Clinical trial NCT02864498
Conditions: Atopic Dermatitis
Sponsor: DS Biopharma
Start date: 2017-01-01; Completion date: 2018-06-01
Enrollment: 321 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether orally administered DS107 (1g and 2g doses) is effective in the treatment of moderate to severe atopic dermatitis.

Oral DS107 capsules will be administered for 8 weeks and will be compared against placebo.

The study will enroll approximately 300 subjects.

Detailed description:
The study will consist of 3 treatment arms, each consisting of approximately 100 subjects.

Treatment Arm 1 will receive 1g Oral DS107 daily. Treatment Arm 2 will receive 2g Oral DS107 daily. Treatment Arm 3 will receive placebo daily.

The primary objective of the study is to assess the efficacy and safety of daily 1g and 2g doses of Oral DS107 versus placebo.

Subjects will come to the clinic on 7 occasions: Screening, Baseline, Week 2, Week 4, Week 6, Week 8 (end of treatment/early termination) and Week 10 (follow-up). The primary efficacy variable will be the IGA (Investigator's Global Assessment). Secondary efficacy variables will include IGA, EASI (Eczema Area and Severity Index), and NRS (Numeric Rating Scale),

Arms: arm 1: 1g DS107 (2 DS107 capsules and 2 placebo capsules) orally administered once-daily for 8 weeks. arm 2: 2g DS107 (4 DS107 capsules) orally administered once-daily for 8 weeks. arm 3: Placebo (4 placebo capsules) orally administered once-daily for 8 weeks.
Interventions: intervention 1: DS107 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
 Confidential / Clinical Study Protocol No. DS107G-03 Version 3.0 
 
Page 1 of 71 
 
 
 
 
 
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 
 
 
 
 
Protocol Number # DS107G-03 
 
Amendment 3 
Version 3.0 
14 July 2017 
 
 
 
 
 
Sponsor: 
 
 
 
 
 
 
DS Biopharma,  
Trintech Building,  
South County Business Park, 
Leopardstown,  
Dublin 18, 
Republic of Ireland. 
 
 
 
 


 
 
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CONTACT INFORMATION 
 
Sponsor Medical Expert: 
Dr. Markus Weissbach, 
Chief Operating Officer/Medical Director, 
DS Biopharma,  
Trintech Building,  
South County Business Park, 
Leopardstown,  
Dublin 18, 
Republic of Ireland. 
Tel: +353 1 293 3590 
 
 
 
Clinical Expert: 
 
Prof. Mark Lebwohl 
5 East 98th St,  
New York,  
NY 10029,  
United States 
 
Pharmacovigilance/Medical 
Monitor: 
Safety Physician, 
Product Life Ltd., 
The Jeffreys Building, 
St. John’s Innovation Park,  
Cowley Road, 
Cambridge CB4 0DS,  
United Kingdom. 
Tel: +44 (0) 1223 402660 
Toll Free US: +1-800-879-8146 
Toll Free South Africa: 0-800-992-037 
Email: safety@productlife-group.com 
 
 
 
 
 
 


 
 
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TABLE OF CONTENTS 
CONTACT INFORMATION .................................................................................................................. 2 
TABLE OF CONTENTS ....................................................................................................................... 3 
PRINCIPAL SITE INVESTIGATOR SIGNATURE PAGE .................................................................... 7 
LIST OF ABBREVIATIONS................................................................................................................ 14 
1 
INTRODUCTION ......................................................................................................................... 16 
1.1 
THERAPEUTIC AREA AND DISEASE BACKGROUND ...................................................................... 16 
1.2 
STANDARD TREATMENT ............................................................................................................ 16 
1.3 
DRUG CLASS ........................................................................................................................... 17 
1.4 
PRECLINICAL PHARMACOLOGY ................................................................................................. 17 
1.5 
TOXICOLOGY ........................................................................................................................... 18 
1.6 
PREVIOUS CLINICAL STUDIES WITH DS107 ............................................................................... 19 
2 
RISK BENEFIT ASSESSMENT ................................................................................................. 22 
3 
RATIONALE FOR THE STUDY ................................................................................................. 23 
4 
STUDY OBJECTIVES ................................................................................................................ 24 
5 
STUDY ENDPOINTS .................................................................................................................. 25 
5.1 
PRIMARY ENDPOINT ................................................................................................................. 25 
5.2 
SECONDARY ENDPOINTS .......................................................................................................... 25 
5.3 
EXPLORATORY ENDPOINTS ....................................................................................................... 25 
6 
STUDY DESIGN ......................................................................................................................... 26 
6.1 
GENERAL ................................................................................................................................. 26 
7 
PATIENTS AND SCREENING ................................................................................................... 28 
7.1 
SOURCE OF PATIENTS .............................................................................................................. 28 
7.2 
INCLUSION CRITERIA ................................................................................................................ 28 
7.3 
EXCLUSION CRITERIA ............................................................................................................... 28 
7.4 
SCREENING AND CONSENT ....................................................................................................... 30 
7.5 
WITHDRAWAL OF PATIENTS ...................................................................................................... 30 
7.5.1 
Complete Withdrawal ....................................................................................................... 31 
7.5.2 
Withdrawals from Investigational Product ........................................................................ 31 
7.6 
PATIENT REPLACEMENT ........................................................................................................... 31 
7.7 
PROTOCOL VIOLATIONS ............................................................................................................ 31 
8 
STUDY CONDUCT ..................................................................................................................... 32 
8.1 
STUDY SCHEDULE .................................................................................................................... 32 
8.2 
CLINIC VISITS........................................................................................................................... 32 
8.2.1 
Screening Visit (Visit 1) .................................................................................................... 32 
8.2.2 
Treatment Period .............................................................................................................. 33 
8.2.3 
Baseline (Visit 2) ............................................................................................................... 33 
8.2.4 
Week 2 (Visit 3) ................................................................................................................ 34 
8.2.5 
Week 4 (Visit 4) ................................................................................................................ 35 
8.2.6 
Week 6 (Visit 5) ................................................................................................................ 36 
8.2.7 
Week 8 (Visit 6) / End of Treatment or Early Termination ................................................ 36 
8.2.8 
Week 10 (Visit 7) / Follow up ............................................................................................ 37 
9 
ASSESSMENTS ......................................................................................................................... 39 
9.1 
EFFICACY ASSESSMENTS ......................................................................................................... 39 
9.1.1 
Investigator Global Assessment (IGA) ............................................................................. 39 
9.1.2 
Eczema Area Severity Index (EASI) ................................................................................ 39 
9.1.3 
Pruritus NRS ..................................................................................................................... 39 
9.1.4 
Body Surface Area (BSA) ................................................................................................. 39 
9.1.5 
Dermatology Life Quality Index (DLQI) Questionnaire ..................................................... 39 
9.1.6 
Patient Orientated Eczema Measure (POEM) ................................................................. 40 


 
 
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9.1.7 
Patient Global Impression of Severity (PGI-S) ................................................................. 40 
9.1.8 
Patient Global Impression of Change (PGI-C) ................................................................. 40 
9.2 
SAFETY ASSESSMENTS ............................................................................................................ 40 
9.2.1 
Medical / Surgical History ................................................................................................. 40 
9.2.2 
Physical Examination ....................................................................................................... 40 
9.2.3 
Vital Signs ......................................................................................................................... 41 
9.2.4 
Clinical Laboratory Safety Tests: Haematology, Serum Biochemistry,  and Urinalysis ... 41 
9.2.5 
Pregnancy Test ................................................................................................................ 41 
9.2.6 
Body Mass Index (BMI) .................................................................................................... 42 
9.2.7 
Pharmacokinetic Sampling ............................................................................................... 42 
9.2.8 
Biomarker Sampling ......................................................................................................... 42 
9.2.9 
Sample Storage, Handling and Shipping ......................................................................... 42 
9.2.10 Adverse Event Assessment.............................................................................................. 42 
9.2.11 Concomitant Medication ................................................................................................... 42 
9.2.12 Restrictions ....................................................................................................................... 43 
10 
INVESTIGATIONAL MEDICINAL PRODUCT / INVESTIGATIONAL DRUG ............................ 45 
10.1 
IVESTIGATIONAL MEDICINAL PRODUCT (IMP) ............................................................................ 45 
10.2 
SUPPLY, PACKAGING, LABELLING, HANDLING AND STORAGE ...................................................... 45 
10.3 
DOSAGE AND ADMINISTRATION ................................................................................................. 45 
10.4 
DURATION OF TREATMENT ........................................................................................................ 46 
10.5 
METHODS FOR ASSIGNING PATIENTS TO TREATMENTS .............................................................. 46 
10.6 
DRUG ACCOUNTABILITY............................................................................................................ 47 
11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ....................................................... 48 
11.1 
DEFINITIONS OF ADVERSE EVENTS ........................................................................................... 48 
11.1.1 Seriousness ...................................................................................................................... 48 
11.1.2 Severity ............................................................................................................................. 48 
11.1.3 Relationship to IMP .......................................................................................................... 49 
11.1.4 Reporting of AEs and SAEs ............................................................................................. 49 
11.2 
SERIOUS ADVERSE REACTIONS AND UNEXPECTED ADVERSE REACTIONS ................................... 49 
11.2.1 Definitions ......................................................................................................................... 49 
11.2.2 Reporting of suspected unexpected serious adverse reactions....................................... 50 
11.3 
DIFFERENTIATION OF TREATMENT FAILURE AND AE ................................................................... 50 
11.4 
PREGNANCY REPORTING .......................................................................................................... 50 
12 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT ................................................ 51 
12.1 
STUDY DESIGN ........................................................................................................................ 51 
12.2 
RANDOMISATION ...................................................................................................................... 51 
12.3 
ESTIMATION OF SAMPLE SIZE ................................................................................................... 51 
12.4 
BLINDING AND CODE BREAKING INSTRUCTIONS ......................................................................... 52 
12.5 
INTERIM ANALYSIS ................................................................................................................... 52 
12.6 
DATA ANALYSIS ....................................................................................................................... 52 
12.7 
ANALYSIS POPULATIONS .......................................................................................................... 52 
12.8 
SAFETY ANALYSIS .................................................................................................................... 53 
12.9 
STATISTICAL ANALYSIS PLAN .................................................................................................... 53 
12.9.1 Pharmacokinetic Analysis................................................................................................. 53 
12.9.2 Primary variables .............................................................................................................. 53 
12.9.3 Secondary variables ......................................................................................................... 54 
12.9.4 Safety variables ................................................................................................................ 54 
12.10 DATA COLLECTION / CASE REPORT FORMS ............................................................................... 54 
12.11 DATA MANAGEMENT ................................................................................................................. 54 
12.12 PROTOCOL DEVIATIONS ........................................................................................................... 55 
13 
REGULATORY AND ADMINISTRATIVE PROCEDURES ........................................................ 56 
13.1 
INSTITUTIONAL REVIEW ............................................................................................................ 56 
13.2 
GCP ....................................................................................................................................... 56 
13.3 
ESSENTIAL DOCUMENTS ........................................................................................................... 56 
13.4 
RECORD RETENTION ................................................................................................................ 56 
13.5 
MONITORING / QUALITY CONTROL ............................................................................................ 56 


 
 
