juliane.kukla@tfscro.com 
 
Project Management 
Dr. Thomas Bickert 
Tel 
+49 40 55 44 01 182 
Fax 
+49 40 55 44 01 291 
Email thomas.bickert@tfscro.com 
 
Statistics 
Johanna Bewert 
Tel 
+49 40 55 44 01 134 
Fax: 
+49 40 55 44 01 291 
Email johanna.bewert@tfscro.com 
 
Data Management 
Franziska Laaß 
Tel 
+49 40 55 44 01 132 
Fax 
+49 40 55 44 01 291 
Email franziska.laass@tfscro.com 
 
Medical Writing 
Dr. Wiebke Griemberg 
Tel 
+49 40 55 44 01 129 
Fax 
+49 40 55 44 01 291 
Email wiebke.griemberg@tfscro.com 
 
Quality Management 
Tanja Henselmann 
Tel 
+49 40 55 44 01 118 
Fax 
+49 40 55 44 01 291 
Email  tanja.henselmann@tfscro.com 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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Coordinating Investigator 
 
 
Dr. med Dagmar Wilsmann-Theis 
Department for Dermatology and Allergy 
University Bonn 
Sigmund-Freud-Str. 25 
53105 Bonn, Germany 
Tel 
+49 228 287 15370 
Fax 
+49 228 287 11176 
Email  dagmar.wilsmann-theis@ukb.uni-
bonn.de 
Laboratory(ies) or medical / technical 
departments 
 
Serum / plasma immunological marker 
analysis and skin biopsy immunological 
marker analysis sub-study 
Dr. med. Robert Sabat 
Psoriasis Research and Treatment Center 
(PRTC),  
Department of Dermatology and Allergy and 
Institute of Medical Immunology 
Charité - Universitätsmedizin Berlin, 
Charitéplatz 1 
10117 Berlin, Germany 
Tel 
+49 30 4505 18 625 
Fax 
+49 30 4505 18 964 
Email robert.sabat@charite.de 
 
 




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Clinical Study Protocol 
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Final 3.0, 07. June 2018 
 
 
 
 
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Statement(s) of Principal Investigator(s) 
I have thoroughly read this study protocol and have understood the requirements as well as 
the conditions of this clinical study protocol. I agree to following points: 
 
to perform the clinical study according to this protocol and all applicable laws and 
regulations including, but not limited to, the Medicinal Products Act 
(Arzneimittelgesetz AMG) (1), the international Good Clinical Practice guideline 
(ICH E6) (2)and the ethics principles that have their origins in the Declaration of 
Helsinki (3) 
 
to record accurately all required data on the case report forms (CRFs) 
 
to provide direct access to source data / documents (source document 
verification) 
 
to permit study-related monitoring, audits, IRB / IEC review, and regulatory 
inspections 
 
to use the study material only as specified in this protocol 
 
to report within 24 hours any adverse event that is serious, whether considered 
treatment-related or not 
 
to instruct and train all delegates in my institution, who will take over tasks within 
this clinical study 
 
 
 
Principal Investigator: 
 
 
________________________________________ 
Name 
 
 
_________________________________________ 
______________ 
Signature 
Date 
 
 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 17 of 75 
 
5 
List of Abbreviations and Definition of Terms 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT (sGPT) 
Alanine transaminase (serum glutamic-pyruvic transaminase) 
AMG 
Medicinal Products Act (Arzneimittelgesetz) 
AST (sGOT) 
Aspartate 
transaminase 
(serum 
glutamic-oxaloacetic 
transaminase) 
ATC-Code 
Anatomic-Therapeutically-Chemical Code 
BGB 
Bürgerliches Gesetzbuch (civil code of Germany) 
BID 
Bis in die (twice a day) 
BMI 
Body Mass Index 
cAMP 
Cyclic adenosine monophosphate 
CCL2 
Chemokine (C-C motif) ligand 2 
CCR2 
C-C chemokine receptor type 2 
CD11c+ 
CKD-EPI 
Integrin alpha X chain protein-positive 
Chronic Kidney Diseas-Epidemiology Collaboration 
CPMP / CHMP 
Committee for Proprietary Medicinal Products, now CHMP, 
Committee for Medicinal Products for Human Use 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CXCL8 
CXC-Motiv-Chemokin 8 (= IL8) 
CYP3A4 
Cytochrome P450 3A4 
DLQI 
Dermatology Life Quality Index 
EC 
Ethics Committee 
eGFR 
ELISA 
Estimated Glomerular Filtration Rate 
Enzyme Linked Immunosorbent Assay 
FAS 
Full Analysis Set 
FPI 
First Patient In 
GCP 
Good Clinical Practice 
H&F PGA 
Hand and Feet Physician Global Assessment 
HBV 
Hepatitis B Virus 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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ICH 
International Council for Harmonization (formerly the International 
Conference on Harmonization) 
ID 
Identification 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon- γ 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
LPO 
Last Patient Out 
MACE 
Major Adverse Cardiac Events 
MBO 
(Model) Professional Code for Physicians in Germany 
MCP-1 
Monocyte chemoattractant protein-1 (= CCL2) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
Messenger Ribonucleic Acid 
n, N 
Number 
PASI 
Psoriasis Area and Severity Index 
PDE / PDE4 
Phosphodiesterase / Phosphodiesterase 4 
PGA 
Physician Global Assessment 
PP 
Per Protocol (set) 
PPP 
Palmoplantar pustulosis 
PPPASI 
Palmoplantar Pustulosis Psoriasis Area and Severity Index 
PPPASI 50 / 75 
50% / 75% decrease in PPPASI 
PsA 
Psoriasis Arthritis 
PT 
Preferred Term 
PUVA 
Psoralen plus ultraviolet A radiation 
qPCR 
Real-time Polymerase Chain Reaction on reverse transcribed 
mRNA 
RMP 
Risk Management plan 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
sP-selectin 
Soluble P-selectin 
ThX 
T Helper Cell X 


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Clinical Study Protocol 
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Final 3.0, 07. June 2018 
 
 
 
 
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TNF 
Tumor Necrosis Factor 
TEAE 
Treatment emergent AE 
ULN 
Upper limit of normal 
UVB 
Ultraviolet B 
V 
Visit 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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Definitions 
Baseline  
Data collected for all patients at the beginning of a clinical 
study before any study treatment. These data include 
demographics, such as age and gender, and study-specific 
measures. 
Eligible Patient  
Any potential participant who upon entrance into the treatment 
phases of the study meets all of the inclusion criteria and none 
of the exclusion criteria set forth in the protocol and had signed 
a valid Ethics Committee (EC) approved informed consent 
form. 
End of Study / Study 
Completion Date 
Final date on which data is collected (i.e. date of the last visit 
of the last patient). 
Screening  
Evaluation of patients for participation in a clinical study 
according to inclusion and exclusion criteria. 
 
 


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APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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6 Introduction 
Psoriasis in difficult to treat locations includes visible and therefore stigmatizing body regions 
such as the hands, the face and the scalp. Other difficult to treat areas may impact the daily 
life aspects and function such as palms and soles and / or nails. Under normal conditions, 
these locations require particular management and have a significant impact on the health-
related quality of life (physical, functional, emotional impact) (4-6). As this is such an important 
factor for the patients it is often higher ranking than corresponding disease indexes. 
 
6.1 
Background and Rationale 
Palmoplantar pustulosis (PPP) is a rare condition in which erythematous and scaly plaques 
studded with sterile pustules persist on the palms or soles. The disease is chronic and very 
resistant to treatment. It is much more common in those who smoke (or have smoked in the 
past). PPP is a disease of adults and is rare in children. It usually starts in the fifth or sixth 
decade of life, although age of onset can also be earlier. 
In most series, there has been a predominance of women. The disease presents itself with 
one or more well-delineated scaly erythematous plaques. Within this plaque, pustules are 
present, usually 2-5mm in diameter. Fresh pustules are yellow; older ones are yellow-brown 
or dark brown as the pustule dries up. Eventually, the desiccated pustule is exfoliated. Usually, 
pustules in all stages of evolution are seen. Itching is variable, but often serious; often, the 
patients report a 'burning' discomfort in the lesions. On the hands, the thenar eminence is the 
predilection site. On the feet, the instep, the medial or lateral border of the foot at the level of 
the instep, or the sides or back of the heel are frequently involved. A striking symmetry of the 
lesions on the hands or feet is common, but sometimes a solitary lesion may persist for weeks 
or months before other lesions appear. Additionally, patients are often unable to walk or to 
work due to the pain and thus are severely affected in activities of daily life (7). 
Palmoplantar pustulosis is a therapeutically challenging condition that can significantly impact 
patient quality of life (8). It often affects smokers, but quitting smoking does not always help 
clear the disease. Apart from intense topical therapy (with or without occlusion), phototherapy, 
and psoralen plus ultraviolet A (PUVA), oral retinoids (acitretin) have traditionally been the first 
drug of choice. Phototherapy including PUVA therapy has the disadvantage, apart from 
cancerogenicity, that it has to be performed several times per week at an outpatient clinic or a 
private practice of a dermatologist. Acitretin is usually not given to girls and women of 
childbearing potential due to its teratogenic potential that persists for up to three years after 
discontinuation of the drug. Methotrexate or cyclosporine have been described to be effective 
in PPP in some patients as well (9-12). Alternative treatment options for patients with PPP who 
do not respond to conventional antipsoriatic therapies include the use of antimycotics (13) or 
antibiotics (14), which have been described in single case reports and studies. However, oral 
alitretinoin treatment has recently been proven not to be effective (15). 
Several biologics that have been approved for plaque-type psoriasis have been tried in small 
case series or small studies in the treatment of PPP.  
Ustekinumab, a monoclonal antibody targeting Interleukin (IL)-12/23 has been tried in the 
treatment of PPP, but results have been ambiguous. In a case series of four patients, two failed 
to improve (16). Bissonnette et al. (17) were not able to show clinical benefit with licensed 
doses of ustekinumab, while others recently presented a series of five, respectively nine, case 
reports successfully treated with ustekinumab (18;19). 
A small placebo-controlled pilot study (n=15) with etanercept, a fusion protein targeting Tumor 
Necrosis Factor (TNF)-α, at a dose of 50 mg twice weekly, showed a statistically significant 
difference in Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) response 


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Final 3.0, 07. June 2018 
 
 
 
 
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at 24 weeks. At 12 weeks etanercept was numerically, but not statistically significantly better 
than placebo (20). 
Alefacept is approved for plaque-type psoriasis in the United States but not in Europe and has 
been reported to be moderately effective in PPP with reductions in PPPASI of 49,6% after 16 
weeks of treatment (21). 
Despite the impact of PPP on daily activities including the ability to work, few clinical studies 
address treatment, and there is a lack of data and quality-of-life assessment during therapy 
beyond anecdotal case reports and small studies as described above (9;10;13;14;16-
18;20;21).  
Only Acitretin, Dapsone and glucocorticosteroids have the approval for the treatment of 
pustular skin diseases, and no other systemic antipsoriatic treatment has been approved for 
PPP.  
Biologics are approved for plaque-type psoriasis and/or psoriasis arthritis, and they have also 
been described in some investigations to be successful in patients with PPP (17;18;20;21). 
However, there are no published phase III trials of biologics in the indication PPP, and 
treatment of PPP with biologics or traditional antipsoriatic drugs, with the exception of acitretin, 
can only be performed in an off-label setting. 
Moreover, treatment of PPP often does not achieve a lasting good clinical response or may 
have to be discontinued due to side effects. 
Apremilast (Otezla®, marketing authorization holder Celgene Europe Ltd., approved for 
treatment of Psoriasis and Psoriasis Arthritis in Europe), an oral small-molecule inhibitor of 
phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro- and anti-
inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific 
phosphodiesterase (PDE) and the dominant PDE in inflammatory cells. Inhibition of PDE4 
elevates intracellular cAMP levels, which in turn downregulates the inflammatory response by 
modulating the expression of TNF-α, IL-23, and other inflammatory cytokines. Elevation of 
cAMP also increases anti-inflammatory cytokines such as IL-10. These pro- and anti-
inflammatory mediators have been implicated in psoriasis and psoriatic arthritis. Interestingly, 
apremilast has anti-inflammatory effects on a wide variety of cell types. Not only does it exert 
anti-inflammatory effects on T-cells, but also on immune cells of the innate immune system 
including neutrophils and on cells mediating the connection of innate and adaptive immune 
system such as plasmacytoid dendritic cells (22). In line with the importance of PDE4 on the 
regulation of a wide variety of cell types and cytokines, apremilast affects a number of 
cytokines. It can reduce production of both Th1 and Th17 cytokines (23). In addition, it 
influences the cytokines that are considered to be important mediators of the crosstalk between 
innate and adaptive immune functions: TNFα, IL-1 and interferons (22-24). For example, 
apremilast has been shown to increase levels of the anti-inflammatory IL1 receptor antagonist 
alpha in patients with psoriatic arthritis treated with apremilast, while it reduced concentration 
of monocyte chemoattractant protein-1 (MCP-1) (also called chemokine (C-C motif) ligand 2 
(CCL2)) (23). Interestingly, C-C chemokine receptor type 2 (CCR2), a receptor of CCL2 on 
neutrophils, has recently been shown to be crucial in the recruitment of neutrophils into joints 
in rheumatoid arthritis (25).  
This wide spectrum of antiinflammatory actions of apremilast might be important in the therapy 
of PPP. PPP is characterized by a strong inflammation in lesional skin, in which both the innate 
and adaptive immune systems are represented (26). While PPP has great similarities in the 
cytokine profiles compared to plaque-type psoriasis, including overexpression of IL17 and 
TNFα (26;27), neutrophils are more prominent both clinically (pustules) and in histopathology 
in PPP compared to plaque-type psoriasis. 
Apremilast has already proven to be effective in the treatment of plaque-type psoriasis and 
psoriatic arthritis, and in a sub-analysis also in palmoplantar involvement of plaque-psoriasis 


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Clinical Study Protocol 
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Final 3.0, 07. June 2018 
 
 
 
 
Page 23 of 75 
 
(28). Given the wide overlap of clinical, immunological and histological features of PPP and 
plaque-type psoriasis in conjunction with the observation that apremilast also effectively 
targets the innate immune system (e.g. neutrophils) it may be speculated that apremilast can 
successfully be used in the treatment of PPP. 
The planned study is a multicenter, open label, single-arm pilot study intended to gain 
information on safety, clinical efficacy and the mechanistical effects of apremilast on PPP. 
 
6.2 
Potential Risks and Benefits 
According to the ‘summary of the risk management plan (RMP) for Otezla® (apremilast)’ (29), 
by blocking the action of PDE4, apremilast reduces the symptoms of psoriasis and psoriasis 
arthritis. Because of exclusion of patients with moderate / severe kidney disorders, liver 
disorders, children and pregnant or breastfeeding patients from clinical trials, there is no 
information on safety or effectiveness of Otezla® for these patients. However, these patient 
groups will also be excluded for the clinical study presented here. 
Important identified risks include: 
 
weight decrease in patients with Body Mass Index (BMI) <20 kg/m2 
 
depression 
Important potential risks include: 
 
inflammation of blood vessels (vasculitis) 
 
risk of triggering suicide (suicidal thoughts) 
 
tumors (malignancies) 
 
nervousness and anxiety 
 
serious infections 
 
major heart problems (major adverse cardiac events [MACE] and tachyarrhythmia) 
 
effects on the developing child if used during pregnancy 
For more detailed information on these identified and potential risks please refer to the 
‘summary of the risk management plan (RMP) for Otezla® (apremilast)’ (29) and the ‘Rote 
Hand Brief’ (30). 
Otezla® has been approved for the treatment of patients with moderate to severe plaque 
psoriasis and for the treatment of patients with active psoriatic arthritis. Overall, no serious 
safety issues are associated with Otezla® and the benefit-risk profile for Otezla® is acceptable 
and the risks can be mitigated though professional labeling. 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 24 of 75 
 
7 
Study Objectives and Purpose 
7.1 
Primary Objective 
The primary objective of this study is: 
 
To demonstrate a significant improvement of PPPASI at week 20 compared with 
baseline in moderate to severe chronic palmoplantar pustulosis under apremilast 
therapy. 
 
7.2 
Secondary Objective(s) 
The secondary objectives of the study are: 
 
To evaluate an improvement of PPPASI at all assessment times compared with 
baseline in moderate to severe chronic palmoplantar pustulosis under apremilast 
therapy. 
 
To evaluate differences during the treatment with apremilast in life quality assessment 
measures: Dermatology Life Quality Index (DLQI) at all assessment times compared 
with baseline 
 
To evaluate safety of apremilast in patients with moderate to severe palmoplantar 
pustulosis 
 
Exploratory objectives are: 
 
Time course of Hand and Feet Physician Global Assessment (H&F PGA) at all 
assessment times. 
 
