Clinical trial NCT03817190
Conditions: Atopic Dermatitis
Sponsor: DS Biopharma
Start date: 2019-09-19; Completion date: 2020-09-03
Enrollment: 219 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to compare the efficacy and safety of orally administered DS107 (2g) versus placebo in the treatment of moderate to severe Atopic Dermatitis (AD).

Oral DS107/Placebo capsules will be administered for 16 weeks. The study will enrol approximately 220 subjects.

Detailed description:
This study involves a comparison of 2g DS107 with placebo, administered orally once daily for a total of 16 weeks. Patients will be randomized to one of the two treatment arms in a 1:1 ratio.

The primary endpoint will be the vIGA (Validated Investigator's Global Assessment) and EASI (Eczema Area and Severity Index). Other endpoints include vIGA, EASI, SCORAD, BSA (Body Surface Area) and NRS (Numeric Rating Scale).

Arms: arm 1: 2g DS107 (4 DS107 capsules) administered once-daily for 16 weeks arm 2: Placebo (4 placebo capsules) orally administered once-daily for 16 weeks
Interventions: intervention 1: DS107 intervention 2: Placebo
Intervention descriptions: intervention 1: DS107 Capsule intervention 2: Placebo capsule

Protocol documents:
Prot_000.pdf: 
 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 1 of 83 
 
 
 
 
 
A Randomised, Double-blind, Placebo-controlled Study to Assess 
the Efficacy and Safety of Orally Administered DS107 in Adult 
Patients with Moderate to Severe Atopic Dermatitis 
 
 
 
 
Protocol Number # DS107G-05-AD3 
 
 
 
Version 5.0 
18 March 2020 
 
EudraCT Number: 2019-000932-25 
 
 
 
 
Sponsor: 
 
 
 
 
 
 
DS Biopharma,  
Trintech Building,  
South County Business Park, 
Leopardstown,  
Dublin 18, 
Republic of Ireland. 
 
 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 2 of 83 
 
CONTACT INFORMATION 
 
Sponsor Medical Expert: 
Dr. Markus Weissbach, 
Chief Medical Officer, 
DS Biopharma,  
Trintech Building,  
South County Business Park, 
Leopardstown,  
Dublin 18, 
Republic of Ireland. 
 
Tel: +353 1 293 3590 
 
 
 
Clinical Expert: 
 
Prof. Emma Guttman-Yassky 
Icahn School of Medicine at Mount Sinai, 
New York,  
NY 10029,  
United States 
 
Tel: +1 212 241 3288 
 
Pharmacovigilance/Medical 
Monitor: 
Safety Physician, 
spm2 – safety projects & more GmbH, 
Goldbeckstraße 5, 
69493 Hirschberg a.d. Bergstraße,  
Germany 
 
Tel: +49 (6201) 84640-0  
Fax: +49 (6201) 84640-10 
Email: DSBiopharma-PhV@spm2-safety.com 
 
24 hour contact details- Toll Free Numbers: 
Austria: 0800 080799 
Germany: 0800 0009460 
Latvia: 80 200202 
Poland: 800 702796 
United States: 800 5600069 
 
 
 
 
 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 3 of 83 
 
Table of Contents 
CONTACT INFORMATION ............................................................................................................................ 2 
PRINCIPAL SITE INVESTIGATOR SIGNATURE PAGE ......................................................................... 7 
PROTOCOL SYNOPSIS ................................................................................................................................... 8 
LIST OF ABBREVIATIONS .......................................................................................................................... 16 
1 
INTRODUCTION ................................................................................................................................... 19 
1.1 
THERAPEUTIC AREA AND DISEASE BACKGROUND ............................................................................... 19 
1.2 
STANDARD TREATMENT ....................................................................................................................... 19 
1.3 
DRUG CLASS ........................................................................................................................................ 20 
1.4 
PRECLINICAL PHARMACOLOGY ............................................................................................................ 20 
1.5 
TOXICOLOGY ........................................................................................................................................ 21 
1.6 
PREVIOUS CLINICAL STUDIES WITH DS107 .......................................................................................... 22 
2 
RISK BENEFIT ASSESSMENT ............................................................................................................ 28 
3 
RATIONALE FOR THE STUDY .......................................................................................................... 29 
4 
STUDY OBJECTIVES ............................................................................................................................ 30 
5 
STUDY ENDPOINTS .............................................................................................................................. 31 
5.1 
PRIMARY ENDPOINT ............................................................................................................................. 31 
5.2 
SECONDARY ENDPOINTS ...................................................................................................................... 31 
5.3 
EXPLORATORY ENDPOINTS .................................................................................................................. 32 
6 
STUDY DESIGN ...................................................................................................................................... 33 
7 
PATIENTS AND SCREENING ............................................................................................................. 34 
7.1 
SOURCE OF PATIENTS ........................................................................................................................... 34 
7.2 
INCLUSION CRITERIA ............................................................................................................................ 34 
7.3 
EXCLUSION CRITERIA ........................................................................................................................... 35 
7.4 
SCREENING AND CONSENT ................................................................................................................... 37 
7.5 
WITHDRAWAL OF PATIENTS ................................................................................................................. 37 
7.6 
PATIENT REPLACEMENT ....................................................................................................................... 38 
7.7 
PROTOCOL VIOLATIONS ....................................................................................................................... 38 
7.8 
STOPPING CRITERIA ............................................................................................................................. 38 
8 
STUDY CONDUCT ................................................................................................................................. 39 
8.1 
STUDY SCHEDULE ................................................................................................................................ 39 
8.2 
SCREENING ........................................................................................................................................... 39 
8.2.1 
Screening Visit (Visit 1) ............................................................................................................... 39 
8.3 
TREATMENT PERIOD ............................................................................................................................. 40 
8.3.1 
Baseline (Visit 2) ........................................................................................................................... 40 
8.3.2 
Week 1 (Visit 3) ............................................................................................................................ 41 
8.3.3 
Week 4 (Visit 4) ............................................................................................................................ 42 
8.3.4 
Week 8 (Visit 5) ............................................................................................................................ 43 
8.3.5 
Week 12 (Visit 6) .......................................................................................................................... 44 
8.3.6 
Week 16 (Visit 7) / End of Treatment or Early Termination ................................................... 44 
8.3.7 
Week 18 (Visit 8) / Follow-up 1 ................................................................................................... 45 
8.3.8 
Week 20 (Visit 9) / Follow up 2 ................................................................................................... 46 
9 
ASSESSMENTS ....................................................................................................................................... 47 
9.1 
EFFICACY ASSESSMENTS ...................................................................................................................... 47 
9.1.1 
Validated Investigator Global Assessment (vIGA-ADTM) ........................................................ 47 
9.1.2 
Eczema Area Severity Index (EASI) .......................................................................................... 47 
9.1.3 
Pruritus NRS ................................................................................................................................ 47 
9.1.4 
Body Surface Area (BSA) ............................................................................................................ 47 
9.1.5 
Dermatology Life Quality Index (DLQI) Questionnaire .......................................................... 47 
9.1.6 
Patient Orientated Eczema Measure (POEM) .......................................................................... 48 
9.1.7 
SCORing Atopic Dermatitis (SCORAD) ................................................................................... 48 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 4 of 83 
 
9.1.8 
Athens Insomnia Scale (AIS)....................................................................................................... 48 
9.1.9 
Patient Oriented SCORAD (PO-SCORAD) .............................................................................. 49 
9.2 
SAFETY ASSESSMENTS ......................................................................................................................... 49 
9.2.1 
Medical / Surgical History ........................................................................................................... 49 
9.2.2 
Physical Examination .................................................................................................................. 49 
9.2.3 
Vital Signs ..................................................................................................................................... 49 
9.2.4 
Clinical Laboratory Safety Tests: Haematology and Serum Biochemistry ............................ 49 
9.2.5 
Pregnancy Test ............................................................................................................................. 50 
9.2.6 
Virology ......................................................................................................................................... 50 
9.2.7 
Electrocardiogram (ECG) ........................................................................................................... 50 
9.2.8 
Body Mass Index (BMI) .............................................................................................................. 50 
9.2.9 
DGLA Plasma Concentration Sampling .................................................................................... 50 
9.2.10 Biomarker Sampling .................................................................................................................... 51 
9.2.11 Sample Storage, Handling and Shipping ................................................................................... 51 
9.2.12 Adverse Event Assessment .......................................................................................................... 51 
9.2.13 Concomitant Medication ............................................................................................................. 51 
9.2.14 Restrictions ................................................................................................................................... 52 
9.2.15 Rescue Treatment ........................................................................................................................ 53 
10 
INVESTIGATIONAL MEDICINAL PRODUCT / INVESTIGATIONAL DRUG .......................... 54 
10.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) .................................................................................. 54 
10.2 
SUPPLY, PACKAGING, LABELLING, HANDLING AND STORAGE ............................................................. 54 
10.3 
DOSAGE AND ADMINISTRATION ........................................................................................................... 54 
10.4 
DURATION OF TREATMENT................................................................................................................... 55 
10.5 
METHODS FOR ASSIGNING PATIENTS TO TREATMENTS ........................................................................ 55 
10.6 
DRUG ACCOUNTABILITY ...................................................................................................................... 55 
11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................................... 57 
11.1 
DEFINITIONS OF ADVERSE EVENTS ...................................................................................................... 57 
11.1.1 Seriousness .................................................................................................................................... 57 
11.1.2 Severity ......................................................................................................................................... 57 
11.1.3 Relationship to IMP ..................................................................................................................... 58 
11.1.4 Reporting of AEs and SAEs ........................................................................................................ 58 
11.2 
SERIOUS ADVERSE REACTIONS AND UNEXPECTED ADVERSE REACTIONS ........................................... 58 
11.2.1 Definitions ..................................................................................................................................... 58 
11.2.2 Reporting of suspected unexpected serious adverse reactions ................................................. 59 
11.3 
DIFFERENTIATION OF TREATMENT FAILURE AND AE ........................................................................... 59 
11.4 
PREGNANCY REPORTING ...................................................................................................................... 59 
12 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT .................................................. 60 
12.1 
STUDY DESIGN ..................................................................................................................................... 60 
12.2 
RANDOMISATION .................................................................................................................................. 60 
12.3 
ESTIMATION OF SAMPLE SIZE ............................................................................................................... 60 
12.4 
BLINDING AND CODE BREAKING INSTRUCTIONS .................................................................................. 61 
12.5 
DATA ANALYSIS ................................................................................................................................... 61 
12.6 
ANALYSIS SETS .................................................................................................................................... 61 
12.7 
SAFETY ANALYSIS................................................................................................................................ 62 
12.8 
STATISTICAL ANALYSIS PLAN .............................................................................................................. 62 
12.8.1 Pharmacokinetic Analysis ........................................................................................................... 62 
12.8.2 Primary variables ......................................................................................................................... 62 
12.8.3 Secondary variables ..................................................................................................................... 63 
12.8.4 Safety variables ............................................................................................................................ 63 
12.9 
INTERIM ANALYSIS .............................................................................................................................. 64 
12.10 DATA COLLECTION / CASE REPORT FORMS .......................................................................................... 64 
12.11 DATA MANAGEMENT ........................................................................................................................... 64 
12.12 PROTOCOL DEVIATIONS ....................................................................................................................... 65 
13 
REGULATORY AND ADMINISTRATIVE PROCEDURES ............................................................ 66 
13.1 
INSTITUTIONAL REVIEW ....................................................................................................................... 66 
13.2 
GCP ..................................................................................................................................................... 66 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 5 of 83 
 
13.3 
ESSENTIAL DOCUMENTS....................................................................................................................... 66 
13.4 
RECORD RETENTION............................................................................................................................. 66 
13.5 
MONITORING / QUALITY CONTROL ...................................................................................................... 66 
13.6 
QUALITY ASSURANCE .......................................................................................................................... 67 
13.7 
INSURANCE AND LIABILITY .................................................................................................................. 67 
13.8 
END OF TRIAL ....................................................................................................................................... 67 
13.9 
CONFIDENTIALITY ................................................................................................................................ 67 
13.10 DATA PROTECTION ............................................................................................................................... 67 
13.11 REPORT AND PUBLICATION .................................................................................................................. 67 
13.12 COVID-19 CONTINGENCY ................................................................................................................... 67 
14 
REFERENCES ......................................................................................................................................... 69 
15 
APPENDICES .......................................................................................................................................... 71 
15.1 
APPENDIX 1: STUDY FLOW-CHART ...................................................................................................... 71 
15.2 
APPENDIX 2: DIAGNOSTIC FEATURES 
OF ATOPIC DERMATITIS (AMERICAN ACADEMY 
OF 
DERMATOLOGY CONSENSUS CRITERIA) ............................................................................................... 73 
15.3 
APPENDIX 3: VALIDATED INVESTIGATOR’S GLOBAL ASSESSMENT FOR ATOPIC DERMATITIS (VIGA-
ADTM) .................................................................................................................................................. 74 
15.4 
APPENDIX 4: ECZEMA AREA AND SEVERITY INDEX (EASI) ................................................................. 75 
15.5 
APPENDIX 5: NUMERICAL RATING SCALE FOR ASSESSMENT OF PRURITUS ........................................... 76 
15.6 
APPENDIX 6: DERMATOLOGY LIFE QUALITY INDEX (DLQI) ................................................................ 77 
15.7 
APPENDIX 7: PATIENT ORIENTATED ECZEMA MEASURE ...................................................................... 79 
15.8 
APPENDIX 8: SCORING ATOPIC DERMATITIS (SCORAD) ................................................................... 80 
15.9 
APPENDIX 9: ATHENS INSOMNIA SCALE ............................................................................................... 81 
15.10 APPENDIX 10: PATIENT-ORIENTED SCORAD ...................................................................................... 82 
15.11 APPENDIX 11: COVID-19 CONTINGENCY INVESTIGATOR ASSESSMENT PHONE VISITS ....................... 83 
 
 
 
LIST OF FIGURES 
Figure 1: Structure of DGLA ........................................................................................................................ 20 
Figure 2: Study Outline ……………………………………………………………………………………33 
 
LIST OF TABLES 
Table 1: Summary of DS107 Capsules Use in Human Healthy Volunteers/Patients ................................... 22 
Table 2: Clinical Laboratory Safety Tests .................................................................................................... 50 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 6 of 83 
 
 
SIGNATURE PAGE 
 
The signatures below constitute the approval of this protocol and the attachments, and provide the 
necessary assurances that this trial will be conducted according to local legal and regulatory 
requirements, applicable country regulations, the International Conference on Harmonization (ICH) 
Good Clinical Practices Guidelines and the Declaration of Helsinki. 
 
 
SPONSOR: 
 
 
 
Signature: 
 
Date: 
 
Dr. Markus Weissbach 
Chief Medical Officer, DS Biopharma 
 
 
 
 
CLINICAL EXPERT: 
 
 
 
 
Signature: 
 
Date: 
 
Prof. Emma Guttman-Yassky 
Prof of Dermatology at Icahn School of Medicine at Mount Sinai 
 
 
 
STATISTICIAN: 
 
 
 
 
Signature: 
 
Date: 
 
Winfried Koch 
Statistical Consultant, BDS Koch 
 
 
 
 
 
 
 
 
 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 7 of 83 
 
PRINCIPAL SITE INVESTIGATOR SIGNATURE 
PAGE 
 
 
 
 
Investigator name: 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
 
 
 
 
Institution Name: 
 
 
 
 
By my signature, I agree to personally supervise the conduct of this study at my study site 
and to ensure its conduct is in compliance with the protocol, informed consent, Independent 
Ethics Committee (IEC) procedures, instructions from DS Biopharma representatives, the 
Declaration of Helsinki, International Conference on Harmonization (ICH) Good Clinical 
Practices Guidelines, and national/local regulations governing the conduct of clinical studies. 
 
The signature also confirms that the Investigator agrees that the results of this study may be 
used for submission to national and/or international registration and supervising authorities. 
The authorities will be notified of the Investigators name, address, qualifications and extent 
of involvement. 
 
 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 8 of 83 
 
PROTOCOL SYNOPSIS 
STUDY TITLE: 
A Randomised, Double-blind, Placebo-controlled Study to Assess 
the Efficacy and Safety of Orally Administered DS107 in Adult 
Patients with Moderate to Severe Atopic Dermatitis  
 
SHORT TITLE: 
Efficacy and Safety of Orally Administered DS107 in Adult 
Patients with Moderate to Severe Atopic Dermatitis  
 
PHASE: 
II 
STUDY DURATION: 
20 weeks (Treatment Duration: 16 weeks) 
INVESTIGATIONAL 
PRODUCT: 
DS107 Capsules  
 
Placebo 
 
OBJECTIVE:  
Efficacy Objective: 
 
• 
To compare the efficacy of orally administered DS107 
versus placebo, in the treatment of adult patients with 
moderate to severe Atopic Dermatitis (AD). 
 
Safety Objective: 
  
• 
To assess the safety of orally administered DS107 versus 
placebo, in adult patients with moderate to severe AD. 
 
PRIMARY ENDPOINTS: 
 
• 
Proportion of patients achieving a vIGA-ADTM score of 0 
(clear) or 1 (almost clear) and a decrease of at least 2 points 
in vIGA-ADTM in treated population compared to placebo 
population from baseline at Week 16. 
 
• 
Proportion of patients achieving EASI-75 (≥75% 
improvement from baseline) in treated population compared 
to placebo population at Week 16. 
 
Note: 
Each of the independent primary endpoints will be analysed 
separately. Success in either of the primary endpoints denotes 
successful proof of efficacy. 
 
SECONDARY 
ENDPOINTS: 
• Proportion of patients achieving a vIGA-ADTM score of 0 
(clear) or 1 (almost clear) and a decrease of at least 2 points 
in vIGA-ADTM in treated population compared to placebo 
population from baseline to Week 4, 8, 12, 18 and 20 and the 
change in proportion of patients from Week 16 to Week 18 
and 20.  
 
• Proportion 
of 
patients 
achieving 
EASI-75 
(≥75% 
improvement from baseline) in treated population compared 
to placebo population at Week 4, 8, 12, 18 and 20 and the 
change in proportion of patients from Week 16 to Week 18 
and 20.  
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 9 of 83 
 
• Change from baseline in vIGA-ADTM score in treated 
population compared to placebo population to Week 4, 8, 12, 
16, 18 and 20, and from Week 16 to Week 18 and 20. 
 
• Change from baseline in EASI in treated population 
compared to placebo population to Week 4, 8, 12, 16, 18 and 
20, and from Week 16 to Week 18 and 20. 
 
• Proportion of patients achieving a decrease of at least 4 points 
in worst itch NRS in treated population compared to placebo 
population from baseline to Week 4, 8, 12, 16, 18 and 20 and 
the change in proportion of patients from Week 16 to Week 
18 and 20.  
 
• Proportion of patients achieving a decrease of at least 3 points 
in worst itch NRS in treated population compared to placebo 
population from baseline to Week 4, 8, 12, 16, 18 and 20 and 
the change in proportion of patients from Week 16 to Week 
18 and 20.  
 
• Change from baseline in worst itch NRS in treated population 
compared to placebo population to Week 4, 8, 12, 16, 18 and 
20, and from Week 16 to Week 18 and 20. 
 
• Proportion 
of 
patients 
achieving 
EASI-50 
(≥50% 
improvement from baseline) in treated population compared 
to placebo population at Week 4, 8, 12, 16, 18 and 20 and the 
change in proportion of patients from Week 16 to Week 18 
and 20.  
 
• Change from baseline in the Body Surface Area (BSA) 
affected by AD in treated population compared to placebo 
population to Week 4, 8, 12, 16, 18 and 20, and from Week 
16 to Week 18 and 20. 
 
• Change from baseline in the SCORing Atopic Dermatitis 
(SCORAD) score in treated population compared to placebo 
population to Week 4, 8, 12, 16, 18 and 20, and from Week 
16 to Week 18 and 20. 
 
• Incidence of treatment emergent adverse events (TEAEs) and 
serious adverse events (SAEs) 
 
 
EXPLORATORY 
ENDPOINTS: 
• Proportion of patients achieving a decrease of at least 2 points 
in vIGA-ADTM in treated population compared to placebo 
population from baseline to Week 4, 8, 12, 16, 18 and 20 and 
the change in proportion of patients from Week 16 to Week 
18 and 20.  
 
• Change from baseline in the Dermatology Life Quality Index 
(DLQI) score in treated population compared to placebo 
population to Week 4, 8, 12, 16, 18 and 20, and from Week 
16 to Week 18 and 20. 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 10 of 83 
 
 
• Change from baseline in the Patient Orientated Eczema 
Measure (POEM) score in treated population compared to 
placebo population to Week 4, 8, 12, 16, 18 and 20, and from 
Week 16 to Week 18 and 20. 
 
• Change in sleep quality assessment (Athens Insomnia Scale) 
in treated population compared to placebo population from 
baseline to Week 4, 8, 12, 16, 18 and 20, and from Week 16 
to Week 18 and 20.  
 
• Change from baseline in the Patient-Oriented SCORAD (PO-
SCORAD) score in treated population compared to placebo 
population to Week 4, 8, 12, 16, 18 and 20, and from Week 
16 to Week 18 and 20. 
 
• Trough plasma levels in treated population compared to 
placebo population at Baseline/Day 0, Week 4, Week 8 and 
Week 16. 
 
• Determination of AD biomarkers in treated population 
compared to placebo population at Baseline/Day 0 and Week 
16. 
 
SAFETY VARIABLES: 
• Adverse event (AE) and serious adverse event (SAE) 
frequency and severity. 
 
• Safety laboratory parameters (haematology, clinical 
chemistry). 
 
• Clinical safety examinations (vital signs, physical 
examination). 
 
STUDY DESIGN: 
This is a multicenter, double-blind, placebo controlled, 2-arm, 
Phase II study with 16 weeks of active treatment and a 4 week 
follow up period.  
 
Patients will be randomized (1:1) at baseline visit to either receive 
2g DS107 once daily or placebo once daily for 16 weeks. 
 
TOTAL NUMBER OF 
RANDOMISED 
PATIENTS: 
220 
STUDY POPULATION: 
INCLUSION CRITERIA:  
 
 
 
 
 
 
 
 
 
 
1. Patients with a clinically confirmed diagnosis of active AD 
according to the American Academy of Dermatology 
Consensus Criteria that has been present for at least 6 
months before the screening visit. 
  
2. Patients with moderate to severe AD at baseline as defined 
by a vIGA-ADTM score of 3 or 4 at baseline. 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 11 of 83 
 
 
 
 
 
 
 
 
 
 
3. Patients with an EASI score of ≥16 at screening and 
baseline. 
 
4. Patients with AD covering a minimum 10% of the body 
surface area (BSA) at baseline. 
 
5. Patients with a worst itch NRS score in a day of ≥4 (on 11 
point NRS) at the screening and baseline visits. 
 
6. Patients whose pre-study clinical laboratory findings do not 
interfere with their participation in the study, in the opinion 
of the Investigator. 
 
7. Patients who are able and willing to stop all current 
treatments for AD throughout the study (except for allowed 
emollients). 
 
8. Patients who are on a stable dose of a bland emollient for at 
least 7 days prior to baseline. 
 
Note: 
Patients who have been on a stable emollient with an active 
ingredient (for example urea, ceramide and hyaluronic 
acid)  for at least 12 weeks prior to screening and are 
otherwise eligible may continue using their pre-existing 
emollients, if deemed appropriate by the investigator and if 
they are willing and able to continue using the same stable 
emollient for the duration of the study.  
 
9. Male or female patients aged 18 years and older on the day 
of signing the informed consent form (ICF). 
 
10. Female patients and male patients with female partners of 
child bearing potential must use highly effective birth 
control methods or have a sterilised partner for the duration 
of the study. 
 
Note: 
• 
Highly effective birth control methods are defined as 
methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly. Such 
methods include systemic hormonal contraceptives, 
intrauterine device or sexual abstinence. 
 
• 
Hormonal contraceptives must be on a stable dose for at 
least one month before baseline. 
 
• 
Sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual 
lifestyle of the patient. 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 12 of 83 
 
 
11. Recent history (within 6 months before the screening visit) 
of inadequate response to treatment with topical medications 
or for whom topical treatments are otherwise medically 
inadvisable (e.g., because of important side effects or safety 
risks). 
 
Note: 
• 
Inadequate response is defined as failure to achieve and 
maintain remission or a low disease activity state 
(comparable to vIGA-ADTM 0=clear to 2=mild) despite 
treatment with a daily regimen of topical corticosteroids 
(TCS) of medium to higher potency (± topical calcineurin 
inhibitors (TCI) as appropriate), applied for at least 28 
days or for the maximum duration recommended by the 
product prescribing information (e.g., 14 days for super-
potent TCS), whichever is shorter. 
 
• 
Patients with documented systemic treatment for AD (for 
example systemic corticosteroids, cyclosporine) in the 
past 6 months are also considered as inadequate 
responders to topical treatments and are potentially 
eligible for treatment with DS107 after appropriate 
washout. 
 
• 
Important side effects or safety risks are those that 
outweigh the potential treatment benefits and include 
intolerance to treatment, hypersensitivity reactions, 
significant skin atrophy, and systemic effects, as assessed 
by the Investigator or by the patient’s treating physician. 
 
12. Patients who are able to communicate well with the 
Investigator, to understand and comply with the 
requirements of the study, and understand and sign the 
written informed consent prior to initiation of any study 
specific activities or procedures. 
 
EXCLUSION CRITERIA: 
1. Patients with other skin conditions that might interfere with 
AD diagnosis and/or evaluation (such as psoriasis or current 
active viral, bacterial and fungal topical skin infections) as 
assessed by the Investigator. 
2. Patients who have used systemic treatments that could affect 
AD less than 4 weeks prior to Baseline Visit (Day 0), e.g. 
retinoids, methotrexate, cyclosporine, hydroxycarbamide 
(hydroxyurea), 
azathioprine 
and 
oral/injectable 
corticosteroids. Intranasal corticosteroids and inhaled 
corticosteroids for stable medical conditions are allowed. 
3. Patients with previous exposure to DS107. 
4. Patients who have used any topical medicated treatment for 
AD (except for emollients) two weeks prior to start of 
treatment/Baseline (Day 0) including but not limited to, 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 13 of 83 
 
topical corticosteroids, calcineurin inhibitors, tars, bleach, 
antimicrobials and bleach baths. 
5. Patients who use emollients containing urea, ceramides or 
hyaluronic acid less than 12 weeks prior to Baseline (Day 
0). 
6. Patients who have had excessive sun exposure, have used 
tanning booths or other ultraviolet (UV) light sources four 
weeks prior to Baseline (Day 0) and/or are planning a trip to 
a sunny climate or to use tanning booths or other UV sources 
between screening and follow-up visits. 
7. Patients who have a history of hypersensitivity to any 
substance in DS107 or placebo capsules. 
8. Patients who have a history of hypersensitivity to soy beans 
or soy lecithin.  
9. Patients who have a white cell count or differential white 
cell count outside of the normal reference range at 
screening. 
 
Note: 
For patients with a mild leucocytosis or leucopenia and 
otherwise a normal white cell blood count may be enrolled 
following consultation with the medical monitor by the 
investigator. 
 
10. Patients who have any clinically significant controlled or 
uncontrolled medical condition or laboratory abnormality 
that would, in the opinion of the Investigator, put the patient 
at undue risk or interfere with interpretation of study results.  
11. Patients who have a clinically significant impairment of 
renal or hepatic function. 
12. Patients with significant uncontrolled cardiovascular, 
neurologic, 
malignant, 
psychiatric, 
respiratory 
or 
hypertensive disease, as well as uncontrolled diabetes and 
flouride arthritis or any other illness that, in the opinion of 
the Investigator, is likely to interfere with completion of the 
study. 
13. Patients with active infectious diseases (e.g., hepatitis B, 
hepatitis C or advanced disease secondary to infection with 
human immunodeficiency virus). 
14. Patients with a history of clinically significant drug or 
alcohol abuse in the opinion of the Investigator in the last 
year prior to Baseline (Day 0). 
15. Patients who have participated in any other clinical study 
with an investigational drug within 3 months before the first 
day of administration of study treatment. 
16. Patients who have had treatment with biologics as follows:  


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 14 of 83 
 
a. Any cell-depleting agents including but not 
limited to rituximab: within 6 months before the 
screening visit, or until lymphocyte count returns 
to normal, whichever is longer, 
b. Other biologics influencing cell proliferation: 
within 6 months before the screening visit. 
c. Dupilumab or other monoclonal antibodies 
within 5 half-lives (if known) or 16 weeks prior 
to baseline visit, whichever is longer  
 
17. Patients 
who 
are 
pregnant, 
planning 
pregnancy, 
breastfeeding and/or are unwilling to use adequate 
contraception (as specified in Inclusion Criterion 10) during 
the trial. 
18. Patients, in the opinion of the Investigator, not suitable to 
participate in the study. 
TEST PRODUCT, DOSE 
AND MODE OF 
ADMINISTRATION: 
DS107 capsules will be provided as a capsule containing 500mg 
DGLA per unit dose. 
Placebo will be provided as a matching capsule. 
This study will involve one dose level of DS107 for 16 weeks 
(2g DS107 OD = 4 capsules) or placebo (OD = 4 matching 
capsules). 
Investigational Medicinal Product (IMP) will be administered 
approximately 2 hours after food consumption at the same time 
each day. Patients will be instructed to not consume food for 
approximately 1 hour after IMP administration 
EVALUATION CRITERIA: 
SAFETY 
 
• Physical examination 
• Vital signs, including blood pressure (BP), pulse and 
temperature 
• Clinical laboratory tests (haematology, biochemistry) 
• Pregnancy test for females of child bearing potential 
• AEs 
• Concomitant medications (CMs) 
BEHAVIOURAL 
RESTRICTIONS 
• Patients will be asked to refrain from any travel to sunny 
climates or use of tanning equipment, saunas and swimming 
throughout the duration of the study. 
 