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13.6 
QUALITY ASSURANCE ............................................................................................................... 57 
13.7 
INSURANCE AND LIABILITY ........................................................................................................ 57 
13.8 
END OF TRIAL .......................................................................................................................... 57 
13.9 
CONFIDENTIALITY ..................................................................................................................... 57 
13.10 REPORT AND PUBLICATION ....................................................................................................... 57 
14 
REFERENCES ............................................................................................................................ 58 
15 
APPENDICES ............................................................................................................................. 61 
15.1 
APPENDIX 1: STUDY FLOW-CHART ............................................................................................ 61 
15.2 
APPENDIX 2: DIAGNOSTIC FEATURES OF ATOPIC DERMATITIS (HANIFIN AND RAJKA CRITERIA) .... 63 
15.3 
APPENDIX 3: INVESTIGATOR’S GLOBAL ASSESSMENT (IGA) ....................................................... 64 
15.4 
APPENDIX 4: ECZEMA AREA AND SEVERITY INDEX (EASI) .......................................................... 65 
15.5 
APPENDIX 5: NUMERICAL RATING SCALE FOR ASSESSMENT OF PRURITUS .................................. 66 
15.6 
APPENDIX 6: DERMATOLOGY LIFE QUALITY INDEX (DLQI).......................................................... 67 
15.7 
APPENDIX 7: PATIENT ORIENTATED ECZEMA MEASURE ............................................................. 69 
15.8 
APPENDIX 8: PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) ............................................. 70 
15.9 
APPENDIX 9: PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) .............................................. 71 
 
 
LIST OF FIGURES 
Figure 1: Structure of DGLA ............................................................................................ 17 
Figure 2: Study Outline ..................................................................................................... 26 
 
LIST OF TABLES 
Table 1: Summary of DS107 Capsules Use in Human Healthy Volunteers/Patients ....... 19 
Table 2: Clinical Laboratory Safety Tests ........................................................................ 41 
 
 


 
 
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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 Operating Officer/Medical Director,  
DS Biopharma 
 
 
 
 
CLINICAL EXPERT: 
 
 
 
 
Signature: 
 
Date: 
 
Prof. Mark Lebwohl 
Chairman, Department of Dermatology, Mount Sinai School of Medicine 
 
 
 
STATISTICIAN: 
 
 
 
 
Signature: 
 
Date: 
 
Philip Lavin, PhD 
Principal, Lavin Consulting LLC. 
 
 
 
 
 
 
 
 
 
 
 


 
 
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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. 
 
 
 
 


 
 
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Protocol synopsis 
STUDY TITLE: 
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 
SHORT TITLE: 
Efficacy and Safety Study of Orally Administered DS107 in 
Moderate to Severe Atopic Dermatitis Patients 
PHASE: 
2b 
STUDY DURATION: 
10 weeks (Treatment Duration: 8 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 ENDPOINT: 
Proportion of patients achieving an Investigator’s Global 
Assessment (IGA) of 0 (clear) or 1 (almost clear) and a decrease 
of at least 2 points in IGA in treated population compared to 
placebo population at Week 8. 
SECONDARY 
ENDPOINTS: 
 
Proportion of patients achieving an IGA score of 0 (clear) or 
1 (almost clear) and a decrease of at least 2 points in IGA in 
treated population compared to placebo population from 
baseline to Week 2, 4, 6 and 10. 
 
 
Proportion of patients achieving a decrease of at least 2 points 
in IGA in treated population compared to placebo population 
from baseline to Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in Eczema Area and Severity Index 
(EASI) in treated population compared to placebo population 
at Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in Numeric Rating Scale (NRS) for 
Pruritus in treated population compared to placebo population 
at Week 2, 4, 6, 8 and 10. 
 
EXPLORATORY 
ENDPOINTS: 
 
Change from baseline in the Dermatology Life Quality Index 
(DLQI) score in treated population compared to placebo 
population at Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Orientated Eczema 
Measure (POEM) score in treated population compared to 


 
 
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placebo population at Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Global Impression of 
Severity (PGI-S) score in treated population compared to 
placebo population at Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Global Impression of 
Change (PGI-C) score in treated population compared to 
placebo population at Week 2, 4, 6, 8 and 10. 
 
 
Plasma DGLA concentrations in treated population compared 
to placebo population  at Baseline/Day 0, Week 4, Week 8 
and Week 10 (samples to be retained and analysed for the 
potential analysis at a later date).  
 
 
Determination of AD biomarkers  at Baseline/Day 0, and 
Week 8   (samples to be retained for the potential analysis at 
a later date). 
 
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: 
A minimum of 300 patients with moderate to severe AD will be 
included in this multicenter, double-blind, placebo controlled, 3-
arm phase 2b study. 
All patients will sign an informed consent and undergo screening 
for study eligibility. Patients will be randomized (1:1:1) at 
baseline visit to either receive 1g DS107 once daily, 2g DS107 
once daily or placebo once daily for 8 weeks. 
Patients will come to the clinic on 7 occasions: at Screening, 
Baseline, Week 2, Week 4, Week 6, Week 8 (end of 
treatment/early termination) and Week 10 (follow-up). All 
patients will exit the study at the Week 10 visit.  
TOTAL NUMBER OF 
RANDOMISED 
PATIENTS: 
 300 
 
STUDY POPULATION: 
INCLUSION CRTIERIA: 
 
 
 
1. Patients with a clinically confirmed diagnosis of active AD 
according to Hanifin and Rajka criteria. 
 
2. Patients with moderate to severe AD at baseline as defined by 
an IGA of minimum 3 at baseline. 
 
3. Patients with an EASI score of ≥12 at screening and baseline. 
 


 
 
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4. Patients with AD covering a minimum 10% of the body 
surface area at baseline. 
 
5. Patients whose pre-study clinical laboratory findings do not 
interfere with their participation in the study, in the opinion 
of the Investigator. 
 
6. Patients who are able and willing to stop all current treatments 
for AD throughout the study (except for allowed emollients). 
 
7. Patients who are on a stable dose of a bland emollient applied 
BD (twice daily) for at least 7 days prior to baseline. 
 
8. Male or female patients who are aged 18 years and older on 
the day of signing the informed consent form (ICF). 
 
9. Female patients and male patients with female partners of 
child bearing potential must use adequate contraception or 
have a sterilized partner for the duration of the study. 
Adequate contraception is defined as: systemic hormonal 
contraceptives, intrauterine device or barrier method of 
contraception in conjunction with spermicide, or agree to 
sexual abstinence. Hormonal contraceptives must be on a 
stable dose for at least one month before baseline. 
 
10. 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. 
 
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 (other than 
biologics) 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 who have used any topical medicated treatment for 
AD two weeks prior to start of treatment/ Baseline (Day 0), 
including but not limited to, topical corticosteroids, tars and 
bleach. 
 
4. Patients who use topical products containing urea, ceramides 
or hyaluronic acid two weeks prior to Baseline. 
 


 
 
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5. Patients who use anti-histamines for AD within 2 weeks of 
baseline. Non-sedative anti-histamines for other indications 
may be used throughout the study provided the patient is on a 
stable dose for 4 weeks prior to Baseline. 
 
6. Patients with the presence of an active or chronic allergic 
reaction as evidenced by an irregular white cell count 
determined by eosinophils > 0.3 x 109 /L at the screening visit. 
 
7. 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. 
 
8. Patients who have a history of hypersensitivity to any 
substance in DS107 or placebo capsules. 
 
9. 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.  
 
10. Patients who have a clinically significant impairment of renal 
or hepatic function. 
 
11. Patients with significant uncontrolled cardiovascular, 
neurologic, 
malignant, 
psychiatric, 
respiratory 
or 
hypertensive disease, as well as uncontrolled diabetes and 
fluoride arthritis or any other illness that, in the opinion of the 
investigator, is likely to interfere with completion of the 
study. 
 
12. Patients with  chronic infectious diseases (e.g., hepatitis B, 
hepatitis C or infection with human immunodeficiency virus). 
 
13. 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). 
 
14. 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. 
 
15. 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, 


 
 
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b. Other biologics influencing cell proliferation: within 6 
months before the screening visit. 
 
16. Patients who are pregnant, planning pregnancy, breastfeeding 
and/or are unwilling to use adequate contraception (as 
specified in inclusion criterion 9) during the trial. 
 
17. 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 two dose levels of DS107 for 8 weeks (1g 
DS107 OD or 2g DS107 OD) and a placebo control (OD)  
EVALUATION CRITERIA: 
SAFETY 
 
 Physical examination, including height and weight. 
 Vital signs, including blood pressure (BP), pulse and 
temperature. 
 Clinical laboratory tests (haematology, biochemistry, 
virology and urinalysis). 
 Pregnancy test for females of child bearing potential. 
 Adverse Events. 
 Concomitant medications. 
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 will be prohibited 
within four weeks of the trial and during the trial. 
 
STATISTICAL ANALYSIS  
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. 
All statistical tests will be two-sided and will be performed with 
significance of 0.05. No adjustment for multiplicity will be 
applied. 
A generalised linear mixed model (GLMM) will be used to model 
the primary endpoint, IGA-response at Week 8.  The model will 
include Treatment Arm as a factor and baseline IGA score as a 
covariate, with the treatment-by-visit interaction term as a random 
effect to account for missing data at Week 8. 


 
 
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IGA-responders at other time points will also be analysed using 
GLMM. 
Change from baseline endpoints (EASI, NRS, DLQI, POEM, 
PGI-S and PGI-C) will be analysed using mixed model with 
repeated measures (MMRM) with Treatment Arm as a factor and 
baseline value as a covariate, with the treatment-by-visit 
interaction term as the repeated effect to account for missing data. 
Sensitivity analyses will be performed to assess the robustness of 
the Missing at Random (MAR) assumptions that underpin the 
GLMM methods above for imputing missing data. 
SPONSOR: 
DS Biopharma 


 
 
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LIST OF ABBREVIATIONS 
15-HETrE 
AD 
15-hydroxyeicosatrienoic acid 
Atopic Dermatitis 
AE 
Adverse Event 
BD 
Bis Die (Twice Daily) 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPM 
COX 
Beats Per Minute 
Cyclooxygenase 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organisation 
CRF 
CsA 
CTA 
Case Report Form 
Cyclosporin A 
Clinical Trials Agreement 
DGLA 
Dihomo-Gamma-Linolenic Acid 
DLQI 
DM 
Dermatology Life Quality Index 
Data Manager 
EASI 
EC 
ECG 
Eczema Area and Severity Index 
Ethics Committee 
Electrocardiography 
EDC 
FAS 
FSH 
Electronic Data Capture 
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 
International Conference on Harmonisation 
Interferon-Gamma 
IGA 
IgE 
Investigators Global Assessment 
Imunnoglobulin E 


 
 
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IL 
IMP 
Interleukin 
Investigational Medicinal Product 
ISF 
Investigator Site File 
IWRS 
Interactive Web Response System 
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 
PGD1 
Over The Counter 
Prostaglandin D1 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PIS 
Patient Information Sheet  
PK 
Pharmacokinetics 
POEM 
Patient Orientated Eczema Measure 
PP 
PPS 
PUVA 
Per Population 
Per Protocol Set 
Psoralen & Ultraviolet A  
PV CRO 
Pharmacovigilance Contract Research Organisation 
SAE 
SAF 
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 
TNF-α 
Suspected Unexpected Serious Adverse Reaction 
Tumor Necrosis Factor-Alpha  
UV-A/B 
VAS 
Ultraviolet-A/B 
Visual Analogue Scale 
 
 


 
 
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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 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 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 where 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 very 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) 


 
 
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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 proinflammatory cytokines (IL-2, IL-3, IL-4, IL-5, IFN-γ, TNF-
α) (Gutfreund et al. 2013). Inhibiting cytokine production leads to decreased inflammation and also 
serves to block T-cell activation which can trigger and maintain skin inflammation (Simpson, 2010). 
They 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 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 and Bieber 2003).  
 