Pustules count 50 response and Pustules count 75 response, defined as a 50% and 
75% decrease in Pustules count from baseline, during the 20 weeks treatment period 
 
To evaluate differences in the mean change from baseline at all assessment times of 
VAS pruritus / itch, VAS discomfort / pain at all assessment times relatively to day 0 
(baseline)  
 
To evaluate changes in Psoriasis Area Severity Index (PASI), Physician Global 
Assessment (PGA) and dynamic H&F PGA if plaque psoriasis is present between 
baseline and all assessment times 
 
To explore the effect of apremilast on immunological markers in serum / plasma  
 
To explore the effect of apremilast on immunological markers in skin biopsies (sub-
study, see Section 12.1.10.2) 
 


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Final 3.0, 07. June 2018 
 
 
 
 
Page 25 of 75 
 
8 
Study Design 
This study will be conducted in accordance with applicable laws and regulations including, but 
not limited to, the ICH E6 guideline ‘Note for Good Clinical Practice’ (CPMP/ICH/135/95) (2) 
based on the principles of the Declaration of Helsinki (3). The study will be duly conducted in 
compliance with the Medicinal Products Act (Arzneimittelgesetz AMG), (§§ 40-42) (1). An 
independent ethics committee and the competent authority must review and approve the study 
before any patients are enrolled.  
 
8.1 
Description of the Study Design 
This is a multicenter, open-label, single-arm, phase II, pilot study to evaluate the efficacy and 
safety of apremilast involving approximately 20 patients with PPP. The screening period is up 
to 4 weeks and treatment takes place over 20 weeks per patient. No follow up period takes 
place. No extension is planned. 
Recruitment period is 4 months; hence study duration from FPI to LPO is approx. 9 months. 
4 patients per site are expected to be recruited, assuming enrolment of both genders with 
distribution according to prevalence of condition. If recruitment is not running as anticipated 
after 2 months, recruitment will be opened to become competitive.  
Patient recruitment will take place at approximately 5 sites in Germany. The investigators 
should have relevant expertise in diagnosing and treating PPP or be specialized in 
dermatology. Patients will be enrolled until 20 patients are included into the study. Drop-outs 
will not be replaced. 
Please refer to the Study Flow Chart in the synopsis for the time schedule of the assessments. 
Five visits per patients are planned including: 
Visit 1 at week -4 - -1 (screening) 
Visit 2 at week 0 (baseline) 
Visit 3 at week 4 
Visit 4 at week 12 
Visit 5 at week 20 (end of study) 
After completion of participation in the study, patients are advised to follow medical 
management of their treating physician (see as well Section 10.6.1). 
 
8.2 
Study Endpoints 
8.2.1 Primary Endpoint(s) 
 
Percentage change from baseline in PPPASI after 20 weeks of treatment with 
apremilast 
 
8.2.2 Secondary Endpoint(s) 
 
Absolute and percent change from baseline in PPPASI during the 20 weeks 
treatment period 


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Clinical Study Protocol 
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Final 3.0, 07. June 2018 
 
 
 
 
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 
PPPASI 50 response and PPPASI 75 response, defined as a 50% and 75% 
decrease in PPPASI from baseline, during the 20 weeks treatment period 
 
DLQI bands (0-1 no effect, 2-5 small effect, 6-10 moderate effect, 11-20 very 
large effect, 21-30 extremely large effect) during the 20 weeks treatment period 
 
Absolute and percent change from baseline in DLQI during the 20 weeks 
treatment period 
 
Safety as assessed by treatment-emergent adverse events (TEAEs), vital signs and 
physical examination 
 
8.2.3 Exploratory Endpoints 
 
Absolute and percentage change from baseline in level of immunological markers 
in plasma / serum during the 20 weeks treatment period with apremilast 
 
Percentage change from baseline in level of immunological markers in skin 
biopsy samples after 20 weeks of treatment with apremilast (sub-study) 
 
8.3 
Patient Identification 
Patients will be identified from the investigator’s database. 
Upon enrolment, each patient will receive a 5 digit patient number (XX-XXX) starting with: 
 
2 digits for the site 
 
separated by hyphen 
 
3 digits for the patient (ascending order) 
 
E.g. 01-001 
Within each site, the investigator will allocate the patient numbers in ascending order of 
patients screened and include each screened patient in a screening, enrolment and 
randomization log with site number, a running patient number and year of birth. All patients will 
be identified by the unique patient number in a patient identification log in the investigator site 
file. 
As this study is an open label, single-arm study no randomization will take place. 
Patients who drop out will not be replaced. 
 
8.4 
Withdrawal of Patients 
In accordance with the informed consent and the Declaration of Helsinki (3), any patient can 
refuse to participate or withdraw from the study without giving reasons at any time without any 
penalty or loss of benefits to which the patient is otherwise entitled. When appropriate, patients 
may be placed on other conventional therapy when clinically indicated. 
Patients have to be withdrawn from the study by the investigator if at least one of the following 
events occurs  
 
Withdrawal of informed consent 
 
Pregnancy 


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 
Any study medication discontinuation or dose reduction during the up-titration 
(days 1 to 6) 
 
Study medication discontinuation (i.e. no study medication taken) during the 
maintenance phase irrespective of the reason for more than 5 days in a row or a 
total of 10 days, or dose reduction (i.e. ≤1 tablet per day) during the maintenance 
phase (from day 6 onwards) irrespective of the reason for more than 5 days in a 
row or a total of 10 days 
 
Major protocol violation (e.g. patient requires the use of medication and / or 
treatments not permitted by the study protocol) 
 
Severe treatment emergent adverse events that in the opinion of the investigator 
results in a risk / benefit assessment with negative results 
 
Patients are also to be withdrawn at any time if the investigator concludes that it 
would be in the patient’s best interest for any reason 
 
Depression worsening under treatment 
Patients are to be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, become lost to follow up for any other reason, or if any of the following occur: discovery 
of patient ineligibility; errors in treatment compliance; missed or incorrect assessments. 
Protocol violations do not necessarily lead to the patient’s withdrawal unless they constituted 
a significant risk to the patient’s safety. For patients not completing the entire study, all used 
and unused study drug should be returned by the patients to the defined personnel at the site. 
Patients who prematurely withdraw from the study will be scheduled for an end-of-study visit 
as soon as possible (11.2.6). An end-of-study page will be completed, giving the date and 
primary reason for stopping treatment if provided. Patients prematurely withdrawn from the 
study will not be replaced. Patients who prematurely withdraw from the study for any reason 
at any time are excluded from the continuation of the study and will be treated if indicated as 
for any event still ongoing at the end of a clinical study according to standard practice under 
supervision by an experienced dermatologist or will be referred to a dermatologic practice for 
further treatment according to standard practice. In the case of premature discontinuation due 
to an adverse event (AE), the investigator should ensure that the patient receives a suitable 
therapy appropriate to his / her conditions. 
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show due diligence by documenting in the source documents steps taken to contact the 
patient, e.g., dates of telephone calls, registered letters, etc. 
 
8.5 
Discontinuation of Entire Study 
The study must be terminated prematurely for the following reason(s): 
 
Updated risk / benefit assessment with negative results (sponsors’ and 
coordinating investigators’ assessment) 
 
Study cannot be completed within a reasonable time frame due to slow patient 
recruitment 
 
The regulatory authorities and the Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) must be notified of premature termination of the study. The investigator may 


Confidential 
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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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be informed of additional procedures to be followed in order to assure that adequate 
consideration is given to the protection of the patient’s interests. 
In addition, a site may be discontinued at any time by the sponsor and all study materials 
removed. Possible reasons for termination of the study at the site include, but are not limited 
to: 
 
Safety concerns based on reported data 
 
Unsatisfactory enrolment with respect to quantity or quality 
 
Inaccurate or incomplete data collection 
 
Falsification of records 
 
Failure to adhere to the protocol 
 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 29 of 75 
 
9 
Selection of Patients 
9.1 
Inclusion / Exclusion Criteria 
The investigator must ensure that all patients who meet the following inclusion and exclusion 
criteria are offered enrolment in the study. Patients will be enrolled if all inclusion and none of 
the exclusion criteria are met. All patients screened to participate in the study will be 
documented and the reason for study exclusion will be documented to avoid enrolment bias.  
 
9.1.1 Inclusion Criteria 
 
Male and female patients aged 18 years or more at screening visit. 
 
Patients with chronic PPP (disease history of at least 6 months of diagnosis), who 
are eligible for treatment with systemic therapy defined as having PPP 
inadequately controlled by topical treatment and / or phototherapy and / or 
previous systemic therapy 
 
Patients with chronic moderate to severe PPP defined as patients with a PPPASI 
≥ 12 with or without concomitant plaque-type psoriasis 
 
Negative result of a urine pregnancy test taken at screening and at baseline for 
all women, except those who are surgically sterile or at least 1 year 
postmenopausal (i.e. at least 12 consecutive months with amenorrhea without 
other known or suspected medical cause) 
 
Willingness and capability of using a highly effective contraceptive measures 
from Screening visit until the end of at least one menstrual cycle (but not less 
than 28 days) following discontinuation of apremilast as defined below: 
o Female patient of childbearing potential (fertile, following menarche and 
until becoming post-menopausal unless permanently sterile) using a 
highly effective method of contraception OR female patients of non-
childbearing potential (surgically sterilized [e.g. hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy] or post-menopausal) 
o Male patient, and their female partner of childbearing potential, using a 
highly effective method of contraception  
o Adequate contraceptive method defined as: 
 
A method with less than 1% failure rate (e.g. permanent 
sterilization, hormone implants, hormone injections, some 
intrauterine devices, or vasectomized partner)  
OR 
 
The use of two methods of contraception (e.g. one barrier method 
[condom, diaphragm or cervical/vault caps] with spermicide and 
one hormonal contraceptive [e.g. combined oral contraceptives, 
patch, vaginal ring, injectables and implants]) 
 
Patient is capable of understanding and giving written, voluntary informed 
consent before study screening. 
 
Willingness and capability of complying with all study procedure requirements, as per 
the Investigator’s judgment (e.g. patient able to swallow the apremilast tablets, blood 
sampling). 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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9.1.2 Exclusion Criteria 
General 
 
Pregnant or breast-feeding women. 
 
Current or history of psychiatric disease that would interfere with the ability to comply 
with the study protocol or give informed consent. 
 
Patients known to have had a substance abuse (drug or alcohol) problem within 
the previous 12 month 
 
Individuals who are involved in the organization of the study 
 
Patients who are in any way dependent on the investigator 
 
Patients who are participating in a clinical study 
 
Relatives, partner or staff of any clinical site personnel 
Disease-related 
 
Evidence of skin conditions (e.g. eczema) other than PPP / psoriasis that would 
interfere with evaluations of the effect of study medication on PPP or psoriasis. 
 
Laboratory values from routine blood test taken within the 8 weeks prior to 
screening with any of the following: 
o Serum creatinine >1.4 x upper limit of normal (ULN) for age and gender 
o Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m2 according 
to the CKD-EPI equation  
 
Pustular psoriasis lesions on the part of body other than hands or feet 
 
Significant concurrent medical conditions at the time of screening, including: 
o Risk factors for renal toxicity (renal inflammation) 
o Severe hepatic dysfunction 
o Unstable angina pectoris 
o Uncompensated congestive heart failure 
o Severe pulmonary disease requiring hospitalization or supplemental oxygen 
therapy 
o Immunodeficiency disorders: primary or secondary 
o Known positive HIV test result, hepatitis B surface (HBS) antigen or hepatitis 
C (HCV) test result  
o Uncontrolled Insulin-dependent diabetes mellitus 
o Cancer or history of cancer (except for resected cutaneous basal cell or 
squamous cell carcinoma) in the last 5 years 
o Open cutaneous ulcers 
 
Any condition that, in the judgment of the investigator, might cause this study to be 
detrimental to the patient. 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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Medication-related 
 
Ultraviolet B (UVB) therapy, topical steroids, topical calcineurin inhibitors, topical 
Vitamin A or D analog preparations, or anthralin within 14 days of baseline 
Exceptions: low potency topical corticosteroids (class I and II, according to European 
classification for potency of topical corticosteroids) will be allowed as therapy for the 
face, groin, axillae in accordance with the manufacturer’s suggested usage dose 
 
Psoralen plus ultraviolet A radiation (PUVA), ciclosporin, acitretin, alitretinoin, alefacept 
(Amevive®), anakinra (Kineret®), systemic corticosteroids, methotrexate, fumaric acids 
or any other systemic anti-psoriasis therapy within 28 days of baseline 
 
Prior (within the last 2 years) or concomitant use of antipsoriatic biologic therapy with 
TNF-alpha blocker and / or ustekinumab and / or ixekizumab and / or secukinumab 
and / or brodalumab and / or guselkumab 
 
Concomitant use of strong cytochrome P450 3A4 (CYP3A4) enzyme inductors (e.g. 
rifampicin, phenobarbital, carbamazepin, phenytoin and St. John`s wort) 
 
Use of an investigational drug within 4 weeks prior to baseline or 5 pharmacokinetic / 
pharmacodynamics half-lives (whichever is longer) 
 
Prior treatment with apremilast / Otezla® 
 
Receipt of any live (attenuated) vaccine within 28 days prior to baseline  
 
Concomitant use of any other PDE4 inhibitor 
 
Patients with are hereditary problems of galactose intolerance, lapp lactase deficiency 
or glucose-galactose malabsorption 
 
For patients with skin biopsy samples taken: patients with clinically relevant 
coagulation disorders or medication or known hypersensitivity against local 
anesthetics 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 32 of 75 
 
10 
Study Medication 
10.1 Investigational and Control Drugs 
The investigational product apremilast is manufactured, packaged and supplied by Celgene 
Europe Ltd. Table 1 gives an overview of the pharmaceutical information. For labelling refer to 
Section 10.3. 
Table 1: Pharmaceutical information 
Formulation 
 
Appearance 
The Otezla 10 mg film-coated tablet is a pink, diamond 
shaped film-coated tablet with “APR” engraved on one side 
and “10” on the opposite side. 
The Otezla 20 mg film-coated tablet is a brown, diamond 
shaped film-coated tablet with “APR” engraved on one side 
and “20” on the opposite side. 
The Otezla 30 mg film-coated tablet is a beige, diamond 
shaped film-coated tablet with “APR” engraved on one side 
and “30” on the opposite side. 
Active ingredient / 
concentration 
apremilast 10 / 20 / 30 mg 
Additional ingredients 
tablet core: 
microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, magnesium stearate 
film-coating: 
polyvinyl alcohol, titanium dioxide (E171), macrogol, talc, 
iron oxide red (E172) 
20 mg film-coated tablet also contains iron oxide yellow 
(E172), 30 mg film-coated tablet also contains iron oxide 
yellow (E172) and iron oxide black (E172) 
 
10.2 
Route of Administration, Dosage, Dosage Regimen and 
Treatment Period 
Apremilast will be taken orally twice daily (except day 1). Patients will receive tablets in a 
blister/bottles sufficient for one month. To mitigate potential gastrointestinal side effects 
(primarily mild-to-moderate nausea and diarrhea), dose titration will be implemented in this 
study in accordance with the treatment guideline for Psoriasis and Psoriasis Arthritis given in 
the SmPC (31). A titration pack will include tablets of 10, 20 and 30 mg for a period of one 
month. During the first 1 to 5 days, the dosage will be up-titrated (Table 2). From day 6 
onwards, patients will receive the 30 mg BID dose. Subsequent packs include only tablets of 
30 mg strength. 
Table 2: Dosing information 
Day 
Morning Dose 
Evening Dose 
Total Daily Dose 
1 
10 mg (pink) 
- 
10 mg 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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Day 
Morning Dose 
Evening Dose 
Total Daily Dose 
2 
10 mg (pink) 
10 mg (pink) 
20 mg 
3 
10 mg (pink) 
20 mg (brown) 
30 mg 
4 
20 mg (brown) 
20 mg (brown) 
40 mg 
5 
20 mg (brown) 
30 mg (beige) 
50 mg 
6 onwards 
30 mg (beige) 
30 mg (beige) 
60 mg 
 
10.3 Packaging and Labelling 
Medication labels will comply with the legal requirements (Directive 2003/15/EC Art. 15, AMG 
§ 10 section 10 and GCP-V § 5). 
 
10.4 Storage of Study Medication 
Until dispensed to the patients, study medication will be stored in a securely locked area, 
accessible to authorized personnel only. 
Apremilast should not be stored above 30°C; under this condition, it is stable for 21 months. 
 
10.5 Study Medication Supply and Re-supply, Accountability
 
Procedures 
The study sites will be supplied by the sponsor or its designee with sufficient study medication. 
Study medication must be received by a designated person at the investigation site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designated personnel has access. 
All study drug sent to the investigator will be accounted for and in no case used in any 
unauthorized situation. They are to be dispensed only in accordance with the protocol. 
Upon receipt, all study medication should be stored according to the instructions specified on 
the drug labels (section 10.3). Trained study personnel at each site will be responsible for 
dispensing / taking back the study medication to / from the patient. Each patient will receive 
sufficient study medication at the study visit indicated in the flow chart (see also Section 10.6). 
Used (empty), partially-used and unused study medication must be returned to the 
investigation site at the end of the study (visit 5 or early termination) at the latest. Study 
medication will not be provided once patients have completed or discontinued the study. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
medication in a drug accountability form. All medication will be counted before dispensing and 
after returning. The site monitor will perform monitoring of drug accountability during site visits 
and at the completion of the study before database lock. At the conclusion of the study and as 
appropriate during the course of the study, the site monitor will collect or the investigator will 
return all used and unused study medication, packaging, drug labels, and a copy of the 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 34 of 75 
 
completed drug accountability form to the sponsor or its designee provided in the investigator 
site folder at each site. The returned study medication will be destroyed. 
 