• Extensive UV exposure or UV-B devices within four weeks 
of the trial and during the trial. 
RESCUE TREATMENT 
If medically necessary (i.e., to control intolerable AD symptoms), 
rescue treatment for AD may be provided to study patients at the 
discretion of the investigator. If possible, investigators should 
avoid administration of rescue treatments before Week 4 due to 
the expected time to onset of treatment-response following DS107 
treatment. 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 15 of 83 
 
For the purpose of efficacy analysis, patients who receive rescue 
treatment during the study treatment period will be considered 
treatment failures from the time rescue treatment is used. 
Topical corticosteroids or calcineurin inhibitors may be used for 
rescue, but should be reserved for problem areas only, eg, face, 
neck, intertriginous and genital areas, etc. If a patient receives 
rescue treatment with systemic corticosteroids or non-steroidal 
systemic immunosuppressive drugs (cyclosporine, methotrexate, 
mycophenolate mofetil, azathioprine, etc.) study treatment will be 
immediately discontinued. 
Investigators should make every attempt to conduct efficacy and 
safety assessments (eg, disease severity scores, safety labs) 
immediately before administering any rescue treatment. 
STATISTICAL ANALYSIS  
The primary analysis will be conducted in the full analysis set 
(FAS) population. 
A longitudinal mixed model for binary outcomes (GENMOD) 
will be used to separately analyze the binary primary and 
secondary efficacy endpoints at Week 16.  
Change from baseline for secondary and exploratory endpoints 
(vIGA-ADTM, EASI, NRS, BSA, SCORAD, DLQI, POEM, AIS 
and PO-SCORAD) will be analysed using mixed model with 
repeated measures (MMRM). The models will include Treatment 
Arm as a factor and respective baseline value as a covariate, with 
the treatment-by-visit interaction term as a random effect to 
account for missing data at Week 16. 
Sensitivity analyses will be performed to assess the robustness of 
the Missing at Random (MAR) assumptions that support the 
GENMOD methods above for imputing missing data. 
SPONSOR: 
DS Biopharma 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 16 of 83 
 
LIST OF ABBREVIATIONS 
15-HETrE 
AD 
15-hydroxyeicosatrienoic acid 
Atopic Dermatitis 
AE 
AIS 
ALP 
ALT 
API 
AST 
AUC 
Adverse Event 
Athens Insomnia Scale 
Alkaline Phosphatase 
Alanine Aminotransferase 
Active Pharmaceutical Ingredient 
Aspartate Aminotransferase 
Area Under the Curve 
BD 
BDRM 
Bis Die (Twice Daily) 
Blind Data Review Meeting 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPM 
BSA 
BUN 
CM 
Cmax 
CMH 
COX 
CPK 
Beats Per Minute 
Body Surface Area 
Blood Urea Nitrogen 
Concomitant Medication 
Maximum Concentration 
Cochran-Mantel-Haenszel test 
Cyclooxygenase 
Creatinine Phosphokinase 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organisation 
CRF 
CRL 
CsA 
CTA 
Case Report Form 
Charles River Laboratories 
Cyclosporin A 
Clinical Trials Agreement 
DGLA 
Dihomo-Gamma-Linolenic Acid 
DLQI 
DM 
Dermatology Life Quality Index 
Data Manager 
EASI 
Eczema Area and Severity Index 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 17 of 83 
 
EC 
EDC 
ECG 
eCRF 
ET 
EU 
Ethics Committee 
Electronic Data Capture 
Electrocardiography 
electronic Case Report Form  
Early Termination 
European Union 
FAS 
FSH 
Full Set Analysis 
Follicle Stimulating Hormone 
GCP 
GLP 
GLMM 
Good Clinical Practice 
Good Laboratory Practice 
Generalised Linear Mixed Model  
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
ICH 
 
IFN-γ 
IGA 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
Interferon-Gamma 
Investigator Global Assessment 
IgE 
Immunoglobulin E 
IL 
IMP 
Interleukin 
Investigational Medicinal Product 
ISF 
Investigator Site File 
IWRS 
kg 
LDH 
LSLV 
Interactive Web Response System 
Kilogram 
Lactate Dehydrogenase 
Last Subject Last Visit 
MAR 
Missing at Random 
MedDRA 
MMRM 
NOAEL 
NRS 
Medical Dictionary for Regulatory Activities 
Mixed Model with Repeated Measures 
No Observed Adverse Event Limit 
Numeric Rating Scale 
OD 
Once Daily 
OTC 
Over The Counter 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 18 of 83 
 
PDE4 
PGD1 
Phosphodiesterase 4 
Prostaglandin D1 
PGI-C 
Patient Global Impression of Change 
PGI-S 
PI 
Patient Global Impression of Severity 
Principal Investigator 
PIS 
Patient Information Sheet  
PK 
Pharmacokinetics 
POEM 
Patient Orientated Eczema Measure 
PO-SCORAD 
Patient Oriented Scoring of Atopic Dermatitis 
PP 
PPS 
PUVA 
Per Population 
Per Protocol Set 
Psoralen & Ultraviolet A  
PV CRO 
Pharmacovigilance Contract Research Organisation 
SAE 
SAS 
Serious Adverse Event 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SCORAD 
Scoring of Atopic Dermatitis 
SDV 
SOP 
SPC 
Source Data Verification 
Standard Operating Procedure 
Summary of Products Characteristics 
SUSAR 
TCI 
TCS 
TNF-α 
UAE 
US 
Suspected Unexpected Serious Adverse Reaction 
Topical Calcineurin Inhibitors 
Topical Corticosteroids 
Tumor Necrosis Factor-Alpha  
Unexpected Adverse Event 
United States 
UV-A/B 
VAS 
Ultraviolet-A/B 
Visual Analogue Scale 
vIGA-ADTM 
Validated Investigator Global Assessment Scale for Atopic Dermatitis.  
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 19 of 83 
 
1 
INTRODUCTION  
1.1 
Therapeutic Area and Disease Background 
 
AD is a common chronic inflammatory skin disease that affects 15 to 30% of children and 2 to 10% of 
adults (Williams and Flohr 2006, Silverberg et al. 2013).  
 
AD progresses with erratic and often unpredictable flare-ups/exacerbations and is characterized by 
extremely dry, itchy skin which leads to scratching, resulting in further irritation and inflammation. As 
the skin loses moisture from the epidermal layer, it becomes increasingly dry and may begin to crack, 
weep, crust, and scale. This damage to the integrity of the skin renders it less protective and more prone 
to infection and environment influences (allergens and irritants). 
 
AD demonstrates specific age-dependent manifestations. Adult patients in the chronic phase 
demonstrate lichenified lesions which are associated with dryness, erythema and pruritus. The lesions 
most commonly occur on flexural folds; the face, the neck, the upper arms and back, and the dorsa of 
the hands, feet, fingers and toes. Adult patients may also develop exudation and crusting as a result of 
bacterial infections (Schultz-Larsen & Hanifin 2002).  
 
In all stages of AD, pruritus that continues throughout the day and worsens at night, causes sleep loss, 
irritability and generalised stress, which substantially impairs the patient's quality of life (Simpson 2010, 
Suarez et al. 2012). 
 
The mechanisms underlying the pathogenesis of AD remain unclear. Many studies have demonstrated 
the involvement of genetic predisposition, immune dysfunction, emotional and environmental stimuli 
and epidermal barrier dysfunction in its development and progression. It is well recognised however 
that IgE-mediated reactions (Bos et al. 1994) and elevated eosinophil levels (Kapp 1993) are involved 
in causing inflammation associated with AD. Additionally the overactiveation of acute, allergic Th2 
response results in the secretion of pro-inflammatory mediators. The chronic phase is characterised by 
a predominantly Th1 response as the disease progresses. The multifactorial pathology likely accounts 
for the heterogeneity associated with AD onset and severity and suggests a requirement for a multimodal 
therapeutic approach (Leung & Guttman-Yassky 2014).  
 
DS107 is being studied in oral (capsule) and topical (cream) formulation.  
 
DS107 capsules, contain >95% pure dihomo-γ-linoleic acid (DGLA) as active pharmaceutical 
ingredient, has been developed for the treatment of AD due to its potent antibacterial and anti-
inflammatory properties. The multimodal mechanism of action of both topical and DS107 capsules has 
been shown to improve the signs and symptoms of AD including pruritus and patient quality of life in 
two previous proof-of-concept Phase 2a studies. 
1.2 
Standard Treatment 
 
Currently, there is no treatment available to cure AD. Generally, symptomatic repeated treatments are 
necessary to achieve a stable state in which flare-ups are controlled and the number of flares reduced. 
 
First-line therapy includes topical corticosteroids during an exacerbation and long-term emollient use 
thereafter. Other available treatment for AD includes topical calcineurin inhibitors, phototherapy, and 
systemic corticosteroid therapy or Cyclosporin A (CsA) in more difficult cases (Eichenfield et al. 2014). 
 
Emollients have long been used to improve epidermal barrier function and alleviate dry skin in patients 
with AD. However, emollients alone rarely control AD unless it is of mild severity. Topical 
corticosteroids have been the pillar of medicated therapy for AD since their introduction nearly 50 years 
ago. However, the common side effects (skin atrophy, striae, burning, pruritus, and folliculitis) 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 20 of 83 
 
associated with the use of corticosteroids mean that they can only be used as a short-term therapy 
(Eichenfield et al. 2014). 
 
The introduction of topical calcineurin inhibitors represented the first new class of medication approved 
for the treatment of AD since topical corticosteroids. Topical calcineurin inhibitors pimecrolimus 
(Elidel®) and tacrolimus (Protopic®) are immunomodulating agents that act locally on T-cells by 
suppressing transcription and release of pro-inflammatory cytokines (IL-2, IL-3, IL-4, IL-5, IFN-γ, 
TNF­α) (Gutfreund et al. 2013). Inhibiting cytokine production leads to decreased inflammation and 
serves to block T-cell activation which can trigger and maintain skin inflammation (Simpson 2010). 
These agents have been shown to reduce the extent, severity, and symptoms of AD in adults and 
children; however, they can cause skin irritation at the site of the application.  Common local side effects 
include burning sensations, itching, erythema, and infection (Ashcroft et al. 2005). 
 
Phototherapy can be a useful adjunct in the treatment of AD (Reynolds et al. 2001). However, it can 
cause short-term adverse effects including erythema, skin pain, itching, and pigmentation as well as 
long-term effects including premature skin aging and cutaneous malignant diseases (Leung & Bieber 
2003). 
 
The use of systemic treatments to manage the symptoms of AD has been rare. Oral corticosteroids, 
immunosuppressants, antifolates, and antihistamines have been used in the past with moderate efficacy 
and poor safety profiles resulting in a short treatment window (Eichenfield et al. 2014). 
 
Recent regulatory approvals of the monoclonal antibody dupilumab, an IL-4Rα antagonist that inhibits 
the signalling of Th2 cytokines IL-4 and IL-13; and crisaborole a topically applied PDE4 inhibitor have 
introduced two new treatment options for AD.  
 
Despite recent advances, there is still an unmet need for safe and effective oral treatment options for 
patients with moderate to severe AD. 
1.3 
Drug Class 
DS107 capsules contain the active pharmaceutical ingredient (API) DGLA a long-chain 
polyunsaturated fatty acid endogenously present in the body.  
 
Figure 1: Structure of DGLA 
 
 
 
1.4 
Preclinical Pharmacology 
Numerous preclinical studies have been performed to determine the mechanisms of action of DS107 in 
inflammatory skin diseases including AD. The results of the studies have highlighted a multi-modal 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 21 of 83 
 
mechanism of action in which DS107 exerts its therapeutic effect, including direct anti-bacterial 
mechanisms as well as direct and indirect anti-inflammatory mechanisms.  
The effect of DS107 on the release of proinflammatory cytokines from human monocytes has been 
studied and shows that DS107 significantly reduces the secretion of IL-1β and IL-8 from triggered 
monocytes. Both IL-1β and IL-8 play an important role in the pathogenesis of AD. Inhibition of these 
pro-inflammatory pathways with DS107 capsules may provide significant improvements in the clinical 
manifestations of AD. It has been shown that metabolism of DGLA via COX-1 and COX-2 pathways 
results in the production of potent anti-inflammatory eicosanoids such as prostaglandins (specifically 
PGD1) and thromboxanes (Kawashima et al. 2008; Amagai et al. 2015).  Additionally, lipoxygenation 
of DGLA results in the production of monohydroxy fatty acid 15-hydroxyeicosatrienoic acid (15-
HETrE) which has shown potent anti-inflammatory properties (Iverson et al. 1992).   
In addition to anti-inflammatory mechanisms, DS107 significantly inhibits the growth of 
Staphylococcus aureus and Propionibacterium acnes and also has direct bactericidal activity against 
both (Desbois & Lawlor 2013). 
DGLA has been reported to supress acute and chronic inflammation in whole preclinical mouse studies. 
Oral administration of up to 600 mg/kg DGLA has shown dose dependent improvements in severity of 
skin lesions in animal models of AD. DGLA treatment is correlated with decreased plasma total IgE 
concentrations which may contribute to resolving the AD lesions (Kawashima et al. 2008). 
In the same study DGLA also significantly decreases the number of scratch events and duration of 
scratching in animal models of AD (Kawashima et al. 2008; Amagai et al. 2015). The improvement in 
clinical scores and pruritus has been associated with the generation of PGD1 via DGLA metabolism 
(Amagai et al. 2015). 
1.5 
Toxicology 
 
Oral Toxicology 
A 13-week oral study in rats using DGLA did not show any significant treatment-related adverse events 
and so the No Observed Adverse Event Limit (NOAEL) was set at 2000 mg/kg per day. Read-across 
from linoleic acid would suggest that repeated exposure to DS107 capsules at levels found in this 
product is unlikely to cause adverse effects (Kawashima et al. 2009).  
DS107 was very well tolerated in rats given up to 2,000 mg/kg/day for up to 26 weeks. Safety margins 
at the NOAEL in this study (2,000 mg/kg/day) were very large (i.e., 18- to 30-fold and 11- to 24-fold 
that seen in human subjects given 4g/day DS107 when based on unesterified DGLA for AUC and Cmax, 
respectively). In dogs, a pattern of dose-related, intermittent/sporadic, limb withdrawal and/or limited 
limb usage was seen at repeated doses >150 mg/kg/day in the 39-week study. This effect was completely 
reversible upon cessation of dosing. There was no correlative finding, including histopathology at the 
affected joints that could explain this effect. The NOAEL for this effect was 50 mg/kg/day, which 
corresponded to a safety margin of 1.1- to 1.6-fold and 3.1- to 3.7-fold greater than that seen in human 
subjects given 4g/day DS107 for AUC and Cmax, respectively. Lack of similar DS107 related effects on 
mobility in rats (doses up to 2g/kg/day for 26 weeks) and humans (doses up to 4g/day for 8 weeks) 
suggests the effect in dogs is species specific. 
 
Topical Toxicology 
Local tolerance has been assessed in several non-clinical studies, the most relevant of which is the GLP-
compliant toxicity study, conducted by Charles River Laboratories (CRL Study-521831, 2012),  in 
which DS107 cream was applied topically daily for 13 weeks to minipigs. Reaction to treatment was 
seen at the administration sites as very slight to well-defined erythema with red spots on or outside the 
edges of sites and dry flaky skin in some cases. Reactions were mild to moderate and 91-day treatments 
were completed for most animals. All findings were reversible. In this study there were no 
histopathology findings at main study kill (Day 92) attributed to treatment. Microscopic findings at the 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 22 of 83 
 
different treatment sites were considered to have arisen spontaneously and/or to have been associated 
with the administration procedure. Other microscopic findings observed were considered incidental, of 
the nature commonly observed in this strain and age of minipig. They were of similar incidence and/or 
severity in control and treated animals and were therefore considered unrelated to administration of 
DS107 Cream. Toxicokinetic analysis of plasma samples taken from the minipigs over the 13-week 
treatment period did not show any significant systemic exposure of DS107 following topical 
administration.  
 
Mutagenicity 
Previously, DGLA exhibited no mutagenicity in an Ames test regardless of the presence or absence of 
S9 mix (Kawashima et al. 2009). A recent DS Biopharma sponsored Ames test showed no substantial 
increases in revertant colony numbers with any of the tester strains following exposure to DS107, at 
any dose level, in the presence or absence of S9 mix. Therefore, DS107 was considered to be negative 
for the induction of mutagenicity in this in vitro assay when tested in accordance with regulatory 
guidelines. Furthermore, in a mouse lymphoma assay sponsored by the company, DS107 was not 
associated with genotoxicity in the presence or absence of metabolic activation. 
 
Conclusion 
No undue toxicological hazard or risk for patients treated with DS107 capsules has been identified in a 
battery of non-clinical toxicology studies. 26-week rat and 39-week dog chronic toxicity studies with 
greater systemic exposure at the determined NOAEL than human subjects receiving doses of oral 
DS107 capsules of up to 4g daily are considered adequate to support further clinical trials of greater 
than 6 months duration (per ICH M3 (R2)) for subjects given daily oral DS107 doses of up to 4g daily. 
 
1.6 
Previous Clinical Studies with DS107  
DS107 is being studied in oral (capsule) and topical (cream) formulation. Topical DS107 has been 
administered to 524 subjects during the course of one Phase 1 trial (DS107E-01) and five Phase 2 trials 
(DS107E-02, DS107E-03, DS107E-04, DS107E-05, DS107E-06). In addition, three well-controlled 
clinical studies have been conducted to assess the safety and efficacy of DS107 capsules. To date, 
DS107 capsules has been administered to 304 healthy volunteers/patients during the course of one Phase 
1 trial (DS107G-01) and two Phase 2 trials (DS107G-02 & DS107G-03) for AD. Up to 4g DS107 
capsules has been clinically tested and is well tolerated in healthy volunteers and patients with moderate 
to severe AD. Below are a list of the completed studies which utilise DS107 capsules. 
 
Table 1: Summary of DS107 Capsules Use in Human Healthy Volunteers/Patients 
 
DS107G-01 
A Randomised, Double-Blind, Placebo-Controlled, Single-Ascending Dose and Multiple Dose 
Phase 1 Study to Assess the Safety, Pharmacokinetics and Effect of Food on Orally Administered 
DS107 in Healthy Subjects. 
Phase 
Duration 
Indication 
IMP  
Concentration 
# Healthy 
Volunteers 
Status 
1 
(safety) 
Single Dose and 
Multiple Dose 
(28 days) 
Healthy 
Volunteers 
500mg 
1g 
2g 
4g 
48 
Completed 
DS107G-02 
A Randomised, Double-blind, Placebo-Controlled, Phase 2 Study to Assess the Efficacy and Safety 
of Orally Administered DS107 to Patients with Moderate to Severe AD 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 23 of 83 
 
Phase 
Duration 
Indication 
IMP  
Concentration. 
# Patients 
Status 
2a 
(safety & 
efficacy) 
8 Weeks 
Moderate to 
Severe AD 
2g 
102 
Completed 
DS107G-03 
A Randomised, Double-blind, Placebo-controlled, Phase 2b Study to Assess the Efficacy and 
Safety of Orally Administered DS107 in Patients with Moderate to Severe Atopic Dermatitis 
Phase 
Duration 
Indication 
IMP  
Concentration. 
# Patients 
Status 
2b  
(safety & 
efficacy) 
8 Weeks 
Moderate to 
Severe AD 
1g 
2g 
321 
Completed 
 
 
DS107 Capsules Phase 1 Study (DS107G-01) 
This study was a randomised, double-blind, placebo-controlled, single-ascending dose and multiple 
dose Phase 1 study to assess the safety, pharmacokinetics and effect of food on orally administered 
DS107 in 48 healthy volunteers. In the single dose part of the study healthy volunteers were randomised 
to 4 cohorts and administered either 500mg, 1g, 2g or 4g DS107 capsules. In the multiple dose of the 
study healthy volunteers were randomised to 2 cohorts and administered either 2g or 4g DS107 capsules 
once daily for 28 days. 
Under fasted conditions, both free and total DGLA increased in a linear manner following oral 
administration. Although not evaluated statistically, administration of a single 1g dose of DS107 
capsules under fasted conditions resulted in an approximately 50% higher rate.  
There were no deaths, Serious Adverse Events (SAEs), discontinuations due to AEs, considered to be 
not recovered/resolved, or AEs considered to be definitely related to study drug in this study. The most 
common AEs were gastrointestinal in nature which were of relatively short duration and resolved 
without intervention. 
Overall, DS107 capsules administered to 48  healthy volunteers as a single 500mg, 1g, 2g, or 4g dose 
under fasted conditions; as a single 1g dose under fed conditions; and as multiple 2g and 4g doses taken 
once daily for 28 consecutive days was well tolerated.  
 
DS107 Capsules Phase 2a Study (DS107G-02) 
This 8 week study was a randomized, placebo-controlled, double-blind, multi-centre Phase 2a trial to 
investigate the efficacy, safety, tolerability and bioavailability of  2g DS107 administered orally once 
daily versus 2g placebo administered orally once daily in adult patients with moderate to severe AD. 
The primary efficacy endpoint was defined as the proportion of patients achieving an Investigator 
Global Assessment (IGA) of 0 (clear) or 1 (almost clear) and a decrease of at least two points in IGA 
at Week 8. Secondary efficacy variables included IGA measurements, pruritus (obtained from the 
SCORAD VAS), EASI, BSA, POEM, DLQI and SCORAD.  
There was a trend toward a statistically significant higher number of patients who achieved an IGA 
score of 0 or 1 and a 2 point drop in the DS107 capsules group at Week 8 in comparison to placebo: 11 
(21.6%) responders in the DS107 capsules group, and 6 (11.8%) in the placebo group (p-value: 0.057). 
A similar trend was also observed in the number of patients achieving a decrease of at least 2 points in 
the IGA score at Week 8 with 14 (27.5%) in the DS107 capsules group and 8 (15.7%) in the placebo 
group (p-value: 0.065). 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 24 of 83 
 
Further analysis was performed on the severity groups (moderate and severe/very severe at baseline) 
comparing the DS107 capsules group to the placebo group in terms of responders, using the Cochran-
Mantel-Haenszel (CMH) test stratified for site. The proportion of responders was always greater in the 
DS107 capsules group compared to the placebo group in both the moderate and the severe/very severe 
populations.  
The proportion of moderate patients achieving an IGA of 0 (clear) or 1 (almost clear) and a decrease in 
2 point in IGA score was significantly greater in the DS107 capsules group (8/29 patients, 28%) 
compared to placebo group (6/38 patients, 16%) in patients with moderate AD at baseline (p = 0.036). 
Similar efficacy trends were observed in the severe/very severe population where 3 out of 22 patients 
(13%) treated with DS107 capsules met the responder criteria compared to 0 out of 13 patients in the 
placebo group. Statistical significance could not be achieved due to the low number of patients in each 
group and lack of primary response in placebo. 
The effect of DS107 capsules was consistently higher than placebo for all of the efficacy endpoints 
evaluated in this study, both investigator scores and patient scores. Pruritus is the most important 
symptom for patients suffering from AD. It has a significant impact on sleep and quality of life (Hong 
et al. 2011). Pruritus sensation was significantly decreased from Baseline at Week 4 in patients 
receiving DS107 compared to patients receiving placebo. This difference in pruritus was both 
statistically and clinically significant as shown by a decrease in pruritus of 39.5% for patients 
randomized to DS107 and of only 10.05% in patients randomized to placebo at Week 4.   
No deaths or SAEs were observed throughout the course of this study. There were no drug related AEs 
associated with safety lab results, physical exams or vital signs. AEs were mild to moderate and 
transient. The most common AEs observed in the DS107 group were gastrointestinal in nature. Overall 
the tolerance of DS107 capsules administered over 8 weeks was acceptable in comparison with placebo 
and DS107 appears safe and well tolerated. 
 
DS107 Capsules Phase 2b Study (DS107G-03) 
This was a randomised, double-blind, placebo-controlled, Phase 2b study to assess the efficacy and 
safety of 1g or 2g DS107 administered orally once daily versus placebo administered orally once daily 
in adult patients with moderate to severe AD. The primary efficacy endpoint was defined as the 
proportion of patients achieving an IGA of 0 (clear) or 1 (almost clear) and a decrease of at least two 
points in IGA at Week 8. Secondary and exploratory efficacy variables included IGA measurements, 
pruritus (obtained from the NRS), EASI, BSA, POEM, DLQI, Patient Global Impression of Severity 
(PGI-S) score and Patient Global Impression of Change (PGI-C) score.  
When the data was analyzed by baseline AD severity, a clear trend towards a dose-dependent IGA 
response was observed in the severe sub-group (n=45). At Week 8, there was a dose-dependent IGA 
response; more patients in the DS107 treatment groups (2g DS107 – 41.7%, 1g DS107 – 37.5%) than 
the placebo treated group (25.0%) achieved treatment success. 
The trend of improvement displayed no evidence of treatment plateau, suggesting that greater clinically 
meaningful improvements from baseline could be expected with a larger sample size or if treatment 
were to be continued for a longer time period. 2g DS107 (50.0%) and 1g DS107 (50.0%) demonstrated 
a trend towards sustained superiority in IGA response over placebo (33.3%) at Week 10 (Follow-up). 
Although most scores and indexes achieved clinically meaningful improvements at Week 8, with 
improvements at each time point during the study, no statistically significant differences among the 
treatment groups were observed, with notably high placebo responses across multiple endpoints. 
Similar to the primary endpoint, a clear trend towards a dose-dependent improvement in pruritus NRS 
is observed in the severe sub-group. At Week 8, there was a dose-dependent NRS mean change from 
baseline; patients in the DS107 treatment groups (2g DS107 – 3.9 point reduction, 1g DS107 – 3.4 point 
reduction) achieved clinically meaningful and greater changes from baseline than placebo treated 
patients (2.3 point reduction). 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 25 of 83 
 
Pharmacodynamics findings from the recent Oral Phase 2b study have helped to elucidate the 
mechanisms by which DS107 exerts its anti-inflammatory effects. Serum biomarker analysis revealed 
that DS107 reverses the high-grade systemic immune activation of AD by downregulating cytokines 
associated with inflammation, immune activation and angiogenesis. Biomarker data indicate that 
DS107 exerts many of its effects by inhibiting T-cell activation and can potentially be an oral disease 
modifying agent for AD. The expression of CD40 and other promoters of T-cell activation and 
differentiation was significantly inhibited. Additionally, multiple markers of fibrosis and cellular 
proliferation were significantly inhibited by DS107 highlighting its previously undescribed potential to 
treat fibrotic diseases. 
DS107 capsules were well tolerated with no significant differences in reported treatment-emergent 
adverse events, event severity, or seriousness versus placebo. 
Overall, the percentage of patients experiencing at least one AE during their participation in the study 
was similar among treatment groups (33.7%, 38.9%, and 32.7% for 1 g DS107, 2 g DS107, and placebo 
patients, respectively).  More treated with 2g DS107 experienced at least 1 AE assessed to be related to 
study drug compared to patients treated with placebo most of which were gastrointestinal and 
mild/moderate in severity.  No other significant differences were noted in occurrence of AEs.  
Most AEs were mild or moderate in severity. No deaths occurred in this study. Three SAEs were 
reported during this study. All were assessed by the reporting Investigator to be severe in intensity and 
unrelated to study drug. Additionally, all resolved without sequelae.   
 