The use of systemic treatments to manage the symptoms of AD has been rare. Oral corticosteroids, 
immunosuppressants, anti-folates and anti-histamines have been used in the past with moderate efficacy 
and poor safety profiles resulting in a short treatment window (Eichenfield et al. 2014). There is 
currently an unmet need for a safety and effect systemic treatment for patients with moderate to severe 
AD. 
1.3 
Drug Class 
DS107 capsules contain the 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 
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 showing that DS107 significantly reduces the secretion of IL-1β and IL-8 from triggered 


 
 
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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 Advese 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).  
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 
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 


 
 
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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 
Overall in these non-clinical safety studies it was concluded that DS107 is well tolerated and safe. 
Therefore it can be concluded that there are no safety concerns to indicate undue toxicological hazard 
or risk for patients treated with DS107 capsules. 
1.6 
Previous Clinical Studies with DS107  
Two well-controlled clinical studies have been conducted to assess the safety and efficacy of DS107 
capsules. To date, DS107 capsules has been administered  to 87 healthy volunteers/patients during the 
course of one Phase 1 trial (DS107G-01) and one Phase 2a trial (DS107G-02) 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 
500 mg 
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 
Phase 
Duration 
Indication 
IMP  
Concentration. 
# Patients 
Status 
2a 
(safety & 
efficacy) 
8 weeks 
Moderate to 
Severe AD 
2g 
102 
Completed 
 
 
DS107 Capsules Phase 1 Study 
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.  


 
 
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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 
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 
Scoring of Atopic Dermatitis [SCORAD] visual analog scale [VAS]), Eczema Area and Severity Index 
[EASI], body surface area (BSA), Patient-Oriented Eczema Measure (POEM), Dermatology Life 
Quality Index (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). 
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 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 AE’s 
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 


 
 
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the tolerance of DS107 capsules administered over 8 weeks was acceptable in comparison with Placebo 
and DS107 appears safe and well tolerated. 
 
Topical DS107 
Three 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, 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. 
Two Phase 2 proof-of-concept studies were completed with DS107 cream: Study DS107E-02 in patients 
affected by mild to moderate AD, and Study DS107E-03 in patients with mild to moderate acne 
vulgaris. 
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 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-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. 
 
 


 
 
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2 
RISK BENEFIT ASSESSMENT 
 
To date, DS107 capsules has been administered to 87 healthy volunteers/patients during the course of 
one Phase 1 trial and one Phase 2a trial for moderate to severe AD. Up to 4g DS107 capsules was well 
tolerated in healthy volunteers up to 4 weeks. 2g DS107 capsules was well tolerated and safe in 51 
patients with moderate to severe AD. The effect of DS107 capsules on the signs and symptoms of AD 
was consistently higher than placebo for all of the efficacy endpoints evaluated in this study, both 
investigator scores and patient scores. Following a battery of toxicology studies, and considering the 
endogenous nature of this molecule, it was concluded that DS107 is safe and well tolerated. 
 
Based on both the favourable safety profile and the therapeutic potential of DS107 capsules in a disease 
that currently lacks effective 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. 


 
 
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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 Phase I safety study. 
 
The proof-of-concept Phase 2a study 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 a similar 
efficacy observed in severe/very severe AD patients, however, the sample size was deemed too 
small to determine the statistical significance.  
The two previous clinical studies indicate that DS107 capsules is well tolerated and safe in both 
healthy patients and patients with moderate to severe AD. The Phase 2a study highlights the 
efficacy of DS107 capsules and indicates that further efficacy could be obtained by optimizing 
the dosing regime and/or concentration. Therefore, the goal for this dose-finding study is to 
examine the efficacy of 2g DS107 capsules OD and 1g DS107 capsules OD for a treatment 
period of 8 weeks in patients with moderate to severe AD.  
 
The design of the current study is a randomised, placebo-controlled, and double-blind parallel 
group comparison in which the efficacy and safety of an 8 week treatment with DS107 capsules 
is assessed in 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, the positive signals in the Phase 2a study in patients there is a clear rationale for 
the further development of DS107 capsules as a treatment for patients with moderate to severe 
AD.  
 
 
 


 
 
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4 
STUDY OBJECTIVES 
Efficacy Objective: 
 
 
To compare the efficacy of orally administered DS107 versus placebo, in the treatment 
of adult patients with moderate to severe AD. 
 
Safety Objective: 
  
 
To assess the safety of orally administered DS107 versus placebo, in adult patients 
with moderate to severe AD. 
 
 


 
 
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5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
 
 
Proportion of patients achieving an Investigator’s Global Assessment (IGA) of 0 
(clear) or 1 (almost clear) and a decrease of at least 2 points in IGA in treated 
population compared to placebo population at Week 8. 
5.2 
Secondary Endpoints 
 
 
Proportion of patients achieving an IGA score of 0 (clear) or 1 (almost clear) and a 
decrease of at least 2 points in IGA in treated population compared to placebo 
population from baseline to Week 2, 4, 6 and 10. 
 
 
Proportion of patients achieving a decrease of at least 2 points in IGA in treated 
population compared to placebo population from baseline to Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in Eczema Area and Severity Index (EASI) in treated population 
compared to placebo population at Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in Numeric Rating Scale (NRS) for Pruritus in treated population 
compared to placebo population at Week 2, 4, 6, 8 and 10. 
 
5.3 
Exploratory Endpoints 
 
 
Change from baseline in the Dermatology Life Quality Index (DLQI) score in treated 
population compared to placebo population at Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Orientated Eczema Measure (POEM) score in 
treated population compared to placebo population at Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Global Impression of Severity (PGI-S) score in 
treated population compared to placebo population at Week 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Global Impression of Change (PGI-C) score in 
treated population compared to placebo population at Week 2, 4, 6, 8 and 10. 
 
 
Plasma DGLA concentrations in treated population compared to placebo population  at 
Baseline/Day 0, Week 4, Week 8 and Week 10 of (samples to be retained and analysed 
for the potential analysis at a later date).  
 
 
Determination of AD biomarkers  at Baseline/Day 0, and Week 8   (samples to be 
retained and analysed at a later date for the potential analysis). 
 
 


 
 
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6 
STUDY DESIGN 
6.1 
General 
This is a randomised, placebo-controlled, double-blind, parallel group, multi-centre 3-arm 
Phase 2b study to investigate the efficacy of orally administered DS107 and the dose-response 
relationship between DS107 capsules and placebo in AD patients 18 years and older. 
It is planned that at least 300 patients with at least 100 patients per treatment group, 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. Patients will be randomized (1:1:1) at 
baseline visit to either receive 2g DS107, 1g DS107 or placebo once daily for 8 weeks.  
Patients will come to the clinic on 7 occasions: at Screening/Visit 1, Baseline/Visit 2, Week 
2/Visit 3, Week 4/Visit 4, Week 6/Visit 5 and /Week 8/Visit 6 (end of treatment) and Week 
10/Visit 7 (follow-up). Early termination visits will be recorded for patients who withdraw from 
the study early. All patients will exit the study at the Week 10 visit. At the screening visit, after 
giving informed consent to participate, patients will be assessed using the screening 
examinations. Patients who meet the inclusion criteria and who do not meet the exclusion 
criteria will be enrolled.   
Unlike other oral treatments for AD (e.g. steroids) a treatment effect of DS107 capsules is not 
immediately expected to occur after start of treatment, but to increase constantly over time 
reaching its maximum effect within a time period over 4-6 weeks. Therefore, every effort 
should be undertaken to continue treatment with DS107 at least for 4 weeks to determine the 
efficacy of DS107. Patients not willing to continue to participate in the study due to the apparent 
lack of efficacy within the first 4 weeks of treatment therefore should be replaced. 
A schematic diagram of the overall timeframe of the study is given in Figure 2. 
Figure 2: Study Outline 
 
 
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 9.2.11. 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 9.2.11). 
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 three parallel group treatment regimens in a 1:1:1 randomization: 


 
 
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 Treatment group A: 1g DS107 (2 DS107 capsules and 2 placebo capsules) 
administered once-daily for 8 weeks  
 
 
Treatment group B: 2g DS107 (4 DS107 capsules) administered once-daily for 8 
weeks  
 
 
Treatment group C: Placebo (4 placebo capsules) orally administered once-daily for 8 
weeks 
 
To maintain the double-blind conditions, DS107 capsules and Placebo will be identical in 
appearance. 
 
 


 
 
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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. Patients should only be permitted to screen for this study if they 
are free of any sub-clinical infection (indicated by the presence of an Eosinophil count below 
0.3 x 109 /L within 1 month of screening). 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 Hanifin and Rajka 
criteria. 
 
2. Patients with moderate to severe AD at baseline as defined by an IGA of minimum 3 at 
baseline. 
 
3. Patients with an EASI score of ≥12 at screening and baseline. 
 
4. Patients with AD covering a minimum 10% of the body surface area at baseline. 
 
5. Patients whose pre-study clinical laboratory findings do not interfere with their 
participation in the study, in the opinion of the investigator. 
 
6. Patients who are able and willing to stop all current treatments for AD throughout the study 
(except for allowed emollients). 
 
7. Patients who are on a stable dose of a bland emollient applied BD (twice daily) for at least 
7 days prior to baseline. 
 
8. Male or female patients who are aged 18 years and older on the day of signing the informed 
consent form (ICF). 
 
9. Female patients and male patients with female partners of child bearing potential must use 
adequate contraception or have a sterilized partner for the duration of the study. Adequate 
contraception is defined as: systemic hormonal contraceptives, intrauterine device or 
barrier method of contraception in conjunction with spermicide, or agree to sexual 
abstinence. Hormonal contraceptives must be on a stable dose for at least one month before 
baseline. 
 
10. 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. 
 
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. 
 


 
 
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2. Patients who have used systemic treatments (other than biologics) 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 who have used any topical medicated treatment for AD two weeks prior to start of 
treatment/ Baseline (Day 0), including but not limited to, topical corticosteroids, tars and 
bleach. 
 
4. Patients who use topical products containing urea, ceramides or hyaluronic acid two weeks 
prior to Baseline. 
 
5. Patients who use anti-histamines for AD within 2 weeks of baseline. Non-sedative anti-
histamines for other indications may be used throughout the study provided the patient is 
on a stable dose for 4 weeks prior to Baseline. 
 
6. 
Patients with the presence of an active or chronic allergic reaction as evidenced by an 
irregular white cell count  determined by eosinophils > 0.3 x 109 /L at the screening visit. 
  
7. 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. 
 