10.6 Instructions for Supplying and Taking the Study Medication 
At visit 2, patients will receive a starter pack containing tablets of 10, 20 and 30 mg strength.  
During the first 1 to 5 days, the dosage will be up-titrated according to Table 2. From day 6 
onwards, patients will receive the 30 mg BID dose. Study medication shall be taken as 
described in section 10.2 (i.e. according to SmPC(31)). 
As applicable, bottles with tablets of 30 mg strength will be handed out at visits to cover the 
study period between visits. 
At visits 3, 4 and 5 patients are requested to bring back their used medication (empty and filled 
blisters/bottles) to site for checking the drug accountability. 
At each visit (except screening and V5 / End of study) the patient will be reminded how to take 
the study medication. 
 
10.6.1 Treatment after End of Study 
After the end of study participation the investigator will ensure that the patient receives a 
suitable therapy appropriate to patient’s condition (see as well Section 8.1). 
 
10.7 
Permitted 
Study 
Medication 
Dose 
Adjustments 
and 
Interruptions 
For patients who are unable to tolerate the protocol-specified dosing scheme, the following 
interruptions and / or dose adjustments are permitted: 
At the discretion of the investigator treatment may be interrupted during the maintenance 
phase for a maximum of 5 days in a row or a total of 10 days (see also Section 8.4). In addition, 
a reduction of the dose from day 6 onwards (only during the maintenance phase) is allowed: 
the dose may be reduced to one tablet (30 mg) per day for a maximum of 5 days in a row or a 
total of 10 days. All interruptions and adjustments of study treatment must be recorded in the 
Case Report Form (CRF). 
Patients who experience any uncomfortable event should contact the investigator to assess 
the need for safety assessments (AEs and SAEs). In case of any AE a discontinuation may be 
decided by the principal investigator.  
AEs and SAEs will be recorded in the corresponding AE page of the CRF. In case of a SAE, 
a SAE form is to be completed (see also Section 13.3). If the patient does not prematurely 
discontinue the study, the next regular scheduled visit should be performed as planned. If the 
patient does prematurely discontinue the study at a visit on site, this visit should be considered 
as the end-of-study visit. 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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10.8 Prior and Concomitant Treatment 
All prior (taken within 3 month before study start) and concomitant therapies (drugs, such as 
prescription, over-the-counter, birth control pills etc., and non-drug therapies) will be recorded 
in the CRF. Other key medications and therapies, including previous treatment for tuberculosis 
or relevant diseases, should be recorded. 
All medications and therapies for psoriasis, including systemic and topical medications (topical 
only those taken within the last three months, see Section 12.3.3) and all medications for 
psoriatic arthritis should also be recorded, including the stop dates for medications and 
therapies prohibited in the study. Responses to prior psoriasis therapies should be recorded. 
 
10.8.1 Permitted Treatments 
Concomitant medication (except those listed under exclusion criteria, Section 9.1.2) required 
for the treatment of concomitant diseases and not known to interfere with the study drug or to 
mask the effect of the study drug, is unrestricted and may be continued during the study. 
Low potency topical corticosteroids (class I and II, according to European classification for 
potency of topical corticosteroids) will be allowed as background therapy for the treatment of 
the face, axillae, and groin in accordance with the manufacturer’s suggested usage during the 
course of the study except for lesions selected for clinical evaluations. 
An unmedicated skin moisturizer (without urea) is permitted for body lesions only. Patients 
should not use the unmedicated skin moisturizer within 12 hours prior to the clinic visit on 
lesions selected for clinical evaluations.  
After consultation with Investigators, the Sponsor will provide a list of concomitant medication 
for background therapy (low potency topical corticosteroids or unmedicated skin moisturizers) 
in a separate document. Due to the wide availability of moisturizing products, this list will be 
periodically updated based on feedback during the study from Investigators.  
 
10.8.2 Prohibited Treatments 
For prohibited prior and concomitant treatments please refer to the medication-related 
exclusion criteria (Section 9.1.2). 
 
10.9 Procedures for Monitoring Compliance 
The investigator should promote compliance by instructing the patient to apply the study drug 
exactly as prescribed and by emphasizing that compliance is necessary for the patient’s safety 
and the validity of the study. The patient will be instructed how to apply the medication and to 
contact the investigator if he is unable for any reason to apply the study drug as prescribed. 
The study medication will be dispensed as indicated in the flow chart. Patients will be instructed 
to return all used and unused medication containers during and at the end of the study. 
Documentation also includes: medication not returned because it was taken / used and 
medication not returned because of other reasons (e.g. medication lost). Compliance with the 
treatment assignments will be controlled by the investigator and the study site personnel at 
every visit. Patients will be questioned regarding irregularities in terms of application since the 
last visit (e.g. missing doses, overdoses, failures in the application technique, frequency of 
application). Any kinds of irregularities are documented in the CRF. All CRFs are monitored by 
a site monitor for compliance with the protocol. 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 36 of 75 
 
Celgene will inform the sponsor on any annual IB or SmPC update becoming available and 
will supply the sponsor with the document for distribution to the respective study PIs/ 
Investigators 
 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 37 of 75 
 
11 
Study Schedule 
11.1 Study Flow Chart 
Please refer to Study Flow Chart in the synopsis. The flow chart lists all of the assessments and 
indicates with an ‘X’ the visits at which they will be performed. 
 
11.2 Study Visit Description 
11.2.1 Visit 1 - (Screening / Day -28 - -1) 
 
The investigator informs the patient about the study and obtains the informed consent 
form (ICF). The form must be dated and signed by both the patient and the investigator. 
One signed original will be provided to the patient. 
 
After informed consent form is signed a patient identification number will be assigned 
to the patient. 
 
Inclusion and exclusion criteria for entry into the study will be verified 
 
PPPASI will be assessed (must be ≥ 12 for inclusion). 
 
A urine pregnancy test (β-hCG) will be performed in females with childbearing potential. 
 
Demography and educational status will be documented. 
 
Medical and psoriasis history and prior medication will be documented. 
 
Psoriasis Arthritis (PsA, present Yes / No) and comorbidity will be documented. 
 
Concomitant medication will be documented. 
 
The patient will be interviewed concerning the occurrence of SAEs. 
 
Nicotine anamnesis will be documented. 
 
Physical examination including weight and height (BMI) and vital signs will be 
assessed. 
 
Routine blood test / urinalysis must be available within the ranges given in the exclusion 
criteria not older than 8 weeks prior to screening. 
 
A return appointment for the baseline visit will be scheduled (maximum 28 days after 
screening). 
 
11.2.2 Visit 2 - (Baseline / Day 0) 
 
Inclusion and exclusion criteria for entry into the study will be verified. 
 
A urine pregnancy test (β-hCG) will be performed in females with childbearing potential. 
 
Physical examination including weight and vital signs will be assessed. 
 
PsA and comorbidity will be documented. 
 
Concomitant medication will be documented. 
 
The patient will be interviewed concerning the occurrence of SAEs. 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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 
Serum and plasma samples will be taken. 
 
The investigator will 
o ask the patient to rate their pruritus and pain on hands and feet using the VAS 
and to fill in the DLQI questionnaire. 
o assess the PASI, PPPASI, PGA, H&F PGA and pustules count. 
 
The study medication will be dispensed and patients instructed how to take the study 
medication. 
 
The patient will be instructed to return all study medication to the next visit. 
 
Photographs will be taken (optional). 
 
Biopsies will be taken (two lesional biopsies from feet or hands). The taking of biopsies 
is optional. 
 
A return appointment for the next visit will be scheduled. 
 
11.2.3 Visit 3 - (Week 4, Day 28 ±4) 
 
A urine pregnancy test (β-hCG) will be performed in females with childbearing potential. 
 
Vital signs will be assessed. 
 
Concomitant medication will be documented. 
 
The patient will be interviewed concerning the occurrence of AEs. 
 
Serum and plasma samples will be taken. 
 
The investigator will 
o ask the patient to rate their pruritus and pain on hands and feet using the VAS. 
o assess the PASI, PPPASI, PGA, H&F PGA, dynamic H&F PGA and pustules 
count. 
 
Study medication will be collected for drug accountability and documentation for 
treatment compliance. Further study medication will be dispensed. The patient will be 
reminded and re-instructed on when and how to take the study medication. 
 
The patient will be instructed to return all study medication to the next visit. 
 
A return appointment for the next visit will be scheduled. 
 
11.2.4 Visit 4 - (Week 12, Day 84 ±4) 
 
A urine pregnancy test (β-hCG) will be performed in females with childbearing potential. 
 
Vital signs will be assessed. 
 
PsA and comorbiditiy will be documented. 
 
Concomitant medication will be documented. 
 
The patient will be interviewed concerning the occurrence of AEs. 
 
Serum and plasma samples will be taken. 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 39 of 75 
 
 
The investigator will 
o ask the patient to rate their pruritus and pain on hands and feet using the VAS 
and to fill in the DLQI questionnaire. 
o assess the PASI, PPPASI, PGA, H&F PGA, dynamic H&F PGA and pustules 
count. 
 
Study medication will be collected for drug accountability and documentation for 
treatment compliance. Further study medication will be dispensed. The patient will be 
reminded and re-instructed on when and how to take the study medication. 
 
The patient will be instructed to return all study medication to the next visit. 
 
A return appointment for the next visit will be scheduled. 
 
11.2.5 Visit 5 - (Week 20, Day 140 ±7) 
 
A urine pregnancy test (β-hCG) will be performed in females with childbearing potential. 
 
Nicotine anamnesis will be documented. 
 
Physical examination including weight and vital signs will be assessed. 
 
PsA and comorbidity will be documented. 
 
Concomitant medication will be documented. 
 
The patient will be interviewed concerning the occurrence of AEs. 
 
Serum and plasma samples will be taken. 
 
The investigator will 
o ask the patient to rate their pruritus and pain on hands and feet using the VAS 
and to fill in the DLQI questionnaire. 
o assess the PASI, PPPASI, PGA, H&F PGA, dynamic H&F PGA and pustules 
count. 
 
Study medication will be collected for drug accountability and documentation for 
treatment compliance. 
 
Photographs will be taken (optional). 
 
Biopsies will be taken (two lesional biopsies from feet or hands). The taking of biopsies 
is optional. 
 
11.2.6 Early Termination Visit 
In case of early termination of a patient, effort will be made to schedule an early termination 
visit and assess the following, if possible: 
 
The reason for discontinuation will be documented. 
 
A urine pregnancy test (β-hCG) will be performed in females with childbearing potential. 
 
Physical examination including weight and vital signs will be assessed. 
 
PsA and comorbidity will be documented. 
 
Concomitant medication will be documented. 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 40 of 75 
 
 
The patient will be interviewed concerning the occurrence of AEs. 
 
Serum and plasma samples will be taken. 
 
Biopsies will be taken (two lesional biopsies from feet or hands). The taking of biopsies 
is optional. 
 
The investigator will 
o ask the patient to rate their pruritus and pain on hands and feet using the VAS. 
o assess the PASI, PPPASI, PGA, H&F PGA, dynamic H&F PGA and pustules 
count. 
 
Study medication will be collected for drug accountability and documentation for 
treatment compliance. 
 
11.2.7 Unscheduled Visits 
Due to clinically significant reasons additional visits can be required. Parameters examined at 
these visits should be documented in a similar way as with all other visits (e.g. patent file and 
CRF). 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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12 
Assessments 
Every effort should be made to ensure that the investigator who performs the assessments for 
a patient at screening should also perform the assessments for the patient at all subsequent 
visits. For timing of the assessments please refer to the flow chart in the synopsis or study visit 
description (11.2). 
 
12.1 Efficacy Assessments 
12.1.1 Dermatology Life Quality Index (DLQI) 
The DLQI is a dermatology-specific quality of life instrument designed to assess the impact of 
a disease on the patient’s daily life (32). It is a 10-item questionnaire and can be used to assess 
6 different aspects: symptoms and feelings, leisure, daily activities, work or school 
performance, personal relationship and treatment. The DLQI is calculated by summing the 
score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, 
the more quality of life was impaired. The DLQI could also be expressed as a percentage of 
the maximum possible score of 30. 
For further details see Appendix 21.1. 
 
12.1.2 Psoriasis Area and Severity Index (PASI) 
The PASI is a measure of psoriatic disease severity taking into account qualitative lesion 
characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement 
on defined anatomical regions. The PASI is a validated instrument that has become standard 
in clinical trials for psoriasis. 
PASI scores range from 0 to 72, with higher scores reflecting greater disease severity (33). 
Erythema, 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. These values for each anatomic region are summed to yield the PASI score. 
For more details refer to Appendix 21.2. 
 
12.1.3 Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) 
The PPPASI will assess palms of hands and soles of feet for psoriasis involvement. 
For more details refer to Appendix 21.3. 
 
12.1.4 Physician’s Global Assessment (PGA) 
The PGA describes the severity of psoriasis using 5 categories. 
For more details refer to Appendix 21.4. 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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12.1.5 Dynamic Hand and Feet (H&F) Physician’s Global Assessment 
The dynamic H&F PGA describes the global improvement compared with baseline. It relies on 
the physician’s memory of the baseline severity to evaluate the level of alteration. 
For more details refer to Appendix 21.5. 
 
12.1.6 Hand and Feet (H&F) Physician’s Global Assessment 
The H&F PGA describes the severity of psoriasis on the hands and / or feet using 5 categories. 
For more details refer to Appendix 21.6. 
 
12.1.7 Pustules Count 
A pustule count of both hands and feet to assess the response with regard to pustular lesions 
will be performed (total pustules count). 
To be included in the count, pustules must be macroscopically visible, white / yellow/brown in 
color, with or without crust, and present on the glabrous skin of the palms and / or soles. 
 
12.1.8 Visual Analogue Scale (VAS) 
A VAS is used to assess pruritus (itch) and discomfort / pain on hands and feet. 
The patient will be asked to place a vertical stroke on a 100 mm VAS on which the left-hand 
boundary represents either no pruritus (itch) or discomfort / pain, and the right-hand boundary 
represents either pruritus (itch) or discomfort / pain as severe as can be imagined. The distance 
from the mark to the left-hand boundary will be recorded. 
For more details refer to Appendix 21.7. 
 
12.1.9 Photo Documentation 
Optional, high-quality, color, digital photographs of the hands (dorsum and palm) and / or feet 
will be obtained at baseline (visit 2) and at the end of the study at visit 5 (week 20) have given 
their consent for taking photographs before study start. Photographs will not be formally 
standardized and therefore will not be used to evaluate efficacy and are intended for visual 
comparison only. 
Photographs will be taken with any suitable device. An exemplary photograph will be provided 
at the beginning of the study for guidance of the right field of view. The photographs will be 
identified with:  
 
Study Number (069-008) 
 
Patient’s Identification number 
 
Date (YYYYMMDD) 
 
Visit number (VX); 
 
View (left / right hand (dorsum / palm), left / right foot)); 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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 
Example: 069-008_XX-XXX_20170413_V2_left hand palm. 
As appropriate, pictures must be modified to retain the patient’s anonymity. Pictures will be 
provided on a memory stick or CD-ROM to the sponsor. 
12.1.10 
Exploratory assessments 
Samples will be shipped to the Psoriasis Research and Treatment Center (PRTC, Department 
of Dermatology and Allergy and Institute of Medical Immunology, Charité - Universitätsmedizin 
Berlin, Charitéplatz 1, D-10117 Berlin, Germany). The person responsible will be Dr. Robert 
Sabat in consultation with the sponsor. Instructions for the preparation and shipping will be 
provided separately. This exploratory analysis will be performed by the PRTC or companies / 
scientific group working with PRTC.  
These samples may be banked for future use (e.g. validation of markers identified in future 
studies) that will enable further research on the described analyses once new scientific 
knowledge is generated. Thus, the samples will be retained for no longer than 10 years after 
study completion.  
The results of the exploratory assessments are not applicable for clinical decision-making or 
patient management; therefore the investigators will not be informed of individual results. 
Aggregate data will be used in scientific publications or presented at medical conventions. 
Exploratory research / validation studies data will be published or presented only in a way that 
does not identify any individual patient.  
 
12.1.10.1 
Serum / plasma immunological marker analysis 
Serum / plasma samples will be collected to explore the effect of apremilast on levels of 
immunological markers and/or PPP-specific alterations. The analyses of markers in blood may 
include, but are not be limited to, the quantification by enzyme-linked immunosorbent assays 
(ELISA) of concentrations of markers in serum or plasma such as (i) IL-22, (ii) β-defensin 2, 
and / or (iii) sP-selectin.  
For these analyses samples (27 ml per time point: 9 ml serum tubes, 9 ml EDTA tubes, 9 ml 
Lithium-Heparin tubes) will be taken at the following time points: baseline (before treatment) 
and after 4, 12 and 20 weeks of treatment. 
 
12.1.10.2 
Skin biopsy immunological marker sub-study 
Skin biopsy samples will be collected in an optional (voluntary) exploratory sub-study to explore 
the effect of apremilast on levels of immunological markers in skin and/or PPP-specific 
alterations (separate Informed Consent Form will need to be completed by consenting 
patients). Details on this sub-study, which will be performed separately from the main study by 
Dr. Sabat (PRTC) and colleagues, will be outlined in a separate document and will not be 
included in the Clinical Study Report.  
Skin markers 
The analyses of skin markers may include, but are not be limited to, (i) total transcriptome 
analysis, (ii) specific messenger ribonucleic acid (mRNA) quantification, and / or (iii) 
immunohistochemistry. 
 