Topical DS107 
Six studies have been completed with DS107 Cream.  
A Phase 1 clinical study (DS107E-01) was carried out to investigate the safety and tolerability of  
topically administered DS107 cream in human volunteers at five dose levels (0.1%, 0.5%, 1%, 2.5% 
and 5%) applied twice daily for 14 days (with a matched placebo cream).  
Topical administration of DS107 cream at dose strengths of 0.1%, 0.5%, 1%, 2.5% and 5% (up to 30 
mg topical DGLA/day) had no clinically significant effect on any of the following parameters; vital 
signs, electrocardiogram (ECG) or laboratory safety parameters; haematology, biochemistry, urinalysis. 
No serious or non-serious expected or unexpected adverse events related to the IMP were observed. 
There were no clinically significant abnormalities or changes from baseline values in the local 
tolerability assessments. There were no clinically significant abnormalities or changes from baseline 
values in the local tolerability assessments. All patients completed study procedures as per protocol and 
there were no significant protocol deviations affecting the safe conduct of the study. 
Study DS107E-02 was a randomized, double-blind, placebo-controlled Phase 2 study to assess the 
efficacy and safety of topically applied DS107 cream in patients with mild to moderate AD. Four 
parallel groups of patients with confirmed AD were investigated in this study to compare three different 
doses of DS107 cream (0.1%, 1%, and 5%) with placebo over a 28-day treatment period. During the 28 
days of treatment, patients liberally applied their assigned treatment to all affected or commonly 
affected areas twice daily (morning and evening).  
DS107 Cream treatment groups in Study DS107E-02 were similar to the vehicle group for number of 
adverse events, event severity and seriousness. No deaths or SAEs occurred during the study. Except 
for creatinine phosphokinase (CPK), no large treatment differences were seen in any of the laboratory 
parameter mean values. The mean values of the vital sign parameters were largely stable across 
treatment groups. Overall, DS107 cream was well tolerated, with a safety profile similar to the vehicle 
cream. 
Study DS107E-03 was a Phase 2 proof-of-concept study in patients with mild to moderate Acne 
Vulgaris carried out as a double-blind, randomised study with two active treatment groups of 1% and 
5% DS107 and a vehicle group. The study consisted of a washout period (maximum 14 days); a 12-


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 26 of 83 
 
week treatment period and a 4-week follow-up period. During the 12 weeks of treatment, patients 
applied the assigned treatment to all affected areas of skin twice daily (morning and evening). 
The safety profile of 1% and 5% DS107 Cream in Study DS107E-03 did not significantly differ from 
the vehicle treatment group. A very low incidence of AEs was reported during the trial, with no 
significant differences between treatment groups; most of the AEs were of mild intensity. Of these, a 
minority of cases were assessed as treatment-related. The results of the laboratory and vital sign 
assessments did not reveal any safety concerns during the study for any treatment group. 
DS107E-04 was a randomised, vehicle-controlled, double-blind, exploratory clinical trial to assess the 
efficacy and steroid sparing potential of DGLA cream topically applied to patients with moderate to 
severe AD. The primary objective was to evaluate the clinical efficacy of alternating treatment with 
Mometasone Furoate and 5% topical DGLA formulation OD compared to Mometasone Furoate and 
vehicle OD for 1 week, with a 4 week follow-up with either DGLA formulation alone twice daily (BD) 
or vehicle alone BD in adult patients with moderate to severe AD. Secondary objectives included the 
evaluation of DGLA cream in the treatment of itch severity, improvement of clinical signs and 
symptoms in AD EASI, IGA, SCORAD, target lesion score, improvement of quality of life, 
investigation of skin barrier function, days to relapse and rescue medication use as well as assessment 
of skin tolerability. The overall assessment of the Investigator at Visit 7 (Day 42) or at early termination 
(ET) with respect to the subject’s response to the effects of the IMP yielded similar results for both 
treatment groups. A clinically significant response was assessed for 7 of 16 patients with data (43.75%) 
of the DGLA group and for 8 of 18 patients with data (44.44%) in the vehicle group. 
Overall, analyses of the secondary efficacy variables in the PPS showed similar results for the two 
treatments. 
One SAE occurred during this study. It applied to a patient in the DGLA group who was hospitalised 
due to the event. The event was of severe intensity and the relationship to the IMP was judged by the 
Investigator as unrelated. No patient died during the study. Overall, there were only small changes 
between baseline and the last treatment visit in the means of the evaluated safety parameters. No 
relevant differences between the treatment groups could be observed. 
DS107E-05 was a randomised, vehicle-controlled, double-blind, exploratory clinical trial to assess the 
efficacy and steroid sparing potential of DGLA cream topically applied to early childhood patients with 
moderate to severe AD. Due to unsatisfactory recruitment progress, the study was terminated 
prematurely. The small amount of data collected and the fact that no patients completed the study, data 
analysis are not robust enough to draw any efficacy conclusions. 
There were 19 AEs reported in the five patients enrolled in this study; all AEs were considered by the 
Investigator to be not related to the administration of study drug. There was also one SAE which was 
deemed to be not related to the administration of study drug. No other SAEs or deaths were reported. 
There were no clinically meaningful abnormalities or trends identified in observed values or changes 
from baseline. Overall, there were no safety signals seen during the study conduct. The study IMP 
appeared to be well tolerated by patients.  
DS107E-06 was a randomised, double-blind, vehicle-controlled, Phase 2b study to assess the efficacy 
and safety of topically applied DS107 Cream to adults with mild to moderate AD. The primary 
endpoints were to observe a change from baseline in NRS for pruritus in the treated population 
compared to vehicle at Week 8 as well as a change in baseline in EASI in treated versus vehicle 
populations at Week 8. Secondary and exploratory efficacy variables included IGA measurements, 
BSA, POEM, DLQI, PGI-S score and PGI-C score.  
Analysis of EASI scores based on the binary response regulatory endpoint EASI-75 (proportion 
of patients achieving an improvement from baseline of at least 75% on the Eczema Area and 
Severity) revealed a dose-response trend of superiority of DS107 versus vehicle cream. An 
improvement from baseline to Week 8 of at least 75% on the Eczema Area and Severity Index 
(EASI-75) was reported in more patients who received 5% DS107 (41.0%) than in patients who 
received vehicle (30.0%). 5% DS107 (48.2%) demonstrated statistically significant superiority in 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 27 of 83 
 
EASI-75 over vehicle (30.9%) at Week 10 (p=0.0194), with no evidence of a plateau in treatment 
effect. At Week 8, there was a similar dose-dependent trend in the proportions of subjects 
achieving an IGA score of 0 or 1 and a decrease of at least 2 points from baseline as more patients 
in the DS107 treatment groups (5% DS107 – 30.1%, 1% DS107 – 23.5%) achieved treatment 
success than in the vehicle group (18.8%). At Week 10, 5% DS107 demonstrated sustained and 
statistically significant superiority in IGA response over both 1% DS107 and vehicle. The trend 
of improvement for both IGA treatment response and EASI-75 treatment response displayed no 
evidence of treatment plateau, suggesting that greater clinically meaningful improvements from 
baseline could be expected if treatment were to be continued for a longer time period. 
No deaths occurred in this study. Two SAEs were reported during this study. One subject treated 
with 1% DS107 and one vehicle-treated subject experienced an SAE during their participation in 
this trial. Both were by the reporting Investigator to be unrelated to study drug. Additionally, both 
resolved without sequelae.   
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 28 of 83 
 
2 
RISK BENEFIT ASSESSMENT 
 
To date, DS107 capsules has been administered to 304 healthy volunteers/patients during the course of 
one Phase 1 trial (DS107G-01) and two Phase 2 trials (DS107G-02 & DS107G-03) for AD. Up to 4g 
DS107 capsules has been clinically tested and is well tolerated in healthy volunteers and patients with 
moderate to severe AD. 2g DS107 capsules was well tolerated and safe in 164 patients with moderate 
to severe AD. 
The effect of DS107 capsules on the signs and symptoms of AD, efficacy endpoints and 
pharmacodynamic biomarkers was consistently superior to placebo in Phase 2 clinical studies in 
patients with moderate to severe AD, with a similar pattern in both Investigator scores and patient 
scores. 
Based on the endogenous nature of the active pharmaceutical ingredient,  exposure margins from non-
clinical toxicology studies, a favourable clinical safety profile observed in three clinical studies and the 
observed therapeutic efficacy of DS107 capsules in a disease with a persistent unmet need for additional 
effective and well tolerated therapies, it can be concluded that there is a positive risk-benefit ratio for 
the continued investigation of DS107 capsules as a treatment for moderate to severe AD.


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 29 of 83 
 
 
3 
RATIONALE FOR THE STUDY 
 
DS Biopharma (the Sponsor) showed a good safety profile for DS107 capsules for doses up to 
4g, based on results of the Phase I safety study. 
 
The proof-of-concept Phase 2a study then demonstrated a significant improvement in clinical 
efficacy measures after 8 weeks of treatment with DS107 capsules in patients with AD. 
Importantly, there was a significant improvement in the number of moderate AD patients who 
achieved the primary endpoint compared to placebo treated patients. There was also a similar 
efficacy observed in severe/very severe AD patients, however, the sample size was deemed too 
small to determine the statistical significance.   
 
When data from the Phase 2b study was analyzed by baseline AD severity, a clear trend towards 
a dose-dependent IGA response was observed in the severe sub-group (n=45). At Week 8, more 
patients in the DS107 treatment groups (2g DS107 – 41.7%, 1g DS107 – 37.5%) than the 
placebo treated group (25.0%) achieved treatment success. However, due to a profound placebo 
effect statistically significant differences versus placebo could not be detected. This study also 
displayed no evidence of treatment plateau, suggesting that greater clinically meaningful 
improvement from baseline could be expected if treatment were to be continued for a longer 
time period.  
 
The three previous clinical studies indicate that DS107 capsules is well tolerated and safe in 
both healthy patients and patients with moderate to severe AD. They highlight the efficacy of 
DS107 capsules and indicate that further efficacy could be obtained by optimizing the dosing 
regime and/or concentration and treatment duration.  
 
Therefore, the goal for this study is to examine the efficacy of 2g DS107 capsules OD for a 
treatment period of 16 weeks in patients with moderate to severe AD.  
 
The design of the current study is a randomised, placebo-controlled, double-blind, parallel 
group comparison in which the efficacy and safety of a 16 week treatment with DS107 capsules 
is assessed in adult patients with moderate to severe AD. The design of the study minimises 
bias during the safety and efficacy assessments.  
The novel mechanism of action and safety profile of DS107 capsules offer a potential benefit 
to AD patients and would represent a new class of medicine for this disease. 
 
Based on the afore mentioned preclinical studies demonstrating the efficacy of DS107 in animal 
models of AD and the positive signals in the Phase 2a and Phase 2b patient studies there is a 
clear rationale for the further development of DS107 capsules as a treatment for patients with 
moderate to severe AD.  
 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 30 of 83 
 
 
4 
STUDY OBJECTIVES 
Efficacy Objective: 
 
• 
To compare the efficacy of orally administered DS107 (2g) versus placebo, in the 
treatment of adult patients with moderate to severe AD. 
 
Safety Objective: 
  
• 
To assess the safety of orally administered DS107 (2g) versus placebo, in adult patients 
with moderate to severe AD. 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 31 of 83 
 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
 
• 
Proportion of patients achieving a vIGA-ADTM score of 0 (clear) or 1 (almost clear) 
and a decrease of at least 2 points in vIGA-ADTM in treated population compared to 
placebo population from baseline at Week 16.  
 
• 
Proportion of patients achieving EASI-75 (≥75% improvement from baseline) in 
treated population compared to placebo population at Week 16. 
 
 
Note: Each of the independent primary endpoints will be assessed separately. Success in either 
of the primary endpoints denotes treatment success.  
 
5.2 
Secondary Endpoints 
 
• 
  Proportion of patients achieving a vIGA-ADTM score of 0 (clear) or 1 (almost clear) and 
a decrease of at least 2 points in vIGA-ADTM in treated population compared to placebo 
population from baseline to Week 4, 8, 12, 18 and 20 and the change in proportion of 
patients from Week 16 to Week 18 and 20. 
 
• 
Proportion of patients achieving EASI-75 (≥75% improvement from baseline) in 
treated population compared to placebo population at Weeks 4, 8, 12, 18 and 20 and 
the change in proportion of patients from Week 16 to Week 18 and 20. 
 
• 
Change from baseline in vIGA-ADTM score in treated population compared to placebo 
population to Weeks 4, 8, 12, 16, 18 and 20, and from Week 16 to Week 18 and 20.  
 
• 
Change from baseline in EASI in treated population compared to placebo population 
to Weeks 4, 8, 12, 16, 18 and 20, and from Week 16 to Week 18 and 20. 
 
• 
Proportion of patients achieving a decrease of at least 4 points in worst itch NRS in 
treated population compared to placebo population from baseline to Week 4, 8, 12, 16, 
18 and 20 and the change in proportion of patients from Week 16 to Week 18 and 20. 
 
• 
Proportion of patients achieving a decrease of at least 3 points in worst itch NRS in 
treated population compared to placebo population from baseline to Week 4, 8, 12, 16, 
18 and 20 and the change in proportion of patients from Week 16 to Week 18 and 20. 
 
• 
Change from baseline in worst itch NRS in treated population compared to placebo 
population to Week 4, 8, 12, 16, 18 and 20 and from Week 16 to Week 18 and 20. 
 
• 
Proportion of patients achieving EASI-50 (≥50% improvement from baseline) in 
treated population compared to placebo population at Week 4, 8, 12, 16, 18 and 20 and 
the change in proportion of patients from Week 16 to Week 18 and 20.  
 
• 
Change from baseline in the Body Surface Area (BSA) affected by AD in treated 
population compared to placebo population to Weeks 4, 8, 12, 16, 18 and 20, and from 
Week 16 to Week 18 and 20. 
 
• 
Change from baseline in the SCORing Atopic Dermatitis (SCORAD) score in treated 
population compared to placebo population to Weeks 4, 8, 12, 16, 18 and 20, and from 
Week 16 to Week 18 and 20. 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 32 of 83 
 
 
• 
Incidence of treatment emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
 
5.3 
Exploratory Endpoints 
 
• 
Proportion of patients achieving a decrease of at least 2 points in vIGA-ADTM in treated 
population compared to placebo population from baseline to Week 4, 8, 12, 16, 18 and 
20 and the change in proportion of patients from Week 16 to Week 18 and 20. 
 
• 
Change from baseline in the Dermatology Life Quality Index (DLQI) score in treated 
population compared to placebo population to Weeks 4, 8, 12, 16, 18 and 20, and from 
Week 16 to Week 18 and 20. 
 
• 
Change from baseline in the Patient Orientated Eczema Measure (POEM) score in 
treated population compared to placebo population to Weeks 4, 8, 12, 16, 18 and 20, 
and from Week 16 to Week 18 and 20. 
 
• 
Change in sleep quality assessment (Athens Insomnia Scale) in treated population 
compared to placebo population from baseline to Week 4, 8, 12, 16, 18 and 20 and from 
Week 16 to Week 18 and 20.  
 
• 
Change from baseline in the Patient-Oriented SCORAD (PO-SCORAD) score in 
treated population compared to placebo population to Weeks 4, 8, 12, 16, 18 and 20, 
and from Week 16 to Week 18 and 20. 
 
• 
Trough plasma levels in treated population compared to placebo population at 
Baseline/Day 0, Week 4, Week 8 and Week 16. 
 
• 
Determination of AD biomarkers in treated population compared to placebo population 
at Baseline/Day 0 and Week 16. 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 33 of 83 
 
6 
STUDY DESIGN 
 
This is a randomised, placebo-controlled, double-blind, parallel group, multi-centre 2-arm 
Phase 2 study to investigate the efficacy of orally administered DS107 in AD patients. 
It is planned that at least 220 patients suffering from moderate to severe AD will be included in 
this study. All patients will sign an informed consent and undergo screening for study eligibility.  
Before the comparative treatment period can commence, patients will return to the site for a 
baseline assessment of their disease and eligible patients will be randomly allocated to one of 
the treatment regimens in a 1:1 randomization: 
 
• 
2g DS107 (4 DS107 capsules) orally administered once daily for 16 weeks  
 
• 
Placebo (4 placebo capsules) orally administered once daily for 16 weeks 
 
There is a 4 week follow-up period.  
 
To maintain the double-blind conditions, DS107 capsules and placebo will be identical in 
appearance. 
 
 
A schematic diagram of the overall timeframe of the study is given in Figure 2. 
 
Figure 2: Study Outline 
 
 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 34 of 83 
 
7 
PATIENTS AND SCREENING 
In order to participate in this study the patients must meet all of the following inclusion criteria 
and must not meet any of the following exclusion criteria. Inclusion in the trial starts with the 
informed consent signature. The inclusion and exclusion criteria are to be verified at the 
screening visit (Visit 1) and at the start of treatment/baseline visit (Visit 2).  
 
7.1 
Source of Patients 
The study population will consist of male and female patients with confirmed diagnosis of AD 
aged 18 years or older. Patients will be identified and recruited by the investigational sites. 
 
7.2 
Inclusion Criteria 
1. Patients with a clinically confirmed diagnosis of active AD according to the American 
Academy of Dermatology Consensus Criteria that has been present for at least 6 months 
before the screening visit. 
 
2. Patients with moderate to severe AD at baseline as defined by a vIGA-ADTM score of 3 or 
4 at baseline. 
 
3. Patients with an EASI score of ≥16 at screening and baseline. 
 
4. Patients with AD covering a minimum 10% of the body surface area (BSA) at baseline. 
 
5. Patients with a worst itch NRS score in a day of ≥4 (on 11 point NRS) at the screening and 
baseline visits. 
6. Patients whose pre-study clinical laboratory findings do not interfere with their 
participation in the study, in the opinion of the Investigator. 
 
7. Patients who are able and willing to stop all current treatments for AD throughout the study 
(except for allowed emollients). 
8. Patients who are on a stable dose of a bland emollient for at least 7 days prior to baseline. 
 
Note: 
Patients who have been on a stable emollient with an active ingredient (for example urea, 
ceramide and hyaluronic acid) for at least 12 weeks prior to screening and are otherwise 
eligible may continue using their pre-existing emollients, if deemed appropriate by the 
investigator and if they are willing and able to continue using the same stable emollient 
for the duration of the study 
 
 
9. Male or female patients aged 18 years and older on the day of signing the informed consent 
form (ICF). 
 
10. Female patients and male patients with female partners of child bearing potential must use 
highly effective birth control methods or have a sterilised partner for the duration of the 
study. 
 
Note: 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 35 of 83 
 
• 
Highly effective birth control methods are defined as methods that can achieve a failure 
rate of less than 1% per year when used consistently and correctly. Such methods 
include systemic hormonal contraceptives, intrauterine device or sexual abstinence. 
 
• 
Hormonal contraceptives must be on a stable dose for at least one month before 
baseline. 
 
• 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
 
11. Recent history (within 6 months before the screening visit) of inadequate response to 
treatment with topical medications or for whom topical treatments are otherwise medically 
inadvisable (e.g., because of important side effects or safety risks). 
 
Note: 
• 
Inadequate response is defined as failure to achieve and maintain remission or a low 
disease activity state (comparable to vIGA-ADTM 0=clear to 2=mild) despite treatment 
with a daily regimen of Topical corticosteroids (TCS) of medium to higher potency (± 
Topical calcineurin inhibitors (TCI) as appropriate), applied for at least 28 days or for 
the maximum duration recommended by the product prescribing information (e.g., 14 
days for super-potent TCS), whichever is shorter. 
 
• 
Patients with documented systemic treatment for AD (for example systemic 
corticosteroids, cyclosporin) in the past 6 months are also considered as inadequate 
responders to topical treatments and are potentially eligible for treatment with DS107 
after appropriate washout. 
 
• 
Important side effects or safety risks are those that outweigh the potential treatment 
benefits and include intolerance to treatment, hypersensitivity reactions, significant 
skin atrophy, and systemic effects, as assessed by the Investigator or by the patient’s 
treating physician. 
 
12. Patients who are able to communicate well with the Investigator, to understand and comply 
with the requirements of the study, and understand and sign the written informed consent 
prior to initiation of any study specific activities or procedures. 
 
7.3 
Exclusion Criteria  
1. Patients with other skin conditions that might interfere with AD diagnosis and/or 
evaluation (such as psoriasis or current active viral, bacterial and fungal skin infections) 
as assessed by the Investigator. 
 
2. Patients who have used systemic treatments that could affect AD less than 4 weeks prior to 
baseline visit (Day 0), e.g. retinoids, methotrexate, cyclosporine, hydroxycarbamide 
(hydroxyurea), azathioprine and oral/injectable corticosteroids. Intranasal corticosteroids 
and inhaled corticosteroids for stable medical conditions are allowed. 
 
3. Patient with previous exposure to DS107. 
 
4. Patients who have used any topical medicated treatment for AD (except for emollients) two 
weeks prior to start of treatment/ Baseline (Day 0), including but not limited to, topical 
corticosteroids, calcineurin inhibitors, tars, bleach, antimicrobials and bleach baths. 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 36 of 83 
 
5. Patients who use emollients containing urea, ceramides or hyaluronic acid less than twelve 
weeks prior to Baseline. 
 
6. Patients who have had excessive sun exposure, have used tanning booths or other 
ultraviolet (UV) light sources four weeks prior to Baseline (Day 0) and/or are planning a 
trip to a sunny climate or to use tanning booths or other UV sources between screening and 
follow-up visits. 
 
7. Patients who have a history of hypersensitivity to any substance in DS107 capsules or 
placebo capsules. 
 
8. Patients who have a history of hypersensitivity to soy beans or soy lecithin.  
 
9. Patients who have a white cell count or differential white cell count outside of the normal 
reference range at screening.  
 
       Note: 
For patients with a mild leucocytosis or leucopenia and otherwise a normal white cell 
blood count may be enrolled following consultation with the medical monitor by the 
investigator. 
 
10. Patients who have any clinically significant controlled or uncontrolled medical condition 
or laboratory abnormality that would, in the opinion of the Investigator, put the patient at 
undue risk or interfere with interpretation of study results.  
 
11. Patients who have a clinically significant impairment of renal or hepatic function. 
 
12. Patients with significant uncontrolled cardiovascular, neurologic, malignant, psychiatric, 
respiratory or hypertensive disease, as well as uncontrolled diabetes and floride arthritis or 
any other illness that, in the opinion of the Investigator, is likely to interfere with 
completion of the study. 
 
13. Patients with active infectious disease (e.g., hepatitis B, hepatitis C or advanced disease 
secondary to infection with human immunodeficiency virus). 
 
14. Patients with a history of clinically significant drug or alcohol abuse in the opinion of the 
Investigator in the last year prior to Baseline (Day 0). 
 
15. Patients who have participated in any other clinical study with an investigational drug 
within 3 months before the first day of administration of study treatment. 
 
16. Patients who have had treatment with biologics as follows:  
a. Any cell-depleting agents including but not limited to rituximab: within 6 months 
before the screening visit, or until lymphocyte count returns to normal, whichever is 
longer, 
b. Other biologics influencing cell proliferation: within 6 months before the screening 
visit. 
c. Dupilumab or other monoclonal antibodies within 5 half-lives (if known) or 16 weeks 
prior to baseline visit, whichever is longer  
 
17. Patients who are pregnant, planning pregnancy, breastfeeding and/or are unwilling to use 
adequate contraception (as specified in Inclusion Criterion 10) during the trial. 
 
18. Patients, in the opinion of the Investigator, not suitable to participate in the study. 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 37 of 83 
 
7.4 
Screening and Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable to local regulation), to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives and 
potential risks/benefits of the study. Patients will be given the opportunity to ask questions to 
the investigational team. It must also be explained to the patients that they are completely free 
to refuse to enter the study or to withdraw from it at any time for any reason. The patient will 
be given sufficient time to consider participation in the study. If, after this, the patient agrees to 
participate, they will be asked to sign and date one original copy of the written ICF. The patients 
will then receive a copy of the signed and dated patient information sheet (PIS)/ICF. The 
original signed ICF will be filed in the Investigator Site File (ISF). The PIS will contain site 
contact information in case of any questions or medical emergency.  
If new safety information results in significant changes in the risk/benefit assessment or any 
new information presents that may affect willingness to continue to participate, the consent 
form should be updated and approved if necessary by the Research Ethics Board/Institutional 
Review Board. All patients (including those already being treated) should be informed of the 
new information, given a copy of the revised form and asked to give their consent to continue 
in the study. Any written information given to potential patients will be submitted to, and 
approved by, the respective Ethics Committee(s) (EC) prior to implementation.  
The Investigator will maintain a Patient Screening Log to collect information on all patients 
who sign an ICF regardless of whether or not they meet the study eligibility criteria following 
completion of the screening evaluations. After completion of screening, all patients deemed 
eligible to take part in this study will be entered onto an Enrolment Log. 
7.5 
Withdrawal of Patients 
Patients have the right to withdraw from the study at any time for any reason without penalty. 
The Investigator must explain this to the patient and that this will in no way prejudice their 
future treatment. The Investigator also has the right to withdraw patients from the study if he 
feels it is in the best interest of the patient or if the patient is uncooperative or non-compliant. 
It is understood by all concerned that an excessive rate of withdrawal can render the study un-
interpretable, therefore, unnecessary withdrawal of patients should be avoided. Should a patient 
decide to withdraw, all efforts will be made to complete and report the observations, particularly 
the follow-up examination, as thoroughly as possible. 
 
The Investigator or one of his or her staff members should contact the patient either by 
telephone or through a personal visit to determine as completely as possible the reason for the 
withdrawal, and record the reason in patient’s source document and case report form (CRF). A 
complete final early termination evaluation at the time of the patient’s withdrawal should be 
made with an explanation of why the patient is withdrawing from the study when ever possible. 
If the reason for removal of a patient is an adverse event or an abnormal laboratory test result, 
the principal specific event or test will be recorded. Patients who discontinue the study before 
Week 16/Visit 7 visit will be asked to come for an early termination visit as soon as possible 
and have the assessments listed at Week 16/Visit 7 performed. They will also be asked to return 
two weeks later for the safety assessments listed at Week 18/Visit 8. 
 
Patients who develop Grade 3 or higher National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), that is determined to be possibly or probably 
attributable to the study drug will be discontinued. 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 38 of 83 
 
7.6 
Patient Replacement 
Patients who are withdrawn from the study due to an adverse event or lack of effect will not be 
replaced. Patients who are withdrawn for other reasons (such as lost to follow up, personal 
reasons) may be replaced.  
 
7.7 
Protocol Violations 
All protocol violations will be reviewed by the Medical Monitor as and when each violation is 
detected. Based on this review a decision on the patient’s continuation in the trial will be 
reached and this decision will be documented as appropriate. Notification will be made to the 
relevant authorities as required. 
 
7.8 
Stopping Criteria 
Trial will be stopped if more than one patient has a Grade 3 or higher AE on the CTCAE scale 
in any one category that is determined to be possibly or probably attributable to study drug. 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 39 of 83 
 
8 
STUDY CONDUCT 
 
8.1 
Study Schedule 
Patients will come to the clinic on 8 occasions: at Screening/Visit 1, Baseline/Visit 2, Week 
4/Visit 4, Week 8/Visit 5, Week 12/Visit 6, Week 16/Visit 7 (end of treatment), Week 18/ Visit 
8 (follow up) and Week 20/Visit 9 (follow-up). A telephone visit will also be performed at 
Week 1/Visit 3.   
 
Patients who discontinue the study early will be asked to attend the investigative site as soon as 
possible so that assessments scheduled for Visit 7 can be conducted at an Early Termination 
visit. 
 
In the event that treatment is occurring, a wash out period of up to 4 weeks may be necessary. 
At the Screening Visit, after giving informed consent to participate, patients will be assessed 
using the screening examinations. Eligible patients with confirmed AD using the American 
Academy of Dermatology Consensus Criteria and who meet all the inclusion criteria and do 
not meet the exclusion criteria at the baseline visit will be enrolled.  
 
During the treatment period and follow-up period patients will be restricted from using any 
other treatment for AD, with the exception of the same emollients they have been consistently 
using since the screening visit. A tabulated flow chart of the study is presented in Appendix 1 
(Section 15.1). 
8.2 
Screening 
8.2.1 
Screening Visit (Visit 1) 
 
The patient must sign and date the ICF before any study-specific procedures are conducted.  
 
Once informed consent has been obtained, the Investigator will assign a Patient Number (as per 
Section 10.5) and the following screening procedures/assessments will occur: 
 
• 
Demographic data 
• 
Medical / surgical history (as detailed in Section 9.2.1) 
• 
Assessment of inclusion/exclusion criteria (Sections 7.2 & 7.3) 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry and FSH 
levels (when applicable) as detailed in Section 9.2.4) 
• 
Sample for pregnancy test (only female patients of child-bearing potential, as detailed 
in Section 9.2.5) 
• 
Virology (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3)  
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Body Mass Index (as detailed in Section 9.2.8) 
• 
Body Surface Area (as detailed in Section 9.1.4) 
• 
Validated Investigator’s Global Assessment (as detailed in Section 9.1.1) 
• 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
• 
NRS Pruritus Assessment (as detailed in Section 9.1.3) 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
Emollient use capture (as detailed in Section 9.2.13.1) 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 40 of 83 
 
8.3 
Treatment Period 
 
Following completion of a successful screening visit, patients will begin the comparative 
treatment period (16 weeks).  
 
At the start of the comparative treatment period, after confirmation of continued eligibility, 
patients will be randomly assigned at the baseline visit (Visit 2) to one of the two treatment 
regimens.  
 
Patients will be instructed to take 4 capsules of IMP which will contain either 2g DS107 or 
placebo. Every effort should be made to ensure IMP administration is at the same time each 
day. Each self-administration of IMP will be recorded in a patient compliance log. 
 
Unscheduled visits may occur when a patient needs to make a visit in between the scheduled 
visit dates due to an adverse event (AE), difficulty complying with the study protocol 
requirements, or a significant change in their disease state. All procedures that are medically 
necessary should be followed.  
 
Once patients are enrolled on the study they will be restricted from using any other treatment 
for AD, with the exception of emollients, as defined in Section 9.2.13.1. Any medication 
(prescription as well as over the counter (OTC) drugs) or therapeutic intervention deemed 
necessary for the patient, and which in the opinion of the Investigator do not interfere with the 
safety and efficacy evaluations, may be continued unless they are included in the list of 
‘Concomitant Medications’ (Section 9.2.13). 
Patients who discontinue the study early will have all study procedures scheduled for Visit 7 
(see Section 8.3.6) performed as soon as possible after patient withdrawal so that all study-
related information can be recorded. 
 
8.3.1 
Baseline (Visit 2) 
Note: it must be ensured that inclusion criteria regarding the severity of the disease 
remain relatively unchanged since screening in order to exclude patients responding to 
the emollient use since screening visit i.e. IGA score must be unchanged and EASI score 
should not change by more than 10%. Patients will attend the investigational site at Visit 2 
when the following procedures/assessments will occur.  
 
• 
Verification of inclusion/exclusion criteria (Sections 7.2 & 7.3) 
• 
Patient Randomisation (as detailed in Section 10.5) 
• 
Samples for clinical laboratory safety tests (haematology and serum biochemistry as 
detailed in Section 9.2.4) 
• 
Pharmacokinetic Sampling (as detailed in Section 9.2.9) 
• 
Biomarker Sampling (as detailed in Section 9.2.10) 
• 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3);  
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Electrocardiogram (ECG) (as detailed in Section 9.2.7) 
• 
Dispense Study Drug  
• 
Dispense Patient Compliance Log  
• 
Body Surface Area (as detailed in Section 9.1.4) 
• 
Validated Investigator’s Global Assessment (as detailed in Section 9.1.1) 
• 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
• 
NRS Pruritus assessment (as detailed in Section 9.1.3) 
• 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 41 of 83 
 
• 
Patient Orientated Eczema Measure (POEM) questionnaire (as detailed in Section 
9.1.6) 
• 
SCORing AD (SCORAD) questionnaire (as detailed in Section 9.1.7) 
• 
Athens Insomnia Scale (AIS) (as detailed in Section 9.1.8) 
• 
Patient- Orientated SCORAD questionnaire (as detailed in Section 9.1.9) 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
Review emollient usage and capture 
• 
AE assessment (as detailed in Section 11) 
 
If all study entry criteria are satisfied the Investigator will randomize the patient and provide 
the patient with the DS107 capsules or placebo capsules from one of the patient treatment packs 
available at the site (allocated via the central randomization). 
 