8. Patients who have a history of hypersensitivity to any substance in DS107 capsules or 
placebo capsules. 
 
9. 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.  
 
10. Patients who have a clinically significant impairment of renal or hepatic function. 
 
11. 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. 
 
12. Patients with chronic infectious disease (e.g., hepatitis B, hepatitis C or infection with 
human immunodeficiency virus). 
 
13. 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). 
 
14. 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. 
 
15. 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, 


 
 
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b. Other biologics  influencing cell proliferation: within 6 months before the screening 
visit. 
 
16. Patients who are pregnant, planning pregnancy, breastfeeding and/or are unwilling to use 
adequate contraception (as specified in inclusion criterion 9) during the trial. 
 
17. Patients, in the opinion of the investigator, not suitable to participate in the study. 
 
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 informed consent 
form (ICF). The patients will then receive a copy of the signed and dated patient information 
sheet (PIS)/informed consent form (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 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. 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 8/Visit 6 visit will be asked to come for an 
early termination visit as soon as possible and have the assessments listed at Week 8/Visit 6 
performed. They will also be asked to return two weeks later for the safety assessments listed 
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There will be two main categories for withdrawals from the study: “complete withdrawal” and 
“withdrawals from investigational product”. 
7.5.1 
Complete Withdrawal 
Discontinuation of investigational product and all efficacy and safety evaluations. Standard 
reasons for withdrawing from further participation in the study and from the follow-up visits 
may be: 
 
Patients decision (withdrawal of consent to participate) 
 
Patient lost to follow-up (drop-out) 
 
7.5.2 
Withdrawals from Investigational Product 
Discontinuation of investigational product, but continued follow-up visits, including efficacy 
and safety evaluations. Standard reasons for withdrawing from taking further investigational 
product, but continuing follow-up visits and safety evaluations may be: 
 
Unacceptable adverse events 
 
Patient request 
 
Investigator’s discretion 
 
Intercurrent illness 
 
Lack of efficacy  
 
Pregnancy 
7.6 
Patient Replacement 
Patients who are withdrawn from the study due to an adverse event 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. 
 
 


 
 
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8 
STUDY CONDUCT 
 
8.1 
Study Schedule 
During the study, six visits to the clinic are scheduled at least one week after the screening visit: 
one at the start of the comparative treatment period/baseline (Day 0/Visit 2) and five in the 
comparative treatment period (Week 2/Visit 3, Week 4/Visit 4, Week 6/Visit 5 and Week 
8/Visit 6). A final safety follow-up visit (Visit 7) will be conducted two weeks after Visit 6 or 
two weeks after the final visit attended if the patient does not complete the study. The baseline 
visit must be performed, at the latest 30 days after the screening visit. 
 
Patients who discontinue the study early will be asked to attend the investigative site as soon as 
possible so that assessments scheduled for Visit 6 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 Hanifin and 
Rajka 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 at the baseline visit. Any medication (prescription as well as 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. A list of ‘medications 
and therapeutic regimens excluded from the study’ is defined below (Section 9.2.11.2).  
8.2 
Clinic Visits 
A tabulated flow chart of the study is presented in Appendix 1 (Section 15.1). 
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) 
 
Hanifin and Rajka criteria review (as detailed in Appendix 2 [15.2]) 
 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, 
urinalysis 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) 
 
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 9.2.6) 
 
Body Surface Area (as detailed in Section 9.1.4) 
 
Investigator’s Global Assessment (as detailed in Section 9.1.1) 
 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 


 
 
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 
NRS Pruritus Assessment (as detailed in Section 9.1.3) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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. 
8.2.2 
Treatment Period 
 
Following completion of a successful screening visit, patients will begin the comparative 
treatment period (8 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 three treatment 
regimens.  
 
Patients will be instructed to take 4 capsules of IMP which will contain either 1g  DS107 or 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 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.  
 
Patients who discontinue the study early will have all study procedures scheduled for Visit 6 
(see Section 8.2.7) performed as soon as possible after patient withdrawal so that all study-
related information can be recorded. 
 
8.2.3 
Baseline (Visit 2) 
Note: it must be ensured that all inclusion regarding the severity of the disease remain 
unchanged since the screening in order to exclude patients reacting to the emollient use 
since screening visit. 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) 
 
Hanifin and Rajka criteria review (as detailed in Appendix 2 (15.2)) 
 
Patient Randomisation (as detailed in Section 10.5) 
 
Samples for clinical laboratory safety tests (haematology, serum biochemistry,  
urinalysis as detailed in Section 9.2.4) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.7) 
 
Biomarker Sampling (as detailed in Section 9.2.8) 
 
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 9.2.6) 
 
Dispense Study Drug  
 
Dispense Patient Compliance Log  
 
Body Surface Area (as detailed in Section 9.1.4) 
 
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) 


 
 
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 
Patient Orientated Eczema Measure (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire as detailed in Section 9.1.7) 
 
Patient Global Impression of Change Questionnaire as detailed in Section 9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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 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 baseline through 
to the follow up visit. Emollient use will also be captured on a daily basis for the same period. 
 
Collection of AE’s will begin after the first administration of IMP has occurred. 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site at Visit 3 and to bring with them the unused DS107 capsules/Placebo patient 
packs, the used DS107 capsules/Placebo patient packs, and the patient compliance log.  
 
8.2.4 
Week 2 (Visit 3) 
 
Patients will return to the investigational site at Week 2/Visit 3.  
 
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: 
 
 
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) 
 
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 (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire as detailed in Section 9.1.7) 
 
Patient Global Impression of Change Questionnaire as detailed in Section 9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
AE assessment (as detailed in Section 11) 


 
 
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DS107 capsules or Placebo patient packs will be returned and additional patient treatment packs 
of DS107 capsules or placebo capsules will be supplied to the patient.  
 
IMP will continue to be administered approximately 2 hours after food consumption at the same 
time each day. 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 
baseline 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.  
 
8.2.5 
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 3. Patients will be 
required to provide the patient compliance log for confirmation of compliance.  
 
The following procedures/assessments will occur: 
 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.7) 
 
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) 
 
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 (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire as detailed in Section 9.1.7) 
 
Patient Global Impression of Change Questionnaire as detailed in Section 9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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. The patient compliance log will be provided to the patient who will be instructed 
to complete this as before.  
 


 
 
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An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
baseline 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 5 and to bring with them the unused DS107/Placebo patient packs, 
the used DS107/Placebo patient packs, and the patient compliance log.  
8.2.6 
Week 6 (Visit 5) 
 
Patients will return to the investigational site at Week 6/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: 
 
 
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) 
 
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 (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire as detailed in Section 9.1.7) 
 
Patient Global Impression of Change Questionnaire as detailed in Section 9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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.  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 
baseline 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.  
 
8.2.7 
Week 8 (Visit 6) / End of Treatment or Early Termination 
 


 
 
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Patients will return to the investigational site at Visit 6. The last dose of DS107/Placebo should 
be taken the day before Visit 6. 
For accountability purposes, patients will be required to bring both the used DS107/Placebo 
patient packs and unused DS107/Placebo supplied at Visit 5. 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, serum biochemistry, 
urinalysis as detailed in Section 9.2.4) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.7) 
 
Biomarker Sampling (as detailed in Section 9.2.8) 
 
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) 
 
Body Mass Index (as detailed in Section 9.2.6) 
 
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) 
 
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 (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire as detailed in Section 9.1.7) 
 
Patient Global Impression of Change Questionnaire as detailed in Section 9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
AE assessment (as detailed in Section 11) 
 
The DS107or Placebo patient packs will be returned. No further DS107or 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 9.2.11 
and 9.2.12.  
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
baseline 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 to assess any AEs since this visit, and conduct safety and efficacy 
assessments.  
8.2.8 
Week 10 (Visit 7) / Follow up 
 
Two weeks after Visit 6 (or early withdrawal visit), patients will return to the investigational 
site and the final procedures/assessments will occur: 
 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, 
urinalysis as detailed in Section 9.2.4) - Only if clinically significant change from 
baseline in safety lab results at Week 8 / Visit 6 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.7) 
 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3);  


 
 
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 
Physical examination (as detailed in Section 9.2.2) 
 
Body Surface Area (as detailed in Section 9.1.4) 
 
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 (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire as detailed in Section 9.1.7) 
 
Patient Global Impression of Change Questionnaire as detailed in Section 9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
AE assessment (as detailed in Section 11) 
 
 


 
 
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9 
ASSESSMENTS 
9.1 
Efficacy Assessments 
 
9.1.1 
Investigator Global Assessment (IGA) 
 
The clinical severity of AD will be evaluated by the investigator at each visit using the IGA 
scale (Appendix 3) (Futamura et al. 2016).  
 
The IGA 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). 
IGA uses clinical characteristics of erythema, infiltration, papulation and oozing/crusting as 
scoring guidelines for the overall severity assessment. IGA will be assessed at every visit. 
 
9.1.2 
Eczema Area Severity Index (EASI) 
 
EASI (Appendix 4) will be assessed at Screening, Baseline/Visit 2, Week 2/Visit 3, Week 
4/Visit 4, Week 6/Visit 5,  Week 8/Visit 6/ET and Follow up Week 10/Visit 7. It 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 at screening and then daily starting at 
baseline 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 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 Baseline/Visit 
2, Week 2/Visit 3, Week 4/Visit 4, Week 6/Visit 5, Week 8/Visit 6/ET and Follow up Week 
10/Visit 7 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  


 
 
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 
Question unanswered = 0  
 
Question 7: “prevented work or studying” = 3  
 
9.1.6 
Patient Orientated Eczema Measure (POEM) 
 
The POEM will be assessed at each visit, except the screening visit. The POEM developed by 
Charman et.al. 2005 (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 
Patient Global Impression of Severity (PGI-S) 
 
The self-report PGI-S is a global index that may be used to rate the severity of a specific 
condition (a single-state scale) (Appendix 8) (Viktrup et al. 2012).  It is a simple, direct, easy 
to use scale that is intuitively understandable to clinicians. The PGI-S is a single question asking 
the patient to rate how their AD is now on a scale of 1 (Normal Skin) to 4 (Severe). This will 
be assessed by the patient at Baseline/Visit 2, Week 2/Visit 3, Week 4/Visit 4, Week 6/Visit 5, 
Week 8/Visit 6/ET and Follow up Week 10/Visit 7. 
9.1.8 
Patient Global Impression of Change (PGI-C) 
 
The self-report measure PGI-C reflects a patient’s belief about the efficacy of treatment. PGI-
C is a 7 point scale depicting a patient’s rating of overall improvement (Appendix 9) 
(Rampakakis et al. 2015). Patients rate their change as “very much improved,” “much 
improved,” “minimally improved,” “no change,” “minimally worse,” “much worse,” or “very 
much worse.” This will be assessed by the patient at Baseline/Visit 2, Week 2/Visit 3, Week 
4/Visit 4, Week 6/Visit 5, Week 8/Visit 6/ET and Follow up Week 10/Visit 7. 
 
 
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) at every visit 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 


 
 
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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 signs measurements will be performed as per the Study Flow Chart (Appendix 1) at every 
visit. 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, Serum Biochemistry,  and 
Urinalysis 
 
Blood and urine samples will be taken as per the Study Flow Chart (Appendix 1) for routine 
haematology, serum biochemistry and urinalysis tests. All samples will be analysed in the 
central laboratory. 
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. 
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.  
Urinalysis: 
pH, protein, glucose, blood. 
 