 
 
 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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Total transcriptome analysis 
mRNA expression of lesional skin will be analyzed by total mRNA sequencing. Respective skin 
biopsy samples (2 lesional 4 mm biopsies) will be taken at baseline (before treatment) and 
after 20 weeks of treatment.  
 
Specific mRNA quantification 
The mRNA expression of markers, such as e.g. IL-23 p19, IL-17A, CXCL (CXC Motif 
Chemokine) 8, β-defensin 2, will be individually quantified by real-time polymerase chain 
reaction on reverse transcribed mRNA (qPCR) lesional skin. 
Samples will be taken at the following time points: baseline (before treatment) and after 20 
weeks of treatment. 
 
Immunohistochemistry 
The number of immune cells, such as T cells will be quantified by immunohistochemistry of 
lesional skin. 
Samples will be taken at the following time points: baseline (before treatment) and after 20 
weeks of treatment.  
 
12.2 Safety Assessments 
12.2.1 Adverse Events (AE) 
The investigator will assess and record any AEs (for definition, see Section 13.1) starting from 
baseline in detail including the date of onset, intensity, relationship of the AE to study drug, 
action(s) taken, seriousness, time course, duration and outcome. All AEs with onset from visit 
2 are to be reported on the AE page of the CRF with complete information as required (see 
Section 13.2). If AEs occur, the main concern will be the safety of the study patients. At time 
of the informed consent signature, each patient must be given the name and phone number of 
investigation site personnel for reporting AEs and medical emergencies. 
 
12.2.2 Pregnancy Test 
A urine pregnancy test will be performed for female patients of childbearing potential at the site 
at all visits. 
 
12.2.3 Physical Examination and Vital Signs 
The physical examination will include the determination of height and weight. 
If indicated based on the symptoms or medical history, additional exams will be performed at 
the discretion of the investigator.  
Information for all physical examinations must be included in the source documentation. 
Significant findings that are present prior to enrolment must be included in the medical history 
on the CRF. Serious findings made after ICF signature which meet the definition of an SAE 
must be recorded as SAE. 
Evaluation of vital signs will be performed after 10 minutes resting. Assessments should be 
performed by the same person throughout the study. 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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Pulse rate and blood pressure will be measured on the same arm on each occasion with the 
patient sitting. These data will be recorded in the CRF.  
Blood pressure (systolic / diastolic) will be measured with a mercury manometer or an 
automated device (same type of device for all measurements). Normal blood pressure will be 
defined as a systolic pressure of 90 - 120 mmHg and diastolic pressure of 60 - 80 mmHg. 
Notable blood pressure will be hypertension (systolic pressure >140 mmHg and / or diastolic 
pressure >90 mmHg) or hypotension (systolic pressure <90 mmHg and / or diastolic pressure 
<60 mmHg). A blood pressure indicative of prehypertension (systolic pressure 120 - 
140 mmHg and / or diastolic pressure 80 - 90 mmHg) will not be regarded as notable according 
to the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, 
and Treatment of High Blood Pressure (34). 
A normal pulse rate will be defined as a rate of 60 - 100 beats per minute. Notable pulse rates 
are a rate above 100 bpm (tachycardia) and under 60 bpm (brachycardia). 
Whether action needs to be taken to address notable vital signs will be decided by the 
investigator, taking into account the overall status of the patient. No specific action is foreseen 
as part of the study protocol. 
 
12.3 Demographics and Baseline Characteristics 
Demographics and Baseline Characteristics consist of those parameters that are assessed 
only at screening / baseline. 
 
12.3.1 Patient Demography 
Patient demography consists of: 
 
Age at screening 
 
Height 
 
Weight 
 
Race 
 
Sex 
 
Educational status 
 
12.3.2 Medical History 
The medical history will be obtained by asking the patient or by inspecting his / her medical 
records.  
Any previous diseases within the last 3 months before screening and any concomitant 
diseases will be documented in the CRF. 
 
12.3.3 Psoriasis History 
For the documentation of the psoriasis history, the patient will be asked or his / her medical 
records will be inspected for: 


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Clinical Study Protocol 
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Final 3.0, 07. June 2018 
 
 
 
 
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 
Age at first diagnosis of psoriasis 
 
Prior psoriasis therapies 
Any previous and concomitant topical therapies within the last 3 months before 
screening will be documented in the CRF. Any systemic psoriasis therapy and 
phototherapy will be documented in the CRF. 
 
Reason(s) for therapy discontinuation or change 
 
Psoriasis arthritis (yes / no; verified diagnosis (i.e. diagnosed by a rheumatologist) 
 
Involvement of nails (yes / no) 
 
Involvement of scalp (yes / no) 
 
12.3.4 Nicotine Anamnesis 
 
Current smoker, past smoker, non-smoker 
 
For current and past smoker:  
Cigarettes per day 
Years being a smoker (Start date, end date in case of previous smoker) 
Pack per year (cigarettes per day x years being a smoker / 20) 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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13 
Adverse Event Reporting 
13.1 Definitions 
Adverse Event (AE): 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
 
Adverse Drug Reaction (ADR): 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. 
 
Unexpected Adverse Drug Reaction: 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., the IB for Otezla®). 
 
Serious adverse event (SAE): 
A SAE is any AE that: 
 
results in death 
 
is life-threatening (the term ‘life-threatening’ refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it was more severe.) 
 
requires in-patient hospitalization or prolongation of existing hospitalization, 
except of: 
- 
An overnight stay in the hospital that is only due to transportation, organization, or 
accommodation problems and without medical background does not need to be 
handled/ documented as a SAE. 
- 
Hospitalization, that was planned before inclusion of the patient in the study for 
elective operations or treatments does not need to be handled/ documented as a 
SAE. 
 
 
results in persistent or significant disability / incapacity (i.e., a substantial 
disruption in a patient’s ability to conduct normal activities of daily living) 
 
is a congenital anomaly / birth defect 
 
is an important medical event that, while it may not result in death or be 
immediately life-threatening or requires / prolongs hospitalization, may jeopardize 
the patient and / or may require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or the development of drug 
dependency or drug abuse. 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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In-patient hospitalization is considered to have occurred if the patient has had to stay for a 
night at the hospital. The criterion for prolongation of hospitalization is also defined as an extra 
night at the hospital. This does not include an emergency room visit or admission to an 
outpatient facility. Hospitalization for an elective or planned procedure to treat a pre-existing 
condition is not considered an SAE unless it results in one of the outcomes listed above (but it 
has to be documented as planned). 
 
13.2 Record of Adverse Events 
All AEs from baseline (visit 2, onset of treatment) until the patient’s last study visit and all SAEs 
upon ICF signature (visit 1) until 30 days after the patient has stopped study participation as 
well as those SAEs made known to the investigator at any time thereafter that are suspected 
of being related to the investigational product will be collected.  
AEs / SAEs will be recorded according to the ICH E6 guidelines on an AE page of the CRF. 
SAEs will be additionally documented on a SAE report form. Documentation includes the 
following information: description of AEs in detail including the date of onset, stop date, 
intensity, relationship of the AE to study drug, action(s) taken, seriousness, time course, 
duration and outcome. There should be an attempt to report a diagnosis rather than signs, 
symptoms or abnormal laboratory values. 
The clinical intensity of an AE is classified as: 
Mild: 
Signs and symptoms which could be easily tolerated and are transient.  
Moderate: 
Causes discomfort and interferes with normal functioning and interrupts the 
patient’s usual activities but is tolerable.  
Severe: 
Affects considerable usual daily activities, prevents the patient from carrying out 
his / her daily activities. 
An AE is considered to be related to the investigational product if a causal relationship between 
the investigational product and the AE is at least a reasonable possibility (assessed as 
‘related’, ‘probable’ or ‘possible’), i.e. the relationship cannot be ruled out. If an AE is 
considered not to be related to the investigational product, the degree of causality to the study 
drug will be described as ‘not related’. 
All AEs should be treated appropriately. The action(s) taken regarding the AE are classified as 
follows: 
Treatment for event:  
 
None 
 
Concomitant medication given or changed (to be specified on concomitant 
medication form) 
 
Others  
Action taken with study medication: 
 
Dose not changed 
 
Dose reduced 
 
Dose interrupted 
 
Dose withdrawn 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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 
Dose increased 
 
Unknown 
 
Not applicable 
The outcome of the AE is classified as follows: recovered / resolved, recovered / resolved with 
sequelae, not recovered / not resolved, fatal, unknown. 
Data pertaining to AEs and SAEs are collected during each study visit through the patient’s 
spontaneous description or through the investigator’s inquiry or examination of the patient.  
Once an AE is detected it is followed until its resolution or until it is judged to be permanent. 
An assessment of any changes in intensity, the suspected relationship to the treatment, 
seriousness, the interventions required to treat it and the outcome is made at each scheduled 
visit. 
Patients will be supplied with a 24-hour hotline telephone number by the study sites that allows 
them to notify the study staff of any local reactions on the treated area or any other AEs whether 
or not related to treatment. 
 
13.3 Procedures for Reporting Serious Adverse Events 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see below. 
To ensure patient safety, every SAE, regardless of suspected causality/relatedness to study 
drug, occurring after the patient has provided informed consent until 30 days after the patient 
has stopped study participation must be reported to the sponsor within 24 hours of learning of 
its occurrence. The SAE form will be sent to  
 
 
 
 
 
TFS Drug Safety 
 
safety.tfs@tfscro.com 
 
 
 
 
Fax: +46 46 2801919 
 
The Sponsor or its designee will inform relevant Regulatory Authorities and Ethics Committees; 
 
Of all relevant information about serious unexpected events suspected to be 
related to the investigational product suspected to be related to the investigational 
product that are fatal or life-threatening as soon as possible, and in any case no 
later than seven days after knowledge of such a case. Relevant follow-up 
information for these cases will be subsequently be submitted within an additional 
eight days. 
 
Of all other serious unexpected events suspected to be related to the 
investigational product as soon as possible, but within a maximum of fifteen days 
of first knowledge by the investigator.  
Any SAEs experienced after this 30-day period have to be reported to the sponsor if the 
investigator assumes a causal relationship to the treatment. 
Recurrent episodes, complications, or progression of the initial SAE have to be reported as 
follow-up to the original episode, regardless of when the event occurred. This report has to be 
submitted within 24 hours of the investigator’s receiving the follow-up information. An SAE that 
is considered completely unrelated to a previously-reported one has to be reported separately 
as a new event. 


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Clinical Study Protocol 
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Final 3.0, 07. June 2018 
 
 
 
 
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Information about all SAEs has to be collected and recorded on the SAE report form. The 
investigator has to assess the relationship to study drug, complete the SAE report form, and 
send the completed, signed form by fax within 24 hours to the sponsor or its responsible 
contact person. The telephone and fax number are listed in the investigator site file provided 
to the study site as well as in the heading of the SAE report form. The original copy of the SAE 
report form and the fax confirmation sheet must be kept with the CRF documentation at the 
study site. 
Follow-up information has to be sent to the same person, to whom the original SAE report form 
was sent, using a new SAE report form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information has to specify whether 
the event is resolved or continues, if and how it was treated and whether the patient continued 
or withdrew from study participation.  
 
13.4 Pregnancy 
Prior to enrolment, all patients must be advised of the importance of avoiding pregnancy during 
study participation and the potential risk factors for a pregnancy.  
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test 
in a female patient of childbearing potential regardless of age or disease state) occurring while 
the patient is receiving apremilast, or within the time between the end of at least one menstrual 
cycle (but not less than 28 days) following discontinuation of apremilast, are considered 
immediately reportable events. The investigational product is to be discontinued immediately. 
The female patient may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation. 
The investigator will follow the female patient until completion of the pregnancy, and must notify 
the Sponsor or its designee immediately about the outcome of the pregnancy (either normal 
or abnormal outcome). 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
investigator should report the abnormal outcome as an AE. If the abnormal outcome meets 
any of the serious criteria, it must be reported as an SAE within 24 hours of the investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the investigator suspects is 
related to the in utero exposure to the investigational product should also be reported as an 
SAE within 24 hours of the Investigator’s knowledge of the event using the SAE Report Form, 
or approved equivalent form. 
If a female partner of a male patient taking investigational product becomes pregnant, the male 
patient taking investigational product should notify the investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately.  
If a pregnancy related event is reported in a female partner of a male patient, the investigator 
should ask if the female partner is willing to share information with the Sponsor or its designee 
and allow the pregnancy related event to be followed up to completion. 
 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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14 
Statistics 
A Statistical Analysis Plan (SAP) will be written as a separate document to be completed after 
finalizing the protocol developed during the conduct of the study. The SAP will be finalized 
prior to database closure.  
Any changes to the statistical analyses planned in the protocol will be justified and documented 
in the SAP if they were decided before database lock. Any changes made to the SAP after the 
database lock will be documented in the final study report. 
Summary statistics for continuous variables will include number (n), mean, standard deviation, 
median, minimum first quartile, third quartile, and maximum. 
Summary statistics for discrete variables will include frequencies and percentages. 
If not otherwise specified, p-values will be presented as two-sided p-values and the level of 
significance is set to 5% (two-sided). 
The statistical analysis will be performed using the software SAS version 9.3 or higher. 
Exploratory analyses (e.g. inflammatory markers) will not be part of statistical analyses and 
will be analyzed outside of the study setting. 
 
14.1 Protocol Deviations 
Deviations from the protocol including violations of inclusion / exclusion criteria will be 
assessed as ‘minor’ or ‘major’ on a case by case basis in cooperation with the sponsor. This 
assessment will take place during a data review meeting, which will take place after the last 
observation of the last patient and prior to database closure. Major deviations from the protocol 
will lead to the exclusion of a patient from the per protocol set.  
 
14.2 Analysis Populations 
The following two analysis sets are defined in this study: 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) is defined as all patients who received at least one dose of study 
drug. 
Per Protocol Set (PP) 
The Per Protocol Set (PP) is defined as all patients who received at least one dose of study 
drug who completed the study with no major protocol violations. 
The definition of the PP set will be finalized in the data review meeting prior to database 
closure. 
The FAS and PP will be used for analyses of efficacy endpoints. Since the FAS consists of all 
patients who received at least one dose of study drug, the FAS will additionally serve as safety 
analysis set and will be used for analysis of safety endpoints. 
 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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14.3 Demographics and Baseline Characteristics 
The analyses of patient demographic data will be presented for the FAS and PP. Other 
baseline characteristics including medical history will be based on the FAS. 
Demographics and Baseline Characteristics 
Summary statistics will be presented for demographic and baseline characteristic variables. 
The number and percentage of patients in each category will be presented for categorical 
variables. 
Medical History 
Frequency tables for medical history will present the number and percentage of patients per 
Medical Dictionary for Regulatory Activities (MedDRA), system organ classes (SOC) and 
preferred terms (PT). 
 
14.4 Treatments 
Prior and Concomitant Medications 
Frequency tables for prior and concomitant medications will present the number and 
percentage of patients per Anatomic-Therapeutically-Chemical Code (ATC) class 2 
(therapeutic main group) and ATC class 3 (pharmacological sub-group). 
Prior medications are defined as medications taken prior to first intake of study drug. Any 
medication given at least once after the first intake of study drug will be considered as 
concomitant medication. This means, a medication might be assigned to both, prior and 
concomitant medications. If no unambiguous assignment to prior and concomitant medication 
is possible due to incomplete or missing dates, the medication will be assigned to both, prior 
and concomitant medications. 
 
14.5 Analysis of Primary Endpoint 
14.5.1 Primary Endpoint 
The primary endpoint is the percentage change from baseline in PPPASI after 20 weeks of 
treatment with apremilast, defined in 8.2.1. 
 
14.5.2 Statistical Methods of Analysis 
The primary endpoint percent change from baseline in PPPASI after 20 weeks of treatment 
will be summarized as continuous variable together with 95%-confidence limits. Statistical 
comparison between post- versus pre-treatment values will be done based on the Wilcoxon 
signed-rank test with two-sided p-value <0.05 indicating significance. Missing values will be 
replaced using last-observation-carried-forward (LOCF) method for the analysis of the primary 
endpoint based on the FAS. 
The analysis of the primary endpoint will be repeated for the PP set, this analysis will be 
considered as supportive. 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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14.6 Analysis of Secondary Efficacy Endpoints 
Analyses of secondary efficacy endpoints will be based on the FAS and PP set. 
Summary statistics will be provided for the secondary efficacy endpoints which are defined as 
follows: 
 
Absolute and percent change from baseline in PPPASI during the 20 weeks 
treatment period 
 
PPPASI 50 response and PPPASI 75 response, defined as a 50% and 75% 
decrease in PPPASI from baseline, during the 20 weeks treatment period 
 
DLQI bands (0-1 no effect, 2-5 small effect, 6-10 moderate effect, 11-20 very 
large effect, 21-30 extremely large effect on the disease related quality of life) 
during the 20 weeks treatment period 
 
Absolute and percent change from baseline in DLQI during the 20 weeks 
treatment period 
All other endpoints except for PPPASI and DLQI are only briefly described within this study 
protocol: Statistical comparison between post- versus pre-treatment values will be done based 
on the Wilcoxon signed-rank test with two-sided p-value <0.05 indicating significance. 
 