The first administration of DS107 or placebo will be carried out after the Baseline visit. 
Following this DS107 capsules or placebo medication will be administered once daily. IMP 
will be administered approximately 2 hours after food consumption at the same time each day. 
Patients will be instructed to not consume food for approximately 1 hour after IMP 
administration.  
 
Patients will be given a compliance log to document administration of DS107 capsules or 
placebo. Clinical staff will explain to the patient how to use the compliance log to document 
IMP administration compliance. 
 
An NRS for the assessment of pruritus will be captured on a daily basis from screening through 
to the follow up visit.  
 
Similarly, emollient use will also be captured on a daily basis from screening through to the 
follow-up visit. 
 
Collection of AEs will begin after the first administration of IMP has occurred. 
 
On completion of this visit, patients will be advised that they will be contacted by telephone 
one week later to discuss their progress on the trial. They will then be required to return to the 
investigational site at Week 4/Visit 4 and to bring with them the unused DS107 
capsules/placebo patient packs, the used DS107 capsules/placebo patient packs, and the patient 
compliance log.  
 
8.3.2 
Week 1 (Visit 3) 
 
Patients will receive a telephone call from site staff at Week 1.  
 
IMP compliance and administration will be discussed to ensure correct dosing. Patients will 
also be asked to discuss the patient logs for confirmation of compliance.  
 
The following procedures/assessments will also occur: 
 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
AE assessment (as detailed in Section 11) 
 
The patient will be reminded that IMP will continue to be administered approximately 2 hours 
after food consumption at the same time each day. Patients will be reminded to not consume 
food for approximately 1 hour after IMP administration. 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 42 of 83 
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
screening to the follow-up visit. Emollient use will also continue to be captured on a daily basis 
for the same period. 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site at Visit 4 and to bring with them the unused DS107/placebo patient packs, 
the used DS107/placebo patient packs, and the patient compliance log.  
 
8.3.3 
Week 4 (Visit 4) 
 
Patients will return to the investigational site at Week 4/Visit 4.  
 
For accountability purposes, patients will be required to bring both the used DS107/placebo 
patient packs and unused DS107/placebo patient packs supplied at Visit 2. Patients will be 
required to provide the patient compliance log for confirmation of compliance.  
 
The following procedures/assessments will occur: 
 
• 
Samples for clinical laboratory safety tests (haematology and serum biochemistry as 
detailed in Section 9.2.4) 
• 
Pharmacokinetic Sampling (as detailed in Section 9.2.9) 
• 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3);  
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Dispense Study Drug  
• 
Collect Study Drug  
• 
Dispense Patient Compliance Log  
• 
Collect and Review Patient Compliance Log  
• 
IMP Accountability (as detailed in Section 10.6) 
• 
Body Surface Area (as detailed in Section 9.1.4) 
• 
Validated Investigator’s Global Assessment (as detailed in Section 9.1.1) 
• 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
• 
NRS Pruritus assessment (as detailed in Section 9.1.3) 
• 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
• 
Patient Orientated Eczema Measure (POEM) questionnaire (as detailed in Section 
9.1.6) 
• 
SCORing AD (SCORAD) questionnaire (detailed in Section 9.1.7) 
• 
Athens Insomnia Scale (AIS) (as detailed in Section 9.1.8) 
• 
Patient- Orientated SCORAD questionnaire (as detailed in Section 9.1.9) 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
Review emollient usage and capture 
• 
AE assessment (as detailed in Section 11) 
 
DS107 or placebo patient packs will be returned and additional patient treatment packs of 
DS107 or placebo will be supplied to the patient.  
 
IMP will continue to be administered approximately 2 hours after food consumption at the same 
time each day. Patients will be reminded to not consume food for approximately 1 hour after 
IMP administration. The patient compliance log will be provided to the patient who will be 
instructed to complete this as before.  
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
screening to the follow-up visit. Emollient use will also continue to be captured on a daily basis 
for the same period. 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 43 of 83 
 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site at Visit 5 and to bring with them the unused DS107/placebo patient packs, 
the used DS107/placebo patient packs, and the patient compliance log.  
8.3.4 
Week 8 (Visit 5) 
Patients will return to the investigational site at Week 8/Visit 5.  
 
For accountability purposes, patients will be required to bring both the used DS107 /Placebo 
patient packs and unused DS107/Placebo patient packs supplied at Visit 4. Patients will be 
required to provide the patient compliance log for confirmation of compliance.  
 
The following procedures/assessments will occur: 
 
• 
Samples for clinical laboratory safety tests (haematology and serum biochemistry as 
detailed in Section 9.2.4) 
• 
Pharmacokinetic Sampling (as detailed in Section 9.2.9) 
• 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3);  
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Dispense Study Drug  
• 
Collect Study Drug  
• 
Dispense Patient Compliance Log  
• 
Collect and Review Patient Compliance Log  
• 
IMP Accountability (as detailed in Section 10.6) 
• 
Body Surface Area (as detailed in Section 9.1.4) 
• 
Validated Investigator’s Global Assessment (as detailed in Section 9.1.1) 
• 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
• 
NRS Pruritus assessment (as detailed in Section 9.1.3) 
• 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
• 
Patient Orientated Eczema Measure (POEM) questionnaire (as detailed in Section 
9.1.6) 
• 
SCORing AD (SCORAD) questionnaire (detailed in Section 9.1.7) 
• 
Athens Insomnia Scale (AIS) (as detailed in Section 9.1.8) 
• 
Patient- Orientated SCORAD questionnaire (as detailed in Section 9.1.9) 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
Review emollient usage and capture 
• 
AE assessment (as detailed in Section 11) 
 
DS107 or placebo patient packs will be returned and additional patient treatment packs of 
DS107 or placebo will be supplied to the patient.  
 
IMP will continue to be administered approximately 2 hours after food consumption at the same 
time each day. Patients will be reminded to not consume food for approximately 1 hour after 
IMP administration. The patient compliance log will be provided to the patient who will be 
instructed to complete this as before.  
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
screening to the follow up visit. Emollient use will also continue to be captured on a daily basis 
for the same period. 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site at Visit 6 and to bring with them the unused DS107/placebo patient packs, 
the used DS107/placebo patient packs, and the patient compliance log.  


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 44 of 83 
 
8.3.5 
Week 12 (Visit 6) 
Patients will return to the investigational site at Week 12/Visit 6.  
 
For accountability purposes, patients will be required to bring both the used DS107/placebo 
patient packs and unused DS107/placebo patient packs supplied at Visit 5. Patients will be 
required to provide the patient compliance log for confirmation of compliance.  
 
The following procedures/assessments will occur: 
 
• 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3);  
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Dispense Study Drug  
• 
Collect Study Drug  
• 
Dispense Patient Compliance Log  
• 
Collect and Review Patient Compliance Log  
• 
IMP Accountability (as detailed in Section 10.6) 
• 
Body Surface Area (as detailed in Section 9.1.4) 
• 
Validated Investigator’s Global Assessment (as detailed in Section 9.1.1) 
• 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
• 
NRS Pruritus assessment (as detailed in Section 9.1.3) 
• 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
• 
Patient Orientated Eczema Measure (POEM) questionnaire (as detailed in Section 
9.1.6) 
• 
SCORing AD (SCORAD) questionnaire (detailed in Section 9.1.7)  
• 
Athens Insomnia Scale (AIS) (as detailed in Section 9.1.8) 
• 
Patient- Orientated SCORAD questionnaire (as detailed in Section 9.1.9) 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
Review emollient usage and capture 
• 
AE assessment (as detailed in Section 11) 
 
DS107 or placebo patient packs will be returned and additional patient treatment packs of 
DS107 or placebo will be supplied to the patient.  
 
IMP will continue to be administered approximately 2 hours after food consumption at the same 
time each day. Patients will be reminded to not consume food for approximately 1 hour after 
IMP administration. The patient compliance log will be provided to the patient who will be 
instructed to complete this as before.  
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
screening to the follow-up visit. Emollient use will also continue to be captured on a daily basis 
for the same period. 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site at Visit 7 and to bring with them the unused DS107/placebo patient packs, 
the used DS107/placebo patient packs, and the patient compliance log.  
 
8.3.6 
Week 16 (Visit 7) / End of Treatment or Early Termination 
 
Patients will return to the investigational site at Visit 7. The last dose of DS107/placebo should 
be taken the day before Visit 7. 
For accountability purposes, patients will be required to bring both the used DS107/Placebo 
patient packs and unused DS107/Placebo supplied at Visit 6. Patients will be required to provide 
the patient compliance log for confirmation of compliance.  


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 45 of 83 
 
 
The following procedures/assessments will occur: 
 
• 
Samples for clinical laboratory safety tests (haematology and serum biochemistry as 
detailed in Section 9.2.4) 
• 
Pharmacokinetic Sampling (as detailed in Section 9.2.9) 
• 
Biomarker Sampling (as detailed in Section 9.2.10) 
• 
Sample for pregnancy test (only female patients of child-bearing potential, as detailed 
in Section 9.2.5) 
• 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3);  
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Electrocardiogram (ECG) (as detailed in Section 9.2.7) 
• 
Body Mass Index (as detailed in Section 9.2.8) 
• 
Collect Study Drug  
• 
Collect and Review Patient Compliance Log  
• 
IMP Accountability (as detailed in Section 10.6) 
• 
Body Surface Area (as detailed in Section 9.1.4) 
• 
Validated Investigator’s Global Assessment (as detailed in Section 9.1.1) 
• 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
• 
NRS Pruritus assessment (as detailed in Section 9.1.3) 
• 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
• 
Patient Orientated Eczema Measure (POEM) questionnaire (as detailed in Section 
9.1.6) 
• 
SCORing AD (SCORAD) questionnaire (detailed in Section 9.1.7) 
• 
Athens Insomnia Scale (AIS) (as detailed in Section 9.1.8) 
• 
Patient- Orientated SCORAD questionnaire (as detailed in Section 9.1.9) 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
Review emollient usage and capture 
• 
AE assessment (as detailed in Section 11) 
 
The DS107 or placebo patient packs will be returned. No further DS107 or placebo patient 
packs or patient compliance logs will be issued. Following completion of the study assessments 
at this visit, there will be continued study restrictions in line with those described in Sections 
9.2.12.  
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
screening to the follow up visits. Emollient use will also continue to be captured on a daily basis 
for the same period. 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site at Visit 8 to assess any AEs since this visit, and conduct safety and efficacy 
assessments.  
8.3.7 
Week 18 (Visit 8) / Follow-up 1 
 
Two weeks after Visit 7 (or early withdrawal visit), patients will return to the investigational 
site and the follow up procedures/assessments will occur: 
 
• 
Samples for clinical laboratory safety tests (haematology and serum biochemistry as 
detailed in Section 9.2.4) – for abnormal values developed during treatment only.  
• 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3);  
• 
Physical examination (as detailed in Section 9.2.2) 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 46 of 83 
 
• 
Body Surface Area (as detailed in Section 9.1.4) 
• 
Validated Investigator’s Global Assessment (as detailed in Section 9.1.1) 
• 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
• 
NRS Pruritus assessment (as detailed in Section 9.1.3) 
• 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
• 
Patient Orientated Eczema Measure (POEM) questionnaire (as detailed in Section 
9.1.6) 
• 
SCORing AD (SCORAD) questionnaire (detailed in Section 9.1.7)  
• 
Athens Insomnia Scale (AIS) (as detailed in Section 9.1.8) 
• 
Patient- Orientated SCORAD questionnaire (as detailed in Section 9.1.9) 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
Review emollient usage and capture 
• 
AE assessment (as detailed in Section 11) 
 
8.3.8 
Week 20 (Visit 9) / Follow up 2 
 
Two weeks after Visit 8, patients will return to the investigational site and the final 
procedures/assessments will occur: 
 
• 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3);  
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Body Surface Area (as detailed in Section 9.1.4) 
• 
Validated Investigator’s Global Assessment (as detailed in Section 9.1.1) 
• 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
• 
NRS Pruritus assessment (as detailed in Section 9.1.3) 
• 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
• 
Patient Orientated Eczema Measure (POEM) questionnaire (as detailed in Section 
9.1.6) 
• 
SCORing AD (SCORAD) questionnaire (detailed in Section 9.1.7) 
• 
Athens Insomnia Scale (AIS) (as detailed in Section 9.1.8) 
• 
Patient- Orientated SCORAD questionnaire (as detailed in Section 9.1.9) 
• 
Concomitant medication assessment (as detailed in Section 9.2.13) 
• 
Review emollient usage and capture 
• AE assessment (as detailed in Section 11) 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 47 of 83 
 
9 
ASSESSMENTS 
9.1 
Efficacy Assessments 
 
9.1.1 
Validated Investigator Global Assessment (vIGA-ADTM) 
 
The clinical severity of AD will be evaluated by the Investigator at each visit using the vIGA-
ADTM scale (Appendix 3). 
 
The vIGA-ADTM scale awards a score of 0-4 based on a 5-point severity scale from clear to 
severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe 
disease). The scale uses clinical characteristics of erythema, infiltration, papulation and 
oozing/crusting as scoring guidelines for the overall severity assessment. vIGA-ADTM will be 
assessed at every clinic visit. 
 
9.1.2 
Eczema Area Severity Index (EASI) 
 
EASI (Appendix 4) quantifies the severity of a patient’s AD based on both lesion severity and 
the percent of BSA affected (Hanifin et al. 2001). The EASI is a composite score ranging from 
0-72 that takes into account the degree of erythema, induration/papulation, excoriation, and 
lichenification (each scored from 0 to 3 separately, half points are permitted) for each of four 
body regions, with adjustment for the percent of BSA involved for each body region and for 
the proportion of the body region to the whole body.  
 
9.1.3 
Pruritus NRS 
 
Severity of pruritus related to AD will be self-assessed by patients daily using the NRS 
(Appendix 5). Patients will be asked to estimate the intensity of pruritus at its worst over the 
previous 24 hours. The Pruritus NRS is a single-question assessment tool that will be used to 
assess the patient’s worst itch as a result of AD in the previous 24 hours. Patients will score 
their pruritus due to AD on a scale of 0 – 10, with 0 (no itch) and 10 (worst itch imaginable) 
(Phan et al. 2012). Patients will complete the rating scale daily starting at screening through to 
the last study visit. 
 
 
9.1.4 
Body Surface Area (BSA) 
 
The overall BSA affected by AD will be evaluated (from 0 to 100%) at each visit. One patient’s 
palm represents 1% of his/her total BSA. BSA will be evaluated at every clinic visit. 
 
 
9.1.5 
Dermatology Life Quality Index (DLQI) Questionnaire 
 
The effect of AD on patient quality of life will be self-assessed by the patient at every clinic 
visit starting from baseline, using the DLQI (Appendix 6) developed by Finlay and Khan 
(1994).  
 
DLQI has a maximum value of thirty based on the patients response to ten questions scored 
according to the following scale:  
 
• 
Very Much = 3  
• 
A lot = 2  
• 
A little = 1  
• 
Not at all = 0  
• 
Not relevant = 0  
• 
Question unanswered = 0  


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 48 of 83 
 
• 
Question 7: “prevented work or studying” = 3  
 
9.1.6 
Patient Orientated Eczema Measure (POEM) 
 
The POEM will be assessed at each clinic visit, except the screening visit. The POEM 
developed by Charman et.al. 2004 (Appendix 7) is a self-assessment of disease severity by the 
patient. POEM has a maximum value of twenty eight based on the patient’s response to seven 
questions scored according to the following scale: 
 
- 
No Days = 0 
- 
1-2 Days = 1 
- 
3-4 Days = 2 
- 
5-6 Days = 3 
- 
Everyday = 4 
9.1.7 
SCORing Atopic Dermatitis (SCORAD) 
 
SCORAD will be measured at each clinic visit, except the screening visit. The SCORAD 
grading system was developed by the European Task Force on Atopic Dermatitis (1993) and 
has been a standard tool to assess the AD severity in clinical studies. Six items (erythema, 
edema/papulation, oozing/crusts, excoriation, lichenification, and dryness) will be selected to 
evaluate the AD severity. The overall BSA affected by AD will be evaluated (from 0 to 100%) 
and included in the SCORAD scores. Loss of sleep and pruritus will be evaluated by patients 
on a visual analog scale (0-10). The sum of these measures represents the SCORAD which can 
vary from 0 to 103. The detailed procedure of SCORAD score calculation is provided in 
Appendix 8. 
 
9.1.8 
Athens Insomnia Scale (AIS) 
 
The severity of sleep disturbance will be self-assessed daily starting from baseline using the 
Athens Insomnia Scale (AIS). 
The AIS is a self-administered psychometric instrument consisting of eight items (Appendix 
11). The first five items of the AIS (assessing difficulty with sleep induction, awakenings during 
the night, early morning awakening, total sleep time, and overall quality of sleep) correspond 
to Criterion A for the diagnosis of insomnia according to ICD-10 (International Statistical 
Classification of Diseases and Related Health Problems 10th Revision), while the requirements 
of a minimum frequency (at least three times a week) and duration (1 month) of any complaint 
correspond to Criterion B of the ICD-10. The ICD-10 requirements of marked distress caused 
by the sleep problem and/or interference with ordinary activities of daily living (Criterion C) 
are covered through the strictly subjective nature of the response options for every item of the 
scale as well as through the content of the last three items pertaining to the next day 
consequences of insomnia (problems with sense of well-being, functioning, and sleepiness 
during the day). 
 
Each item of the AIS can be rated 0-3 as detailed in Appendix 9. 
The responders are requested to rate positively if they had experienced the sleep difficulty 
described in each item at least three times a week between the study visits (Soldatos et al. 2000). 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 49 of 83 
 
9.1.9 
Patient Oriented SCORAD (PO-SCORAD) 
 
The PO-SCORAD will be measured at each clinic visit, except the screening visit. The PO-
SCORAD is the SCORAD completed by the patients themselves. It is a self-evaluation tool 
developed by the European Task Force on Atopic Dermatitis (2011). Six items (erythema, 
edema/papulation, oozing/crusts, excoriation, lichenification, and dryness) will be selected to 
evaluate the AD severity. The overall surface affected, loss of sleep and pruritus will also be 
evaluated by patients on a visual analog scale. The detailed procedure of PO-SCORAD is 
provided in Appendix 10. 
 
 
9.2 
Safety Assessments 
9.2.1 
Medical / Surgical History 
 
A complete review of the patient’s medical history will be undertaken by the Investigator or 
designee at the Screening Visit (Visit 1) to ensure that no exclusion criteria have been met. Any 
concomitant disease, whether considered relevant for the study or not by the Investigator, must 
be reported in the CRF. The date of diagnosis or duration of the condition should be noted 
where possible. 
9.2.2 
Physical Examination 
 
A physical examination will be performed by the Investigator as per the Study Flow Chart 
(Appendix 1) in accordance with local practices. This examination will be symptom-directed, 
i.e., a standard panel of body systems will not be assessed unless indicated by patient. For 
example should the patient report to the Investigator the presence of ‘rash’ then the skin would 
be evaluated. It is not required that additional body systems are assessed unless clinically 
warranted. Any clinically significant abnormal results should be recorded in the CRF. Changes 
in findings of the physical examination compared with the baseline examination should be 
recorded as an AE. 
9.2.3 
Vital Signs 
 
Vital sign measurements will be performed as per the Study Flow Chart (Appendix 1). 
Measurements to be taken include: 
- 
Blood pressure: will be performed as supine (after at least 5 minutes of rest) systolic 
and diastolic blood pressure (in mmHg) 
- 
Heart rate: taken at rest (in bpm) 
- 
Temperature: will be taken as per clinic practice. Temperature and route will be 
recorded in the CRF.  
Vital signs measurements will be performed before any blood samples are taken. All new 
findings or changes to previous findings considered clinically significant will be recorded in 
the CRF as an AE if the finding is made after the patient has signed the ICF. 
9.2.4 
Clinical Laboratory Safety Tests: Haematology and Serum Biochemistry 
Blood samples will be taken as per the Study Flow Chart (Appendix 1) for routine haematology 
and serum biochemistry tests. All samples will be analysed in the central laboratory. 
 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 50 of 83 
 
Table 2: Clinical Laboratory Safety Tests 
 
Haematology: 
Full blood count to include red cell count, haemoglobin, haematocrit, 
white cell count, differential white cell count, platelet count and 
reticulocyte count. 
Serum biochemistry: 
Urea (blood urea nitrogen; BUN), creatinine, uric acid, total 
bilirubin, potassium, , alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), lactate 
dehydrogenase (LDH), creatine phosphokinase (CPK), albumin, 
total protein, cholesterol, triglycerides, glucose.  
 
If required a Follicle-Stimulating Hormone (FSH) test to confirm non-child bearing potential 
will be carried out at screening only. 
Details of the volume of blood to be taken, sample preparation and handling are contained in a 
separate Laboratory Procedures Manual. Laboratory results will be reviewed for clinically 
significant values by each Investigator following sample analysis and verification. The report 
must be signed and dated by the Investigator before insertion in the CRF.  
 
Additional blood may be required for repeats of safety laboratory test. 
 
 
9.2.5 
Pregnancy Test 
 
For female patients of childbearing potential, a pregnancy test will be carried out at screening 
and Week 16/Visit 7/ET Visit, as per the Study Flow Chart (Appendix 1). 
 
9.2.6 
Virology 
A blood sample will be taken to perform virology tests including human immunodeficiency 
virus (HIV), Hepatitis C and Hepatitis B at screening as detailed in Study Flow Chart (Appendix 
1). 
9.2.7 
Electrocardiogram (ECG) 
 
A 12-lead ECG 10 mm/1 mv, 25 mm/s with a 10 second lead II rhythm strip will be recorded 
on the days indicated in Study Flow Chart (Appendix 1). Patients will be rested quietly in a 
fully supine position for 5 minutes before the ECG is taken.  
Use of a 6-lead ECG is acceptable if no 12-lead ECG is available. 
 
9.2.8 
Body Mass Index (BMI) 
 
Weight (kg) and height (cm) will be collected to calculate the BMI (kg/m²), and will be recorded 
at Screening/Visit 1and Week 16/Visit 7/Early Termination (ET). The height will only be 
recorded once at the screening visit and the same value will be used for BMI calculation at 
Week 16/Visit 7/ET visits. 
 
9.2.9 
DGLA Plasma Concentration Sampling 
 
Blood samples for trough total DGLA plasma concentration analysis will be collected via direct 
venepuncture as per the Study Flow Chart (Appendix 1).  
 
The detailed instruction for DGLA plasma sample collection, processing, storage and shipment 
will be provided in a separate procedure. 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 51 of 83 
 
9.2.10 Biomarker Sampling 
 
Blood samples will be collected via direct venepuncture as per the Study Flow Chart (Appendix 
1). The samples will be stored for the potential analysis of AD biomarkers at a later date.  
 
The detailed instruction for biomarker sample collection, processing, storage and shipment will 
be provided in a separate procedure. 
9.2.11 Sample Storage, Handling and Shipping 
 
Sample storage, handling and shipping will be done as per standard operating procedures and 
as specified in the Laboratory Procedures Manual. 
9.2.12 Adverse Event Assessment 
 
See Section 11. 
9.2.13 Concomitant Medication 
 
Any medication (prescription as well as over the counter (OTC) drugs, vitamins and antacids) 
or therapeutic intervention deemed necessary for the patient, and which, in the opinion of the 
Investigator, do not interfere with the safety and efficacy evaluations, may be continued unless 
they are included in the list of ‘medications and therapeutic regimens excluded from the study’ 
outlined below. However, the Investigator should be cautious in evaluating the need for change 
in dosage and should carefully assess if any concomitant medication is necessary.  
 
Any medications, herbal medicines, natural health remedies and nutritional supplements used 
within 30 days prior to Screening (Visit 1) until completion (Visit 8) are to be recorded in the 
concomitant medication module in the CRF system. The generic name of the medication (i.e., 
not local trade names), along with start date, stop date, dose, route, regimen and indication shall 
be recorded as applicable in the CRF system.  
 
Any new medications or changes to the dose or regimen of pre-existing medications will be 
updated on a routine basis during the study.  
 
Investigational new drugs (i.e. drugs that are not marketed in the local market) should not be 
co-administered with the IMPs during the entire period of the study.  
 
9.2.13.1 
Permitted Therapies 
9.2.13.1.1 Emollients 
 
All patients should be applying bland emollient, initiated at least 7 days prior to Baseline/Day 
0, usually twice a day on their skin including AD lesions. Emollient use must continue at the 
same frequency and on the same skin areas throughout the study. Any change in the frequency, 
application of the skin area or the emollient by the patient must be documented in the patient’s 
compliance log. Patients will be asked to avoid using emollients containing any active 
ingredient which has or may have an effect on AD including the following ingredients: 
 
• 
Urea 
• 
Ceramide 
• 
Hyaluronic acid 
 
Note: 
Patients who have been on a stable emollient with an active ingredient (for example urea, 
ceramide and hyaluronic acid) for at least 12 weeks prior to screening and are otherwise 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 52 of 83 
 
eligible may continue using their pre-existing emollients, if deemed appropriate by the 
investigator and if they are willing and able to continue using the same stable emollient 
for the duration of the study 
 
Every effort should be made to use the same emollient throughout the study. The commercial 
name of the selected emollient(s) will be recorded in the source document and the eCRF, along 
with the frequency and quantity. Patients will also record on a daily basis their emollient use as 
instructed by the clinic staff. No other products may be applied to the lesions during the study. 
On the day of the visit, patients should apply emollient after all assessments have taken place.  
 
 
9.2.13.1.2 Other Permitted Therapies 
 
Non-sedative anti-histamines (e.g. loratadine, fexofenadine) are allowed during the study only 
if used to treat medical conditions other than AD. Such medications are allowed during the 
study only if the patient has been on a stable dose for at least 4 weeks prior to Baseline/Day 0 
and continues to use the same agent everyday throughout the study. 
 
Inhaled and intranasal corticosteroids for stable medical conditions are allowed.  
 
9.2.13.2 
Medications and therapeutic regimens excluded from use in the study  
 
The following topical therapies or procedures are prohibited during the study for all patients: 
 
• 
Topical medicated treatments that could affect AD, including but not limited to: 
− 
topical corticosteroids 
− 
tars 
• 
Any topical product containing urea, ceramides or hyaluronic acid 
• 
Systemic therapy that could affect AD, e.g. retinoids, methotrexate, cyclosporine, 
hydroxycarbamide (hydroxyurea), azathioprine and oral/injectable corticosteroids  
• 
Any biological agent  
• 
UV-A or UV-B phototherapy 
• 
Psoralen + Ultraviolet A (PUVA) therapy  
• 
Use of tanning booth 
• 
Any other investigational medicinal product 
• 
Traditional medicine, herbal extracts and supplements used to treat AD 
 
9.2.14 Restrictions 
 
Behavioural 
 
Patients will be asked to refrain from any travel to sunny climates or use of tanning equipment, 
saunas and swimming throughout the duration of the study. 
 
Extensive UV exposure or UV-B devices will be prohibited within 4 weeks of the start of the 
trial and during the trial. 
 
Other 
 
Patients will be instructed to abstain from using any drugs/treatments that may influence AD 
(refer to exclusion criteria and prohibited therapies or procedures section) throughout the study.  
 
Patients will be required to administer the drug 2 hours after the consumption of food. 
Medication(s) for other conditions that are permitted in the study can be taken as usual. Patients 
will also be instructed to not consume food for approximately 1 hour after IMP administration.  


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 53 of 83 
 
 
9.2.15 Rescue Treatment 
 
If medically necessary (ie, to control intolerable AD symptoms), rescue treatment for AD may 
be provided to study patients at the discretion of the investigator. If possible, investigators 
should avoid administration of rescue treatments before Week 4 due to the expected time to 
onset of treatment-response following DS107 treatment. 
 
For the purpose of efficacy analysis, patients who receive rescue treatment during the study 
treatment period will be considered treatment failures from the time rescue treatment is used. 
 
Topical corticosteroids or calcineurin inhibitors may be used for rescue, but should be reserved 
for problem areas only, eg, face, neck, intertriginous and genital areas, etc. If a patient receives 
rescue treatment with systemic corticosteroids or non-steroidal systemic immunosuppressive 
drugs (cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, etc.) study treatment 
will be immediately discontinued. 
 
Investigators should make every attempt to conduct efficacy and safety assessments (eg, disease 
severity scores, safety labs) immediately before administering any rescue treatment. 
 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 54 of 83 
 
10 
INVESTIGATIONAL MEDICINAL PRODUCT / 
INVESTIGATIONAL DRUG 
10.1 Investigational Medicinal Product (IMP)  
 
The following medication supplies will be used in the study:  
 
DS107 capsules:  
 
Each DS107 capsule contains 500mg DGLA as an active ingredient in an opaque, oval soft 
gelatin capsule.  
 
Placebo capsule:  
 
Each matching placebo capsule contains 500mg of liquid paraffin in an opaque oval soft gelatin 
capsule.  
 
10.2 Supply, Packaging, Labelling, Handling and Storage 
DS107 capsules will be provided by the Sponsor as opaque, oval soft gelatin capsules 
containing 500mg of DGLA. 
 
Placebo capsules will also be provided by the Sponsor as opaque, oval soft gelatin capsules 
containing 500mg of liquid paraffin. 
 
DS107 capsules will be supplied in manufactured form (blinded), packaged in cold formed 
aluminium foil blisters of 28 units. Placebo will be presented in identical blisters and packs and 
stored/packaged the same as DS107 capsules. Study medication will be labelled according to 
EU and US regulations. 
 
The study medication will be provided by the Sponsor to the Investigator and will be kept, on 
site, in a locked room or cabinet with limited access. DS107 and placebo capsules should be 
stored at a controlled room temperature between 15-25°C and will only be supplied to patients 
in the trial under the supervision of the Investigator. 
 