If required a Follicule-Stimulating Hormone (FSH) test to confirm non-child bearing potential 
will be carried out at screening only. 
Details of the volume of blood or urine 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 8 /Visit 6/ET visit, as per the Study Flow Chart (Appendix 1). 


 
 
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9.2.6 
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 1, Baseline/Visit 2 and Week 8/Visit 6/ET. The height will only be 
recorded once at the screening visit and the same value will be used for BMI calculation at 
Baseline/Visit 2 and Week 8/Visit 6 visits. 
 
9.2.7 
Pharmacokinetic Sampling 
 
Blood samples for PK analysis will be collected via direct venepuncture as per the Study Flow 
Chart (Appendix 1) at Baseline/Visit 2, Week 4/Visit 4, Week 8/Visit 6/ET and Week 10/Visit 
7/Follow up.  
 
The detailed instruction for PK sample collection, processing, storage and shipment will be 
provided in a separate procedure. 
 
9.2.8 
Biomarker Sampling 
 
Blood samples will be collected via direct venepuncture as per the Study Flow Chart (Appendix 
1) at Baseline/Visit 2, and Week 8/Visit 6/ET  and 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. 
9.2.9 
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. 
9.2.10 Adverse Event Assessment 
 
See section 11. 
9.2.11 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 7) 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.  


 
 
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9.2.11.1 
Permitted Therapies 
 
9.2.11.1.1 
Emollients 
 
All patients should be applying a bland emollient of their choice, initiated at least 7 days prior 
to Baseline/Day 0, 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. Patients will be 
requested 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 
 
Every effort should be made to keep 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. 
 
9.2.11.1.2 
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.  
 
9.2.11.2 
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 
 
bleach 
 
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  
 
Anti-histamines used for AD 
 
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 
 
9.2.12 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. 
 


 
 
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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. 
 
 


 
 
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10 
INVESTIGATIONAL 
MEDICINAL 
PRODUCT 
/ 
INVESTIGATIONAL DRUG 
10.1 Ivestigational 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 
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 and 1g) with placebo, administered orally once 
daily for a total duration of 8 weeks. The last study drug administration should occur on the 
day preceding Week 8 (Visit 6) / Early Termination (ET) visit. Patients will be randomized 
to one of the three treatment groups in a 1:1:1 ratio: 
 
 Treatment group A: 1g DS107 (2 DS107 capsules and 2 placebo capsules) 
administered once-daily for 8 weeks  
 
 
Treatment group B: 2g DS107 (4 DS107 capsules) administered once-daily for 8 
weeks  
 
 
Treatment group C: Placebo (4 placebo capsules) orally administered once-daily for 8 
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. 
 


 
 
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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: 
 
 
 
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 8 consecutive weeks. 
10.5 Methods for Assigning Patients to Treatments 
 
Approximately 300 patients will be randomized into double-blind treatment groups in a 1:1:1 
ratio by an Interactive Web Response System (IWRS) as follows: 
 
 Treatment group A: 1g DS107 (2 DS107 capsules and 2 placebo capsules) 
administered once-daily for 8 weeks  
 
 
Treatment group B: 2g DS107 (4 DS107 capsules) administered once-daily for 8 
weeks  
 
 
Treatment group C: Placebo (4 placebo capsules) orally administered once-daily for 8 
weeks 
 
  
A randomization list permuted 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 


 
 
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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 IMPs 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 
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.  
 


 
 
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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.  


 
 
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 
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 contact the 
Pharmacovigilance (PV) CRO monitor by phone, fax or e-mail, and in any case no later 
than 24 hours after the knowledge of such a case.  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 a copy of 
the SAE reporting form to PV CRO at the number provided in the Investigator Site File. The 
faxed 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.  


 
 
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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.  
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. 
 
 


 
 
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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 
 
At least 300 patients will be randomized into double-blind treatment groups in a 1:1:1 ratio by 
an IWRS.  
 
 Treatment group A: 1g DS107 (2 DS107 capsules and 2 placebo capsules) 
administered once-daily for 8 weeks  
 
 
Treatment group B: 2g DS107 (4 DS107 capsules) administered once-daily for 8 
weeks  
 
 
Treatment group C: Placebo (4 placebo capsules) orally administered once-daily for 8 
weeks 
 
  
A randomization list permuted 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. Assuming these rates and a significance of 5%, 300 evaluable patients 
(100 patients per treatment arm) will yield 45% power for comparisons between the active 
doses and placebo in this study. 


 
 
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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 Interim Analysis 
An interim analysis will be conducted once 50% of planned patients have completed their Week 
8 assessments. This will be conducted in accordance with sponsor SOP “Interim Analysis of 
Clinical Studies”. 
12.6 Data Analysis 
Data analysis will be performed at the CRO.  All computations will be completed using SAS® 
version 9.1.3 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. 
 
12.7 Analysis Populations 
Enrolled Population 
The Enrolled Population consists of all patients who sign informed consent. 
 
Screen Failures  
Screen Failures are patients from the Enrolled Population who do not meet the eligibility 
requirements and are withdrawn from the study prior to Randomisation. 
 
Randomised Population 
The Randomised Population 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. SAF 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 are 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 


 
 
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during this meeting. PPS is a supportive analysis population for efficacy endpoints. Analysis 
will be done according to the treatment patients were randomised to. 
 
12.8 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 and severity. 
Clinical laboratory values (haematology, biochemistry, and urinalysis) 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.  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 day. 
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. 
12.9 Statistical Analysis Plan 
In addition to the summarised analysis plan outlined below, a separate document, Statistical 
Analysis Plan (SAP) for DS107G-03 will detail all analyses to be performed.  
 
12.9.1 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. 
12.9.2 Primary variables 
 
The primary variable will be the proportion of patients achieving an IGA score of 0 (clear) or 
1 (almost clear) and a decrease of at least 2 points in IGA from baseline at Week 8. 
 
The primary endpoint will be analysed using a Generalised Linear Mixed Model (GLMM) with 
treatment arm and baseline IGA value as factors, with the treatment-by-visit interaction term as 
the random effect to account for missing data. The primary analysis will be based on the FAS, 
and repeated for the PPS as a supportive sensitivity analysis. 
 
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.  Because of 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. (J Biopharm Stat, 2013; 
23(6):1352-71) 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.  The sensitivity analyses for missing data will be 
performed on the FAS only. 


 
 
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12.9.3 Secondary variables 
 
IGA-responders at other time points will also be analysed using a GLMM model similar to that 
described in Section 12.8.2. 
 
The continuous efficacy variables and their changes from baseline will be summarized with 
descriptive statistics per treatment group and visit. This applies to the IGA, EASI, NRS scores 
for pruritus, DLQI, POEM, PGI-S and PGI-C. Change from baseline endpoints will be analysed 
using Mixed Model with Repeated Measures (MMRM) with Treatment Arm as a factor and 
baseline value as a covariate, and with the treatment-by-visit interaction term as the repeated 
effect to account for missing data. The secondary efficacy analyses will be based on the FAS 
only. 
12.9.4 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.  
 
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. 
12.10 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 


 
 
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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.  
 


 
 
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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 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.  
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 Conference on 
Harmonisation (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, 


 
 
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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 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 Report and Publication 
Production of a clinical study report in accordance with the ICH guidelines will be the 
responsibility of CRO.  No information from the study will be published without the prior 
written consent of the Sponsor. 
 
 


 
 
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14 
REFERENCES 
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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, Krol, A, Paller, AS, Schwarzenberger, K, 
Bergman, JN, Chamlin, SL, Cohen, DE, Cooper, KD, Cordoro, KM, Davis, DM, 
Feldman, SR, Hanifin, JM, Margolis, DJ, Silverman, RA, Simpson, EL, Williams, HC, 
Elmets, CA, Block, J, Harrod, CG, Smith Begolka, W & Sidbury, R. 2014. ‘Guidelines 
of care for the management of atopic dermatitis: section2. Management and treatment 
of atopic dermatitis wth topical therapies.’ J Am Acad Dermatol. 2014 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. 
 
 
Futamura, M, Leshem, YA, Thomas, KS, Nankervis, H, Williams, HC & Simpson, EL 
2016. ‘A systematic review of Investigator Global Assessment (IGA) in atopic 
dermatitis (AD) trials: Many options, no standards.’ J Am Acad Dermatol; 74(2), pp. 
288 - 294. 
 


 
 
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 
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 & Rajka, G 1980. ‘Diagnostic features of atopic dermatitis.’ Acta 
Dermatol Venereol.; 92, pp. 44-7. 
 
 
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. 
 
 
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. 
 
 
Rampakakis, E, SteMarie, PA, Sampalis, JS, Karellis, A, Shir, Y & Fitzcharles, M 
2015. ‘Real-life assessment of the validity of patient global impression of change in 
fibromyalgia.’ RMD Open;1, e000146.  
 
 
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. 
 


 
 
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 
Schultz-Larsen, FV & Haniﬁn, JM 2002. ‘Epidemiology of atopic dermatitis.’ Immunol 
Allergy Clin North Am; 22, pp. 1-24. 
 
 
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. 
 
 
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. 
 
 
Viktrup, L, Hayes, RP, Want, P & Shen, W 2012. ‘Construct validation of patient 
global impression of severity (PGI-S) and improvement (PGI-I) questionnaires in the 
treatment of men with lower urinary tract symptoms secondary to benign prostatic 
hyperplasia.’ BMC Urol; 12, pp.  30. 
 
 
Williams, H & Flohr C 2006. ‘How epidemiology has challenged 3 prevailing concepts 
about atopic dermatitis.’ J Allergy Clin Immunol; 118, pp. 209-213. 
 


 
 
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15 
APPENDICES 
15.1 Appendix 1: Study Flow-Chart 
 
Visit 
Screening/  
Visit 1 
Baseline /  
Visit 2 
Week 2 /  
Visit 3 
Week 4 /  
Visit 4 
Week 6 /  
Visit 5 
Week 8 / 
Visit 6 / Early 
Termination 
Week 10 / 
Visit 7 / 
Follow up 
Day 
-30 to -1 
0 
14  
28  
42  
56  
70  
Visit Window 
 
 
+/-2 days 
+/-2 days +/-2 days 
+/-2 days 
+/-3 days 
Informed Consent 
X 
 
 
 
 
 
 
Assign Patient identifier number 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical / Surgical History 
X 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
Hanifin and Rajka criteria 
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Safety labs: Serum Biochemistry 
(including FSH levels at screening 
when applicable1), Hematology, 
Urinalysis 
X  
X 
 
 
 
X 
X2 
Pharmacokinetic Sampling 
 
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 
Physical Examination 3 
X 
X 
X 
X 
X 
X 
X 
BMI 
X 
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 
 
IMP Accountability 
 
 
X 
X 
X 
X 
 
BSA 
X 
X 
X 
X 
X 
X 
X 
IGA 
X 
X 
X 
X 
X 
X 
X 
EASI assessment 
X 
X 
X 
X 
X 
X 
X 
NRS Pruritus assessment  5 
X 
X------------------------------------------------------------------------------------------X 
DLQI questionnaire 
 
X 
X 
X 
X 
X 
X 
POEM questionnaire 
 
X 
X 
X 
X 
X 
X 
PGI-S questionnaire 
 
X 
X 
X 
X 
X 
X 
PGI-C questionnaire 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Emollient use capture  5 
 
X------------------------------------------------------------------------------------------X 
Adverse Events    6 
 
X 
X 
X 
X 
X 
X 
 
1. FSH requirement to confirm female 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 a laboratory AE recorded at Week 8. In  that case only the sample which is the cause of the 
AE should be re-tested. 
3. Physical Examination will be symptom-directed as per section 9.2.2. 
4. Patients will be instructed to take their last study drug dose the day preceding Week 8 visit. 
5. NRS/Emollient use will be captured electronically through the IWRS by the patient. Patients may use 
paper to document these assessments also. 