14.7 Analysis of Secondary Safety Endpoints 
All safety evaluations will be performed on the FAS, which consists of all patients who received 
at least one dose of study drug. 
Frequency tables and/or summary statistics will be provided as described below for the 
secondary safety endpoint which is defined as: 
 
Safety as assessed by adverse events (AEs), vital signs and physical examination 
 
Adverse Events (AEs) 
Treatment emergent AEs (TEAEs) are defined as AEs which started after first intake of study 
drug. If no unambiguous assignment to treatment emergent is possible due to incomplete or 
missing dates, the AE will be considered as treatment emergent. 
Frequency tables for TEAEs will present the number and percentage of patients per SOC and 
PT. Frequency tables will also be presented for TEAEs related to study medication, TEAEs 
leading to study drug discontinuation, serious TEAEs, and serious TEAEs related to study 
medication. Additional summaries will be provided for TEAEs by intensity. 
 
Vital Signs and Physical Examination 
Summary statistics will be provided for each parameter per visit. 
 
14.8 Exploratory Analysis 
Exploratory endpoints (plasma / serum immunological marker analysis and the skin biopsy 
immunological marker sub-study) will be analyzed outside of the study setting by a research 
laboratory (Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 54 of 75 
 
Germany). Summary statistics for immunological marker data derived from plasma / serum 
samples will be incorporated into the results of the Clinical Study Report. 
Immunological marker data derived from skin biopsy samples will not be included in the Clinical 
Study Report. 
14.9 Handling of Missing Values 
Missing values will be replaced using last-observation-carried-forward (LOCF) method for the 
analysis of the primary endpoint based on the FAS. 
For all other analyses, missing values will not be replaced. 
 
14.10 Examination of Subgroups 
No subgroup analyses are planned. 
 
14.11 Sample Size Calculation 
This is a pilot study intended to gain first information on the possible clinical and mechanistical 
effects of apremilast on PPP; therefore the sample size is not based on statistical 
considerations. 
 
14.12 Interim Analyses 
No interim analysis is planned. 
 
14.13 Multiple Comparison / Multiplicity 
No formal hypothesis testing will be performed. Any comparison will only be performed 
exploratory, without adjustment for multiplicity. 
 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 55 of 75 
 
15 
Data Handling and Record Keeping 
15.1 Data Collection 
All patient data relevant for the study are captured on paper CRFs. Completed CRFs are 
checked by the monitor during the periodic monitoring visits according to defined scope. Data 
reported on the CRF, derived from source documents, have to be consistent with the source 
documents or the discrepancies should be explained. A source data location list is filed in the 
investigator site file. Once completeness and correctness has been confirmed by the monitor, 
the original CRF pages are collected by the monitor. A copy of each CRF remains at the site. 
Data Management staff register the CRFs received by monitor in a study-specific tracking 
register. First CRFs of each site are checked for completeness, accuracy and plausibility. 
Subsequently data from the CRFs are entered into the clinical study database by using double 
data entry method performed by two different individuals. Discrepancies between first and 
second data entry are resolved by checking the original CRFs, the database will be updated 
as appropriate. The data entry staff is trained on the study-specific data entry guideline and is 
supervised by the responsible data manager. 
Validation of data is done according to the study-specific data validation plan. Data checks 
include automatic edit checks within the database as well as data review listings and manual 
queries performed by data manager or site monitor. 
Obvious errors are corrected by data management staff using the self-evident correction list, 
if available. All other discrepancies are sent to the investigation site for resolution by 
investigator using a data clarification form. The completed and signed original data clarification 
forms are sent to data management. The data management updates the database according 
to the resolved data clarification forms and files these with the CRFs. A copy of the data 
clarification form is kept with the CRFs at the investigation site.  
A database quality control of key safety and efficacy data is performed prior to locking the 
database. When all queries have been resolved, database quality control has been completed 
and the analysis populations have been assigned during the blind data review meeting the 
database will be locked. After database lock the treatment codes will be made available for 
data analysis.  
Any changes to the database after the database has been locked require joint written 
agreement between clinical project manager, statistician and sponsor. 
AEs are coded according to international used MedDRA classification, prior and concomitant 
medications are coded according to WHO ATC classification. 
 
15.2 Source Documentation 
All information on CRFs must be traceable to the source documents in the patient’s file. All 
data obtained during this study shall be entered in the CRFs promptly. All source documents 
from which CRF entries are derived shall be placed in the patient’s medical records. In general, 
the patient’s medical records shall be the only source documents.  
The original CRFs for each patient will be checked against source documents at the study site 
by the CRO site monitor.  
After review by the site monitor, completed CRFs will be forwarded to Data Management. 
Instances of missing or uninterpretable data will be discussed with the investigator for 
resolution. 


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Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
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15.3 Archiving 
The investigator must make arrangements to store the essential study documents (as defined 
in ICH E6, section 8 ‘Essential Documents for the Conduct of a Clinical Study’(2)) including the 
investigator site file, until the sponsor or its designee informs the investigator that the 
documents are no longer to be retained.  
The ICH E6 guideline (section 5.5.11) states that essential documents be retained ‘until at 
least 2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational 
product’.  
In addition, the investigator is responsible for archiving all relevant source documents, patient’s 
files and patient’s identification codes for a minimum of 10 years (in Germany according to 
MBO - (Model) Professional Code for Physicians in Germany and BGB §630e, GCP-V §13). 
The sponsor or its designee stores the original CRFs and the above essential documents for 
at least 15 years (2003/83/EC, section 5.2c) in case the medicinal product and / or the 
comparator are already on the market, except for source documents pertaining to the individual 
site, which are kept only by the investigator. 
 


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Clinical Study Protocol 
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16 
Quality Control and Quality Assurance 
The study is conducted in compliance with the applicable international and local regulatory 
requirements as well as applicable ICH E6 guideline(2), the Declaration of Helsinki (3) and in 
respect of the TFS and / or sponsor Standard Operating Procedures (SOPs) for study 
preparation, conduct, close out and monitoring. 
16.1 Personnel Training 
Site monitors and other applicable personnel will be trained prior to the study initiation to 
familiarize them with the SOPs, the protocol and all study-specific items. 
The investigator must ensure that all site staff involved in the conduct of the study is familiar 
with the protocol and study-specific procedures and have appropriate knowledge of the study 
drugs. The transfer of duties and a listing of all sub-investigators must be recorded in the 
investigator site file. 
 
16.2 Clinical Monitoring 
The conduct of the study will be closely monitored to verify adherence to ICH E6 guideline(2), 
AMG (1) and applicable SOPs. An experienced site monitor will advise the investigator during 
the clinical investigation and will perform the monitoring activities at the site which may include 
an initiation visit, periodic monitoring visits during the study, and a close-out visit.  
At the initiation visit, the site monitor will amongst others review the investigator site file, the 
protocol and the CRF with the investigator and his / her staff. During the study visit it is the 
responsibility of the site monitor to secure that the documents required are present in the study 
documentation according to ICH E6 guideline(2). 
Periodic monitoring visits will take place on a regular basis according to a schedule fixed by 
mutual agreement documented in the monitoring plan. During these visits the site monitor will 
check the completeness of patient records, the accuracy of entries on the CRFs, the adherence 
to the protocol and to GCP and the progress of enrolment. The recruitment of patients will be 
monitored by sending inclusion faxes from site to TFS. Furthermore the site monitor has to 
ensure the correctness of storage of study drug and will check study drug dispensing and 
accountability on every visit. 
The close-out visit will occur after LPO at the site. The site monitor will collect all required 
documents, clarify any remaining questions and inform the investigator about the archive 
requirements of investigator site files including signed informed consent forms, patient 
identification lists and CRF copies. 
The investigator will allow the site monitor to have direct access to all study records, CRFs, 
corresponding medical records, study drug dispensing records and study drug area and any 
other documents considered source documentation to confirm their consistency with the CRF 
entries. All information on CRFs must be traceable to these source documents in the patient’s 
file. Data defined before study start as not requiring a separate written record will be recorded 
directly in the CRF and are considered source documentation.  
TFS monitoring standards require full verification for the presence of informed consent, 
adherence to the inclusion / exclusion criteria, documentation of AEs / SAEs, medical history 
according to the monitoring manual and recording of data that will be used for all primary and 
safety variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan.  


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Key study personnel must be available to assist the site monitor during the visit(s). The 
investigator must maintain source documents for each patient in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information. The investigator must also keep the original ICF signed by the patient (one signed 
original is given to the patient). 
 
16.3 
Audits / Inspections 
Audits may be carried out by the sponsor or its designees before, during or after the study. 
The investigator will permit and assist the sponsor, its designee or responsible government 
agencies (as required by law) to have direct access to all source data / documents. 
 


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17 
Ethics 
17.1 Regulatory and Ethics Compliance 
The study will be conducted in accordance with applicable laws and regulations including, but 
not limited to, the Medicinal Products Act (Arzneimittelgesetz AMG) (1), the ICH E6 guideline 
(2) and the ethics principles that have their origins in the Declaration of Helsinki (3). The 
protocol and the proposed ICFs have been reviewed and approved by a properly-constituted 
ethics committee before study start. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his / her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and to 
give access to all relevant data and records to monitors, auditors, IRBs / IECs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory authority, 
the investigator must inform the sponsor or its designee immediately that this request has been 
made. 
 
17.2 Informed Consent 
Informed consent of patients will be obtained in accordance with applicable laws and 
regulations including, but not limited to, the Medicinal Products Act (Arzneimittelgesetz AMG) 
and ICH E6 guideline by the investigator and / or his / her sub-investigator(s) personally prior 
to each inclusion of a patient to the study. 
The nature, objective and importance of the study, the possible benefits and disadvantages or 
risks and the study procedures will be explained to each patient orally and in writing by each 
investigator and / or his / her sub-investigators personally before the patient is to sign the 
informed consent. The patients will also be informed  
 
that their participation is voluntary 
 
that they are free to withdraw from the study at any time 
 
that choosing not to participate would not impact on the patient’s care or future 
treatment 
 
that, by signing the ICF, they explicitly permit access to their personal data 
relating to study by authorized representatives of the sponsor and the regulatory 
authorities without violating the confidentiality of the patient, to the extent 
permitted by the applicable law(s) and / or regulations. The patients will also be 
informed that their consent for use / analyse their already elevated data may not 
be revoked by withdrawing from the trial. 
Each patient will be given sufficient time to read and discuss the ICF with the investigator and 
/ or his / her sub-investigator(s) in person prior to giving his / her written consent. An oral 
consent or written consent given via email or fax is not sufficient. Before entry to the study and 
prior to the conduct of any study-related procedures consent will be recorded by means of the 
patient’s dated signature. The ICF will be signed two times. The patient is then given one (1) 
original of the information sheet and his / her signed consent form. The other original is filed in 
the investigator site file at site. The collection of AE information will start at baseline visit. 
A separate ICF will be prepared and consent obtained from patients willing to provide skin 
biopsy samples for the purposes of this study. 
 


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17.3 Amendments to the Protocol 
Any substantial change or addition to the protocol can only be made in a written protocol 
amendment that must be approved by the sponsor and, where required, regulatory authorities 
and the IRB / IEC. Only amendments that are required for patient safety may be implemented 
prior to IRB / IEC approval.  
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the sponsor 
or its designee should be notified of this action and the site-specific IRB / IEC should be 
informed within 10 working days. 
 
17.4 Confidentiality 
All involved sites have to confirm that they handle the information available in the documents 
handed over strictly in confidence. 
The process of collecting patient information will comply with the standards for protection of 
privacy by applicable local / regional / national requirements for patient confidentiality. All 
records will kept confidential and the patient’s name will not be released at any time. 
Throughout this study all data will not to be released to anyone other than the sponsor / 
sponsor delegates or representatives of the responsible government agencies, if requested. 
Caution will be exercised to guarantee patient’s confidentiality. 
In the event that a potential violation of Data Protection Regulations is detected, the following 
measures will be implemented: as soon as the situation becomes known immediate action will 
be taken to remediate the violation and a full investigation will be carried out to identify whether 
any other subjects are at risk and to ensure appropriate corrective actions are implemented to 
ensure that the situation does not recur. 


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Clinical Study Protocol 
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18 
Financing and Insurance 
18.1 Financing 
A separate agreement is signed between the CRO on behalf of the sponsor and each 
investigator / institution containing supplemental information including the financial aspects. 
An educational grant is being provided by Celgene GmbH to support the sponsor in carrying 
out certain of his obligations in relation to this clinical study. 
All investigators will sign separate financial disclosure forms, if required by CRO, sponsor, or 
regulatory authorities. 
 
18.2 Insurance 
From the start of the study until its termination each patient will be insured against health 
impairment occurring as a result of participation in the study in accordance with each national 
laws and regulations. A copy of the insurance conditions will be handed out to the patient with 
the informed consent. 
 


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19 
Publication Policy 
By signing the study protocol, the investigator agrees with the use of results of the study for 
the purposes of national and international registration, publication, especially to public 
registries at health care bodies (e.g. ClinicalTrials.gov), and information for medical and 
pharmaceutical professionals. If necessary, the authorities will be notified of the investigator's 
name, address, qualifications and extent of involvement. 
An integrated Clinical Study Report will be prepared by TFS and reviewed by the sponsor in 
co-operation with the coordinating investigator. The results from the exploratory sub-studies 
will not be included in the Clinical Study Report (see Section 12.1.10.2). A summary of the 
clinical study report (according to ICH E3 / CPMP/ICH137/95 (35)) should be sent to the 
Regulatory Authorities and IEC according to the relevant guidelines. For the preparation of a 
manuscript with the clinical study data for publication in a scientific journal, Dr. Dagmar 
Wilsmann-Theis and Professor Dr. Rotraut Mössner from the Department of Dermatology at 
the UMG (Universitätsmedizin Göttingen) in Göttingen will be responsible after discussion with 
the sponsor. 
Neither information nor unpublished data given to the investigator may be transmitted to the 
third party without written approval of the sponsor. The investigator agrees that it is not his duty 
to either register or to disclose the study results in the context of the global industry position. 
Neither information nor unpublished data from exploratory analyses given to the investigator 
or sponsor may be transmitted to a third party without written approval of the person 
responsible for the exploratory analyses. For the preparation of a manuscript with the data 
from the exploratory analyses for publication in a scientific journal, Dr. Robert Sabat will be 
responsible after discussion with the sponsor, Dr. Dagmar Wilsmann-Theis and Professor Dr. 
Rotraut Mössner. 
The investigator shall be permitted to use the scientific findings gained upon completion of the 
whole study, meaning after the final report has been transferred to the regulatory database (i) 
for their own scientific, non-commercial teachings and (ii) to publish these for non-commercial 
purposes in accordance with the following stipulations: 
(a) 
Any publication of data and findings prior to publication of the whole study results by 
the sponsor is not permitted. That restriction shall be void, if the sponsor did not publish 
the whole study results within 18 month after completion of the whole study.  
(b) 
The study data being scientifically published or the use of the study data in another 
publication by the parties is only allowed after publication of the whole study results by 
the sponsor or after expiring date set forth above, respectively and shall only be 
published according to the following process:  
(aa)  No less than 60 days prior to a study-related manuscript or other study-related 
materials are to be filed or submitted with a third individual for publication the 
investigator shall provide the sponsor with a copy of such manuscript and / or the 
materials. The sponsor has 60 days from the time of receipt to review these and 
to comment. 
(bb)  In the event the sponsor presents proposals for modification the investigator 
agrees to consider these in the planned publication unless the proposals for 
modification compromise the scientific nature or the neutrality of the publication. 
In the event of a dispute pertaining to the contents of the publication the parties 
will strive to enclose these in the form of a scientific debate. 
(cc)  The investigator further agrees to postpone the publication by an additional 60 
days, if and when required in the opinion of the sponsor to protect intellectual 
property. 


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Clinical Study Protocol 
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(dd)  The investigator agrees to maintain confidentiality on the information to be 
published for the testing time and the extended disqualification period mentioned 
above. 
The sponsor shall not use the investigator’s name in any publication without the prior written 
permission of the investigator. The investigator shall not use the sponsor’s name in any 
publication without the prior written permission of the sponsor. 
 


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20 
References 
 
(1)  Medicinal Products Act (Arzneimittelgesetz AMG) in the version published on 12 
December 2005 (Federal Law Gazette [BGBl.]) Part I p. 3394, last amended by Article 
1 of the Ordinance of 10 October 2013 (BGBl. I S. 3813).  2013 Oct.  
 
(2)  ICH E6 (R2) - Guideline for Good Clinical Practice.  2016.  
 
(3)  Declaration of Helsinki,  64th WMA General Assembly, (2013). 
 
(4)  Handa S. Newer trends in the management of psoriasis at difficult to treat locations: 
scalp, palmoplantar disease and nails. Indian J Dermatol Venereol Leprol 2010 
Nov;76(6):634-44. 
 
(5)  Kragballe K. Management of difficult to treat locations of psoriasis. Scalp, face, 
flexures, palm/soles and nails. Curr Probl Dermatol 2009;38:160-71. doi: 
10.1159/000232309. Epub@2009 Jul 28.:160-71. 
 