10.3 Dosage and Administration 
This study involves a comparison of DS107 (2g) with placebo, administered orally once daily 
for a total duration of 16 weeks. The last study drug administration should occur on the day 
preceding Week 16 (Visit 6) / Early Termination (ET) visit. Patients will be randomized to 
one of the two treatment groups in a 1:1 ratio: 
 
• 
2g DS107 (4 DS107 capsules) administered once-daily for 16 weeks  
 
• 
Placebo (4 placebo capsules) orally administered once-daily for 16 weeks 
 
 
Patients will be required to administer the drug 2 hours after the consumption of food. 
Medication(s) for other conditions that are permitted in the study can be taken as usual. Patients 
will be also be instructed to not consume food for approximately 1 hour after IMP 
administration. On the day of the visit, patients should take dose after all assessments have 
taken place.  
 
Blister packs will consist of 7 rows of 4 capsules with each weekday detailed. Each row 
constitutes one dose. Patients will be instructed to take the 4 capsules from left to right, on the 
relevant day, as shown below: 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 55 of 83 
 
 
 
 
To maintain the blind throughout the study, the DS107 capsules and placebo capsules will be 
identical in appearance. 
10.4 Duration of Treatment 
Patients will be orally administered DS107 or placebo once daily for 16 consecutive weeks. 
10.5 Methods for Assigning Patients to Treatments 
 
Approximately 220 patients will be randomized into double-blind treatment groups in a 1:1 
ratio by an Interactive Web Response System (IWRS) as follows: 
 
• 
2g DS107 (4 DS107 capsules) administered once daily for 16 weeks  
 
• 
Placebo (4 placebo capsules) orally administered once daily for 16 weeks 
 
  
A randomization list permuted by blocks and stratified by site will be generated by the Sponsor 
or its designee. The randomization schedule with study drug assignments will be generated 
prior to the start of the study and will be known only to the individuals responsible for labelling 
the study drug, the statisticians generating the schedule and the IWRS team responsible for 
implementing the schedule. The IWRS will assign a medication kit number to each patient and 
the contents will be based on the randomization code.  
 
At the investigational site, each patient will be assigned a patient identifier number during 
screening that will be used on all patient documentation. The patient identifier number will 
contain the site number and the patient number assigned in numerical order at the screening 
visit (e.g.: 102-10 for the tenth patient screened at the site number 02). Patient numbers will be 
assigned in ascending order starting with 01. 
 
10.6 Drug Accountability 
All IMP supplies for this study must be retained in a safe place at all times of the study. Only 
personnel authorised by the principal Investigator at each site should dispense the IMP and the 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 56 of 83 
 
accountability is the responsibility of the Investigator. The Investigator or pharmacist must 
complete the IMP supply form, verifying the receipt of IMP. The patients should return all used 
and unused packs of IMP to the study site at every visit. Following compliance assessment the 
packs of IMP will be retained in a secure location at the site until the end of the study. After the 
Clinical Research Associate (CRA) has completed a final drug accountability review, the IMP 
may be returned or destroyed only when instructed by the CRA.  
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 57 of 83 
 
11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
11.1 Definitions of Adverse Events  
11.1.1 Seriousness  
Adverse Events (AE):  
Any undesirable experience occurring to a patient that has signed the ICF and who has taken 
their first dose of the study drug, whether or not considered related to the investigational IMP(s). 
All AEs must be recorded in the case report form, defining relationship to IMP and severity. 
AEs should also be recorded by the Investigator in the patient file/notes.  
Serious Adverse Events (SAE):  
If a patient experiences a serious adverse event after the first dose of the study drug, the event 
will be recorded as a serious adverse event.  
A serious adverse event (experience) or reaction is any untoward medical occurrence that at 
any dose: 
• 
results in death 
• 
is life-threatening 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity, or 
• 
is a congenital anomaly/birth defect 
Note: The term "life-threatening" in the definition of "serious" 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 were more severe. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Unexpected Adverse Event (UAE):  
An experience not previously reported in the Investigator's Brochure or similar product 
information sheet such as the Summary of Products Characteristics (SPC).  
 
11.1.2 Severity  
The intensity of an AE is an estimate of the relative severity of the event made by the 
Investigator based on his or her clinical experience. The following definitions are to be used to 
rate the severity of an AE: 
− 
Mild: The adverse event is transient and easily tolerated. 
− 
Moderate: The adverse event causes the patient discomfort and interrupts the patient’s 
usual activities.  


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 58 of 83 
 
− 
Severe: The adverse event causes considerable interference with the patient’s usual 
activities, and may be incapacitating or life-threatening.  
11.1.3 Relationship to IMP  
The Investigator will establish causality of the AE to experimental treatment. The Investigator 
should take into account the patient’s history, most recent physical examination findings, and 
concomitant medications.  
The following definitions will be used to determine causality of an AE:  
- 
Not related: temporal relationship of the onset of the AE, relative to the experimental 
treatment is not reasonable or another cause can explain the occurrence of the AE. 
- 
Related: temporal relationship of the onset of the AE, relative to the experimental 
treatment is reasonable, follows a known response pattern to the treatment, and an 
alternative cause is unlikely. 
11.1.4 Reporting of AEs and SAEs  
All AEs must be recorded in the case report form, defining relationship to IMP and severity. 
The frequency of each AE should always be recorded to indicate if the event is intermittent, 
continuous, one-time event etc. If the same AE occurs repeatedly at approximately the same 
strength in the same patient, this AE should be counted only once. If any aspect of the AE 
changes (including but not limited to severity, frequency, causality), a new AE should be 
recorded. AE start and end dates should be clearly defined in the CRF.  
As soon as the Investigator is aware of a potential SAE, he/she should report the SAE to 
the Pharmacovigilance (PV) CRO by fax or e-mail, and in any case no later than 24 hours 
after the knowledge of such a case. In case of questions regarding an SAE, the investigator 
or authorized study personnel can contact the PV CRO monitor by phone. The contact 
information, is provided in the Investigator Site File. 
At the time of the call, the Investigator must provide as a minimum requirement, the Patient 
number, birth date, nature of the SAE, and a preliminary assessment of causality. The 
Investigator should follow-up the initial notification of the potential SAE by faxing/e-mailing 
a copy of the form to PV CRO at the number/address provided in the Investigator Site File. The 
SAE reporting form should be received to the PV CRO within 24 hours after knowledge of such 
a case.  
Follow-up information on an existing SAE that is fatal or life-threatening should be reported 
by the Investigator to PV CRO within 5 days after the initial report. Where appropriate, 
hospitalisation or autopsy reports should be made available. All SAEs will be followed up until 
resolution (i.e., asymptomatic, stabilisation or death).  
AE’s should be reported for the entire study duration up to and including the follow up period. 
Following completion of the study, if the Investigator becomes aware of any AE that is 
potentially related to the IMP, the Sponsor should be notified.  
11.2 Serious Adverse Reactions and Unexpected Adverse Reactions  
11.2.1 Definitions  
Adverse Reaction:  
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions.  
The phrase "responses to a medicinal product" means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility i.e. the relationship 
cannot be ruled out.  


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 59 of 83 
 
For marketed medicinal products, an adverse reaction is a response to a drug which is noxious 
and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for modification of physiological function.  
Unexpected Adverse Reaction:  
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator's Brochure for an unauthorised investigational product or similar 
product information sheet such as the Summary of Products Characteristics (SPC)). 
Suspected Unexpected Serious Adverse Reaction (SUSAR):  
Any serious adverse reaction that might be related to the IMP and are unexpected according to 
the definition above.  
11.2.2 Reporting of suspected unexpected serious adverse reactions  
Suspected unexpected serious adverse reactions (SUSARs) will be reported by PV CRO 
according to appropriate Competent Authority and Ethics Committee requirements. SUSARs 
will be reported to Investigators according to ICH Good Clinical Practice and to local 
regulations. SUSAR reporting to the Competent Authorities and Ethics Committees will be 
performed according to local regulations in an unblinded manner. The Competent Authorities 
will be notified of all SUSARs through the Eudravigilance database.  
Fatal and life-threatening SUSARs should be reported by PV CRO as soon as possible to the 
Competent Authorities and Ethics Committees according to local regulations, and in any case 
no later than seven calendar days, after knowledge by PV CRO of such a case. Relevant follow-
up information on the case will be subsequently communicated within an additional eight days. 
All other SUSARs shall be reported to the Competent Authorities concerned and to the Ethics 
Committee concerned according to local regulations as soon as possible but within a maximum 
of fifteen days of first knowledge by PV CRO. 
11.3 Differentiation of Treatment Failure and AE 
Please note, that the lack of improvement of the symptoms of AD is not an AE and should be 
reported as treatment failure. 
 
11.4 Pregnancy Reporting 
If a patient or a patient’s partner becomes pregnant during the study, the patient should inform 
the study site as soon as possible. Upon confirmation of the pregnancy, the patient must be 
withdrawn from study drug but may continue study participation. The Investigator must 
complete a study-specific Pregnancy Form upon confirmation of a pregnancy and send it to the 
Sponsor within 24 hours of confirmation of the pregnancy. 
Post-treatment follow-up should be done to ensure patient safety. Pregnancy is not itself an AE 
or SAE, however maternal/foetal complications or abnormalities will be recorded as AEs or 
SAEs as appropriate. The investigator will follow the pregnancy until completion (or until 
pregnancy termination) and notify the Sponsor of the outcome as a follow up to the initial 
Pregnancy Form. 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 60 of 83 
 
12 
STATISTICAL METHODOLOGY AND DATA 
MANAGEMENT 
12.1 Study Design 
This clinical trial employs a randomized, double-blind, placebo-controlled parallel group 
design. Randomisation is used to minimise assignment bias and to increase the likelihood that 
known and unknown patient attributes (e.g. demographic characteristics) are evenly balanced 
across the treatment groups. Blinding is used to reduce potential bias during data collection and 
evaluation of safety and efficacy. The use of placebo as comparator is justified as a reasonable 
design to assess safety and efficacy in patients based on the brevity of the study duration and 
the absence of any possible long-term irreversible damage that may be the result of placebo 
treatment. A full description of the study design is presented in Section 6 above. 
12.2 Randomisation 
 
Approximately 220 patients will be randomized into double-blind treatment groups in a 1:1 
ratio by an IWRS.  
 
• 
2g DS107 (4 DS107 capsules) administered once-daily for 16 weeks  
 
• 
Placebo (4 placebo capsules) orally administered once-daily for 16 weeks 
 
  
A randomization list permuted by blocks and stratified by site will be generated by the Sponsor 
or its designee. The randomization schedule with study drug assignments will be generated 
prior to the start of the study and will be known only to the individuals responsible for labelling 
the study drug, the statisticians generating the schedule and the IWRS team responsible for 
implementing the schedule. The IWRS will assign a medication kit number to each patient and 
the contents will be based on the randomization code.  
 
At the investigational site, each patient will be assigned a patient identifier number during 
screening that will be used on all patient documentation. The patient identifier number will 
contain the site number and the patient number assigned in numerical order at the Screening 
Visit (e.g.: 102-10 for the tenth patient screened at the site number 02). Patient numbers will be 
assigned in ascending order starting with 01. 
 
The treatment assignment procedure will use blocks of sufficient size to maintain a blind and 
balance across treatment arms. Following successful completion of the screening/baseline 
evaluations and confirmation that the patient is eligible for participation, the patient will be 
randomised to treatment. This will be performed by the Investigator using the IWRS which will 
assign a medication number to the patient.  
 
12.3 Estimation of Sample Size 
 
In the Phase 2a trial, IGA response rates of 21.6% and 11.8% were observed for DS107 and 
placebo respectively resulting in a difference in response rates of 9.8%. Due to the prolonged 
treatment period of 16 weeks, a clinically relevant difference in IGA response rates of 15% was 
expected for the current study. 
Assuming a placebo response rate of 12% and a true response rate difference of 15% at Week 
16 and using a two-sided Chi-Square test on a significance of 5%, then 220 evaluable patients 
(110 patients per treatment arm) will be needed for 80% power to detect this difference as 
statistically significant. As the following table shows, the number of patients needed for the 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 61 of 83 
 
discovery of a 15% response rate difference depends also on the placebo response rate shown 
in the left column of the table as decimal numbers: 
 
             Number of patients per study group required under the assumptions as follows 
                                     Chi-square test, 2 x 2 table, Two Proportions, two-sided.                                      
                                    Sample Size 1 as a function of H1: Proportion 1 and Power.                                     
 H1: Proportion 2 - Proportion 1=0,15    Significance Level=0,05    Sample Size 2 / Sample Size 
1=1  
 
______________________________________________________________________________ 
                              H1: Proportion 1  
                                      Power                                       
                              = Response Rate  
                              Placebo                                   0,7           
       0,8                        0,9   
______________________________________________________________________________ 
 
                                    0,06                  
      63,4   
      80,3   
     107,0   
                                    0,08                  
      71,2   
      90,2   
     120,3   
                                    0,10                  
      78,6   
      99,6   
     132,8   
                                    0,12                  
      85,5   
     108,4   
     144,6   
                                    0,14                  
      92,0   
     116,6   
     155,6   
                                    0,16                  
      98,0   
     124,3   
     165,9   
                                    0,18                  
     103,6   
     131,4   
     175,4   
                                    0,20                  
     108,8   
     138,0   
     184,2   
______________________________________________________________________________ 
 
 
 
 
It was assumed that similar estimations apply to the primary endpoint EASI-75. 
 
12.4 Blinding and Code Breaking Instructions 
All study site personnel, as well as the personnel involved in the monitoring or conduct of the 
study, will be blinded to the individual patient treatment assignments. Randomisation details 
will be kept strictly confidential, accessible only in an emergency to authorized persons, until 
the time of formal unblinding. The blinded code for the trial will be broken only after all patient 
data has been recorded and verified and the database locked. 
Emergency unblinding will be carried out through the IWRS system with relevant site personnel 
and pharmacovigilance monitors provided with the required system access to carry out un-
blinding. 
 
12.5 Data Analysis 
Data analysis will be performed at a contract research organisation (CRO). All computations 
will be conducted using SAS® Version 9.2 or later. Graphical summaries will be produced 
using SAS®. A detailed description of the analyses to be performed will be provided in the 
statistical analysis plan (SAP). 
Continuous variables will be summarized in tables and will include the number of patients, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
presented in tables as frequencies and percentages. 
 
12.6 Analysis Sets 
Enrolled Set 
The Enrolled Set consists of all patients who sign informed consent. 
 
Screen Failures  
Screen Failures are patients from the Enrolled Set who do not meet the eligibility requirements 
and are withdrawn from the study prior to randomisation. 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 62 of 83 
 
 
Randomised Set 
The Randomised Set consists of all patients who are randomised to the study. 
 
Safety Analysis Set (SAS) 
The Safety Analysis Set (SAS) consists of all patients who received at least one dose of the 
medication. SAS is the analysis population for all safety endpoints. Analysis will be done 
according to the actual treatment patients received. 
 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) consists of all patients who were randomised to the study and 
received at least one dose of study medication. FAS is the primary analysis population for 
efficacy endpoints. Analysis will be done according to the treatment patients were randomised 
to. 
 
Per Protocol Set (PPS) 
The Per Protocol Set (PPS) is the subset of FAS who completed the study without any major 
violations. Protocol violations will be assessed for each patient in a blinded fashion prior to 
database lock at a Blind Data Review Meeting (BDRM), and the PPS will also be finalised 
during this meeting. PPS is a supportive analysis population for efficacy endpoints. Analysis 
will be done according to the treatment patients were randomised to. 
 
12.7 Safety Analysis 
Demographic, medical history and physical examination data will be listed for each patient and 
summarised descriptively. 
All AEs recorded during the study will be coded to system organ class and preferred terms 
using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). AEs 
will be tabulated and summarised by treatment, relationship to treatment, seriousness and 
severity. 
Clinical laboratory values (haematology and biochemistry) will be listed for each patient by 
treatment and day. Values outside the laboratory normal ranges will be listed separately with 
associated comments as to their clinical significance, with potentially clinically significant 
abnormalities highlighted and summarised by treatment. Most recent clinical laboratory values 
obtained prior to dosing will be defined as baseline values. 
Individual values of vital signs will be listed and summarised descriptively for each treatment 
and visit. 
Concomitant medications (if any), categorised by medication group and subgroup according to 
the latest version of the World Health Organisation drug dictionary, will be listed and 
summarised by treatment. 
12.8 Statistical Analysis Plan 
In addition to the summarised analysis plan outlined below, a separate document, Statistical 
Analysis Plan (SAP) for DS107G-05 AD3 will detail all analyses to be performed.  
 
12.8.1 Pharmacokinetic Analysis 
Plasma concentrations of DGLA will be tabulated and summarised descriptively. Individual 
and mean plasma concentration-time profiles of DGLA will be presented graphically. 
12.8.2 Primary variables 
 
The primary variables will be: 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 63 of 83 
 
 
• 
the proportion of patients achieving an vIGA-ADTM score of 0 (clear) or 1 (almost clear) 
and a decrease of at least 2 points in vIGA-ADTM from baseline to Week 16. 
 
• 
the proportion of patients achieving EASI-75 (≥75% improvement from baseline) at 
Week 16. 
 
Both primary endpoints will be analysed using a Generalised Linear Mixed Model (GLMM) 
with treatment arm, visit, their interaction treatment-by-visit, and baseline vIGA-ADTM value 
as factors, and with patient as random effect; this model will especially be used to estimate 
missing data and the treatment effects at Week 16 taking missing data into account. The primary 
analysis will be based on the FAS, and repeated for the PPS as a supportive sensitivity analysis. 
Success in either of the primary endpoints denotes successful proof of efficacy. 
 
If rescue medication is used, the patient will be specified as a non-responder from the time the 
rescue is used. 
 
The primary statistical analysis assumes “Missing At Random (MAR)” when handling missing 
data. The treatment effect obtained under the MAR assumption is essentially that which could 
have been reached if all patients had fully adhered to treatment or, in other words, the effect a 
patient may expect if they take the medication as directed. This is sometimes known as the ‘de 
jure’ or ‘efficacy’ estimand. Due to the lack of perfect adherence in practice, the ‘de facto’ or 
effectiveness treatment effect will also be estimated. This estimand includes assumptions 
regarding the treatment effects that could be expected to occur when patients discontinue 
treatment. The jump to reference method described by Carpenter et al. (2013) will be used to 
estimate the de facto estimand, using the placebo arm as the reference. This is based on the 
assumption that patients who discontinue from study drug have no alternative oral treatment 
option suitable for longer-term use and so their responses are likely to revert to those of the 
placebo group. An additional sensitivity analysis will evaluate patients who received rescue 
medication as treatment failures from the visit onwards where rescue treatment startedThe 
sensitivity analyses for missing data will be performed on the FAS only. 
 
12.8.3 Secondary variables 
IGA and EASI-75 responders at other time points will also be analysed using a GLMM model 
similar to that described in Section 12.8.2. 
 
The efficacy variables and their changes from baseline will be summarized with descriptive 
statistics per treatment group and visit. This applies to the vIGA-ADTM, EASI, NRS scores for 
pruritus, DLQI, POEM, SCORAD, AIS and PO-SCORAD. Change from baseline endpoints 
will be analysed using Mixed Model with Repeated Measures (MMRM) with Treatment Arm, 
Visit and Treatment x Visit Interaction as a factors and baseline value as a covariate,  to account 
for missing data. The secondary efficacy analyses will be based on the FAS only. For vIGA-
ADTM as a 5-level ordinal variable, mixed ordinal logistic regression will be used with factors 
defined as above and IGA at baseline as a factor too. 
If rescue medication is used, the patient will be specified as a non-responder from the time the 
rescue is used 
12.8.4 Safety variables 
 
The type and frequency of adverse events will be summarised by MedDRA system organ class 
and preferred term per treatment group. In addition, the number and proportion of patients with 
at least one adverse event will be summarised per treatment group.  
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 64 of 83 
 
The number and proportion of patients experiencing serious adverse events, adverse events 
leading to withdrawal and adverse events possibly or probably related to treatment will be 
summarized per treatment group. The secondary safety analysis will be based on the Safety 
Analysis Set only. 
12.9 Interim Analysis 
 
An interim analysis may be conducted after at least 50% of planned enrolled patients have 
completed their Week 16 assessments or an early termination visit. The interim analysis will be 
conducted in accordance with sponsor standard operating procedure (SOP) “Interim Analysis 
of Clinical Studies”. 
 
An unblinded interim analysis will be performed by an unblinded independent statistician. 
Interim data and the results of interim analyses will not be accessible by anyone other than the 
unblinded statistician. The sponsor will remain blinded with procedures in place to ensure the 
confidentiality of the interim data, as per the sponsor SOP “Interim Analysis of Clinical 
Studies”. 
 
The unblinded statistician will make one of the following recommendations to the sponsor 
based solely upon the primary efficacy endpoints:  
• 
Modify the sample size 
• 
Continue the study as originally planned 
 
Further details will be described in an interim statistical analysis plan. 
12.10 Data Collection / Case Report Forms 
 
Data will be collected using a validated electronic data capture (EDC) solution. Electronic Case 
report forms (eCRFs) will be utilised for recording data from each patient meeting the eligibility 
criteria and being randomised in the study; and a limited amount of data will be completed for 
patients who fail to meet eligibility criteria (i.e. screen failures). Electronic access to the CRF 
will be available to all investigator sites. All study staff responsible for entering data into the 
eCRF system will be trained prior to the start-up of the study. A personal log-in will be provided 
for all responsible personnel to allow for an audit trail relating to the study data to be 
maintained.  
 
All evaluations performed shall be entered in a timely manner into the eCRF by a member of 
the site staff delegated responsibility for this specific task by the Principal Investigator of the 
clinical site. It is the responsibility of the Investigator to ensure that the eCRFs are properly 
completed. The data in the eCRFs should be consistent with the relevant source documents. 
The Investigator will sign the designated signature fields of the eCRF to confirm that the 
information on each screen is accurate and complete. All data must be stored in an 
unidentifiable form treated with strict confidentiality in accordance with applicable data-
protection regulations.  
 
Captured data will be monitored electronically and Source Data Verification (SDV) will take 
place at the site where all information will be verified against the individual patient records. 
Any inconsistencies will be presented as queries; either as automatically generated queries if 
raised by the logical data checks of the eCRF system, or by manually generated queries if raised 
by the data validation checks or the SDV performed by the Data Manager (DM) or the CRA 
respectively. Queries shall be resolved in a timely manner by a trained member of the site staff.  
12.11 Data Management 
Data will be transmitted electronically into the web based EDC system. Data will be coded 
according to pre-specified dictionaries and in accordance with the CRO Standard Operating 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 65 of 83 
 
Procedures (SOP). The handling of data, including data quality control, will comply with all 
applicable regulatory guidelines.  
12.12 Protocol Deviations 
Protocol deviations will be captured through site self-reporting, CRA source data verification 
and data management edit checks and will be recorded by the CRA throughout the study in both 
the monitoring visit reports and in a centralised log.  
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 66 of 83 
 
13 
REGULATORY AND ADMINISTRATIVE PROCEDURES 
13.1 Institutional Review  
Investigators will agree that the study will be conducted according to the principles of the ICH 
E6 Guideline on (Good Clinical Practice) GCP and the ethical principles that have their origins 
in the World Medical Association Declaration of Helsinki. The Investigator will conduct all 
aspects of this study in accordance with all national, state, and local laws or regulations. 
This trial was designed and organised taking all ethical considerations into account. The 
Protocol and the Patient Information Sheet / Informed Consent Form will be approved by the 
relevant Competent Authorities and Ethics Committees, and possibly other public bodies 
according to local requirements before commencement. If a protocol amendment is necessary, 
this will be prepared with the agreement of the National Co-ordinating Investigator, and signed 
by the relevant parties. If the amendment is considered to be substantial, it will be submitted to 
the Competent Authorities and Ethics Committees and possibly other public bodies according 
to local requirements for review and approval. The protocol amendment will not be 
implemented before approvals are obtained, if required. Minor amendments which do not affect 
the safety or physical or mental integrity of the clinical trial participants or the scientific value 
of the trial (i.e. non-substantial amendments) do not need to be submitted to Competent 
Authorities until the next substantial amendment.  
SUSAR reports and Periodic Safety Reports will be sent to Competent Authorities and Ethics 
Committees according to local regulations.   
13.2 GCP 
The study will be managed and conducted according to the latest International Council for   
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines for Good Clinical Practice (GCP) and applicable regulatory requirement(s) 
(specifically the principles of GCP in ICH topic E6, as laid down by the Commission Directive 
2005/28/EC and in accordance with applicable local laws and guidelines). A copy of the ICH 
guidelines can be found in the Investigator Site File (ISF). 
13.3 Essential Documents 
The ICH guideline for GCP lists a number of essential GCP documents required prior to, during, 
and after the conduct of the study. It is the responsibility of the monitor to ensure that the 
Investigator is always provided with a copy of such documents prepared by the study 
management, and it is likewise the responsibility of the Investigator to provide the monitor with 
essential documents prepared by the Investigator or the local Ethics Committee. A complete 
list of essential GCP documents can be found in the Investigator Site File. 
13.4 Record Retention 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These records include, 
but are not limited to, the identity of all participating patients, all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and detailed 
records of treatment disposition, and adequate documentation of relevant correspondence. 
The records should be retained by the Investigator according to International Conference on 
Harmonisation (ICH), local regulations, or as specified in the Clinical Trial Agreement (CTA), 
whichever is longest.  
13.5 Monitoring / Quality Control  
Monitoring visits will be conducted during the study at regular intervals. The monitoring visits 
will be conducted to ensure protocol adherence, quality of data, accuracy of entries in the eCRF, 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 67 of 83 
 
drug accountability, compliance with regulatory requirements and continued adequacy of the 
investigational site and its facilities.  
Incorrect or missing entries in the CRFs will be queried and will be corrected appropriately. 
All clinical data will undergo quality control checks prior to clinical database lock. Edit checks 
will then be performed for appropriate databases as a validation routine using SAS ® to check 
for missing data, data inconsistencies, data ranges etc. Each eCRF is reviewed and signed by 
the Principal Investigator (PI). 
 
13.6 Quality Assurance  
The site may be audited during or after the study is completed by the Sponsor representatives 
or regulatory authorities may conduct an inspection. The Investigator(s) will be expected to 
cooperate with such a visit and to provide assistance and documentation (including all study 
documentation, and patient source data) as requested. 
13.7 Insurance and Liability 
Insurance and liability for the study is the responsibility of the Sponsor, DS Biopharma. 
13.8 End of Trial 
End of Trial is defined as Last Subject Last Visit (LSLV). LSLV is defined as the date the 
Investigator reviews the last subject’s safety data and determines that no further evaluation is 
required for the subject to complete the trial. 
13.9 Confidentiality 
All information obtained during the conduct of the study with respect to the patients' state of 
health will be regarded as confidential. This is detailed in the written information provided to 
the patient. An agreement for disclosure of any such information will be obtained in writing 
and is included in the ICF signed by the patient. The study data shall not be disclosed to a third 
party without the written consent of the Sponsor. 
13.10 Data Protection 
All information collected for this study will be kept strictly confidential. The Sponsor 
undertakes to comply with applicable data protection regulations, which are further detailed in 
the written information provided to the patient. In case of data security breach, this will be 
reported to the relevant supervisory authority where the breach presents a risk to the affected 
individuals. This will be reported within 72 hours of becoming aware of the breach. Where a 
breach is likely to result in a high risk to the affected individuals, the Sponsor will also inform 
those individuals without undue delay.  
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the regulatory agency(ies), and 
the IRB/IEC direct access to review the subject’s original medical records for verification of 
study-related procedures and data. For further information, the Sponsor data protection officer 
can be contacted at dataprotection@dsbiopharma.com.  
 
13.11 Report and Publication 
Production of a clinical study report in accordance with the ICH guidelines will be prepared. 
No information from the study will be published without the prior written consent of the 
Sponsor. 
13.12 COVID-19 Contingency 
Due to the unprecedented worldwide COVID-19 pandemic, the Sponsor is implementing 
measures to assure the safety of trial participants, to maintain compliance with GCP and to 
minimize risk to trial integrity. 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 68 of 83 
 
Among these measures are modifications to the protocol to ensure that if difficulties in adhering 
to protocol-speciifc procedures or protocol-mandated visits are encountered by patients, 
investigators or study sites, adequate and appropriate contingencies are in place. 
COVID-19 contingency measures do not replace the existing protocol procedures and visit 
schedule. 
The following contingencies and actions will be implemented in response to the evolving 
COVID-19 pandemic: 
1. An interim analysis will be conducted after at least 50% of patients have completed 
their week 16 or end-of-treatment visits as described in Section 12.9 Interim Analysis. 
Due to the rapidly evolving COVID-19 situation at both a global and country level, a 
modification to the prospectively planned sample size may be necessary if patient 
recruitment is not feasible and must be stopped. The interim analysis will safeguard the 
integrity of the trial and inform whether further patient recruitment is required when 
conditions at participating sites are amenable to re-initiation of patient recruitment. 
2. In a worst-case scenario where a patient is unable to attend the study site for protocol-
mandated visits, due to patient considerations (such as COVID-19 infection or 
quarantine) or study site restrictions; 
A. The investigator will complete all possible assessments via phone for all impacted 
study visits as described in Appendix 11. COVID-19 Contingency Investigator 
Assessment Phone Visits. 
• 
Phone visit assessments must include assessment of adverse events, patient-
reported efficacy endpoints and compliance. 
• 
The patient will be reminded that IMP will continue to be administered 
approximately 2 hours after food consumption at the same time each day. 
Patients will be reminded to not consume food for approximately 1 hour after 
IMP administration. 
• 
The patient will be reminded that NRS for the assessment of pruritus will 
continue to be captured on a daily basis from screening to the follow-up visit. 
Emollient use will also continue to be captured on a daily basis for the same 
period. 
• 
On completion of this visit, patients will be advised that they will be required 
to return to the investigational site at the next scheduled visit and to bring with 
them the unused DS107/placebo patient packs, the used DS107/placebo patient 
packs, and the patient compliance log. 
B. IMP will be couriered directly to the patient. 
Investigators must make every effort possible to ensure that patients adhere to the 
protocol procedures and attend all scheduled visits. COVID-19 contingency measures 
regarding IMP delivery and phone visits must only be used if absolutely necessary and 
after every effort to follow the protocol visit schedule has been exhausted. Investigator 
responsibilities as prescribed by ICH GCP, including oversight of patient safety must 
continue to be observed in all cases whether or not contingency actions relating to 
COVID-19 are required. 
This contingency will facilitate the conduct of appropriate safety monitoring and will preserve 
the investigational product supply chain. 
 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 69 of 83 
 
14 
REFERENCES 
• 
Amagai, Y, Oida, K, Matsuda, A, Jung, K, Kakutani, S, Tanaka, T, Matsuda, K, Jang, 
H, Ahn, G, Xia, Y, Kawashima, H, Shibata, H, Matsuda, H & Tanaka, A 2015. 
‘Dihomo- γ -linolenic acid prevents the development of atopic dermatitis through 
prostaglandin D1 production in NC/Tnd mice.’ J Dermatol Sci; 79(1), pp. 30–7. 
 