 
 
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6. Collection of AE will start after the first study drug administration. 


 
 
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15.2 Appendix 2: Diagnostic Features of Atopic Dermatitis (Hanifin and 
Rajka Criteria)  
 
Patients must have confirmed diagnosis of AD based on the Hanifin and Rajka diagnostic 
criteria. Firm diagnosis of AD requires the presence of at least three of the major criteria 
described below. In addition to having three of the major criteria, a patient should manifest 
three minor criteria which are either less specific or relatively rare. 
Major criteria: 
 
Pruritus 
 
Dermatitis affecting flexural surfaces in adults and the face and extensors in infants and 
children 
 
Chronic or relapsing dermatitis 
 
Personal or family history of cutaneous or respiratory atopy (asthma, allergic rhinitis, 
AD). 
 
Minor criteria can be divided into 4 categories: 
 
Facial features: facial pallor, facial erythema, hypopigmented patches, infraorbital 
darkening, infraorbital folds (Dennie-Morgan folds), cheilitis, recurrent conjunctivitis, 
anterior neck folds. 
 
Triggers: foods, emotional factors, environmental factors, skin irritants. 
 
Complications: susceptibility to cutaneous infections, impaired cell-mediated 
immunity, immediate skin-test reactivity, elevated IgE, keratoconus, anterior 
subcapsular cataracts. 
 
Other: early age of onset, dry skin, ichthyosis, hyperlinear palms, keratosis pilaris, hand 
and foot dermatitis, nipple eczema, white dermatographism, perifollicular 
accentuation. 
 
Hanifin & Rajka, 1980. 
 
 


 
 
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15.3 Appendix 3: Investigator’s Global Assessment (IGA) 
 
IGA Severity 
Morphological Description 
4 – Severe 
Deep/dark red erythema; marked and extensive elevation (papules/infiltration). 
3 – Moderate  
Dull, red, clearly distinguishable erythema; clearly perceptible lesion elevation 
(papules/infiltration) but not extensive. 
2 – Mild  
Visibly detectable, light pink erythema and very slight elevation 
(papules/infiltration). 
1 – Almost Clear 
Barely 
perceptible 
erythema 
and/or 
minimal 
lesion 
elevation 
(papules/infiltration). 
0 – Clear  
No signs of erythema, lesions, papulation or infiltration  
 
 
 
 
 


 
 
Page 65 of 71 
 
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. 
 
 


 
 
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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 


 
 
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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 68 of 71 
 
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 69 of 71 
 
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 70 of 71 
 
15.8 
Appendix 8: Patient Global Impression of Severity (PGI-S) 
 
 
 
Patient ID #: ___ ___ - ___ ___ ___  
 
Patient Initials: ___ ___ ___ 
 
 
 
Visit Day: ___________ 
 
Visit Date (dd-mmm-yyyy):______________ 
 
 
 
Describe, to the best of your abilities, how your Atopic Dermatitis symptoms are now: 
 
 
(1) 
Normal Skin 
 
(2) 
Mild 
 
(3) 
Moderate 
 
(4) 
Severe 
 
 
 
 
 


 
 
Page 71 of 71 
 
 
15.9 
Appendix 9: Patient Global Impression of Change (PGI-C) 
 
 
Patient ID #: ___ ___ - ___ ___ ___  
 
Patient Initials: ___ ___ ___ 
 
 
 
Visit Day: ___________ 
 
Visit Date (dd-mmm-yyyy):______________ 
 
 
Since the start of the study, my overall status is: 
 
 
(1) 
Very Much Improved 
 
 
(2) 
Much Improved 
 
 
(3) 
Minimally Improved 
 
 
(4) 
No Change 
 
 
(5) 
Minimally Worse 
 
 
(6) 
Much Worse 
 
 
(7) 
Very Much Worse 
 
 
 
 

SAP_001.pdf: 
 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
DS Biopharma DS107G-03  
 
Page 1 of 27 
 
 
 
 
  
 
DS Biopharma 
Protocol #: DS107G-03 
A Randomised, Double-blind, Placebo-Controlled, 
Phase 2b Study to Assess the Efficacy and Safety of 
Orally Administrated DS107 in Patients with 
Moderate to Severe Atopic Dermatitis 
  
  
  
Statistical Analysis Plan 
 
 
  
  
  
Created by:  Clinical Trial Data Services, LLC 
40 Nagog Park, Suite #210 
Acton, MA 01720 
  
Lavin Consulting LLC 
3 Cahill Park Drive 
Framingham MA 01702 




 
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Page 3 of 27 
 
LIST OF ABBREVIATIONS 
  
15-HETrE                       
15-hydroxyeicosatrienoic acid 
AD                                  
Atopic Dermatitis 
AE                         
 
Adverse Event 
BD                                   
Bis Die (Twice daily)  
BP                                    
Blood Pressure 
BPM   
 
 
Beats Per Minute 
CM 
 
 
 
Concomitant Medication 
COX  
 
 
Cyclooxygenase  
CRA                                
Clinical Research Associate  
CRO                                
Contract Research Organisation  
CRF                                 
Case Report Form 
CsA                                 
Cyclosporin A 
CDISC 
 
 
Clinical Data Interchange Standards Consortium 
CTA                                
Clinical Trial Agreement 
DGLA                             
Dihomo-Gamma-Linolenic Acid  
DLQI                               
Dermatology Life Quality Index  
DM                                  
Data Manager 
DS                                   
DS Biopharma 
EASI                                
Eczema Area and Severity Index 
EC                                   
Ethics Committee 
EDC                                
Electronic Data Capture 
FAS                                
Full Analysis Set 
FSH                                
Follicule Stimulating Hormone 
GCP   
 
 
Good Clinical Practice 
GENMOD 
 
 
Generalized Linear Model (binary outcomes) 
GLP 
 
 
 
Good Laboratory Practice 
ICF                                  
Informed Consent Form 
ICH                                  
International Conference on Harmonisation 
IGA 
 
 
 
Investigator’s Global Assessment 
IgE 
 
 
 
Imunnoglobulin E  
IMP                                
Investigational Medicinal Product 
ISF                                  
Investigator Site File 
ITT                                  
Intention-To-Treat 
IWRS                              
Interactive Web Response System 
MCAR 
 
 
Missing Completely at Random 
MedDRA  
 
 
Medical Dictionary for Regulatory Activities 
MMRM  
 
 
Mixed Model with Repeated Measures 
MNAR 
 
 
Missing Not at Random 
NOAEL 
 
 
No Observed Adverse Event Limit 
NRS 
 
 
 
Numeric Rating Scale  
OTC                                
Over The Counter 


 
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PBIR  
 
 
Probability of Being in Response  
PGD1                                  
Prostaglandin D1 
PGI-C                              
Patient Global Impression of Change  
PGI-S                              
Patient Global Impression of Severity  
PIS                                   
Patient Information Sheet 
PK                                   
Pharmacokinetics 
POEM                            
Patient Orientated Eczema Measure 
PPS                                  
Per Protocol Analysis Set 
PUVA                             
Psoralen & Ultraviolet A 
PV CRO                          
Pharmacovigilance Contract Research Organisation 
SAE                                 
Serious Adverse Event 
SAS                                 
Statistical Analysis System 
SAP                                 
Statistical Analysis Plan 
SCORAD                         
SCORing AD 
SDV                                 
Source Data Verification 
SDTM                                     Study Data Tabulation Model 
SOP                                 
Standard Operating Procedure 
SPC                                 
Summary of Products Characteristics  
SS 
 
 
 
Safety Analysis Set 
SUSAR  
 
            Suspected Unexpected Serious Adverse Reaction 
Th 
 
            
T helper cell  
TNF-α                             
Tumor Necrosis Factor-Alpha 
UV-A/B                           
Ultraviolet-A/B 
VAS                                 
Visual Analogue Scale 
  
  
  


 
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Page 5 of 27 
 
Table of Contents 
  
1 
PROTOCOL SUMMARY .................................................................................................................................. 6 
2 
STATISTICAL METHODOLOGY ................................................................................................................ 11 
2.1 
GENERAL CONSIDERATIONS ......................................................................................................................... 11 
2.2 
SUBJECT POPULATION .................................................................................................................................. 12 
2.2.1 
Baseline Characteristics/Medical History ........................................................................................... 12 
2.2.2 
Case Disposition .................................................................................................................................. 12 
2.2.3 
Dose Regimen ...................................................................................................................................... 13 
2.2.4 
Study Populations for Analysis ............................................................................................................ 13 
2.2.4.1 
Full Analysis Set (FAS) ................................................................................................................................... 13 
2.2.4.2 
Safety Analysis Set (SAS) ............................................................................................................................... 13 
2.2.4.3 
Per-Protocol Set (PPS) ..................................................................................................................................... 13 
2.2.4.4 
Subgroup Analyses .......................................................................................................................................... 13 
2.2.5 
Study Assessment Time Points ............................................................................................................. 13 
2.2.6 
Methods for Handling Missing Data ................................................................................................... 14 
2.2.7 
Safety Monitoring ................................................................................................................................ 15 
2.2.8 
Statistical Hypotheses .......................................................................................................................... 15 
2.2.9 
Sample Size Justification ..................................................................................................................... 15 
2.2.10 
Interim Analyses .................................................................................................................................. 15 
2.2.11 
Randomization/Unblinding .................................................................................................................. 15 
2.2.11.1 
Randomization Methodology ...................................................................................................................... 15 
2.2.11.2 
Unblinding ................................................................................................................................................... 16 
2.2.12 
Efficacy Analyses ................................................................................................................................. 16 
2.2.12.1 
Primary Endpoint ......................................................................................................................................... 17 
2.2.12.2 
Secondary Endpoints ................................................................................................................................... 17 
2.2.12.3 
Exploratory Endpoints ................................................................................................................................. 19 
2.2.13 
Safety Analyses .................................................................................................................................... 22 
2.2.13.1 
Extent of Exposure ...................................................................................................................................... 22 
2.2.13.2 
Safety Endpoint(s) ....................................................................................................................................... 22 
2.2.13.3 
Adverse Events ............................................................................................................................................ 22 
2.2.13.3.1 
Serious Adverse Events ............................................................................................................................ 23 
2.2.13.3.2 
Deaths ....................................................................................................................................................... 23 
2.2.13.4.3 
Interruptions or Discontinuations of Study Medication Due to an AE ..................................................... 23 
2.2.13.4 
Laboratory Data ........................................................................................................................................... 24 
2.2.13.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety ................................................. 24 
3 
DOCUMENT VERSION CONTROL ............................................................................................................. 25 
APPENDIX A - PROGRAMMING SPECIFICATIONS FOR TABLES AND LISTINGS ............................... 26 
  
  
  
  
  
  
  
  
  


 
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1 Protocol Summary 
  
Title 
A Randomised, Double-blind, Placebo-Controlled, Phase 2b Study 
to Assess the Efficacy and Safety of Orally Administrated DS107 
in Patients with Moderate to Severe Atopic Dermatitis. 
Study Objectives 
Efficacy Objective:  
To compare the efficacy of orally administrated DS107 versus 
placebo in the treatment of adult patients with moderate to severe 
Atopic Dermatitis (AD).  
  