(6)  Wozel G. Psoriasis treatment in difficult locations: scalp, nails, and intertriginous areas. 
Clin Dermatol 2008 Sep;26(5):448-59. 
 
(7)  Griffiths C, Camp R, Barker J. Psoriasis. In: Burns T, Breathnack S, Cox N, et al., 
editors. Rook´s Textbook of Dermatology.Massachusetts, Oxford, Victoria: Blackwell 
Science; 2004. p. 52-3. 
 
(8)  Farley E, Masrour S, McKey J, Menter A. Palmoplantar psoriasis: a phenotypical and 
clinical review with introduction of a new quality-of-life assessment tool. J Am Acad 
Dermatol 2009 Jun;60(6):1024-31. 
 
(9)  Lassus A, Geiger JM. Acitretin and etretinate in the treatment of palmoplantar 
pustulosis: a double-blind comparative trial. Br J Dermatol 1988 Dec;119(6):755-9. 
 (10)  Layton AM, Sheehan-Dare R, Cunliffe WJ. A double-blind, placebo-controlled trial of 
topical PUVA in persistent palmoplantar pustulosis. Br J Dermatol 1991 
Jun;124(6):581-4. 
 (11)  Adisen E, Tekin O, Gulekon A, Gurer MA. A retrospective analysis of treatment 
responses of palmoplantar psoriasis in 114 patients. J Eur Acad Dermatol Venereol 
2009 Jul;23(7):814-9. 
 (12)  Marsland AM, Griffiths CE. Treatments for chronic palmoplantar pustular psoriasis. 
Skin Therapy Lett 2001 Nov;6(12):3-5. 
 (13)  V'lckova-Laskoska MT, Caca-Biljanovska NG, Laskoski DS, Kamberova SJ. 
Palmoplantar pustulosis treated with itraconazole: a single, active-arm pilot study. 
Dermatol Ther 2009 Jan;22(1):85-9. 
 (14)  Bhushan M, Burden AD, McElhone K, James R, Vanhoutte FP, Griffiths CE. Oral 
liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-
blind, placebo-controlled study. Br J Dermatol 2001 Oct;145(4):546-53. 
 (15)  Reich K, Graff O, Mehta N. Oral alitretinoin treatment in patients with palmoplantar 
pustulosis inadequately responding to standard topical treatment: a randomized phase 
II study. Br J Dermatol 2016 Jun;174(6):1277-81. 


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 (16)  Gerdes S, Franke J, Domm S, Mrowietz U. Ustekinumab in the treatment of 
palmoplantar pustulosis. Br J Dermatol 2010 Nov;163(5):1116-8. 
 (17)  Bissonnette R, Nigen S, Langley RG, Lynde CW, Tan J, Fuentes-Duculan J, et al. 
Increased expression of IL-17A and limited involvement of IL-23 in patients with palmo-
plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled 
trial. J Eur Acad Dermatol Venereol 2014 Oct;28(10):1298-305. 
 (18)  Morales-Munera C, Vilarrasa E, Puig L. Efficacy of ustekinumab in refractory 
palmoplantar pustular psoriasis. Br J Dermatol 2013 Apr;168(4):820-4. 
 (19)  Buder V, Herberger K, Jacobi A, Augustin M, Radtke MA. Ustekinumab in der Therapie 
der Pustulosis palmoplantaris - Eine Fallserie mit neun Patienten. J Dtsch Dermatol 
Ges 2016 Nov;14(11):1109-15. 
 (20)  Bissonnette R, Poulin Y, Bolduc C, Maari C, Provost N, Syrotuik J, et al. Etanercept in 
the treatment of palmoplantar pustulosis. J Drugs Dermatol 2008 Oct;7(10):940-6. 
 (21)  Guenther LC. Alefacept is safe and efficacious in the treatment of palmar plantar 
pustulosis. J Cutan Med Surg 2007 Nov;11(6):202-5. 
 (22)  Schafer PH, Parton A, Capone L, Cedzik D, Brady H, Evans JF, et al. Apremilast is a 
selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal 2014 
Sep;26(9):2016-29. 
 (23)  Schafer PH, Chen P, Fang L, Wang A, Chopra R. The pharmacodynamic impact of 
apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory 
biomarkers in patients with psoriatic arthritis: substudy results from a phase III, 
randomized, placebo-controlled trial (PALACE 1). J Immunol Res 2015;2015:906349. 
doi: 10.1155/2015/906349. Epub@2015 Apr@20.:906349. 
 (24)  Boehncke WH, Schon MP. Psoriasis. Lancet 2015 Sep 5;386(9997):983-94. 
 (25)  Talbot J, Bianchini FJ, Nascimento DC, Oliveira RD, Souto FO, Pinto LG, et al. CCR2 
Expression in Neutrophils Plays a Critical Role in Their Migration Into the Joints in 
Rheumatoid Arthritis. Arthritis Rheumatol 2015 Jul;67(7):1751-9. 
 (26)  Hagforsen E, Hedstrand H, Nyberg F, Michaelsson G. Novel findings of Langerhans 
cells and interleukin-17 expression in relation to the acrosyringium and pustule in 
palmoplantar pustulosis. Br J Dermatol 2010 Sep;163(3):572-9. 
 (27)  Murakami M, Hagforsen E, Morhenn V, Ishida-Yamamoto A, Iizuka H. Patients with 
palmoplantar pustulosis have increased IL-17 and IL-22 levels both in the lesion and 
serum. Exp Dermatol 2011 Oct;20(10):845-7. 
 (28)  Bissonnette R, Pariser DM, Wasel NR, Goncalves J, Day RM, Chen R, et al. 
Apremilast, an oral phosphodiesterase-4 inhibitor, in the treatment of palmoplantar 
psoriasis: Results of a pooled analysis from phase II PSOR-005 and phase III Efficacy 
and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) clinical 
trials in patients with moderate to severe psoriasis. J Am Acad Dermatol 2016 
Jul;75(1):99-105. 
 (29)  EMA. Summary of the risk management plan (RMP) for Otezla (apremilast).  2014 Dec.  


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 (30)  Celgene Corporation. Rote Hand Brief - Otezla (Apremilast): Neue wichtige Hinweise 
zu Suizidgedanken und suizidalem Verhalten.  2016 Nov.  
 (31)  Celgene Corporation. Otezla® Fachinformation, Celgene Europe Ltd., Stand Dezember 
2017. Celgene 2017 Dec. 
 (32)  Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical 
measure for routine clinical use. Clinical and Experimental Dermatology 1994 
May;19(3):210-6. 
 (33)  Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a new retinoid. 
Dermatologica 1978;157(4):238-44. 
 (34)  Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., et al. 
Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, 
and Treatment of High Blood Pressure. Hypertension 2003 Dec;42(6):1206-52. 
 (35)  ICH E3 Structure and content of clinical study reports.  1996.  
 (36)  Bhushan M, Burden AD, McElhone K, James R, Vanhoutte FP, Griffiths CE. Oral 
liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-
blind, placebo-controlled study. Br J Dermatol 2001 Oct;145(4):546-53. 
 (37)  Langley RG, Ellis CN. Evaluating psoriasis with Psoriasis Area and Severity Index, 
Psoriasis Global Assessment, and Lattice System Physician's Global Assessment. J 
Am Acad Dermatol 2004 Oct;51(4):563-9. 
 (38)  Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Annals of the 
Rheumatic Diseases 2005 Mar;64 Suppl 2:ii65-ii68. 
 (39)  Pedersen CB, McHorney CA, Larsen LS, Lophaven KW, Moeller AH, Reaney M. 
Reliability and validity of the Psoriasis Itch Visual Analog Scale in psoriasis vulgaris. J 
Dermatolog Treat 2017;28(3):213-20. 
 
  
 


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21 
Appendices 
21.1 Appendix I - Dermatology Life Quality Index (DLQI) 
To be filled out by the patient: 
The Dermatology Life Quality Index or DLQI, developed in 1994, was the first dermatology-
specific Quality of Life instrument. It is a simple 10-question validated questionnaire which has 
been used in 33 different skin conditions in 33 countries and is available in 85 languages. Its 
use has been described in over 800 publications including many multinational studies. At 
present the DLQI is the most frequently used instrument in studies of randomized controlled 
studies in dermatology. (http://www.dermatology.org.uk/quality/dlqi/quality-dlqi.html, accessed 
17-JUN-2011) 
 
The DLQI questionnaire is designed for use in adults, i.e. patients over the age of 16. It is self-
explanatory and is handed to the patient who is asked to fill it in without the need for detailed 
explanation. It addresses the disease-related quality of life over the last 7 days. 
The questionnaire contains the following questions: 
1. Over the last week, how itchy, sore, painful or stinging has your skin been? 
2. Over the last week, how embarrassed or self-conscious have you been because of 
your skin? 
3. Over the last week, how much has your skin interfered with you going shopping or 
looking after your home or garden? 
4. Over the last week, how much has your skin influenced the clothes you wear? 
5. Over the last week, how much has your skin affected any social or leisure activities? 
6. Over the last week, how much has your skin made it difficult for you to do any sport? 
7. Over the last week, has your skin prevented you from working or studying? 
If ‘No’, over the last week how much has your skin been a problem at work or 
studying? 
8. Over the last week, how much has your skin created problems with your partner or 
any of your close friends or relatives? 
9. Over the last week, how much has your skin caused any sexual difficulties? 
10. Over the last week, how much of a problem has the treatment for your skin been, for 
example by making your home messy, or by taking up time? 
 
Scoring 
The scoring of each question is as follows: 
Very much 
scored 3 
A lot 
scored 2 
A little 
scored 1 
Not at all 
scored 0 
Not relevant 
scored 0 
Question unanswered 
scored 0 
Question 7: ‘prevented work or studying’ 
scored 3 


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The DLQI is calculated by summing the score of each question resulting in a maximum of 30 
and a minimum of 0. The higher the score, the more quality of life is impaired. 
 
Meaning of DLQI Scores 
0 to 1 
= 
no effect at all on patient's life 
2 to 5 
= 
small effect on patient's life 
6 to 10 
= 
moderate effect on patient's life 
11 to 20 
= 
very large effect on patient's life 
21 to 30 
= 
extremely large effect on patient's life 
Interpretation of incorrectly completed questionnaires 
There is a very high success rate of accurate completion of the DLQI. However, sometimes 
patients do make mistakes. 
 
If one question is left unanswered this will be scored 0 and the scores will be summed 
and expressed as usual out of a maximum of 30. 
 
If two or more questions are left unanswered the questionnaire will not be scored. 
 
If question 7 is answered 'yes' this will be scored 3. If question 7 is answered 'no' or 
'not relevant' but then either 'a lot' or 'a little' is ticked this will then be scored 2 or 1. 
 
If two or more response options are ticked, the response option with the highest score 
will be recorded. 
 
If there is a response between two tick boxes, the lower of the two score options will be 
recorded. 
 
(32) 


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21.2 Appendix II - Psoriasis Area and Severity Index (PASI) 
To be assessed by the investigator: 
The Psoriasis Area and Severity Index (PASI) is a system used for assessing and grading the 
severity of psoriatic lesions and their response to therapy. The PASI produces a numeric score 
that ranges from 0-72.  
The severity of the disease is calculated by scoring the signs of the disease (erythema, 
induration and scaling) for each of the following 4 body-regions: head (h), trunk (t), upper 
extremities (u) and lower extremities (l). The scoring system for the signs of the disease is:  
0 = none, 1 = slight, 2 = moderate, 3 = severe, 4 = very severe. 
The scale for estimating the area of involvement for psoriatic lesions is outlined below. 
0 
= 
No involvement 
1 
= 
1% to 9% involvement 
2 
= 
10% to 29% involvement 
3 
= 
30% to 49% involvement 
4 
= 
50% to 69% involvement 
5 
= 
70% to 89% involvement 
6 
= 
90% to 100% involvement 
 
To help with the area assessment, the following conventions should be noted: 
a. 
The neck is considered part of the head 
b. 
The axillae and groin are part of the trunk 
c. 
The buttocks are part of the lower extremities 
 
The PASI formula is: 
PASI = 0.1(Eh + Ih+ Sh) Ah + 0.3 ((Et + It+ St) At + 0.2 (Eu + Iu+ Su) Au + 0.4 (El + Il+ Sl) Al 
where E = erythema, I = induration , S = Scaling, and A = area. 
 
(33) 


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Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 70 of 75 
 
21.3 Appendix III: Palmoplantar Pustulosis Psoriasis Area and Severity 
Index (PPPASI) 
To be assesses by the investigator: 
The severity of the disease is calculated by scoring the signs of the disease (erythema, 
pustules and scaling) for each of the following 4 body-regions: right palm (RP), left palm (LP), 
Right Sole (RS) and Left Sole (LS). The scoring system for the signs of the disease is:  
0 = none, 1 = slight, 2 = moderate, 3 = severe, 4 = very severe. 
The scale for estimating the area of involvement for psoriatic lesions is outlined below. 
0 
= 
No involvement 
1 
= 
1% to 9% involvement 
2 
= 
10% to 29% involvement 
3 
= 
30% to 49% involvement 
4 
= 
50% to 69% involvement 
5 
= 
70% to 89% involvement 
6 
= 
90% to 100% involvement 
 
 
Body 
region 
Erythema (E) 
Pustules / (P ) 
 vesicles 
Scaling (D) 
(desquamation) 
Area score (A) 
(based on true 
Area %) * 
Right palm 
(RP) 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = no 
Involvement 
1 = >0 - < 10% 
2 =  10 - <30% 
3 =  30 - <50% 
4 =  50 - <70% 
5 =  70 - <90% 
6 =  90 - 100%  
 
Left 
palm 
(LP) 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = no  
Involvement 
1 = >0 - < 10% 
2 =  10 - <30% 
3 =  30 - <50% 
4 =  50 - <70% 
5 =  70 - <90% 
6 =  90 - 100% 
Right 
sole 
(RS) 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = no 
Involvement 
1 = >0 - < 10% 
2 =  10 - <30% 
3 =  30 - <50% 
4 =  50 - <70% 
5 =  70 - <90% 
6 =  90 - 100% 
Left 
sole 
(LS) 
0 = none 
1 = slight 
0 = none 
1 = slight 
0 = none 
1 = slight 
0 = no  
Involvement 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 71 of 75 
 
2 = moderate 
3 = severe 
4 = very severe 
2 = moderate 
3 = severe 
4 = very severe 
2 = moderate 
3 = severe 
4 = very severe 
1 = >0 - < 10% 
2 =  10 - <30% 
3 =  30 - <50% 
4 =  50 - <70% 
5 =  70 - <90% 
6 =  90 - 100% 
The PPPASI score is calculated using the formula: 
PPPASI = 0.2 (ERP + PRP + DRP) ARP + 0.2 (ELP + PLP + DLP) ALP + 0.3 (ERS + PRS + 
DRS) ARS + 0.3 (ELS + PLS + DLS) ALS 
 
(36) 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 72 of 75 
 
21.4 Appendix IV - Physician’s Global Assessment (PGA) 
To be assessed by the investigator: 
 
Assessment of the average severity of all skin lesions at the assessment timepoint according to the 
following categories: 
 
 
 
 
Adapted from (37) 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 73 of 75 
 
21.5 Appendix V - Dynamic Hand and Feet (H&F) PGA 
To be assesses by the investigator: 
 
Assessment of the global improvement of the H&F Psoriasis lesions compared from baseline to the 
assessment timepoint, reflecting a global consideration of at least erythema, scaling, plaque thickness, 
fissuring and postulation according to the following categories: 
 
 
Category 
Percentage 
Improvement 
Category Description 
Cleared (0) 
100% 
Remission of all clinical signs and symptoms as 
compared with baseline, except for residual 
manifestations such as mild erythema 
Excellent (1) 
75% - 99% 
Improvement of all clinical signs and symptoms as 
compared with baseline, except for residual 
manifestations such as mild erythema 
Good (2) 
50% - 74% 
Improvement of all clinical signs and symptoms as 
compared with baseline 
Fair (3) 
25% - 49% 
Improvement of all clinical signs and symptoms as 
compared with baseline 
Slight (4) 
1% - 24% 
Improvement of all clinical signs and symptoms as 
compared with baseline 
Unchanged (5) 
 
Clinical signs and symptoms unchanged from 
baseline 
Worse (6) 
 
Clinical signs and symptoms deteriorated from 
baseline 
 
(38) 
 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 74 of 75 
 
21.6 Appendix VI - Hand and Feet (H&F) PGA 
To be assessed by the investigator: 
 
Assessment of the average severity of the H&F Psoriasis skin lesions at the assessment timepoint 
according to the following categories: 
 
 
Score 
Category 
Category Description 
0 
Clear 
No signs of plaque psoriasis on the hands and / or feet 
1 
Almost Clear 
Just perceptible erythema and just perceptible scaling on 
the hands and/ or feet 
2 
Mild 
Light pink erythema with minimal scaling and with or 
without pustules on the hands and / or feet 
3 
Moderate 
Dull red, cleary distinguishable erythema with diffuse 
scaling, some thickening of the skin, with or without 
fissures, and with or without pustule formation on the 
hands and / or feet 
4 
Severe 
Deep/ dark red erythema with cleary obvious and diffuse 
scaling and thickening, and numerous fissures with or 
without pustule formation on the hands and / or feet 
 
(28)  
 


Confidential 
Prof. Dr. Kristian Reich 
Clinical Study Protocol 
APLANTUS 069-008 
Final 3.0, 07. June 2018 
 
 
 
 
Page 75 of 75 
 
21.7 Appendix VII - Visual Analogue Scale (VAS) 
To be filled out by the patient: 
Scale will be exactly 100mm in length with a statement at each end representing one extreme of the 
dimension being measured (e.g. intensity of itch, discomfort or pain). After short explanation by the 
treating physician, patient will put a vertical bar at that point of the scale which reflects the current 
patients’ subjective status best. 
 