• 
Ashcroft, DM, Dimmock, P, Garside, R, Stein, K & Williams, HC 2005. ‘Efficacy and 
tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: 
meta-analysis of randomised controlled trials.’ BMJ (Clinical research ed.); 330(7490), 
pp. 516. 
 
• 
Bos, JD, Kapsenberg, ML, & Sillevis Smitt, JH 1994. ‘Pathogenesis of atopic eczema.’ 
Lancet; 343 pp. 1338-1341. 
 
• 
Carpenter, JR, Roger, JH & Kenward, MG 2013. ‘Analysis of longitudinal trials with 
protocol deviations: a framework for relevant, accessible assumptions, and inference 
via multiple imputation.’ J Biopharm Stat;  23(6), pp. 1352-71. 
 
• 
Charman, CR, Venn, AJ, Williams, HC 2004. ‘The patient-oriented eczema measure: 
development and initial validation of a new tool for measuring atopic eczema severity 
from the patients' perspective.’ Arch Dermatol; Dec;140(12) pp. 1513-9. Erratum in: 
Arch Dermatol. 2005 Mar;141(3) pp.381. 
 
• 
CRL Study - 521831. 2012. A 13 Week Study of DS107E DGLA Cream by Dermal 
Administration in Minipigs with a 4 Week Recovery Period. 
 
• 
Desbois, AP & Lawlor, KC 2013. ‘Antibacterial activity of long-chain polyunsaturated 
fatty acids against Propionibacterium acnes and Staphylococcus aureus.’ Mar Drugs; 
11(11) pp. 4544-57. 
 
• 
Eichenfield, LF, Tom, WL, Berger, TG, et al. 2014 ‘Guidelines of care for the 
management of atopic dermatitis: section2. Management and treatment of atopic 
dermatitis with topical therapies.’ J Am Acad Dermatol. Jul;71(1) pp:116-32. 
 
 
• 
Finlay, AY & Khan, GK 1994. ‘Dermatology Life Quality Index (DLQI): A simple 
practical measure for routine clinical use.’ Clinical and Experimental Dermatology; 
19: pp. 210-216. 
 
• 
Gutfreund, K, Bienias, W, Szewczyk, A & Kaszuba A. 2013. ‘Topical calcineurin 
inhibitors in dermatology. Part I: Properties, method and effectiveness of drug use.’ 
Postepy Dermatol Alergol. Jun;30(3) pp:165-9 
 
• 
Hanifin, JM, Thurston, M, Omoto, M, Cherill, R, Tofte, SJ, & Graeber, M 2001. ‘The 
eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. 
EASI Evaluator Group.’ Exp Dermatol. Feb;10(1), pp. 11-8. 
 
• 
Hong, J, Buddenkotte, K, Berger, TG, Steinhoff M. 2011. ‘Management of Itchin in 
Atopic Dermatitis.’ Semin Cutan Med Surg:  Jun; 30(2) pp. 71–86. 
 
• 
Iverson, L, Fogh, K & Kragballe, K 1992. ‘Effect of dihomo gamma linolenic acid and 
its 15-lipoxygenase metabolite on eicosanoid metabolism by human mononuclear 
leukocytes in vitro: selective inhibition of the 5-lipoxygenase pathway.’ Arch Dermatol 
Res; 284(4), pp. 222-6. 
 


 
 
Confidential / Clinical Study Protocol No. DS107G-05-AD3 Version 5.0 
 
Page 70 of 83 
 
• 
Kapp, A 1993. ‘The role of eosinophils in the pathogenesis of atopic dermatitis--
eosinophil granule proteins as markers of disease activity.’ Allergy; 48(1), pp.1–5. 
 
• 
Kawashima, H, Tateishi, N, Shiraishi, A, Teraoka, N, Tanaka, T, Tanaka, A, Matsuda, 
H, & Kiso, Y 2008. ‘Oral Administration of Dihomo-γ-Linolenic Acid Prevents 
Development of Atopic Dermatitis in NC/Nga Mice.’ Lipids; 43 (1), pp. 37-43. 
 
• 
Kawashima, H, Toyoda-Ono, Y, Suwa, Y & Kiso, Y 2009. ’Subchronic (13-week) oral 
toxicity study of dihomo-gamma-linolenic acid (DGLA) oil in rats.’ Food Chem 
Toxicol.; 47(6), pp. 1280-6. 
 
• 
Leung, DYM & Bieber, T 2003. 'AtopicDermatitis.‘ Lancet; 361, pp. 151-160. 
 
• 
Leung, DY & Guttman-Yassky, E 2014. ‘Deciphering the complexities of atopic 
dermatitis: shifting paradigms in treatment approaches.’ J Allergy Clin Immunol. 
134(4), pp. 769-79 
 
• 
Phan, NQ, Blome, C, Fritz, F, Gerss, J, Reich, A, Ebata, T, Augustin, M, Szepietowski, 
JC & Ständer, S 2012. ‘Assessment of pruritus intensity: prospective study on validity 
and reliability of the visual analogue scale, numerical rating scale and verbal rating 
scale in 471 patients with chronic pruritus.’ Acta Derm Venereol; 92 pp. 502–507. 
 
• 
Reynolds, NJ, Franklin, V, Gray, JC, Diffey, BL, & Farr, PM 2001. ‘Narrow-band 
ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a 
randomised controlled trial.’ Lancet; 357, pp. 2012-2016. 
 
• 
Schultz-Larsen, FV & Haniﬁn, JM 2002. ‘Epidemiology of atopic dermatitis.’ Immunol 
Allergy Clin North Am; 22, pp. 1-24. 
 
• 
Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the 
European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31. 
 
 
• 
Silverberg, JI, & Hanifin, JM 2013. ‘Adult eczema prevalence and associations with 
asthma and other health and demographic factors: a US population-based study.’ J 
Allergy Clin Immunol; 132(5), pp.1132-1138. 
 
• 
Simpson, EL 2010. ‘Atopic dermatitis: A review of topical treatment options.’ Curr. 
Med Res Opin; 26(3), pp. 633-40. 
 
• 
Soldatos CR, Dikeos DG, Paparrigopoulos TJ: Athens Insomnia Scale: validation of an 
instrument based on ICD-10 criteria. Journal of Psychosomatical Research 48 (2000) 
555-560.  
 
• 
Stalder, JF et al. 2011. ‘Patient-Oriented SCORAD (PO-SCORAD): a new self-
assessment scale in atopic dermatitis validated in Europe’ Allergy; Aug;66(8):1114-21. 
 
• 
Suarez, AL, Feramisco, JD, Koo, J & Steinhoff, M 2012. ‘Psychoneuroimmunology of 
psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates.’ 
Acta Derm Venereol; 92(1), pp. 7-15. 
. 
 
• 
Williams, H & Flohr C 2006. ‘How epidemiology has challenged 3 prevailing concepts 
about atopic dermatitis.’ J Allergy Clin Immunol; 118, pp. 209-213. 


 
 
Page 71 of 83 
 
 
15 
APPENDICES 
15.1 Appendix 1: Study Flow-Chart 
Visit 
Screening/  
Visit 1 
Baseline / 
Visit 2 
Week 
1/Visit 3 
Week 4/ 
Visit 4 
Week 8 / 
Visit 5   
Week 12/ 
Visit 6 
Week 16/ 
Visit 7 
(EOT) 
Week 18/ 
Visit 8 
(Follow up 
1) 
Week 20/ 
Visit 9  
(Follow up 
2) 
Day 
-14 to -1 
0 
7 
28  
56  
84 
112 
126 
140 
Visit Window 
 
 
+/-2 days 
+/-2 days 
+/-2 days 
+/-2 days 
+/-2 days 
+/-2 days 
+/-2 days 
Type of Visit 
Onsite 
Onsite 
Telephone 
Onsite 
Onsite 
Onsite 
Onsite 
Onsite 
Onsite 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Assign Patient 
Identifier Number 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical/Surgical 
History 
X 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Safety Labs: Serum 
Biochemistry 
(including FSH 
levels at screening 
when applicable1), 
Hematology. 
X  
X 
 
X 
X 
 
X 
X2 
 
Virology 
X 
 
 
 
 
 
 
 
 
Trough Plasma 
Levels 
 
X 
 
X 
X 
 
X 
 
 
Biomarker Sampling 
 
X 
 
 
 
 
X 
 
 
Pregnancy Test (-
hCG if female of 
childbearing 
potential) 
X 
 
 
 
 
 
X 
 
 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical Examination 
3 
X 
X 
 
X 
X 
X 
X 
X 
X 
ECG 
 
X 
 
 
 
 
X 
 
 
BMI 
X 
 
 
 
 
 
X 
 
 
Dispense Study Drug 
4 
 
X 
 
X 
X 
X 
 
 
 
Collect Study Drug 
 
 
 
X 
X 
X 
X 
 
 
Dispense Patient 
Compliance Log 
 
X 
 
X 
X 
X 
 
 
 
Collect and Review 
Patient Compliance 
Log 
 
 
 
X 
X 
X 
   X 
 
 
Discuss Patient 
Compliance Log 
 
 
X 
 
 
 
 
 
 
IMP Accountability 
 
 
 
X 
X 
X 
X 
 
 
Discuss IMP 
Compliance 
 
 
X 
 
 
 
 
 
 
BSA 
X 
X 
 
X 
X 
X 
X 
X 
X 
vIGA-ADTM 
X 
X 
 
X 
X 
X 
X 
X 
X 
EASI Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
NRS Pruritus 
Assessment 
  
     X--------------------------------------------------------------------------------------------------------------------------------X 
DLQI Questionnaire 
 
X 
 
X 
X 
X 
X 
X 
X 
POEM Questionnaire 
 
X 
 
X 
X 
X 
X 
X 
X 
SCORAD 
Questionnaire 
 
X 
 
X 
X 
X 
X 
X 
X 
Athens Insomnia 
Scale 
 
X------------------------------------------------------------------------------------------------------------X 


 
 
Page 72 of 83 
 
 
1. FSH requirement to confirm female of non-child-bearing potential for women greater than 40 
years of age who have had a cessation of menses for at least 12 months. Non-child bearing 
potential may also be confirmed via cessation of menses for at least 24 months without FSH 
levels confirmed. 
2. Only if clinically significant change from baseline in safety laboratory results at Week 16. 
3. Physical Examination will be symptom-directed. 
4. Patients will be instructed to take their last study drug dose the day preceding Week 16 visit. 
5. Collection of AEs will start after the first study drug administration. 
6. Adverse Events and Concomitant Medication will be collected over the phone at this visit.  
PO-SCORAD 
Questionnaire 
 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X6 
X 
X 
X 
X 
X 
X 
Emollient Use 
Capture 
X--------------------------------------------------------------------------------------------------------------------------------X 
Adverse Events 5 
 
X 
X6 
X 
X 
X 
X 
X 
X 


 
 
Page 73 of 83 
 
15.2 Appendix 2: Diagnostic Features of Atopic Dermatitis (American 
Academy of Dermatology Consensus Criteria)  
 
 
Essential features — must be present: 
• Pruritus  
• Eczema (acute, subacute, chronic) 
 • Typical morphology and age specific patterns* 
 • Chronic or relapsing history 
 
*Patterns include: 
 1. Facial, neck, and extensor involvement in infants and children 
 2. Current or previous flexural lesions in any age group 
 3. Sparing of the groin and axillary regions 
 
Important features — seen in most cases, adding support to the diagnosis: 
• Early age of onset 
• Atopy 
 • Personal and/or family history 
 • Immunoglobulin E reactivity 
• Xerosis 
Associated features — These clinical associations help to suggest the diagnosis of 
atopic dermatitis but are too nonspecific to be used for defining or detecting atopic 
dermatitis for research and epidemiologic studies: 
• Atypical vascular responses (e.g. facial pallor, white dermographism, delayed blanch 
response) 
• Keratosis pilaris/ pityriasis alba/ hyperlinear palms/ icthyosis 
• Ocular/periorbital changes 
• Perifollicular accentuation/ lichenification/ prurigo lesions 
Exclusionary conditions — It should be noted that a diagnosis of atopic dermatitis 
depends on excluding conditions, such as: 
• Scabies 
• Seborrheic dermatitis 
• Contact dermatitis (irritant or allergic) 
• Icthyoses 
• Cutaneous T-cell lymphoma 
• Psoriasis  
• Photosensitivity dermatoses 
• Immune deficiency diseases 
• Erythroderma of other causes 
 
 


 
 
Page 74 of 83 
 
15.3 Appendix 3: Validated Investigator’s Global Assessment for Atopic 
Dermatitis (vIGA-ADTM) 
 
Instructions:  
 
The IGA score is selected using the descriptors below that best describe the overall appearance 
of the lesions at a given time point. It is not necessary that all characteristics under 
Morphological Description be present.  
 
 
Score 
Morphological Description 
0 – Clear 
No inflammatory signs of atopic dermatitis (no erythema, no 
induration/papulation, no lichenification, no oozing/crusting). Post-
inflammatory hyperpigmentation and/or hypopigmentation may be 
present.  
1 – Almost Clear Barely perceptible erythema, barely perceptible induration/papulation, 
and/or minimal lichenification. No oozing or crusting.  
2- Mild 
Slight 
but 
definite 
erythema 
(pink), 
slight 
but 
definite 
induration/papulation, and/or slight but definite lichenification. No 
oozing or crusting.  
3- Moderate 
Clearly perceptible erythema (dull red), clearly perceptible 
induration/papulation, and/or clearly perceptible lichenification. Oozing 
and crusting may be present.  
4- Severe  
Marked erythema (deep or bright red), marked induration/papulation, 
and/or marked lichenification. Disease is widespread in extent. Oozing 
or crusting may be present. 
 
 
Notes: 
 
1. In indeterminate cases, please use extent to differentiate between scores. 
 
For example: 
• 
 Patient with marked erythema (deep or bright red), marked papulation and/or 
marked lichenification that is limited in extent, will be considered “3 – 
Moderate”. 
 
2. Excoriations should not be considered when assessing disease severity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright ©2017 Eli Lilly and Company – Used with the permission of Eli Lilly and 
Company under a Creative Commons Attribution-NoDerivatives 4.0 International License - 
https://creativecommons.org/licenses/by-nd/4.0/  


 
 
Page 75 of 83 
 
15.4 Appendix 4: Eczema Area and Severity Index (EASI) 
 
Four anatomic sites – head/neck, upper extremities, trunk and lower extremities – are assessed 
for erythema, induration (papules), excoriation and lichenification as seen on the day of the 
examination. The severity of each sign is assessed using a 4-point scale (half points are 
permitted): 
 
• 
0 = none 
• 
1 = mild 
• 
2 = moderate 
• 
3 = severe 
 
The area affected by AD within a given anatomic site is estimated as a percentage of the total 
area of that anatomic site and assigned a numerical value according to the degree of AD 
involvement as follows: 
 
• 
0 = no involvement 
• 
1 = < 10 % 
• 
2 = 10 to 29% 
• 
3 = 30 to 49% 
• 
4 = 50 to 69% 
• 
5 = 70 to 89% 
• 
6 = 90 to 100 % 
 
The EASI score is obtained by using the formula: 
 
EASI = 0.1 (Eh + Ih + Exh + Lh) Ah + 0.2 (Eu + Iu + Exu + Lu) Au + 0.3 (Et 
+ It + Ext + Lt) At + 0.4 (El + Il + Exl + Ll) Al 
 
Where E, I, Ex, L and A denote erythema, induration, excoriation, lichenification and area, 
respectively, and h, u, t, and l denote head/neck, upper extremities, trunk, and lower extremities, 
respectively. 
 
 


 
 
Page 76 of 83 
 
15.5 
Appendix 5: Numerical Rating Scale for assessment of Pruritus 
 
 
Patient ID #: ___ ___ - ___ ___ ___  
 
Patient Initials: ___ ___ ___ 
 
Visit Day: ___________ 
 
Visit Date (dd-mmm-yyyy):______________ 
 
 
Pruritus assessment (itching) (during the past 24 hours) 
 
To help you assess itching, we have drawn a scale from 0 to 10 where 0 represents no itching 
and 10 represents the worst itching that you can imagine.  We would like you indicate on this 
scale how was your itching at its worst during the past 24 hours.  Once determined, circle one 
number on this scale. 
 
 
 
 
 
 
 
 
 
10 
3 
2 
1 
9 
8 
6 
7 
5 
4 
0 
No itch 
Worst imaginable itch 


 
 
Page 77 of 83 
 
15.6 
Appendix 6: Dermatology Life Quality Index (DLQI) 
 
 
 
Patient ID #: ___ ___ - ___ ___ ___  
 
Patient Initials: ___ ___ ___ 
 
Visit Day: ___________ 
 
Visit Date (dd-mmm-yyyy):______________ 
 
 
DLQI 
 
 
Score:  
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK. Please tick  one box for each question. 
 
1. 
 
Over the last week, how itchy, sore, painful or 
stinging has your skin been? 
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
2. 
 
Over the last week, how embarrassed or self 
conscious have you been because of your skin? 
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
 
3. 
 
Over the last week, how much has your skin 
interfered with you going shopping or looking 
after your home or garden? 
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
4. 
 
Over the last week, how much has your skin 
influenced the clothes you wear? 
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
5. 
 
Over the last week, how much has your skin 
affected any social or leisure activities?  
 
 
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
6 
Over the last week, how much has your skin made 
it difficult for you to do any sport? 
 
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
7 
Over the last week, has your skin prevented you from 
working or studying? 
yes 
no 
 
 
 
 
Not relevant 
 


 
 
Page 78 of 83 
 
If "No", over the last week how much has your skin 
been a problem at work or studying? 
A lot 
A little 
Not at all  
 
 
 
 
 
 
 
8 
Over the last week, how much has your  skin 
created problems with your partner or any of your 
close friends or relatives?  
 
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
9 
Over the last week, how much has your  skin caused 
any sexual difficulties?  
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
1
0 
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? 
Very 
much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
©AY Finlay, GK Khan, April 1992 www.dermatology.org.uk. 
 
Please check you have answered EVERY question. Thank you. 
 
 
 


 
 
Page 79 of 83 
 
15.7 
Appendix 7: Patient Orientated Eczema Measure 
 
 
Patient ID #: ___ ___ - ___ ___ ___  
 
Patient Initials: ___ ___ ___ 
 
Visit Day: ___________ 
 
Visit Date (dd-mmm-yyyy):______________ 
 
Please circle one response for each of the seven questions below about your eczema. Please 
leave blank any questions you feel unable to answer. 
 
1. Over the last week, on how many days has your skin been itchy because of your eczema? 
 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
 
2. Over the last week, on how many nights has your sleep been disturbed because of your 
eczema? 
 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
 
3. Over the last week, on how many days has your skin been bleeding because of your 
eczema? 
 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
 
4. Over the last week, on how many days has your skin been weeping or oozing clear fluid 
because of your eczema? 
 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
 
5. Over the last week, on how many days has your skin been cracked because of your 
eczema? 
 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
 
6. Over the last week, on how many days has your skin been flaking off because of your 
eczema? 
 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
 
7. Over the last week, on how many days has your skin felt dry or rough because of your 
eczema? 
 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
 
 
 
 
© CR Charman, AJ Venn, HC Williams, December 2004. 
 
 
 
 
 
 


 
 
Page 80 of 83 
 
15.8 
Appendix 8: SCORing Atopic Dermatitis (SCORAD) 
 
Six items (erythema, edema/papulation, oozing/crusts, excoriation, lichenification, and 
dryness) are selected to evaluate the AD severity. The intensity of each item is graded using a 
4-point scale: 
 
• 
0 = No symptoms 
• 
1 = Mild 
• 
2 = Moderate 
• 
3 = Severe 
 
The area chosen for grading must be representative (average intensity) for each item. The 
individual intensity ratings for each item will then be added (ranging from 0-18) and multiplied 
by 3.5, giving a maximal score of 63. 
 
The overall BSA affected by AD is evaluated (from 0 to 100%) and divided by 5. One patient’s 
palm represents 1% of his/her total BSA. The maximum is 20. 
 
Subjective items include loss of sleep and the occurrence of pruritus. These are evaluated by 
asking patients to indicate on the 10-cm scale (0-10) of the assessment form the point 
corresponding to the average value for the last three days/nights. The combined maximum score 
of these two is 20. 
 
The sum of the above measures represents the SCORAD which can vary from 0 to 103. If the 
subjective scores of pruritus and loss of sleep are excluded, the SCORAD becomes objective 
SCORAD (score range 0-83). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Page 81 of 83 
 
15.9 
Appendix 9: Athens Insomnia Scale 
 
 
 
1.   SLEEP INDUCTION (time it takes you to fall asleep after turning-off the lights) 
0 
No problem 
1 
Slightly delayed 
2 
Markedly delayed 
3 
Very delayed or did not 
sleep at all 
2.    AWAKENINGS DURING THE NIGHT 
0 
No problem 
1 
Minor problem 
2 
Considerable problem 
3 
Serious problem or did not 
sleep at all 
3.  FINAL AWAKENING EARLIER THAN DESIRED 
0 
Not earlier 
1 
A little earlier 
2 
Markedly earlier 
3 
Much earlier or did not 
sleep at all 
4.  TOTAL SLEEP DURATION 
0 
Sufficient 
1 
Slightly insufficient 
2 
Markedly 
insufficient 
3 
Very insufficient or 
did not sleep at all 
5.  OVERALL QUALITY OF SLEEP (no matter how long you slept) 
0 
Satisfactory 
1 
Slightly unsatisfactory 
2 
Markedly 
unsatisfactory 
3 
Very unsatisfactory or did 
not sleep at all 
6.  SENSE OF WELL-BEING DURING THE DAY 
0 
Normal 
1 
Slightly decreased 
2 
Markedly decreased 
3 
Very decreased 
7.  FUNCTIONING (PHYSICAL AND MENTAL) DURING THE DAY 
0 
Normal 
1 
Slightly decreased 
2 
Markedly decreased 
3 
Very decreased 
8.  SLEEPINESS DURING THE DAY 
0 
None 
1 
Mild 
2 
Considerable 
3 
Intense 
 
 
 
 
 
 
 
 
 
 
 


 
 
Page 82 of 83 
 
15.10 Appendix 10: Patient-Oriented SCORAD 
 
 
 
 
PO-SCORAD on Day .............  
Last name:  ................................................  First name: 
Date of birth:  .......................................  Today’s date: .......................................................  
Who is filling out this questionnaire? 
O The patient 
O The patient, assisted by a parent 
O The patient’s mother 
O The patient’s father 
O The patient’s brother / sister 
O Other (please specify)  ...........................................................  
 
● Surface affected 
O patient under 2 years old O 
patient over 2 years old 
Using the drawing provided, 
shade the areas affected by eczema. 
● Intensity of symptoms 
 
 
● Subjective symptoms: itching + trouble sleeping 
 
You can download a free application that will help you calculate the PO SCORAD automatically. Your computer will create a curve as your eczema evolves and 
you can print it and give it to your doctor. 
Today’s PO SCORAD: 
Please visit: PoScorad sur Google play et Apple store 
www.opened-dermatology.com 
ou www.fondation-dermatite-atopique.org 
 
Criteria 
Intensity (from 0 to 3) 
Dryness* 
Redness 
Swelling 
Oozing/scabs 
Scratch marks 
Thickening of skin 
* Dryness is evaluated on the skin not affected by eczema. 


 
 
Page 83 of 83 
 
15.11 Appendix 11: COVID-19 Contingency Investigator Assessment 
Phone Visits 
 
Only to be used if a patient is unable to attend the Investigational Site due to COVID-19. Every 
effort should be made to complete the Study Visit at the Investigational Site.  
 
Please conduct all of the following: 
 
• Phone call to be completed by PI/Sub-Investigator  
• Please complete all Patient Reported Assessments as listed in the flowchart 
below 
• Please provide/email copies of Patient Scales to Patients prior to Phone call 
• Please document Phone Visit in Source Notes 
• Data to be entered into eCRF 
 
 
 
 
 
Visit 
Week 4/ 
Visit 4 
Week 8 / 
Visit 5   
Week 12/ 
Visit 6 
Week 18/ 
Visit 8 
(Follow up 1) 
Week 20/ 
Visit 9  
(Follow up 2) 
Day 
28  
56  
84 
126 
140 
Visit Window 
+/-2 days 
+/-2 days 
+/-2 days 
+/-2 days 
+/-2 days 
Concomitant 
Medications 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
DLQI Questionnaire 
X 
X 
X 
X 
X 
POEM Questionnaire 
X 
X 
X 
X 
X 
PO-SCORAD 
Questionnaire 
X 
X 
X 
X 
X 
Discuss NRS Pruritus 
Assessment  
X 
X 
X 
X 
X 
Discuss Athens 
Insomnia Scale  
X 
X 
X 
X 
X 
Discuss  
Emollient Use 
Capture  
X 
X 
X 
X 
X 
Discuss Patient 
Compliance Log 
X 
X 
X 
 
 
Discuss IMP 
Compliance 
X 
X 
X 
 
 
Courier Study Drug  
X 
X 
X 
 
 

SAP_001.pdf: 
CONTRACT RESEARCH ORGANIZATION: 
SPONSOR: 
AMS Advanced Medical Services GmbH 
DS Biopharma 
Am Exerzierplatz 2 
Trintech Building 
D-68167 Mannheim 
South County Business Park 
Phone: +49 (0)621 / 70095 100 
Leopardstown 
Fax:     +49 (0)621 / 70095 140 
Dublin 18, 
 
Republic of Ireland 
 
Statistical Analysis Plan 
for Clinical Trial Protocol DS107G-05-AD3 
Study Title 
A Randomised, Double-blind, Placebo-controlled Study to Assess 
the Efficacy and Safety of Orally Administered DS107 in Adult 
Patients with Moderate to Severe Atopic Dermatitis 
Study Medication 
DS107 Capsules 
Type of Study 
Multicenter, double-blind, placebo controlled, 2-arm, Phase II 
study with 16 weeks of active treatment and a 4 week follow up 
period 
Objectives of Study 
The primary objective is to compare the efficacy of orally 
administered DS107 versus placebo, in the treatment of adult 
patients with moderate to severe Atopic Dermatitis (AD). 
The secondary objective is to assess the safety of orally 
administered DS107 versus placebo, in adult patients with 
moderate to severe AD. 
Sponsor Study No.  
DS107G-05-AD3 
EudraCT-No.: 
2019-000932-25 
AMS Study No.  
DS23349 
Responsible 
Biometrician 
Florian Schelz 
AMS Advanced Medical Services GmbH 
Author 
Florian Schelz 
AMS Advanced Medical Services GmbH 
Date 
Sep 24, 2020 
Status of Document 
Final Version 1.0 
Pages 
34 
 
 
CONFIDENTIAL 
 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 2 of 34 
Change management 
 
Version 
Date 
Author 
Description of changes 
0.1 
May 19, 2020 
Florian Schelz 
First Draft Version 
0.2 
Sep 07, 2020 
Florian Schelz 
Second draft Version after Sponsor Review 
0.3 
Sep 21, 2020 
Florian Schelz 
Third draft Version after second Sponsor 
Review 
1.0 
Sep 24, 2020 
Florian Schelz 
Final Version  
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 3 of 34 
Table of Contents 
Table of Contents 
3 
List of Abbreviations and Definition of Terms 
5 
1 
Introduction 
7 
1.1 
Study Objectives 
7 
1.2 
General Study Design 
7 
1.3 
Study Population 
7 
1.4 
Study Medication 
8 
1.5 
Randomisation 
8 
1.6 
Interim Analysis 
8 
1.7 
Time Schedule / Study Duration 
9 
2 
Sample Size 
9 
3 
Analysis Populations 
10 
4 
Data Handling 
11 
4.1 
General 
11 
4.1.1 
Data sources 
11 
4.1.2 
Coding 
11 
4.1.3 
Visits 
11 
4.1.4 
Baseline value 
11 
4.1.5 
Missing values 
11 
4.2 
Algorithms for data calculations and modifications 
12 
4.2.1 
Study Day 
12 
4.2.2 
Age 
12 
4.2.3 
BMI 
12 
4.2.4 
Validated Investigator Global Assessment (vIGA-ADTM) 
12 
4.2.5 
Eczema Area Severity Index (EASI) 
12 
4.2.6 
Pruritus NRS 
13 
4.2.7 
Body Surface Area (BSA) 
13 
4.2.8 
Dermatology Life Quality Index (DLQI) Questionnaire 
13 
4.2.9 
Patient Orientated Eczema Measure (POEM) 
13 
4.2.10 
SCORing Atopic Dermatitis (SCORAD) 
14 
4.2.11 
Athens Insomnia Scale (AIS) 
14 
4.2.12 
Patient Oriented SCORAD (PO-SCORAD) 
14 
4.2.13 
Study medication: Intake and duration of intake 
15 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 4 of 34 
4.2.14 
Previous vs. concomitant medication 
15 
4.2.15 
Adverse events 
15 
5 
Blind Data Review Meeting 
15 
6 
General Methodology 
16 
6.1 
Primary Endpoint Evaluation 
16 
6.2 
Descriptive, Exploratory Analyses 
16 
6.3 
Subgroup analyses 
17 
7 
Final analysis 
17 
7.1 
Demographic and other baseline characteristics 
17 
7.2 
Efficacy - Primary Endpoint Evaluation 
17 
7.3 
Efficacy - Secondary Endpoints Evaluation 
17 
7.4 
Efficacy - Exploratory Endpoints Evaluation 
19 
7.5 
Safety Evaluation 
20 
7.6 
Further Analyses 
22 
8 
Tables and Figures 
23 
9 
References 
34 
 
 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 5 of 34 
List of Abbreviations and Definition of Terms  
AD 
Atopic Dermatitis 
AE 
Adverse Event 
AIS 
Athens Insomnia Scale 
AMS 
AMS Advanced Medical Services GmbH 
ATC 
Anatomical Therapeutic Chemical 
BDRM 
Blind Data Review Meeting 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
DGLA 
Dihomo-Gamma-Linolenic Acid 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
ECG 
Electrocardiography 
eCRF 
electronic Case Report Form 
FAS 
Full Analysis Set 
g 
Gram 
GLMM 
Generalised Linear Mixed Model 
ICH 
International Conference on Harmonization 
IGA 
Investigator Global Assessment 
IMP 
Investigational Medicinal Product 
IWRS 
Interactive Web Response System 
kg 
Kilogram 
MAR 
Missing at Random 
MedDRA 
Medical dictionary for Drug Regulatory Affairs 
MMRM 
Mixed Model with Repeated Measures 
NRS 
Numeric Rating Scale 
No. 
Number 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 6 of 34 
POEM 
Patient Orientated Eczema Measure 
PO-SCORAD 
Patient Oriented Scoring of Atopic Dermatitis 
PPS 
Per-Protocol Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SCORAD 
Scoring of Atopic Dermatitis 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TMF  
Trial Master File 
vIGA-ADTM 
Validated Investigator Global Assessment Scale for Atopic Dermatitis 
WHO 
World Health Organisation 
 
 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 7 of 34 
1 Introduction 
This Statistical Analysis Plan (SAP) refers to the Trial Protocol DS107G-05-AD3, final 
version 5.0 (EU) and version 5.1 (US) dated March 18, 2020 which includes the previously 
approved versions of the protocol. The SAP will be finalised before any analysis will be conducted. 
The specifications included in this SAP which have not been mentioned in the study protocol, are 
restricted to statistical issues, and have no impact on the clinical conduct of the trial.  
This SAP describes the analysis to be performed at the end of the trial.  
Additions or changes to the analysis planned in this SAP may be defined during the BDRM (Blind 
Data Review Meeting) and documented in the BDRM protocol which will be approved by the 
BDRM participants. 
The document is written in compliance with the ICH Guidelines E9 and the AMS SOP ST-02.01 
(Statistical Analysis Plan). 
 