Safety Objective:   
To assess the safety of orally administrated DS107 versus placebo, 
in adult patients with moderate to severe AD. 
Primary Endpoint 
Proportion of patients achieving an Investigator’s Global 
Assessment (IGA) score of 0 (clear) or 1 (almost clear) and a 
decrease of at least 2 points in IGA in treated population compared 
to placebo population at Week 8. 
Secondary Endpoint(s) 
• Proportion of patients achieving an IGA score of 0 (clear) or 1 
(almost clear) and a decrease of at least 2 points in IGA in treated 
population compared to placebo population from baseline to Week 
2, 4, 6 and 10.  
  
• Proportion of patients achieving a decrease of at least 2 points in 
IGA in treated population compared to placebo population from 
baseline to Week 2, 4, 6, 8 and 10.  
  
• Change from baseline in Eczema Area and Severity Index 
(EASI) in treated population compared to placebo population at 
Weeks 2, 4, 6, 8 and 10.    
  
• Change from baseline in Numeric Rating Scale (NRS) for 
Pruritus in treated population compared to placebo population at 
Weeks 2, 4, 6, 8 and 10.   
Exploratory Endpoints 
• Time to response by Week 8. 
 
• Probability of being in response (PBIR) between Weeks 2 and 8. 
 
• Sustained efficacy between Weeks 8 and 10.   
 
• Change from baseline in the Dermatology Life Quality Index 
(DLQI) score in treated population compared to placebo 
population at Week 2, 4, 6, 8 and 10 and from Week 8 to Week 10. 
  


 
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• Change from baseline in the Patient Orientated Eczema Measure 
(POEM) score in treated population compared to placebo 
population at Week 2, 4, 6, 8 and 10 and from Week 8 to Week 10. 
  
• Change from baseline in the Patient Global Impression of 
Severity (PGI-S) score in treated population compared to placebo 
population at Week 2, 4, 6, 8 and 10 and from Week 8 to Week 10. 
  
• Change from baseline in the Patient Global Impression of 
Change (PGI-C) score in treated population compared to placebo 
population at Week 2, 4, 6, 8 and 10 and from Week 8 to Week 10. 
  
• Plasma DGLA concentrations in treated population compared to 
placebo population at Baseline/Day 0, Week4, Week 8 and Week 
10 (samples to be retained for the potential analysis at a later date). 
 
• Determination of AD biomarkers in treated population compared 
to placebo population at Baseline/Day 0 and Week 8/Early 
Termination (samples to be retained for the potential analysis at a 
later date). 
Safety Endpoints 
• Adverse event (AE) and serious adverse event (SAE) frequency 
and severity.  
  
• Safety laboratory parameters (haematology, clinical chemistry).  
  
• Clinical safety examinations (vital signs, physical examination). 
Test Product, Dose and 
Mode of Administration 
  
All study medication will be blinded.  DS107 capsules will be 
provided as a capsule containing 500 mg DGLA per unit dose. 
Placebo will be provided as a matching capsule. This study will 
involve two dose levels of DS107 for 8 weeks (1g DS107 OD or 
2g DS107 OD) and a placebo control (OD) 
  
Study Design: 
A minimum of 300 patients with moderate to severe AD will be 
included in this multicenter, double-blind, placebo controlled, 
3arm, Phase IIb study.  The sample size may be increased at an 
interim analysis (conducted after n=150 complete Week 8/Exit) to 
update primary efficacy endpoint assumptions and to achieve at 
least 80% power and two-sided 5% Type I error. 
  
All patients will sign an informed consent and undergo screening 
for study eligibility. Patients will be randomized (1:1:1) at baseline 
visit to either receive 1g DS107 OD once daily or 2g DS107 OD 


 
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once daily or placebo once daily for 8 weeks.   
  
Patients will come to the clinic on 7 separate visits: Screening, 
Baseline (Day0), Week 2, Week 4, Week 6, Week 8 (end of 
treatment) and Week 10 (follow-up). All patients will exit the 
study at the Week 10 visit. 
Inclusion Criteria 
1. Patients with a clinically confirmed diagnosis of active AD 
according to Hanifin and Rajka criteria. 
2. Patients with moderate to severe AD at baseline as defined by 
an IGA score of minimum 3 at baseline visit.  
3. Patients with an EASI score of ≥12 at screening and baseline. 
4. Patients with AD covering a minimum 10% of the body surface 
area at baseline.  
5. Patients whose pre-study clinical laboratory findings do not 
interfere with their participation in the study, in the opinion of the 
Investigator.  
6. Patients who are able and willing to stop all current treatments 
for AD throughout the study (except for allowed emollients).  
7. Patients who are on a stable dose of a bland emollient applied 
BD (twice daily) for at least 7 days prior to baseline. 
8. Male or female patients aged 18 years and older on the day of 
signing the informed consent form (ICF).  
9. Female patients and male patients with female partners of child 
bearing potential must use adequate contraception or have a 
sterilized partner for the duration of the study. Adequate 
contraception is defined as: systemic hormonal contraceptives, 
intrauterine device or barrier method of contraception in 
conjunction with spermicide, or agree to sexual abstinence. 
Hormonal contraceptives must be on a stable dose for at least one 
month before baseline.  
10. 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. 
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 (other than 
biologics) 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.  


 
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3. Patients who have used any topical medicated treatment for 
AD 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.  
4. Patients who use topical products containing urea, ceramides or 
hyaluronic acid two weeks prior to Day 0.  
5. Patients who use anti-histamines for AD within 3 days of 
baseline. Non-sedative anti-histamines for other indications may 
be used throughout the study provided the patient is on a stable 
dose for 4 weeks prior to Baseline.  
6. Patients with the presence of an irregular white cell count as 
evidenced by eosinophils > 0.3x 109 /L at the screening visit. 
7. 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.  
8. Patients who have a history of hypersensitivity to any substance 
in DS107 or placebo capsules.  
9. 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.   
10. Patients who have a clinically significant impairment of renal 
or hepatic function.  
11. 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.  
12. Patients with chronic infectious diseases (e.g., hepatitis B, 
hepatitis C or infection with human immunodeficiency virus).  
13. 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).  
14. 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. 
15. 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 


 
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visit.   
16. Patients who are pregnant, planning pregnancy, breastfeeding 
and/or are unwilling to use adequate contraception (as specified in 
inclusion criterion 7) during the trial.  
17. Patients, in the opinion of the Investigator, not suitable to 
participate in the study. 
 


 
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2 Statistical Methodology 
2.1 
General Considerations 
The objective of this double-blinded Phase 2b study is to assess the efficacy and safety of 
orally applied DS107 to adults with moderate to severe Atopic Dermatitis.   This study 
uses a randomized (1:1:1, Treatment group A: 1g DS107, Treatment group B: 2g DS107 
and Treatment group C: Placebo), double-blind, placebo-controlled parallel group design.  
Disposition, compliance, demographics, and primary and secondary efficacy results will 
be presented by treatment group separately for moderate and severe AD as well as for 
combined groups. 
  
Study medication will be orally applied once daily for 8 weeks.  An End of Therapy 
(EOT) visit will occur at Week 8 for subjects who complete 8 weeks of treatment or 
earlier if the subject discontinues from the study prematurely.  An End of Study (EOS) 
visit will be conducted at 10 weeks post-treatment for all subjects, even if they withdrew 
early.  For subjects who discontinue early, they will also be asked to return two weeks 
later for the safety assessments listed at Week 10/Visit 7.  
 
All subjects screened into the study 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 102). Patient 
numbers will be assigned in ascending order starting with 01.  All data will be listed in  
subject data listings sorted by site and subject number unless otherwise noted.  Data 
tabulations will be prepared as described in the sections below. 
  
All statistical processing will be performed using Statistical Analysis System (SAS®) 
Version 9.3 or higher, unless otherwise noted.  All analyses will be conducted in 
accordance with ICH E6 and E9 standards and applicable Contract Research 
Organisation (CRO) Standard Operating Procedures (SOPs).  CDISC and SDTM data 
conventions will be followed; these data sets will include DLQI scoring performed by the 
data management group and provided to CTDS in the SDTM datasets.     
 
The 2g DS107 treatment group will be tested against the placebo group using a 
hierarchical approach and if significant at the 0.05 level, then the 1g DS107 treatment 
group will be tested against the placebo at the 0.05 level, otherwise these will be 
presented as descriptive statistics. 
 
Baseline values will be defined as the last non-missing measurement prior to dosing with 
study drug (where baseline record flag=’Y’ in datasets), unless otherwise specified.  
Change from baseline will be defined as the post-baseline visit value minus the baseline 
or previous value unless otherwise specified.  
  


 
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2.2 
Subject Population 
 
2.2.1 Baseline Characteristics/Medical History 
Demographics - gender, age, race (years), ethnicity, country, weight, 
height, BMI and baseline BSA will be summarized by treatment group for 
the Full analysis set (FAS) population.  Demographics will be displayed 
separately for the moderate and severe AD as well as overall.   
 
P-values will be provided for the overall global test and each placebo pair 
(1g DS107 compared to placebo and 2g DS107 compared to placebo) and 
for comparison of 2g DS107 to 1g DS107.  Binary measures (Gender, 
ethnicity, country and Race—white vs non-white) will be compared using 
a two-sided Fisher Exact test, while continuous measures (age, weight, 
height, BMI and baseline BSA) will be compared using ANOVA with 
Tukey option for the comparison of differences in means between the 
groups.   
 
Medical History will be tabulated descriptively, including severity of AD, 
duration of AD (acute, intermediate or chronic) and other relevant medical 
history.   The specific AD medical history reported terms and areas 
affected will be provided in the listings as text fields.    
 
2.2.2 Case Disposition 
All subjects enrolled into the study that are issued a subject number will be 
accounted for in Subject Disposition.  Data will be tabulated by treatment group 
and the numbers and percentages of subjects in each treatment group who are 
enrolled, randomized and treated, who comprise the Full Analysis Set (FAS), 
Safety Analysis Set (SS), and the Per-Protocol Analysis Set (PPS) if there is a 
>10% loss relative to the FAS analysis populations, and who complete the study 
or withdraw prematurely along with the reason for discontinuation will be 
presented.  The number of subjects who were seen at each specified study visit 
will also be tabulated by treatment group and by site.  Results will be displayed 
separately by moderate and severe AD as well as overall.  
 