Patient’s assessment of pruritus / itch 
On average, how much itch have you had because of your condition in the past week? 
 
 
Patient’s assessment of skin discomfort / pain 
On average, how much skin discomfort / pain have you had because of your condition in the 
past week? 
 
 
Please note: VAS above is not drawn to scale and is for illustrative purpose only. 
(39) 
 

SAP_001.pdf: 
 
ST_Template_Statistical Analysis Plan_04 
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CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
 
A multicenter, open label, single-arm pilot study to evaluate the efficacy 
and safety of oral apremilast in patients with moderate to severe 
palmoplantar pustulosis (PPP) (APLANTUS) 
Sponsor Study Code: AP-CL-PSOR-PI-006639 
TFS Project Code: DHM1002 
Sponsor 
 
Prof. Kristian Reich 
 
Business address: 
TFS Trial Form Support GmbH 
Anckelmannsplatz 1 
20537 Hamburg 
 
Product/Compound/Device Apremilast (Otezla®)) 
Phase of the study 
Phase II  
Author 
Sarah Lutkewitz, MSc, Biostatistician 
Company 
TFS Trial Form Support GmbH 
Address 
Anckelmannsplatz 1, 20537 Hamburg, Germany 
Telephone number 
+49 (0)40 55 44 01 0 
Version 
Final 1.0 
Date 20-June-2019 




 
ST_Template_Statistical Analysis Plan_04 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ...................................................................................................... 5 
2 
STUDY OBJECTIVES .............................................................................................. 5 
2.1 
Primary Objective ..................................................................................................... 5 
2.2 
Secondary Objective(s) ............................................................................................ 5 
3 
EFFICACY AND EXPLORATORY ENDPOINTS ...................................................... 6 
3.1 
Primary Efficacy Endpoint ......................................................................................... 6 
3.2 
Secondary Efficacy Endpoints .................................................................................. 6 
3.3 
Exploratory Endpoints ............................................................................................... 6 
4 
OVERALL STUDY DESIGN ..................................................................................... 7 
4.1 
Overview of Study Design ......................................................................................... 7 
4.2 
Determination of Sample Size .................................................................................. 9 
5 
DATA SETS TO BE ANALYSED .............................................................................. 9 
6 
STATISTICAL AND ANALYTICAL PLANS ............................................................... 9 
6.1 
Changes in the Planned Analyses ............................................................................ 9 
6.2 
Data Review ........................................................................................................... 10 
6.3 
Hypotheses and Statistical Methods ....................................................................... 10 
6.3.1 
Definitions ............................................................................................................... 10 
6.3.2 
Summary Statistics ................................................................................................. 14 
6.3.3 
Patient Data Listings ............................................................................................... 14 
6.3.4 
Demographic and Other Baseline Characteristics ................................................... 14 
6.3.5 
Primary Efficacy analysis ........................................................................................ 15 
6.3.6 
Secondary Efficacy Analyses .................................................................................. 16 
6.3.7 
Exploratory Analyses .............................................................................................. 16 
6.3.8 
Exposure to Treatment ........................................................................................... 16 
6.3.9 
Prior and Concomitant Medications ........................................................................ 16 
6.3.10 
Adverse Events (AEs) ............................................................................................. 17 
6.3.11 
Other Safety Assessments ..................................................................................... 18 
6.4 
Level of Significance, Multiple Comparisons and Multiplicity ................................... 18 
6.5 
Adjustment for Covariates ....................................................................................... 18 
6.6 
Handling of Dropouts and Missing Data .................................................................. 18 
6.7 
Examination of Subgroups ...................................................................................... 18 
6.8 
Interim Analysis ...................................................................................................... 18 
6.9 
Data Monitoring ...................................................................................................... 19 
7 
APPENDIX 1 .......................................................................................................... 19 
7.1 
Tables to be Produced for the Clinical Study Report (Section 14 according to 
ICH E3) ................................................................................................................... 19 
7.2 
Listings of Individual Patient Data and Other Information to be Produced for the 
Clinical Study Report (Sections 16.1 and 16.2 in ICH E3) ....................................... 22 


 
ST_Template_Statistical Analysis Plan_04 
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ABBREVIATIONS 
AE 
Adverse Event 
ATC 
Anatomic-Therapeutically-Chemical 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
DLQI 
Dermatology Life Quality Index 
FAS 
Full Analysis Set 
H&F PGA 
Hand and Feet Physician Global Assessment 
LOCF 
Last-Observation-Carried-Forward 
LP 
Left Palm 
LS 
Left Sole 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
PASI 
Psoriasis Area and Severity Index 
PGA 
Physician Global Assessment 
PPP 
Palmoplantar Pustulosis 
PPPASI 
Palmoplantar Pustulosis Psoriasis Area and Severity Index 
PPPASI 50 / 75 
50% / 75% decrease in PPPASI 
PPS 
Per Protocol Set 
PRTC 
Psoriasis Research and Treatment Center 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
RP 
Right Palm 
RS 
Right Sole 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 


 
ST_Template_Statistical Analysis Plan_04 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on Clinical Study Protocol (CSP) Version Final 
3.0, dated June 07th, 2018. 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is: 
 
To demonstrate a significant improvement of Palmoplantar Pustulosis Psoriasis Area 
and Severity Index (PPPASI) at week 20 compared with baseline in moderate to 
severe chronic palmoplantar pustulosis under apremilast therapy 
 
2.2 
Secondary Objective(s) 
The secondary objectives of the study are: 
 
To evaluate an improvement of PPPASI at all assessment times compared with 
baseline in moderate to severe chronic palmoplantar pustulosis under apremilast 
therapy 
 
To evaluate differences in life quality assessment measures during treatment with 
apremilast: Dermatology Life Quality Index (DLQI) at all assessment times compared 
with baseline 
 
To evaluate safety of apremilast in patients with moderate to severe palmoplantar 
pustulosis 
 
Exploratory objectives are: 
 
Time course of Hand and Feet Physician Global Assessment (H&F PGA) at all 
assessment times 
 
Pustules count 50 response and Pustules count 75 response, defined as a 50% and 
75% decrease in pustules count from baseline, during the 20 weeks treatment period 
 
To evaluate differences of Visual Analogue Scale (VAS) pruritus / itch, VAS 
discomfort / pain in the mean change from baseline at all assessment times relatively 
to day 0 (baseline)  
 
To evaluate changes in Psoriasis Area Severity Index (PASI), Physician Global 
Assessment (PGA) and dynamic H&F PGA if plaque psoriasis is present between 
baseline and all assessment times 
 
To explore the effect of apremilast on immunological markers in serum / plasma  


 
ST_Template_Statistical Analysis Plan_04 
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 
To explore the effect of apremilast on immunological markers in skin biopsies (sub-
study*) 
* Skin biopsy samples will be collected in an optional (voluntary) exploratory sub-study to explore the effect of apremilast on 
levels of immunological markers in skin and/or PPP-specific alterations (separate Informed Consent Form will be required). 
Details on this sub-study, which will be performed separately from the main study by Dr. Sabat (Psoriasis Research and 
Treatment Center (PRTC)) and colleagues, will be outlined in a separate document and will not be included in the Clinical Study 
Report (CSR).  
 
3 
EFFICACY AND EXPLORATORY ENDPOINTS 
3.1 
Primary Efficacy Endpoint 
 
Percentage change from baseline in PPPASI after 20 weeks of treatment with 
apremilast 
 
3.2 
Secondary Efficacy Endpoints 
 
Absolute and percent change from baseline in PPPASI during the 20 weeks 
treatment period with apremilast 
 
PPPASI 50 response and PPPASI 75 response, defined as a 50% and 75% 
decrease in PPPASI from baseline, during the 20 weeks treatment period with 
apremilast 
 
DLQI bands (0-1 no effect, 2-5 small effect, 6-10 moderate effect, 11-20 very 
large effect, 21-30 extremely large effect) during the 20 weeks treatment period 
 
Absolute and percent change from baseline in DLQI during the 20 weeks 
treatment period 
 
Safety as assessed by Treatment-Emergent Adverse Events (TEAEs), vital signs and 
physical examination 
 
3.3 
Exploratory Endpoints 
 
Absolute and percentage change from baseline in level of immunological 
markers in plasma / serum during the 20 weeks treatment period with 
apremilast 
 
Percentage change from baseline in level of immunological markers in skin 
biopsy samples after 20 weeks of treatment with apremilast (sub-study) 
 


 
ST_Template_Statistical Analysis Plan_04 
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4 
OVERALL STUDY DESIGN 
4.1 
Overview of Study Design 
This is a multicenter, open-label, single-arm, phase II, pilot study to evaluate the efficacy and 
safety of apremilast involving approximately 20 patients with PPP. The screening period is up 
to 4 weeks and treatment takes place over 20 weeks per patient. No follow up period takes 
place. No extension is planned. 
 
Recruitment period is 4 months; hence, study duration from FPI to LPO is approx. 9 months. 
4 patients per site are expected to be recruited, assuming enrolment of both genders with 
distribution according to prevalence of condition. If recruitment is not running as anticipated 
after 2 months, recruitment will be opened to become competitive. 
  
Patient recruitment will take place at approximately 5 sites in Germany. The investigators 
should have relevant expertise in diagnosing and treating PPP or be specialized in 
dermatology. Patients will be enrolled until 20 patients are included into the study. Drop-outs 
will not be replaced. 
 
Five visits per patients are planned including: 
Visit 1 at week -4 - -1 (screening) 
Visit 2 at week 0 (baseline) 
Visit 3 at week 4 
Visit 4 at week 12 
Visit 5 at week 20 (end of study) 
 
Please refer to the Study Flow Chart below for the time schedule of the assessments. 
 
Study Flow Chart 
Phase 
Screenin
g 
Treatment Phase 
Visits 
V1 
V2 
Baselin
e 
V3 
V4 
V5  
End of 
Study 
Early 
Termi-
nation 
Week 
-4 - -1 
0  
4 
12 
20 
Day 
-28 - -1 
0 
28 ± 4  
84 ± 4  
140 ± 7  
In- / exclusion criteria 
X 
x 
- 
- 
- 
- 
Pregnancy test1 
X 
x 
x 
x 
x 
x 
Informed consent 
X 
- 
- 
- 
- 
- 


 
ST_Template_Statistical Analysis Plan_04 
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Demography, 
educational status 
X 
- 
- 
- 
- 
- 
Medical and psoriasis 
history, prior 
medication 
X 
- 
- 
- 
- 
- 
PsA, comorbidity 
X 
x 
- 
x 
x 
x 
Concomitant 
medications 
X 
x 
x 
x 
x 
x 
Nicotine anamnesis 
X 
- 
- 
- 
x 
- 
Physical examination 
incl. weight and 
height2 (BMI) 
X 
x 
- 
- 
x 
x 
Vital signs3 
X 
x 
x 
x 
x 
x 
Results of routine 
blood test / urinalysis 
available4 
X 
- 
- 
- 
- 
- 
Investigator assessments 
PASI 
- 
x 
x 
x 
x 
x 
PPPASI 
x5 
x 
x 
x 
x 
x 
PGA 
- 
x 
x 
x 
x 
x 
H&F PGA 
- 
x 
x 
x 
x 
x 
Dynamic H&F 
PGA 
- 
 
x 
x 
x 
x 
Pustules count 
- 
x 
x 
x 
x 
x 
Patient reported outcomes 
VAS (pruritus / itch 
and discomfort / 
pain) on hands 
and feet 
- 
x 
x 
x 
x 
x 
DLQI 
- 
x 
- 
x 
x 
- 
Photographs6 
(optional) 
- 
x 
- 
- 
x 
- 
Serum and plasma  
- 
x 
x 
x 
x 
x 
Biopsies7 (optional 
sub-study) 
- 
x 
- 
- 
x 
x 
Documentation for 
drug accountability 
and treatment 
compliance 
- 
x 
x 
x 
x 
x 
Medication 
dispensing8 
- 
x 
x 
x 
- 
- 
Return of study 
medication 
- 
- 
x 
x 
x 
x 
AEs / SAEs 
X 
x 
x 
x 
x 
x 
Reason for 
discontinuation 
 
 
 
 
 
x 
1. 
Urine pregnancy test for female patients of childbearing potential 
2. 
Only at V1: height 
3. 
Sitting blood pressure and pulse rate 
4. 
Within the ranges given in the exclusion criteria not older than 8 weeks prior to screening 
5. 
For inclusion PPPASI must be ≥ 12 


 
ST_Template_Statistical Analysis Plan_04 
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6. 
From both hands and feet (optional) 
7. 
Two lesional biopsies from feet or hands (optional) 
8. 
Including instructions for medication intake 
 
AE / SAE 
Adverse Event / Serious Adverse Event 
BMI 
 
Body Mass Index 
DLQI 
 
Dermatology Life Quality Index 
H&F PGA 
Hand and Feet Physician Global Assessment 
PASI 
 
Psoriasis Area and Severity Index 
PGA 
 
Physician’s Global Assessment 
PPPASI  
Palmoplantar Pustulosis Psoriasis Area and Severity Index 
PsA 
 
Psoriasis Arthritis 
V 
 
Visit 
VAS 
 
Visual Analogue Scale 
 
After completion of participation in the study, patients are advised to follow medical 
management of their treating physician. 
 
4.2 
Determination of Sample Size 
This is a pilot study intended to gain first data on the effects of apremilast on PPP; therefore 
the sample size is not based on statistical considerations. 
 
5 
DATA SETS TO BE ANALYSED 
The following analysis sets will be used for the statistical analysis and presentation of data:  
 
The full analysis set (FAS) will consist of all patients who received at least one dose 
of study drug. 
 
The per protocol set (PPS) will consist of all patients who received at least one dose 
of study drug who completed the study with no major protocol violations. 
 
The definition of the PPS set will be finalized in the data review meeting prior to database 
closure. 
 
The FAS and PPS will be used for analyses of efficacy endpoints. Since the FAS consists of 
all patients who received at least one dose of study drug, the FAS will additionally serve as 
safety analysis set and will be used for analysis of safety endpoints. 
 
6 
STATISTICAL AND ANALYTICAL PLANS 
The planned tables and listings are presented in APPENDIX 1. 
 
6.1 
Changes in the Planned Analyses 
Any changes in the statistical analyses (if needed) once the SAP has been finalised and the 
database has been locked should be documented in a file note and in the CSR. 


 
ST_Template_Statistical Analysis Plan_04 
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6.2 
Data Review 
Before database lock, a data review meeting will take place. During this meeting, study data 
will be reviewed and final decisions regarding protocol violations and analysis populations 
will be taken. The content of this meeting will be described in a separate document outside of 
this SAP. 
 
6.3 
Hypotheses and Statistical Methods 
6.3.1 
Definitions 
 
Baseline 
The assessments performed at Visit 2 (Day 0) will be considered the baseline values. For 
variables that are measured at Visit 1 and not at Visit 2, e.g. demography and educational 
status, baseline is defined as Visit 1 (Day -28 - -1). 
 
 
First intake of study drug 
Date of Visit 2 +1 will be considered as the date of the first intake of study drug. 
 
 
Body mass index (BMI)  
BMI will be calculated as: 
BMI (kg/m2) = weight (kg) / (height (m))2 
 
 
Percentage change from baseline 
Percentage change from Baseline at Visit x is defined as: 
(Visit x – Baseline) / Baseline 
 
 
Absolute change from baseline 
Absolute change from Baseline at Visit x is defined as: 
Visit x – Baseline 
 
 
PPPASI 
To be assessed by the investigator: 
The severity of the disease is calculated by scoring the signs of the disease (erythema, 
pustules and scaling) for each of the following 4 body-regions: Right Palm (RP), Left Palm 
(LP), Right Sole (RS) and Left Sole (LS). The scoring system for the signs of the disease is:  
0 = none, 1 = slight, 2 = moderate, 3 = severe, 4 = very severe. 