1.1 Study Objectives 
The primary objective of this clinical trial is to compare the efficacy of orally administered DS107 
(2g) versus placebo, in the treatment of adult patients with moderate to severe AD. The secondary 
objective is to assess the safety of orally administered DS107 (2g) versus placebo, in adult patients 
with moderate to severe AD. 
It is planned to test the trial medication versus placebo in a total of 220 patients. 
 
1.2 General Study Design 
This clinical trial will be carried out as a randomised, placebo-controlled, double-blind, parallel 
group, multi-centre 2-arm Phase 2 study to investigate the efficacy of orally administered DS107 
in AD patients. 
It is planned that at least 220 patients suffering from moderate to severe AD will be included in 
this study. All patients will sign an informed consent and undergo screening for study eligibility. 
Before the comparative treatment period can commence, patients will return to the site for a 
baseline assessment of their disease and eligible patients will be randomly allocated to one of the 
treatment regimens in a 1:1 randomization: 
• 2g DS107 (4 DS107 capsules) orally administered once daily for 16 weeks 
• Placebo (4 placebo capsules) orally administered once daily for 16 weeks 
There is a 4 week follow-up period. 
To maintain the double-blind conditions, DS107 capsules and placebo will be identical in 
appearance. 
 
1.3 Study Population 
The study population will consist of male and female patients with confirmed diagnosis of AD 
aged 18 years or older. 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 8 of 34 
1.4 Study Medication 
The following medication supplies will be used in the study: 
DS107 capsules: 
Each DS107 capsule contains 500mg DGLA as an active ingredient in an opaque, oval soft gelatin 
capsule. 
Placebo capsule: 
Each matching placebo capsule contains 500mg of liquid paraffin in an opaque oval soft gelatin 
capsule. 
 
1.5 Randomisation 
Approximately 220 patients will be randomized into double-blind treatment groups in a 1:1 ratio 
by an IWRS. 
• 2g DS107 (4 DS107 capsules) administered once-daily for 16 weeks 
• Placebo (4 placebo capsules) orally administered once-daily for 16 weeks 
A randomization list permuted by blocks and stratified by site will be generated by the Sponsor or 
its designee. The randomization schedule with study drug assignments will be generated prior to 
the start of the study and will be known only to the individuals responsible for labelling the study 
drug, the statisticians generating the schedule and the IWRS team responsible for implementing 
the schedule. The IWRS will assign a medication kit number to each patient and the contents will 
be based on the randomization code. 
At the investigational site, each patient will be assigned a patient identifier number during 
screening that will be used on all patient documentation. The patient identifier number will contain 
the site number and the patient number assigned in numerical order at the Screening Visit (e.g.: 
102-10 for the tenth patient screened at the site number 02). Patient numbers will be assigned in 
ascending order starting with 01. 
The treatment assignment procedure will use blocks of sufficient size to maintain a blind and 
balance across treatment arms. Following successful completion of the screening/baseline 
evaluations and confirmation that the patient is eligible for participation, the patient will be 
randomised to treatment. This will be performed by the Investigator using the IWRS which will 
assign a medication number to the patient. 
 
1.6  Interim Analysis  
An interim analysis may be conducted after at least 50% of planned enrolled patients have 
completed their Week 16 assessments or an early termination visit. The interim analysis will be 
conducted in accordance with sponsor standard operating procedure (SOP) “Interim Analysis of 
Clinical Studies”.  
An unblinded interim analysis will be performed by an unblinded independent statistician. Interim 
data and the results of interim analyses will not be accessible by anyone other than the unblinded 
statistician. The sponsor will remain blinded with procedures in place to ensure the confidentiality 
of the interim data, as per the sponsor SOP “Interim Analysis of Clinical Studies”.  
The unblinded statistician will make one of the following recommendations to the sponsor based 
solely upon the primary efficacy endpoints: 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 9 of 34 
• Modify the sample size 
• Continue the study as originally planned  
• Stop the study due to futility 
Further details will be described in an interim statistical analysis plan. No α adjustment will be 
executed. 
Due to the rapidly evolving COVID-19 situation at both a global and country level, a modification 
to the prospectively planned sample size may be necessary if patient recruitment is not feasible 
and must be stopped. The interim analysis will safeguard the integrity of the trial and inform 
whether further patient recruitment is required when conditions at participating sites are amenable 
to re-initiation of patient recruitment. 
 
1.7  Time Schedule / Study Duration 
Patients will come to the clinic on 8 occasions: at Screening/Visit 1, Baseline/Visit 2, Week 4/Visit 
4, Week 8/Visit 5, Week 12/Visit 6, Week 16/Visit 7 (end of treatment), Week 18/ Visit 8 (follow 
up) and Week 20/Visit 9 (follow-up). A telephone visit will also be performed at Week 1/Visit 3. 
Patients who discontinue the study early will be asked to attend the investigative site as soon as 
possible so that assessments scheduled for Visit 7 can be conducted at an Early Termination visit. 
In the event that treatment is occurring, a wash out period of up to 4 weeks may be necessary. At 
the Screening Visit, after giving informed consent to participate, patients will be assessed using 
the screening examinations. Eligible patients with confirmed AD using the American Academy of 
Dermatology Consensus Criteria and who meet all the inclusion criteria and do not meet the 
exclusion criteria at the baseline visit will be enrolled. 
During the treatment period and follow-up period patients will be restricted from using any other 
treatment for AD, with the exception of the same emollients they have been consistently using 
since the screening visit.  
 
2 Sample Size 
In the Phase 2a trial, IGA response rates of 21.6% and 11.8% were observed for DS107 and 
placebo respectively resulting in a difference in response rates of 9.8%. Due to the prolonged 
treatment period of 16 weeks, a clinically relevant difference in IGA response rates of 15% was 
expected for the current study. 
Assuming a placebo response rate of 12% and a true response rate difference of 15% at Week 16 
and using a two-sided Chi-Square test on a significance of 5%, then 220 evaluable patients (110 
patients per treatment arm) will be needed for 80% power to detect this difference as statistically 
significant. As the following table shows, the number of patients needed for the discovery of a 
15% response rate difference depends also on the placebo response rate shown in the left column 
of the table as decimal numbers: 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 10 of 34 
 
It was assumed that similar estimations apply to the primary endpoint EASI-75. 
 
3 
 Analysis Populations 
The assignment of individual patients to the analysis sets will be determined by the members of 
the BDRM. The patients will be assigned to the following analysis sets before unblinding: 
1. Enrolled Set: The Enrolled Set consists of all patients who sign informed consent.  
2. Screen Failures: Screen Failures are patients from the Enrolled Set who do not meet the 
eligibility requirements and are withdrawn from the study prior to randomisation. 
3. Randomised Set: The Randomised Set consists of all patients who are randomised to the 
study. 
4. Safety Analysis Set (SAS): The Safety Analysis Set (SAS) consists of all patients who 
received at least one dose of the medication. SAS is the analysis population for all safety 
endpoints. Analysis will be done according to the actual treatment patients received. 
5. Full Analysis Set (FAS): The Full Analysis Set (FAS) consists of all patients who were 
randomised to the study and received at least one dose of study medication. FAS is the 
primary analysis population for efficacy endpoints. Analysis will be done according to the 
treatment patients were randomised to. 
6. Per-Protocol Set (PPS): The Per Protocol Set (PPS) is the subset of FAS who completed 
the study without any major violations. Protocol violations will be assessed for each patient 
in a blinded fashion prior to database lock at a Blind Data Review Meeting (BDRM), and 
the PPS will also be finalised during this meeting. PPS is a supportive analysis population 
for efficacy endpoints. Analysis will be done according to the treatment patients were 
randomised to. 
For PPS the primary endpoint will only be evaluated in an exploratory sense. 
  


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 11 of 34 
4 Data Handling 
4.1 General 
4.1.1 Data sources 
Most of the data collected in connection with this trial are recorded in an eCRF (electronic Case 
Report Form).  The diary data (NRS, AIS, IMP compliance etc) is recorded in the IRT system. All 
patient data will be entered by the investigator. Details can be found in the data handling manual 
for this study. The entered data are subjected to plausibility checks. These are detailed in the data 
validation plan for this study. 
 
4.1.2 Coding 
The process of coding is performed according to the AMS internal Coding SOP and relevant 
Coding guidelines (e.g. ‘MedDRA Points to consider’ / ‘Best Practices for the use of the WHO 
Drug Dictionaries’). 
The data to be coded is extracted into a coding database where the coding is performed. Details of 
the coding database, the items to be coded, the frequency of coding and the ’MedDRA’ version 
used for coding of diseases and adverse events and the WHO DD version used for coding of 
medications and the update frequency of the dictionaries are defined in the Coding Specification. 
 
4.1.3 Visits 
The analysis visits and points in time will be presented as documented in the database. 
 
4.1.4 Baseline value 
The last non-missing value prior to first treatment will be referred to as baseline value and will be 
used for change from baseline calculations. 
 
4.1.5 Missing values 
If only the day is not known completely, for onset dates or start dates missing day information will 
be assumed as the 1st. If both day and month are missing, the 1st January will be used. For stop 
dates missing day information will be imputed as the last of the month, if both day and month are 
missing, the 31st December will be used. 
However, if for AEs it is not clear whether the event started prior to or in the treatment period, the 
onset at day of first treatment will be assumed. 
If it is not clear due to a missing or incomplete stop date of a medication whether the medication 
was taken at least once after the first treatment of the patient, a stop date after the day of the first 
patient visit will be assumed. The medication will therefore be classified as “concomitant 
medication”. If it is not clear due to a missing or incomplete start date of a medication whether the 
medication was taken at least once before the first treatment of the patient, a start date before the 
day of the first patient visit will be assumed. The medication will therefore be classified as 
“previous medication” (cf. section 4.2.14). 
Data from patients who prematurely terminate the trial will be used to the maximum extent 
possible. 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 12 of 34 
The primary statistical analysis assumes “Missing At Random (MAR)” when handling missing 
data. The treatment effect obtained under the MAR assumption is essentially that which could 
have been reached if all patients had fully adhered to treatment or, in other words, the effect a 
patient may expect if they take the medication as directed. This is sometimes known as the ‘de 
jure’ or ‘efficacy’ estimand. Due to the lack of perfect adherence in practice, the ‘de facto’ or 
effectiveness treatment effect will also be estimated. This estimand includes assumptions 
regarding the treatment effects that could be expected to occur when patients discontinue 
treatment. The jump to reference method described by Carpenter et al. (2013) will be used to 
estimate the de facto estimand, using the placebo arm as the reference. This is based on the 
assumption that patients who discontinue from study drug have no alternative oral treatment option 
suitable for longer-term use and so their responses are likely to revert to those of the placebo group. 
An additional sensitivity analysis will evaluate patients who received rescue medication as 
treatment failures from the visit onwards where rescue treatment started. The sensitivity analyses 
for missing data will be performed on the FAS only. 
 
4.2 Algorithms for data calculations and modifications 
4.2.1 Study Day 
The Study Day of an assessment or event will be defined as 
Study Day = Date of Assessment - Date of first treatment +1 
for assessments performed at/after date of first treatment. 
For assessments prior date of first treatment the definition is as follows: 
Study Day = Date of Assessment - Date of first treatment 
For patients without treatment, study day will not be calculated. 
 
4.2.2 Age 
The age of patients at time of consent [in years] is used as documented in the eCRF. 
 
4.2.3 BMI 
The Body Mass Index (BMI) of patients at screening is used as documented in the eCRF. 
 
4.2.4 Validated Investigator Global Assessment (vIGA-ADTM) 
The clinical severity of AD will be evaluated by the Investigator at each visit using the vIGA-
ADTM scale. 
The vIGA-ADTM scale awards a score of 0-4 based on a 5-point severity scale from clear to severe 
disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease). 
The scale uses clinical characteristics of erythema, infiltration, papulation and oozing/crusting as 
scoring guidelines for the overall severity assessment. vIGA-ADTM will be assessed at every clinic 
visit.  
 
4.2.5 Eczema Area Severity Index (EASI) 
EASI quantifies the severity of a patient’s AD based on both lesion severity and the percent of 
BSA affected (Hanifin et al. 2001). The EASI is a composite score ranging from 0-72 that takes 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 13 of 34 
into account the degree of erythema, induration/papulation, excoriation, and lichenification (each 
scored from 0 to 3 separately, half points are permitted) for each of four body regions, with 
adjustment for the percent of BSA involved for each body region and for the proportion of the 
body region to the whole body. 
 
4.2.6 Pruritus NRS 
Severity of pruritus related to AD will be self-assessed by patients daily using the NRS. Patients 
will be asked to estimate the intensity of pruritus at its worst over the previous 24 hours. The 
Pruritus NRS is a single-question assessment tool that will be used to assess the patient’s worst 
itch as a result of AD in the previous 24 hours. Patients will score their pruritus due to AD on a 
scale of 0 – 10, with 0 (no itch) and 10 (worst itch imaginable) (Phan et al. 2012). Patients will 
complete the rating scale daily starting at screening through to the last study visit.  
The baseline NRS is defined as the prorated average of the NRSs reported continuously for 7 days 
right before and on the baseline visit (i.e. study day -6 to day 1). For post-baseline NRS, the mean 
weekly worst itch NRS is calculated as the prorated average of the reported daily NRS within the 
week. For example, if there are 3 scores in a week, the prorated average = (score1 + score2 + 
score3)/3. 
 
4.2.7 Body Surface Area (BSA) 
The overall BSA affected by AD will be evaluated (from 0 to 100%) at each visit. One patient’s 
palm represents 1% of his/her total BSA. BSA will be evaluated at every clinic visit. 
 
4.2.8 Dermatology Life Quality Index (DLQI) Questionnaire 
The effect of AD on patient quality of life will be self-assessed by the patient at every clinic visit 
starting from baseline, using the DLQI developed by Finlay and Khan (1994). 
DLQI has a maximum value of thirty based on the patients response to ten questions scored 
according to the following scale: 
• Very Much = 3 
• A lot = 2 
• A little = 1 
• Not at all = 0 
• Not relevant = 0 
• Question unanswered = 0 
• Question 7: “prevented work or studying” = 3 
 
4.2.9 Patient Orientated Eczema Measure (POEM) 
The POEM will be assessed at each clinic visit, except the screening visit. The POEM developed 
by Charman et.al. 2004 is a self-assessment of disease severity by the patient. POEM has a 
maximum value of twenty eight based on the patient’s response to seven questions scored 
according to the following scale: 
• No Days = 0 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 14 of 34 
• 1-2 Days = 1 
• 3-4 Days = 2 
• 5-6 Days = 3 
• Everyday = 4 
 
4.2.10 SCORing Atopic Dermatitis (SCORAD) 
SCORAD will be measured at each clinic visit, except the screening visit. The SCORAD grading 
system was developed by the European Task Force on Atopic Dermatitis (1993) and has been a 
standard tool to assess the AD severity in clinical studies. Six items (erythema, edema/papulation, 
oozing/crusts, excoriation, lichenification, and dryness) will be selected to evaluate the AD 
severity. The overall BSA affected by AD will be evaluated (from 0 to 100%) and included in the 
SCORAD scores. Loss of sleep and pruritus will be evaluated by patients on a visual analog scale 
(0-10). The sum of these measures represents the SCORAD which can vary from 0 to 103.  
 
4.2.11 Athens Insomnia Scale (AIS) 
The severity of sleep disturbance will be self-assessed daily starting from baseline using the Athens 
Insomnia Scale (AIS). 
The AIS is a self-administered psychometric instrument consisting of eight items. The first five 
items of the AIS (assessing difficulty with sleep induction, awakenings during the night, early 
morning awakening, total sleep time, and overall quality of sleep) correspond to Criterion A for 
the diagnosis of insomnia according to ICD-10 (International Statistical Classification of Diseases 
and Related Health Problems 10th Revision), while the requirements of a minimum frequency (at 
least three times a week) and duration (1 month) of any complaint correspond to Criterion B of the 
ICD-10. The ICD-10 requirements of marked distress caused by the sleep problem and/or 
interference with ordinary activities of daily living (Criterion C) are covered through the strictly 
subjective nature of the response options for every item of the scale as well as through the content 
of the last three items pertaining to the next day consequences of insomnia (problems with sense 
of well-being, functioning, and sleepiness during the day). 
Each item of the AIS can be rated 0-3. 
The responders are requested to rate positively if they had experienced the sleep difficulty 
described in each item at least three times a week between the study visits (Soldatos et al. 2000).  
The baseline AIS is defined as the prorated average of the AISs reported continuously for 7 days 
right before and on the baseline visit (i.e. study day -6 to day 1). For post-baseline AIS, the mean 
weekly worst itch AIS is calculated as the prorated average of the reported daily AIS within the 
week. For example, if there are 3 scores in a week, the prorated average = (score1 + score2 + 
score3)/3. 
 
4.2.12 Patient Oriented SCORAD (PO-SCORAD) 
The PO-SCORAD will be measured at each clinic visit, except the screening visit. The PO-
SCORAD is the SCORAD completed by the patients themselves. It is a self-evaluation tool 
developed by the European Task Force on Atopic Dermatitis (2011). Six items (erythema, 
edema/papulation, oozing/crusts, excoriation, lichenification, and dryness) will be selected to 
evaluate the AD severity. The overall surface affected, loss of sleep and pruritus will also be 
evaluated by patients on a visual analog scale.  


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 15 of 34 
 
4.2.13 Study medication: Intake and duration of intake 
The duration of intake of study medication will be calculated as day of last dispensed of study 
medication minus day of first dispensed of study medication plus one.  
The intake of study medication will be calculated as the number of capsules dispense per visit. 
 
4.2.14 Previous vs. concomitant medication 
Previous medications are those medications taken at least once before the first treatment of the 
patient. Concomitant medications are those medications taken at least once at/after the first 
treatment of the patient. 
 
4.2.15 Adverse events 
AEs with onset during or after administration of first study medication (study day 1) are defined 
as treatment emergent. 
 
5 Blind Data Review Meeting 
A BDRM will be held prior to database hard lock/unblinding where AMS and Sponsor 
representatives will assess protocol deviations as major or minor with regard to their influence on 
any of the analysis variables and to determine patient inclusion in the analysis sets. 
The AMS biostatistician will prepare blinded review listings. Deviations not apparent in the 
clinical database (e.g. findings during monitoring of the investigational site) will be contributed 
by the sponsor’s clinical project leader. 
The decisions of the BDRM will be documented in writing and will be approved by signature of 
the attendees and may potentially amend methodology/analysis set definitions planned in this SAP. 
The discussion in the review meeting will include but may not be restricted to the following topics: 
• Violations of the study protocol including violations of inclusion/exclusion criteria 
• Identification of patients randomised but not treated 
• Impact assessment of prohibited medications 
• Patients without efficacy data 
• Patients where blind was broken prior to formal unblinding of the study 
• Procedural deviations at the trial sites which are not reflected in the clinical database 
• Premature patient discontinuations (reason and timing). 
• Patients with COVID-19 
• Patients with Week 16 visit window violations 
• Assessment of impact of the COVID19 pandemic on visits occurring during COVID19 
pandemic vs. other visits 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 16 of 34 
Full details on the reviews performed and the decisions made in the BDRM will be given in the 
BDRM protocol. 
 
6 General Methodology 
All analyses will be performed using SAS Version 9.4 or higher. 
If not mentioned otherwise analyses will be stratified by treatment group displaying the following 
treatment groups (in this ordering): DS107, Placebo, Total. Therefore treatment will not be 
mentioned explicitly as stratification variable usually. 
All eCRF data will be listed, therefore listings may not be mentioned explicitly. 
In listings the patient’s screening number will be used as the main patient identifier. Usually 
listings will be sorted by treatment, patient’s screening number and (if applicable) visit/point in 
time. 
 
6.1 Primary Endpoint Evaluation  
The primary endpoint variables will be: 
• the proportion of patients achieving an vIGA-ADTM score of 0 (clear) or 1 (almost clear) 
and a decrease of at least 2 points in vIGA-ADTM from baseline to Week 16. 
• the proportion of patients achieving EASI-75 (≥75% improvement from baseline) at Week 
16. 
Both primary endpoints will be analysed using a Generalised Linear Mixed Model (GLMM) with 
treatment arm, visit, their interaction treatment-by-visit, and baseline vIGA-ADTM value as factors, 
and with patient as random effect; this model will especially be used to estimate missing data and 
the treatment effects at Week 16 taking missing data into account. The primary analysis will be 
based on the FAS, and repeated for the PPS as a supportive sensitivity analysis. Success in either 
of the primary endpoints denotes successful proof of efficacy. 
If rescue medication is used, the patient will be specified as a non-responder from the time the 
rescue is used. 
The handling of missing data in regards with primary statistical analysis and further sensitivity 
analysis using the jump to reference method to estimate the de facto estimand and analysing 
patients who received rescue medication as treatment failures are described in section 4.1.5.   
 
6.2 Descriptive, Exploratory Analyses 
Categorical variables will be displayed by absolute and relative frequencies (percentages). 
Percentages for categorical variables will be based on all non-missing values (=100%). 
Percentages will be rounded to one decimal place and therefore, there may be occasions when the 
total of the percentages does not exactly equal 100%. 
Continuous variables will be summarised with number of observations, mean, standard deviation, 
median, minimum, maximum and the 5%, 25%, 75% and 95% quantiles. These descriptive 
statistics will be calculated for absolute values and for absolute differences to baseline, where 
appropriate. 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 17 of 34 
6.3 Subgroup analyses 
The primary endpoint will be conducted also by subgroups. The following subgroups will be 
considered: 
• Baseline IGA (3, 4)  
 
Further subgroups may be defined in the BDRM protocol if reasonable. 
 
7 Final analysis 
The following chapter summarises all analyses planned for the analysis of data collected within 
this trial. 
 
7.1 Demographic and other baseline characteristics 
Analyses of demographic will be performed as described in chapter 6.2 with the Randomised Set, 
details of the used analysis sets are described in chapter 8. The analysis will only be displayed 
overall. The following variables will be analysed: 
• 
Age at time of consent [years]  
• 
Gender (male, female) 
• 
Height [cm] 
• 
Weight [kg] 
• 
BMI [kg/m2] 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
Demographic data will be listed.  
The incidence of previous and concomitant diseases (“Medical History”) will be displayed by 
MedDRA primary System Organ Class (SOC) and Preferred Term for the FAS.  
 
7.2 Efficacy - Primary Endpoint Evaluation  
Descriptive statistics will be provided for the two primary endpoints separately with the FAS.  
Both primary efficacy endpoints will be analysed as defined in chapter 6.1 with the FAS. 
These analyses will be displayed not only overall but also by subgroups as defined in chapter 6.3. 
The overall analysis will be repeated in an exploratory sense with the PPS. 
 
7.3 Efficacy - Secondary Endpoints Evaluation  
All secondary efficacy analyses will be performed as described in chapter 6.2 with the FAS only. 
IGA and EASI-75 responders at other time points will also be analysed using a GLMM model 
similar to that described in Section 6.1. 
The efficacy variables and their changes from baseline will be summarized with descriptive 
statistics per treatment group and visit. This applies to the vIGA-ADTM, EASI, NRS scores for 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 18 of 34 
pruritus, DLQI, POEM, SCORAD, AIS and PO-SCORAD. Change from baseline endpoints will 
be analysed using Mixed Model with Repeated Measures (MMRM) with Treatment Arm, Visit 
and Treatment x Visit Interaction as a factors and baseline value as a covariate, to account for 
missing data. For vIGA-ADTM as a 5-level ordinal variable, mixed ordinal logistic regression will 
be used with factors defined as above and IGA at baseline as a factor too. 
If rescue medication is used, the patient will be specified as a non-responder from the time the 
rescue is used. 
The following parameters will be analysed as described above: 
• Proportion of patients achieving a vIGA-ADTM score of 0 (clear) or 1 (almost clear) and a 
decrease of at least 2 points in vIGA-ADTM in treated population compared to placebo 
population from baseline to Week 4, 8, 12, 18 and 20  
• Change in proportion of patients achieving a vIGA-ADTM score of 0 (clear) or 1 (almost 
clear) and a decrease of at least 2 points in vIGA-ADTM in treated population compared to 
placebo population from Week 16 to Week 18 and 20. 
• Absolute proportion of patients achieving EASI-75 (≥75% improvement from baseline) in 
treated population compared to placebo population at Week 4, 8, 12, 18 and 20 
• Change from baseline in vIGA-ADTM score in treated population compared to placebo 
population to Week 4, 8, 12, 16, 18 and 20 
• Change from Week 16 in vIGA-ADTM score in treated population compared to placebo 
population to Week 18 and 20. 
• Change from baseline in EASI in treated population compared to placebo population to 
Week 4, 8, 12, 16, 18 and 20 
• Change from Week 16 in EASI in treated population compared to placebo population to 
Week 18 and 20. 
• Absolute proportion of patients achieving a decrease of at least 4 points in worst itch NRS 
in treated population compared to placebo population from baseline to Week 4, 8, 12, 16, 
18 and 20. The NRS endpoint should be recorded weekly (descriptive values), as defined 
in section 4.2.6 and p-values only provided for the weeks defined in the endpoint.  
• Absolute proportion of patients achieving a decrease of at least 3 points in worst itch NRS 
in treated population compared to placebo population from baseline to Week 4, 8, 12, 16, 
18 and 20. The NRS endpoint should be recorded weekly (descriptive values), as defined 
in section 4.2.6 and p-values only provided for the weeks defined in the endpoint.  
• Change from baseline in worst itch NRS in treated population compared to placebo 
population to Week 4, 8, 12, 16, 18 and 20. The NRS endpoint should be recorded weekly 
(descriptive values), as defined in section 4.2.6 and p-values only provided for the weeks 
defined in the endpoint. 
• Change from Week 16 in worst itch NRS in treated population compared to placebo 
population to Week 18 and 20. The NRS endpoint should be recorded weekly (descriptive 
values), as defined in section 4.2.6 and p-values only provided for the weeks defined in the 
endpoint. 
• Absolute proportion of patients achieving EASI-50 (≥50% improvement from baseline) in 
treated population compared to placebo population at Week 4, 8, 12, 16, 18 and 20. 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 19 of 34 
• Change from baseline in the Body Surface Area (BSA) affected by AD in treated 
population compared to placebo population to Week 4, 8, 12, 16, 18 and 20. 
• Change from Week 16 in the Body Surface Area (BSA) affected by AD in treated 
population compared to placebo population to Week 18 and 20. 
• Change from baseline in the SCORing Atopic Dermatitis (SCORAD) score in treated 
population compared to placebo population to Week 4, 8, 12, 16, 18 and 20. 
• Change from Week 16 in the SCORing Atopic Dermatitis (SCORAD) score in treated 
population compared to placebo population to Week 18 and 20. 
 
7.4 Efficacy - Exploratory Endpoints Evaluation  
All Exploratory efficacy analyses will be performed as described in chapter 6.2 with the FAS only. 
Change from baseline for exploratory endpoints (vIGA-ADTM, SCORAD, DLQI, POEM, AIS and 
PO-SCORAD) will be analysed using mixed model with repeated measures (MMRM) as described 
in chapter 7.3. 
The following parameters will be analysed as described above: 
• Absolut proportion of patients achieving a decrease of at least 2 points in vIGA-ADTM in 
treated population compared to placebo population from baseline to Week 4, 8, 12, 16, 18 
and 20. 
• Change in proportion of patients achieving a decrease of at least 2 points in vIGA-ADTM 
from Week 16 to Week 18 and 20. 
• Change from baseline in the Dermatology Life Quality Index (DLQI) score in treated 
population compared to placebo population to Week 4, 8, 12, 16, 18 and 20. 
• Change from Week 16 in the Dermatology Life Quality Index (DLQI) score in treated 
population compared to placebo population to Week 18 and 20. 
• Change from baseline in the Patient Orientated Eczema Measure (POEM) score in treated 
population compared to placebo population to Week 4, 8, 12, 16, 18 and 20. 
• Change from Week 16 in the Patient Orientated Eczema Measure (POEM) score in treated 
population compared to placebo population to Week 18 and 20. 
• Change in sleep quality assessment (Athens Insomnia Scale) in treated population 
compared to placebo population from baseline to Week 4, 8, 12, 16, 18 and 20. The AIS 
endpoint should be recorded weekly (descriptive values), as defined in section 4.2.11 and 
p-values only provided for the weeks defined in the endpoint. 
• Change in sleep quality assessment (Athens Insomnia Scale) in treated population 
compared to placebo population from Week 16 to Week 18 and 20. The AIS endpoint 
should be recorded weekly (descriptive values), as defined in section 4.2.11 and p-values 
only provided for the weeks defined in the endpoint. 
• Change from baseline in the Patient-Oriented SCORAD (PO-SCORAD) score in treated 
population compared to placebo population to Week 4, 8, 12, 16, 18 and 20. 
• Change from Week 16 in the Patient-Oriented SCORAD (PO-SCORAD) score in treated 
population compared to placebo population to Week 18 and 20. 
  


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 20 of 34 
7.5 Safety Evaluation  
Adverse Events 
The analyses of AEs with onset on or after first administration of study medication (“treatment-
emergent AEs”) will be conducted with the Safety Analysis Set whereas AEs occurring before 
first application of study medication will only be listed within the Enrolled Set.  
The incidence of AEs will be displayed by MedDRA primary SOC and Preferred Term. The counts 
in these analyses will reflect numbers of patients reporting one or more AE that map to the 
MedDRA SOC/preferred term. 
For AEs with onset during or after administration of first study medication analysis will be 
performed for the following AE categories: 
• 
All AEs 
• 
Serious adverse events (SAEs) 
• 
AEs with relationship to the study medication 
• 
AEs leading to discontinuation from study (as documented on the AE page) 
 
Furthermore, a summary table with the overall incidences of the above mentioned AEs will be 
created.  
In addition, the analysis of all treatment emergent AEs will also be done by intensity (mild, 
moderate and severe) displaying patients who reported more than one intensity for one AE under 
the worst intensity reported. 
Furthermore the analysis of AEs and SAEs will also be done by outcome (Recovered/Resolved, 
Recovering/Resolving, Not Recovered/Not Resolved, Recovered/Resolved with Sequelae, Fatal 
and Unknown). 
The number/percentage of patients with AEs will also be summarized by MedDRA primary SOC 
and Preferred Term for most frequent non-serious AEs (incidence of preferred term ≥ 5%). In this 
table, the Totals overall or by SOC will consider only those preferred terms with an incidence 
>=5%. 
All listings will use the Enrolled Set and will include study day of AE onset and AE stop as well 
as MedDRA information. Note that treatment-emergent AEs are those AEs with an onset at study 
day 1 or later. Listings will be created for the following topics: 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 21 of 34 
• 
All AEs 
• 
SAEs 
• 
AEs with relationship to the study medication  
• 
Death (Serious criterion “fatal” or outcome “fatal” documented on the AE page) 
• 
AEs leading to study discontinuation  
• 
AEs before 1st administration of study medication 
 
Vital signs 
The analysis of vital sign parameters 
• 
Systolic blood pressure [mmHg] 
• 
Diastolic blood pressure [mmHg] 
• 
Heart rate [beats per min] 
• 
Body temperature [°C] 
• 
Body temperature [°F] 
 
will be performed as described in chapter 6.2 with the Safety Analysis Set (descriptive summary 
of absolute values and changes from baseline). 
 
Physical Examination 
The number and percentage of patients with performed physical examination and the number and 
percentage of patients with abnormalities during the physical examination will be given within the 
Safety Analysis Set. 
 
Safety laboratory 
The analyses of the safety laboratory will be performed as described in chapter 6.2 with the Safety 
Analysis Set. The parameters of clinical chemistry and haematology will be analysed in the 
standardised units reported by the central laboratory.  
In addition the number and percentage of patients with normal values, abnormal values with 
clinical significance and abnormal values without clinical significance will be given for each 
parameter of clinical chemistry and haematology. The worst value per patient per study will be 
used. 
Laboratory values outside the normal range will be listed in detail.  
Additionally, the change of laboratory values in regard to the respective normal ranges (below, 
within and above) from baseline to the last value (up to week 26) will be displayed in shift tables 
for each parameter of clinical chemistry and haematology. 
 
ECG data  
The analysis of ECG parameters will be performed as described in chapter 6.2 with the Safety 
Analysis Set. The listing will also include linked AE verbatim(s) and medical history verbatim(s). 
 
Further safety endpoints 
Childbearing Status / Pregnancy test data and virology data will be listed only. 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 22 of 34 
 
7.6 Further Analyses 
If not stated otherwise, all further analyses will be performed as described in chapter 6.2 with the 
Safety Analysis Set.  
 
Previous and concomitant medication 
The incidence of previous and concomitant medication will be displayed by ATC (Anatomical 
Therapeutic Chemical) classification (level 1 and 2 and preferred term). The analysis will be 
performed separately for previous medications and concomitant medications for the Safety 
Analysis Set. The listing will include a flag indicating if a medication is P (Previous) or C 
(Concomitant) or PC. 
 
Study medication 
• 
Duration of intake of study medication [days] 
• 
Number of capsules dispense 
will be analysed as described in chapter 6.2 with the Safety Analysis Set. 
 
Termination status at end of trial 
The incidence and reason for premature study termination (Screening failure, AE, Patient decision 
(withdrawal of consent to participate), Investigator discretion, Patient lost to follow-up, Lack of 
efficacy, Pregnancy, Other reasons) will be analysed for the Enrolled Set, i.e. including screening 
failures and randomised patients, and Safety Analysis Set. 
Patients discontinued prematurely will be listed. 
The incidence and reason (Violation of Inclusion Criteria X, Violation of Exclusion Criteria Y, 
Other) for Screening failure will be summarised (using non-randomised subjects of the Enrolled 
Set only). 
 
Study duration and analysis sets 
The day of first patient in the study and last patient out of the study will be given for the Enrolled 
Set as well as for the Safety Analysis Set. 
The number of patients in each analysis set will be given by centre and overall. All patients will 
be listed with their assignment to the analysis populations and if applicable the reason for exclusion 
from specific analysis sets. 
 
Protocol violations 
Protocol violations identified in the BDRM will be listed including the decision if these constitute 
a minor or major protocol violation.  
 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 23 of 34 
8 Tables and Figures  
Item No. 
Title  
Population 
Content Description 
Mock 
Table 
14.1.1 
Patient disposition 
14.1.1.1 
Patient disposition 
Enrolled Set 
Descriptive statistics of 
number of patients in 
analysis populations by 
centre and overall 
T1 
14.1.1.2 
Study duration 
Enrolled Set 
Date of first patient in and 
last patient out 
T2 
14.1.1.2.1 
Study duration 
SAS 
Date of first patient in and 
last patient out 
T2 
14.1.2 
Demographic data  
14.1.2.1 
Demographic data I 
Randomised 
Set 
Descriptive statistics of 
continuous variables 
T3 
14.1.2.2 
Demographic data II 
Randomised 
Set 
Frequency table of 
categorical variables 
T4 
14.1.3 
Medical history and baseline evaluation  
14.1.3.1 
Medical history / 
Concomitant diseases by 
MedDRA primary SOC and 
preferred term 
FAS 
Frequency Table 
T5 
14.2 
Efficacy  
14.2.1 
Primary Endpoint 
 
vIGA-ADTM score 
14.2.1.1 
vIGA-ADTM score by visit 
FAS 
Frequency table by visit  
T4a 
14.2.1.2 
vIGA-ADTM score by visit 
and subgroup 
FAS 
Frequency table by visit 
and subgroup 
T4a 
14.2.1.3 
vIGA-ADTM response by 
visit 
FAS 
Descriptive statistics by 
visit 
T4a 
14.2.1.4 
vIGA-ADTM response by 
visit and subgroup 
FAS 
Descriptive statistics by 
visit and subgroup 
T4a 
14.2.1.5 
vIGA-ADTM score 
proportion from baseline to 
week 16 (GLMM) 
FAS 
Proportion (n (%) of 
patients achieving an 
vIGA-ADTM score of 0 
(clear) or 1 (almost clear) 
and a decrease of at least 2 
points in vIGA-ADTM from 
baseline to Week 16 using 
a Generalised Linear Mixed 
Model 
T6.1 
T6.2 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 24 of 34 
14.2.1.5.1 
vIGA-ADTM score 
proportion from baseline to 
week 16 (GLMM) 
PPS 
Proportion of patients 
achieving an vIGA-ADTM 
score of 0 (clear) or 1 
(almost clear) and a 
decrease of at least 2 points 
in vIGA-ADTM from 
baseline to Week 16 using 
a Generalised Linear Mixed 
Model 
T6.1 
T6.2 
14.2.1.6 
vIGA-ADTM score 
proportion from baseline to 
week 16 (GLMM) by 
subgroup 
FAS 
Proportion of patients 
achieving an vIGA-ADTM 
score of 0 (clear) or 1 
(almost clear) and a 
decrease of at least 2 points 
in vIGA-ADTM from 
baseline to Week 16 using 
a Generalised Linear Mixed 
Model by subgroup 
T6.1 
T6.2 
14.2.1.7 
Sensitivity analysis of 
vIGA-ADTM score 
proportion from baseline to 
week 16  (de facto 
estimand) 
FAS 
Jump to reference method 
to estimate the de facto 
estimand 
T7.1 
T7.2 
14.2.1.8 
Sensitivity analysis of 
vIGA-ADTM score 
proportion from baseline to 
week 16 (rescue 
medication)  
FAS 
Patients who received 
rescue medication will be 
evaluated as treatment 
failures 
T6.1 
T6.2 
 
EASI-75 score 
14.2.1.9 
EASI score by visit 
FAS 
Descriptive statistics by 
visit 
T3a 
14.2.1.10 
EASI score by visit and 
subgroup 
FAS 
Descriptive statistics by 
visit and subgroup 
T3a 
14.2.1.11 
EASI-75 response by visit 
FAS 
Descriptive statistics by 
visit 
T4a 
14.2.1.12 
EASI-75 response by visit 
and subgroup 
FAS 
Descriptive statistics by 
visit and subgroup 
T4a 
14.2.1.13 
EASI-75 response from 
baseline to week 16 
(GLMM) 
FAS 
Proportion of patients 
achieving EASI-75 (≥75% 
improvement from 
baseline) at Week 16 using 
a Generalised Linear Mixed 
Model 
T6.1 
T6.2 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 25 of 34 
14.2.1.13.1 
EASI-75 response from 
baseline to week 16 
(GLMM) 
PPS 
Proportion of patients 
achieving EASI-75 (≥75% 
improvement from 
baseline) at Week 16 using 
a Generalised Linear Mixed 
Model 
T6.1 
T6.2 
14.2.1.14 
EASI-75 response from 
baseline to week 16 
(GLMM) by subgroup 
FAS 
Proportion of patients 
achieving EASI-75 (≥75% 
improvement from 
baseline) at Week 16 using 
a Generalised Linear Mixed 
Model by subgroup 
T6.1 
T6.2 
14.2.1.15 
Sensitivity analysis of 
EASI-75 response from 
baseline to week 16  (de 
facto estimand) 
FAS 
Jump to reference method 
to estimate the de facto 
estimand 
T7.1 
T7.2 
14.2.1.16 
Sensitivity analysis of 
EASI-75 response from 
baseline to week 16  (rescue 
medication) 
FAS 
Patients who received 
rescue medication will be 
evaluated as treatment 
failures 
T6.1 
T6.2 
14.2.2 
Secondary Endpoints 
14.2.2.1 
vIGA-ADTM score 
14.2.2.1.1 
vIGA-ADTM score 
proportion from baseline to 
week 4, 8, 12, 18, 20 
(GLMM) 
FAS 
Proportion of patients 
achieving an vIGA-ADTM 
score of 0 (clear) or 1 
(almost clear) and a 
decrease of at least 2 points 
in vIGA-ADTM from 
baseline to Week 4, 8, 12, 
18 and 20 using a 
Generalised Linear Mixed 
Model 
T6.1 
T6.2 
14.2.2.1.2 
Change in vIGA-ADTM 
score proportion at follow-
up (GLMM) 
FAS 
Change in proportion of 
patients achieving an vIGA-
ADTM score of 0 (clear) or 1 
(almost 
clear) 
and 
a 
decrease of at least 2 points 
in vIGA-ADTM from Week 
16 to Week 18 and 20 using 
a Generalised Linear Mixed 
Model 
T6.1 
T6.2 
14.2.2.1.3 
Change in vIGA-ADTM 
score from baseline to week 
4, 8, 12, 16, 18, 20 
(MMRM) 
FAS 
Change 
in 
vIGA-ADTM 
score from baseline to week 
4, 8, 12, 16, 18, 20 using 
Mixed Model with Repeated 
Measures 
T8.1 
T8.2 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 26 of 34 
14.2.2.1.4 
Change in vIGA-ADTM 
score at follow-up 
(MMRM) 
FAS 
Change 
in 
vIGA-ADTM 
score from week 16 to week 
18 and 20 using Mixed 
Model 
with 
Repeated 
Measures 
T8.1 
T8.2 
14.2.2.1.5 
Change in vIGA-ADTM 
score (mixed ordinal 
logistic regression) 
FAS 
Change 
in 
vIGA-ADTM 
score using mixed ordinal 
logistic regression 
T9.1 
T9.2 
14.2.2.2 
EASI score 
14.2.2.2.1 
EASI-75 proportion from 
baseline to week 4, 8, 12, 
18, 20 (GLMM) 
FAS 
Proportion of patients 
achieving EASI-75 (≥75% 
improvement from 
baseline) at Week 4, 8, 12, 
18 and 20 using a 
Generalised Linear Mixed 
Model 
T6.1 
T6.2 
14.2.2.2.2 
Change in EASI score from 
baseline to week 4, 8, 12, 
16, 18, 20 (MMRM) 
FAS 
Change in EASI score from 
baseline to week 4, 8, 12, 
16, 18, 20 using Mixed 
Model with Repeated 
Measures 
T8.1 
T8.2 
14.2.2.2.3 
Change in EASI score at 
follow-up (MMRM) 
FAS 
Change in EASI score from 
week 16 to week 18 and 20 
using Mixed Model with 
Repeated Measures 
T8.1 
T8.2 
14.2.2.2.4 
EASI-50 proportion from 
baseline to week 4, 8, 12, 
16, 18, 20 (MMRM) 
FAS 
Proportion of patients 
achieving EASI-50 (≥50% 
improvement from 
baseline) at Week 4, 8, 12, 
18 and 20 
T8.1 
T8.2 
14.2.2.2.5 
Change in EASI score by 
visit 
FAS 
Descriptive statistics by 
visit 
T3a 
14.2.2.2.6 
EASI-50 response by visit 
FAS 
Descriptive statistics by 
visit 
T4a 
14.2.2.3 
NRS 
14.2.2.3.1 
NRS 4 point decrease 
proportion (MMRM) 
FAS 
Proportion of patients 
achieving a decrease of at 
least 4 points in worst itch 
NRS from baseline to week 
4, 8, 12, 16, 18, 20 
T8.1 
T8.2 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 27 of 34 
14.2.2.3.2 
NRS 3 point decrease 
proportion (MMRM) 
FAS 
Proportion of patients 
achieving a decrease of at 
least 3 points in worst itch 
NRS from baseline to week 
4, 8, 12, 16, 18, 20 
T8.1 
T8.2 
14.2.2.3.3 
Change in NRS (MMRM) 
FAS 
Change from baseline in 
worst itch NRS to week 4, 
8, 12, 16, 18, 20 
T8.1 
T8.2 
14.2.2.3.4 
Change in NRS at follow-
up (MMRM) 
FAS 
Change from week 16 in 
worst itch NRS to week 18 
and 20 
T8.1 
T8.2 
14.2.2.3.5 
NRS score by visit 
FAS 
Descriptive statistics by 
visit 
T3a 
14.2.2.3.6 
Change in NRS score 
FAS 
Descriptive statistics 
T3a 
14.2.2.3.7 
NRS 3 point decrease and 
NRS 4 point decrease 
FAS 
Descriptive statistics 
T4a 
14.2.2.4 
BSA 
14.2.2.4.1 
Change in BSA (MMRM) 
FAS 
Change from baseline in the 
body surface area affected 
by AD to week 4, 8, 12, 16, 
18, 20 
T8.1 
T8.2 
14.2.2.4.2 
Change in BSA at follow-
up (MMRM) 
FAS 
Change from week 16 in 
the body surface area 
affected by AD to week 18 
and 20 
T8.1 
T8.2 
14.2.2.4.3 
Body Surface Area (Value, 
Change from Baseline, 
Change from Wk 16) by 
visit 
FAS 
Descriptive statistics of 
body surface area at 
baseline and week 4, 8, 12, 
16, 18, 20 
T3a 
14.2.2.5 
SCORAD score 
14.2.2.5.1 
Change in SCORAD 
(MMRM) 
FAS 
Change from baseline in the 
SCORAD score to week 4, 
8, 12, 16, 18, 20 
T8.1 
T8.2 
14.2.2.5.2 
Change in SCORAD at 
follow-up (MMRM) 
FAS 
Change from week 16 in 
the SCORAD score to week 
18 and 20 
T8.1 
T8.2 
14.2.2.5.3 
SCORAD (Value, Change 
from Baseline, Change 
from Wk 16) by visit 
FAS 
Descriptive statistics by 
visit 
T3a 
14.2.2.6 
Exploratory Endpoints 
 
vIGA-ADTM score 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 28 of 34 
14.2.2.6.1 
vIGA-ADTM score 2 point 
decrease proportion 
(MMRM) 
FAS 
Proportion of patients 
achieving a decrease of at 
least 2 points in vIGA-
ADTM from baseline to 
Week 4, 8, 12, 16, 18 and 
20 
T8.1 
T8.2 
14.2.2.6.2 
Change in vIGA-ADTM 
score 2 point decrease 
proportion at follow-up 
(MMRM) 
FAS 
Change in proportion of 
patients achieving a 
decrease of at least 2 points 
in vIGA-ADTM from Week 
16 to Week 18 and 20 
T8.1 
T8.2 
 
DLQI  score 
14.2.2.6.3 
Change in DLQI score 
(MMRM) 
FAS 
Change from baseline in the 
DLQI score to week 4, 8, 
12, 16, 18, 20 
T8.1 
T8.2 
14.2.2.6.4 
Change in DLQI score at 
follow-up (MMRM) 
FAS 
Change from week 16 in 
the DLQI score to week 18 
and 20 
T8.1 
T8.2 
14.2.2.6.5 
DLQI score  (Value, 
Change from Baseline, 
Change from Wk 16) by 
visit 
FAS 
Descriptive statistics by 
visit 
T3a 
 
POEM  score 
14.2.2.6.6 
Change in POEM score 
(MMRM) 
FAS 
Change from baseline in the 
POEM score to week 4, 8, 
12, 16, 18, 20 
T8.1 
T8.2 
14.2.2.6.7 
Change in POEM score at 
follow-up (MMRM) 
FAS 
Change from week 16 in 
the POEM score to week 18 
and 20 
T8.1 
T8.2 
14.2.2.6.8 
POEM score (Value, 
Change from Baseline, 
Change from Wk 16) by 
visit 
FAS 
Descriptive statistics by 
visit 
T3a 
 
Athens Insomnia Scale 
14.2.2.6.9 
Change in sleep quality 
assessment (MMRM) 
FAS 
Change from baseline in 
sleep quality assessment 
(Athens Insomnia Scale)  to 
week 4, 8, 12, 16, 18, 20 
T8.1 
T8.2 
14.2.2.6.10 
Change in sleep quality 
assessment at follow-up 
(MMRM) 
FAS 
Change from week 16 in  
sleep quality assessment 
(Athens Insomnia Scale) to 
week 18 and 20 
T8.1 
T8.2 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 29 of 34 
14.2.2.6.11 
Sleep quality assessment 
(Value, Change from 
Baseline, Change from Wk 
16) by visit 
FAS 
Descriptive statistics by 
visit 
T3a 
 
PO-SCORAD Score 
14.2.2.6.12 
Change in PO-SCORAD 
score (MMRM) 
FAS 
Change from baseline in 
PO-SCORAD score to 
week 4, 8, 12, 16, 18, 20 
T8.1 
T8.2 
14.2.2.6.13 
Change in PO-SCORAD 
score at follow-up 
(MMRM) 
FAS 
Change from week 16 in  
PO-SCORAD score to 
week 18 and 20 
T8.1 
T8.2 
14.2.2.6.14 
PO-SCORAD  (Value, 
Change from Baseline, 
Change from Wk 16) by 
visit 
FAS 
Descriptive statistics by 
visit 
T3a 
14.2.3 
Further Analyses 
14.2.3.1 
Previous medication 
SAS 
Descriptive statistics by 
ATC classification (level 1 
and 2 and preferred term) 
T10 
14.2.3.2 
Concomitant medication 
SAS 
Descriptive statistics by 
ATC classification (level 1 
and 2 and preferred term) 
T10 
14.2.3.3 
Reason for Termination 
Enrolled Set 
Frequency Table 
T4 
14.2.3.3.1 
Reason for Termination 
SAS 
Frequency Table 
T4 
14.2.3.4 
Screening failure 
Non-
randomised 
subjects of 
the Enrolled 
Set 
Frequency Table 
T4 
14.3 
Safety 
14.3.1  
Study medication 
14.3.1.1 
DS107 intake duration 
SAS 
Descriptive statistics 
T3 
14.3.1.2 
Capsules 
SAS 
Descriptive statistics of 
number of capsules 
dispensed 
T3 
14.3.2 
Adverse events 
14.3.2.1 
Summary table of Adverse 
Events 
SAS 
Frequency table of patients 
and number of events per 
AE category 
T11 
14.3.2.2 
Adverse Events by 
MedDRA SOC and 
preferred term 
SAS 
Frequency table 
T12 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 30 of 34 
14.3.2.3 
Serious Adverse Events by 
MedDRA SOC and 
preferred term 
SAS 
Frequency table 
T12 
14.3.2.4 
AEs related to DS107 by 
MedDRA SOC and 
preferred term 
SAS 
Frequency table  
T12 
14.3.2.5 
AEs leading to study 
discontinuation by 
MedDRA SOC and 
preferred term 
SAS 
Frequency table 
T12 
14.3.2.6 
AEs by SOC, PT and worst 
intensity  
SAS 
Frequency table 
T13 
14.3.2.7 
AEs by SOC, PT and 
outcome  
SAS 
Frequency table 
T13 
14.3.2.8 
SAEs by SOC, PT and 
outcome  
SAS 
Frequency table 
T13 
14.3.2.9 
Most frequent non-serious 
adverse events by MedDRA 
SOC and preferred term 
SAS 
Frequency table 
T13 
14.3.5 
Vital signs 
14.3.5.1 
Vital signs 
SAS 
Descriptive Statistics 
T3a 
14.3.5.2 
Change in vital signs from 
baseline 
SAS 
Descriptive Statistics 
T3a 
14.3.5.3 
ECG 
SAS 
Descriptive Statistics 
T4a 
14.3.6 
Laboratory values 
14.3.6.1 
Clinical Chemistry & 
Haematology 
SAS 
Descriptive Statistics 
T3a 
14.3.6.2 
Clinical Chemistry & 
Haematology per category 
SAS 
Frequency Table (number 
and percentage of patients 
with normal values, 
abnormal values with 
clinical significance and 
abnormal values without 
clinical significance) 
T4a 
14.3.6.3 
Change in Clinical 
Chemistry & Haematology 
SAS 
Shift Table 
T14 
14.3.7 
Physical Examination 
14.3.7.1 
Physical examination 
SAS 
Frequency table of patients 
with physical examination 
(yes/no) 
T4 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 31 of 34 
14.3.7.2 
Abnormalities during 
physical examination 
SAS 
Frequency table of patients 
with abnormalities during 
physical examination 
T4 
16 
Appendices 
16.2 
Patient data listings 
16.2.1 
Patient disposition 
Enrolled Set 
Individual patient data 
listing to analysis sets by 
cohort including reasons for 
exclusions,  if applicable 
L1 
16.2.2 
Violations of 
inclusion/exclusion criteria 
Enrolled Set 
(only 
patients with 
violations) 
Individual patient data 
listing by cohort 
L6 
16.2.3 
Discontinuation 
Enrolled Set 
Individual patient data 
listing including reasons for 
discontinuation 
L2 
16.2.4 
Demographic data / 
Informed Consent / 
Randomisation 
Randomised 
Set 
Individual patient data 
listing by cohort 
L3 
16.2.5 
Vital Signs 
FAS 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.1 
vIGA-ADTM score 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.2 
EASI score 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.3 
NRS score 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.4 
BSA 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.5 
SCORAD 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.6 
DLQI score 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.7 
POEM score 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.8 
AIS 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 
16.2.6.9 
PO-SCORAD score 
Enrolled Set 
Individual patient data 
listing by cohort and visit 
L6 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 32 of 34 
16.2.7 
Adverse Events Listings 
16.2.7.1 
Adverse events 
Enrolled Set 
Individual patient data 
listing by cohort 
L4 
16.2.7.2 
Serious adverse events 
Enrolled Set 
Individual patient data 
listing by cohort 
L4 
16.2.7.3 
AEs related to DS107 
Enrolled Set 
Individual patient data 
listing by cohort 
L4 
16.2.7.4 
AEs leading to death 
Enrolled Set 
Individual patient data 
listing by cohort 
L4 
16.2.7.5 
AEs leading to study 
discontinuation 
Enrolled Set 
Individual patient data 
listing by cohort 
L4 
16.2.7.6 
AEs before first 
administration of DS107 
Enrolled Set 
Individual patient data 
listing by cohort 
L4 
16.2.8 
Listing of individual laboratory measurements 
16.2.8.1 
Laboratory values 
SAS 
Individual patient data 
listing of laboratory results 
(haematology, clinical 
chemistry) 
L5 
16.2.8.2 
Laboratory values outside 
the normal range 
SAS 
Individual patient data 
listing of laboratory results 
outside the normal range 
L5 
16.2.9 
Other Listing 
16.2.9.1 
Physical examinations 
SAS 
Individual patient data 
listing by cohort and visit 
L6 
16.2.9.2 
Medical History / 
Concomitant diseases 
FAS 
Individual patient data 
listing by cohort 
L6 
16.2.9.3 
Childbearing status and 
Pregnancy test data 
FAS 
Individual patient data 
listing by cohort and visit 
L6 
16.2.9.4 
Virology 
FAS 
Individual patient data 
listing by cohort 
L6 
16.2.9.5 
ECG 
FAS 
Individual patient data 
listing by cohort and visit 
L6 
16.2.9.6 
Study drug dispensed 
SAS 
Individual patient data 
listing by cohort and visit 
L6 
16.2.9.7 
Patient diary compliance 
SAS 
Individual patient data 
listing by cohort and visit 
L6 
16.2.9.8 
IMP accountability and 
IMP compliance 
SAS 
Individual patient data 
listing by cohort and visit 
L6 
16.2.9.9 
Previous and Concomitant 
medication 
FAS 
Individual patient data 
listing by cohort 
L6 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 33 of 34 
16.2.9.10 
Violations of 
inclusion/exclusion criteria 
Enrolled Set 
(only 
patients with 
violations) 
Individual patient data 
listing by cohort 
L6 
16.2.9.11 
Protocol violations  
SAS 
Individual patient data 
listing by cohort  
L6 
 
 


DS Biopharma 
 
Statistical Analysis Plan DS107G-05-AD3 
AMS Advanced Medical Services GmbH 
 
Version 1.0 (final), 24-Sep-2020 
 
SAP 
 CONFIDENTIAL 
 Page 34 of 34 
9 References 
• Carpenter, JR, Roger, JH & Kenward, MG 2013. ‘Analysis of longitudinal trials 
with protocol deviations: a framework for relevant, accessible assumptions, and 
inference via multiple imputation.’ J Biopharm Stat; 23(6), pp. 1352-71. 
• Hanifin, JM, Thurston, M, Omoto, M, Cherill, R, Tofte, SJ, & Graeber, M 2001. 
‘The eczema area and severity index (EASI): assessment of reliability in atopic 
dermatitis. EASI Evaluator Group.’ Exp Dermatol. Feb;10(1), pp. 11-8. 
• Phan, NQ, Blome, C, Fritz, F, Gerss, J, Reich, A, Ebata, T, Augustin, M, 
Szepietowski, JC & Ständer, S 2012. ‘Assessment of pruritus intensity: 
prospective study on validity and reliability of the visual analogue scale, 
numerical rating scale and verbal rating scale in 471 patients with chronic 
pruritus.’ Acta Derm Venereol; 92 pp. 502–507. 
• Soldatos CR, Dikeos DG, Paparrigopoulos TJ: Athens Insomnia Scale: validation 
of an instrument based on ICD-10 criteria. Journal of Psychosomatical Research 
48 (2000) 555-560.