 
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The scale for estimating the area of involvement for psoriatic lesions is outlined below. 
0 
= 
No involvement 
1 
= 
1% to 9% involvement 
2 
= 
10% to 29% involvement 
3 
= 
30% to 49% involvement 
4 
= 
50% to 69% involvement 
5 
= 
70% to 89% involvement 
6 
= 
90% to 100% involvement 
 
Body 
region 
Erythema (E) 
Pustules / (P ) 
 vesicles 
Scaling (D) 
(desquamation) 
Area score (A) 
(based on true 
Area %) * 
Right palm 
(RP) 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = no 
Involvement 
1 = >0 - < 10% 
2 =  10 - <30% 
3 =  30 - <50% 
4 =  50 - <70% 
5 =  70 - <90% 
6 =  90 - 100%  
 
Left palm 
(LP) 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = no  
Involvement 
1 = >0 - < 10% 
2 =  10 - <30% 
3 =  30 - <50% 
4 =  50 - <70% 
5 =  70 - <90% 
6 =  90 - 100% 
Right sole 
(RS) 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = no 
Involvement 
1 = >0 - < 10% 
2 =  10 - <30% 
3 =  30 - <50% 
4 =  50 - <70% 
5 =  70 - <90% 
6 =  90 - 100% 
Left sole 
(LS) 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
0 = no  
Involvement 
1 = >0 - < 10% 
2 =  10 - <30% 
3 =  30 - <50% 
4 =  50 - <70% 
5 =  70 - <90% 
6 =  90 - 100% 
The PPPASI score is calculated using the formula: 


 
ST_Template_Statistical Analysis Plan_04 
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PPPASI = 0.2 (ERP + PRP + DRP) ARP + 0.2 (ELP + PLP + DLP) ALP + 0.3 (ERS + PRS + 
DRS) ARS + 0.3 (ELS + PLS + DLS) ALS 
 
 
PPPASI 50 
PPPASI 50 is defined as: 
Yes: if Visit x ≤ Baseline / 2 
 No:  if Visit x > Baseline / 2 
 
 
PPPASI 75 
PPPASI 75 is defined as: 
Yes: if Visit x ≤ Baseline / 4 
 No:  if Visit x > Baseline / 4 
 
 
DLQI 
To be filled out by the patient: 
 
The Dermatology Life Quality Index or DLQI, developed in 1994, was the first dermatology-
specific Quality of Life instrument. It is a simple 10-question validated questionnaire which 
has been used in 33 different skin conditions in 33 countries and is available in 85 
languages. Its use has been described in over 800 publications including many multinational 
studies. It is a validated questionnaire. At present the DLQI is the most frequently used 
instrument in studies of randomized controlled studies in dermatology. 
(http://www.dermatology.org.uk/quality/dlqi/quality-dlqi.html, accessed 17-JUN-2011). The 
DLQI is validated for use in patients with PPP 
(https://www.ncbi.nlm.nih.gov/pubmed/28541870). 
 
The DLQI questionnaire is designed for use in adults, i.e. patients over the age of 16. It is 
self-explanatory and is handed to the patient who is asked to fill it in without the need for 
detailed explanation. It addresses the disease-related quality of life over the last 7 days. 
 
The questionnaire contains the following questions: 
1. Over the last week, how itchy, sore, painful or stinging has your skin been? 
2. Over the last week, how embarrassed or self-conscious have you been because of 
your skin? 


 
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3. Over the last week, how much has your skin interfered with you going shopping or 
looking after your home or garden? 
4. Over the last week, how much has your skin influenced the clothes you wear? 
5. Over the last week, how much has your skin affected any social or leisure activities? 
6. Over the last week, how much has your skin made it difficult for you to do any sport? 
7. Over the last week, has your skin prevented you from working or studying? 
If ‘No’, over the last week how much has your skin been a problem at work or 
studying? 
8. Over the last week, how much has your skin created problems with your partner or 
any of your close friends or relatives? 
9. Over the last week, how much has your skin caused any sexual difficulties? 
10. Over the last week, how much of a problem has the treatment for your skin been, for 
example by making your home messy, or by taking up time? 
 
Scoring 
The scoring of each question is as follows: 
Very much 
scored 3 
A lot 
scored 2 
A little 
scored 1 
Not at all 
scored 0 
Not relevant 
scored 0 
Question unanswered 
scored 0 
Question 7: ‘prevented work or studying’ 
scored 3 
 
The DLQI is calculated by summing the score of each question resulting in a maximum of 30 
and a minimum of 0. The higher the score, the more quality of life is impaired. 
 
Meaning of DLQI Scores 
0 to 1 
= 
no effect at all on patient's life 
2 to 5 
= 
small effect on patient's life 
6 to 10 
= 
moderate effect on patient's life 
11 to 20 
= 
very large effect on patient's life 
21 to 30 
= 
extremely large effect on patient's life 
 
Interpretation of incorrectly completed questionnaires 


 
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There is a very high success rate of accurate completion of the DLQI. However, sometimes 
patients do make mistakes. 
 
If one question is left unanswered this will be scored 0 and the scores will be summed 
and expressed as usual out of a maximum of 30. 
 
If two or more questions are left unanswered the questionnaire will not be scored. 
 
If question 7 is answered 'yes' this will be scored 3. If question 7 is answered 'no' or 
'not relevant' but then either 'a lot' or 'a little' is ticked this will then be scored 2 or 1. 
 
If two or more response options are ticked, the response option with the highest score 
will be recorded. 
 
If there is a response between two tick boxes, the lower of the two score options will 
be recorded. 
 
6.3.2 
Summary Statistics 
Data will be summarised by means of summary statistics. For continuous data the following 
summary statistics will be presented: number of observations, number of missings, mean, 
standard deviation (SD), minimum (Min), first quartile (Q1), median, third quartile (Q3) and 
maximum (Max). Categorical data will be summarized by the number and percentage of 
patients in each category. The percentages will be calculated based on the number of 
patients in the corresponding analysis set. 
 
6.3.3 
Patient Data Listings 
Data collected in the Case Report Form (CRF) will generally be listed in Appendix 16.2 (see 
section 7.2). CRF check questions [e.g. Lab samples taken (Yes/No)] and reminders will not 
be listed. 
 
Listings will be sorted by study centre and patient number. 
 
6.3.4 
Demographic and Other Baseline Characteristics 
The analyses of patient demographic data will be presented for the FAS and PPS. Other 
baseline characteristics including medical history will be based on the FAS. 
 
Patient disposition, demographic data and other baseline data will be presented using 
summary statistics.  
 
Patient disposition 


 
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Number and percentage of patients enrolled, patients treated, patients on follow-up at each 
study visit, patients completed, patients who discontinued the study and the reasons for 
discontinuation together with date of first screening visit and date of last contact/study 
termination will be summarized for all screened patients, and study populations and inclusion 
and exclusion criteria will be summarised for all enrolled patients.  
 
Demographic data 
The following demographic data will be summarized: age (years), sex and its nested 
variable, ethnicity, highest educational and smoking status.  
 
Psoriasis history 
Descriptive statistics for the following psoriasis data will be provided: age at initial diagnosis 
of psoriasis (years), age of initial diagnosis of PPP (years), current involvement of scalp, 
current involvement of nails and its nested variables, psoriatic arthritis and its nested 
variables, and parallel occurrence of other psoriasis forms at the same time? 
 
Prior psoriasis medication 
Prior psoriasis medication will be coded according to World Health Organization (WHO) 
Anatomic-Therapeutically-Chemical (ATC) classification. The data will be summarized by 
ATC class 2 (therapeutic main group) and ATC class 3 (pharmacological sub-group) and by 
kind of therapy, ATC class 2 and ATC class 3, together with the number of patients with at 
least one prior psoriasis medication. 
 
Medical history 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The data will be summarized by System Organ Class (SOC) and by Preferred 
Term (PT). 
 
Comorbidity 
Any changes of the coexisting forms of psoriasis and its nested variables will be analysed 
with descriptive statistics by visit. 
 
6.3.5 
Primary Efficacy analysis 
The primary endpoint, percentage change from baseline in PPPASI after 20 weeks of 
treatment with apremilast, will be summarized descriptively as continuous variable together 


 
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with 95%-confidence limits. Statistical comparison between post- versus pre-treatment 
values will be done based on the Wilcoxon signed-rank test with two-sided p-value <0.05 
indicating significance. Missing values will be replaced using Last-Observation-Carried-
Forward (LOCF) method for the analysis of the primary endpoint based on the FAS. 
 
The analysis of the primary endpoint will be repeated for the PP set, this analysis will be 
considered as supportive. 
 
6.3.6 
Secondary Efficacy Analyses 
Analyses of secondary efficacy endpoints will be based on the FAS and PPS. 
Summary statistics will be provided for the secondary efficacy endpoints which are defined 
as follows: 
 
Absolute PPPASI at each study visit (baseline, 4 weeks, 12 weeks and 20 
weeks), together with absolute change and percent change (with 95%-
confidence limits) from baseline at 4 weeks, 12 weeks and 20 weeks  
 
PPPASI 50 response and PPPASI 75 response, defined as a 50% and 75% 
decrease in PPPASI from baseline, during the 20 weeks treatment period 
 
DLQI bands (0-1 no effect, 2-5 small effect, 6-10 moderate effect, 11-20 very 
large effect, 21-30 extremely large effect on the disease related quality of life) 
during the 20 weeks treatment period 
 
Absolute DLQI at each study visit (baseline, 4 weeks, 12 weeks and 20 weeks), 
together with absolute change and percent change (with 95%-confidence limits) 
from baseline at 4 weeks, 12 weeks and 20 weeks 
 
6.3.7 
Exploratory Analyses 
Exploratory analyses will not be part of statistical analyses and will be analyzed outside 
of the study setting by Robert Sabat Charite, Berlin. 
 
6.3.8 
Exposure to Treatment 
The variables of modules: return of medication, dispense of medication, dosing and 
treatment compliance assessment, will be summarized descriptively by visit. 
 
6.3.9 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded according to WHO ATC classification. 


 
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Frequency tables for prior and concomitant medications will present the number and 
percentage of patients per ATC class 2 (therapeutic main group) and ATC class 3 
(pharmacological sub-group). 
 
Prior medications are defined as medications taken prior to first intake of study drug. Any 
medication given at least once after the first intake of study drug will be considered as 
concomitant medication. This means, a medication might be assigned to both, prior and 
concomitant medications. If no unambiguous assignment to prior and concomitant 
medication is possible due to incomplete or missing dates, the medication will be assigned to 
both, prior and concomitant medications. 
 
6.3.10 
Adverse Events (AEs) 
All safety evaluations will be performed on the FAS. 
 
AEs will be coded according to the MedDRA system. 
 
TEAEs are defined as AEs which started after first intake of study drug. If no unambiguous 
assignment to treatment emergent is possible due to incomplete or missing dates, the AE will 
be considered as treatment emergent. 
 
A summary table will be presented with No. of patients with TEAEs, No. of patients with 
serious TEAEs, No. of patients with related TEAEs, No. of patients with at least one TEAE 
leading to discontinuation, No. of patients with serious related TEAEs and also the number of 
TEAEs, serious TEAEs, related TEAEs, TEAEs leading to discontinuation and serious 
related TEAEs. 
 
The total number of patients with at least one TEAE and the number of TEAEs will be 
derived and summarised by SOC and PT. A similar table will be created for serious TEAEs 
and TEAEs leading to discontinuation.  
 
TEAEs will also be tabulated versus intensity and causality to study drug. If a patient has 
more than one event classified with the same preferred term, then the worst intensity and the 
worst relationship will be used. Similar tables will be created for serious TEAEs. 
 


 
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All AEs for each patient, including multiple occurrences of the same event, will be listed 
including additionally SOC and PT. Serious AEs and AEs leading to death or withdrawal will 
be listed separately in addition to the listing including all AEs. A separate listing for TEAEs 
leading to discontinuation will be provided. 
 
6.3.11 
Other Safety Assessments 
All safety evaluations will be performed on the FAS. 
 
Vital Signs 
For all vital signs parameters (systolic and diastolic blood pressure and pulse rate), summary 
statistics will be provided by visit.  
 
Physical Examination 
Height, weight, BMI and numbers of values that are normal or abnormal will be tabulated by 
visit.  
 
6.4 
Level of Significance, Multiple Comparisons and Multiplicity 
The level of significance will be 5%. No adjustment for multiple comparisons will be applied. 
 
6.5 
Adjustment for Covariates 
Not applicable. 
 
6.6 
Handling of Dropouts and Missing Data 
Missing values will be replaced using LOCF method for the analysis of the primary endpoint 
based on the FAS. 
 
For all other analyses, missing values will not be replaced. 
 
6.7 
Examination of Subgroups 
Not applicable. 
 
6.8 
Interim Analysis  
There is no interim analysis planned. 
 


 
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6.9 
Data Monitoring 
No Data Monitoring Committee is planned. 
 
7 
APPENDIX 1 
7.1 
Tables to be Produced for the Clinical Study Report (Section 14 according to 
ICH E3) 
(Table numbers refer to section numbers in ICH E3) 
14.1 DEMOGRAPHIC DATA 
14.1.1 
Patient Disposition.  
All screened patients. 
14.1.2 
Study populations.  
All enrolled patients. 
14.1.3 
Inclusion and exclusion criteria.  
All enrolled patients. 
14.1.4 
Demographic data. 
FAS and PPS population. 
14.1.5 
Psoriasis history.  
FAS population. 
14.1.6.1 
Prior psoriasis medication.  
FAS population. 
14.1.6.2 
Prior psoriasis medication by kind of therapy.  
FAS population. 
14.1.7 
Medical history.  
FAS population. 
14.1.8 
Comorbidities by visit. 
FAS population. 
 
14.2 EFFICACY DATA  
Primary efficacy analysis 
14.2.1.1 
Percentage change from baseline in PPPASI after 20 weeks of treatment 
with apremilast.  
Descriptive statistics and Wilcoxon signed-rank test. 


 
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FAS population. 
14.2.1.2 
Percentage change from baseline in PPPASI after 20 weeks of treatment 
with apremilast.  
Descriptive statistics and Wilcoxon signed-rank test. 
FAS (LOCF) population. 
14.2.1.3 
Percentage change from baseline in PPPASI after 20 weeks of treatment 
with apremilast.  
Descriptive statistics and Wilcoxon signed-rank test. 
PPS population. 
 
Secondary efficacy analysis 
14.2.2 
Absolute PPPASI at each study visit. Absolute and percent change from 
baseline in PPPASI by visit.  
Descriptive statistics and 95% CI 
FAS and PPS population. 
14.2.3 
PPPASI 50 response by visit.  
Descriptive statistics. 
FAS and PPS population. 
14.2.4 
PPPASI 75 response by visit.  
Descriptive statistics. 
FAS and PPS population. 
14.2.5 
DLQI bands (0-1 no effect, 2-5 small effect, 6-10 moderate effect, 11-20 
very large effect, 21-30 extremely large effect on the disease related 
quality of life) by vist.  
Descriptive statistics. 
FAS and PPS population. 
14.2.6 
Absolute DLQI at each study visit. Absolute and percent change from 
baseline in DLQI by visit.  
Descriptive statistics and 95% CI. 
FAS and PPS population. 
 
14.3 SAFETY DATA  
14.3.1.1 
Summary of TEAEs. 
FAS population. 


 
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14.3.1.2 
TEAEs by SOC and PT. 
FAS population. 
14.3.1.3 
Serious TEAEs by SOC and PT. 
FAS population. 
14.3.1.4 
TEAEs leading to discontinuation by SOC and PT. 
FAS population. 
14.3.1.5 
TEAEs by SOC and PT stratified by intensity. 
FAS population. 
14.3.1.6 
TEAEs by SOC and PT stratified by causality. 
FAS population. 
14.3.1.7 
Serious TEAEs by SOC and PT stratified by intensity. 
FAS population. 
14.3.1.8 
Serious TEAEs by SOC and PT stratified by causality. 
FAS population. 
 
 
14.3.2.1 
Listings of Deaths, Other Serious and Significant Treatment Emergent 
Adverse Events. 
FAS population. 
14.3.2.2 
Listing of Treatment Emergent Adverse Events leading to discontinuation. 
FAS population. 
 
 
14.3.5.1 
Return of medication by visit. 
FAS population. 
14.3.5.2 
Dispense of medication by visit. 
FAS population. 
14.3.5.3 
Dosing by visit. 
FAS population. 
14.3.5.4 
Treatment compliance assessment by visit. 
FAS population. 
 
 


 
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14.3.6 
Vital signs by visit.  
FAS population. 
14.3.7 
Physical examination by visit.  
FAS population. 
 
 
14.3.8.1 
Prior medications. 
FAS population. 
14.3.8.2 
Concomitant medications. 
FAS population. 
 
 
7.2 
Listings of Individual Patient Data and Other Information to be Produced for 
the Clinical Study Report (Sections 16.1 and 16.2 in ICH E3) 
(Listing numbers refer to the relevant appendix number in ICH E3. CRF check 
questions/reminders will not be listed.) 
 
16.2.1.1 
Discontinued patients, reason for discontinuation 
16.2.1.2 
Visit dates and other important dates (informed consent, first intake of 
study drug, last day on study and last dose of Apremilast) 
 
 
16.2.2 
Protocol deviations 
 
 
16.2.3 
Patients excluded from the analysis populations with reasons for exclusion 
 
 
16.2.4.1 
Demographic data 
16.2.4.2 
Nicotine anamnesis 
16.2.4.3 
Psoriasis history 
16.2.4.4 
Prior psoriasis medication 
16.2.4.5 
Medical history 
16.2.4.6 
Inclusion criteria not met and exclusion criteria met 


 
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16.2.4.7 
Urine pregnancy test 
 
 
16.2.5.1 
Return of medication and dispense of medication and dosing 
16.2.5.2 
Treatment compliance assessment 
 
 
16.2.6.1 
PPPASI 
16.2.6.2 
DLQI 
 
 
16.2.7 
Adverse events 
 
 
16.2.9 
Vital signs 
 
 
16.2.10 
Physical examination 
 
 
16.2.12 
Prior and concomitant medication