Protocol deviations (major and minor) will be defined prospectively and will be 
presented as a listing by treatment group.  Major protocol deviations will be 
tabulated by treatment group.   
 
Reasons for any early withdrawals and the last treatment visit completed prior to 
discontinuation will be provided in a listing. 
 
 


 
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2.2.3 Dose Regimen 
The following three formulations have identical appearance: 1g DS107, 2g DS107 
and Placebo in a 1:1:1 ratio, respectively.  The medication assigned by 
randomization will be orally applied by the patients once daily for 8 weeks.   
Tabulations of exposure to study medication are described in Section 2.2.13.1, 
Extent of Exposure.  Details of study medication use will be provided in a subject 
data listing. 
 
 
2.2.4 Study Populations for Analysis 
 
2.2.4.1 
Full Analysis Set (FAS) 
The FAS consists of all patients who are randomized 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 randomized to.  
 
2.2.4.2 
Safety Analysis Set (SS) 
The SS consists of all patients who received at least one dose of the 
medication. SS is the analysis population for all safety endpoints. Analysis 
will be done according to the actual treatment patients received. 
 
2.2.4.3 
Per-Protocol Analysis Set (PPS) 
The 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 finalized during this meeting. PPS is a 
supportive analysis population for the primary efficacy endpoint. Analysis 
will be done according to the treatment that patients were randomized to.   
 
2.2.4.4 
Subgroup Analyses 
Subgroup analyses will be conducted on the primary and secondary 
endpoints stratifying by severity of atopic dermatitis (moderate or severe), 
defined as an IGA score of 3=moderate or 4=severe at the Baseline/visit 2 
visit, which is consistent with the AD severity used for the entrance 
criteria in the study.  Statistical testing for this subgroup analyses will be 
limited to the primary efficacy endpoint but summary statistics will be 
provided for all secondary efficacy endpoints.   
 
2.2.5 Study Assessment Time Points 
The study consists of seven protocol-specified visits which will be assessed as 
nominal visits from an analysis perspective: 


 
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 Visit 1/Screening visit (Day -30 to -1): Once informed consent has been 
obtained, the Investigator will assign a Patient Number and the subject will 
undergo the screening procedures.  Following completion of a successful 
screening visit, patients will begin the comparative treatment period (8 
weeks). 
 Visit 2/Baseline (Day 0): At the start of the comparative treatment period, after 
confirmation of continued eligibility, patients will be randomly assigned to 
one of the three treatment regimens. Study medication is dispensed at Visit 2.  
The first dose of study medication will be carried out at the site once all 
baseline assessments have been completed. The patient will carry out 
their second dose of study medication in the evening of Day 0. 
 Visits 3, 4 and 5: Follow-up visits at Week 2 (Day 14  2 days), Week 4 (Day 
28  2 days) and Week 6 (Day 42  2 days) respectively. 
 Visit 6 – End of Treatment (EOT): Week 8 (Day 56  2 days) for subjects 
who complete 8weeks of treatment; earlier for subjects who discontinue 
treatment prematurely.   
 Visit 7/Week 10: End of Study visit (Day 70  3 days) for all subjects. 
  Unscheduled Visits: Unscheduled visits may occur when a patient needs to 
make a visit in between the scheduled visit dates due to an 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. 
 
2.2.6 Methods for Handling Missing Data 
PROC GENMOD will be used to account for any missing data and early 
withdrawal for FAS.   
 
The GENMOD procedure will estimate the working correlation from data 
containing both types of missing values by using the all available pairs method, 
in which all non-missing pairs of data are used in the moment estimators of the 
working correlation parameters.  The resulting covariances and standard errors are 
valid under the missing completely at random (MCAR) assumption. 
 
A sensitivity analysis will be performed for the Week 8/Exit outcome under the 
missing at not random (MNAR) assumption for the primary efficacy analyses 
using the FAS.  An extreme analysis will be used to identify the possible outcome 
considering two scenarios: An extreme analysis will be used to identify the 
possible outcome considering the worst case for both active treatments and best 
case for vehicle (Scenario 1) and then the reverse (Scenario 2).  If any extreme 
cases result in statistical significance, then the maximum degree of relaxation per 


 
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treatment group still reaching statistical significance will be displayed for each 
scenario. A two-sided Fisher Exact Test will be utilized for these analyses.    
 
2.2.7 Safety Monitoring 
 
No safety monitoring committees are planned for the study.  
 
2.2.8 Statistical Hypotheses 
The overall null hypothesis (H0) for each analysis is the equality of the means for 
the three treatment groups. A global test will be performed across all three 
treatment groups to allow for a penalty-free comparison of the comparison of the 
1g and 2g concentrations against the placebo control. In the event of a global 
difference (two-sided p<0.05), then the between-treatment comparison of the 2g 
active treatment group to placebo is performed.  If significant (two-sided p<0.05) 
then the between-treatment comparison of the 1 g active treatment group to the 
placebo is performed; otherwise the p-values will be regarded as descriptive 
statistics. The Type I error rate is controlled for by the hierarchical approach. All 
testing will be two-sided; global tests will be performed at the 0.05 level. Testing 
between the 2 active groups will be considered descriptive statistics.  
 
2.2.9 Sample Size Justification   
The sample size for the topical DS107 Phase IIb study was informed from the 
post-hoc analysis of the IGA responder data which will be used as the primary 
endpoint.   The positive efficacy data over 4 weeks showed no sign of a plateau 
and suggests further improvements may be observed at week 8. The sample size 
was estimated following extrapolation of the IGA responder rate data of the Phase 
IIa results at weeks 2, 3 and 4 to week 8.  Assuming a placebo response rate of 
10%, 100 patients per treatment arm (300 patients in total) will be required to 
detect an absolute difference of 15% in the response rate between an active dose 
and placebo.   
 
2.2.10 Interim Analyses  
An interim analysis is planned to assess primary efficacy endpoint futility and to 
adjust sample size; EASI will also be evaluated to judge any futility decision.  
The sample size may be increased at the interim analysis (conducted after n=150 
complete Week 8/Exit) to update primary efficacy endpoint assumptions and to 
achieve at least 80% power and two-sided 5% Type I error. 
 
2.2.11 Randomization/Unblinding 
2.2.11.1 
Randomization Methodology 
At least 300 patients will be randomized to the three blinded treatment 
groups in a 1:1:1 ratio as follows:  
• Treatment group A: 1g DS107 (2 DS107 capsules and 2 placebo 
capsules) administered once-daily for 8 weeks   


 
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• Treatment group B: 2g DS107 capsules (4 DS107 capsules) administered 
once-daily for 8 weeks   
• Treatment group C: Placebo capsules (4 placebo capsules) orally 
administered once-daily for 8 weeks   
  
A randomization list, permuted blocks and stratified by site was generated 
by HMD Clinical (25 Balmuir Avenue, Bathgate, EH48 4BW, U.K.). The 
randomization schedule with study drug assignments was 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.   
  
2.2.11.2 
Unblinding 
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. 
 
Any unblinding (and reason for unblinding) prior to database lock will be 
reported in the final CSR. 
 
 
2.2.12 Efficacy Analyses 
Summary statistics by visit will be provided for all efficacy endpoints. For 
continuous efficacy endpoints, summary statistics will also be provided for 
change from baseline at each post-baseline visit.  Results for the primary 
and secondary efficacy endpoints will be presented separately for 
moderate and severe AD as well as combined across moderate and severe 
AD strata.  Models will include a baseline covariate for moderate/severe 
for all primary and secondary efficacy analyses. Models will be performed 
for the primary efficacy endpoint for the separate AD strata but not for the 
secondary efficacy endpoints. 


 
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2.2.12.1 
Primary Endpoint  
The primary efficacy variable will be the proportion of patients achieving 
an IGA score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 
points in IGA from baseline to week 8.  This is a binary endpoint. 
 
The primary endpoint will be analyzed using a Generalised Linear 
Model (PROC GENMOD) with treatment arm, moderate/severe AD, 
baseline IGA value, visit and DS treatment dose as factors. The primary 
analysis will be based on the FAS and repeated for the PPS as a supportive 
analysis.   
 
This analysis will be performed using SAS PROC GENMOD with code 
similar to the following:  
 
proc genmod data=subjresults descending; 
  class trt visit subj AD; 
  model outcome=trt visit trt*visit  AD B_IGA /dist=bin;  
  repeated subject=subj/corr=unstr; 
  slice trt*visit / sliceby=visit ilink cl diff; 
run; 
 
where fas= Full Analysis Set (FAS), outcome= patients in each treatment 
arm at week 8 who achieve an IGA score of 0 (clear) or 1 (almost clear) 
and a decrease of at least 2 points in IGA from baseline. B_IGA is the 
baseline IGA value..   The dist=bin option of the model statement 
specifies that the logit transformation will be applied to outcome prior to 
analysis. The cl option specifies that two-sided 95% confidence intervals 
will be provided and the ilink option specifies the transformation from the 
logit scale to the probability scale. The between-treatment effects are 
determined from the diff option of the slice statement.  Results will be 
presented separately for moderate and severe AD for both the FAS and 
PPS populations. The model will be used to estimate Week 8 effect. 
 
 
2.2.12.2 
Secondary Endpoints 
 
The secondary endpoints are: 
 
•  Proportion of patients achieving an IGA score of 0 (clear) or 1 (almost 
clear) and a decrease of at least 2 points in IGA in treated population 
compared to placebo population from baseline to Week 2, 4, 6 and change 
from baseline to subject’s last treatment visit.  These analyses will be 


 
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included in the previous analyses for the primary endpoint for Week 8.   A 
separate model will be performed for the change from baseline to week 
10, using the same PROC GENMOD code.    
 
•  Proportion of patients achieving a decrease of at least 2 points in IGA 
in treated population compared to placebo population from baseline to 
Week 2, 4, 6, 8 and change from baseline to subject’s last treatment visit.  
These analyses will be conducted in the same way as the primary 
endpoint analysis. A separate model will be performed for the change 
from baseline to week 10 using the same PROC GENMOD code.    
 
 
•  Change from baseline in Eczema Area and Severity Index (EASI) in 
treated population compared to placebo population at Weeks 2, 4, 6, 8 
and subject’s last treatment visit.   These will be analyzed using PROC 
MIXED with treatment arm, moderate/severe AD, baseline IGA value, 
visit, and DS treatment*visit as factors.  A separate model will be 
performed for the change from baseline to week 10, using the same 
PROC MIXED code.    
 
The change from baseline in EASI will be analyzed for the FAS with 
SAS PROC MIXED using code similar to the following, with CFB_EASI 
and B_EASI representing the change from baseline and the baseline 
EASI, respectively. Method=ml is the maximum likelihood estimate.   
 
proc mixed method =ml data= FAS;  
class trt visit subj AD; 
model CFB_EASI= trt visit vistit*trt AD B_ EASI /CL; 
repeated subject=subj/corr=unstr; 
lsmeans trt*visit / diff CL; 
run; 
 
•  Change from baseline in Numeric Rating Scale (NRS) for Pruritus in 
treated population compared to placebo population at Weeks 2, 4, 6, 8 and 
subject’s last treatment visit.   These will be analyzed using PROC 
MIXED with treatment arm, baseline AD severity, baseline NRS score, 
visit, and DS treatment*visit interaction as factors.   A separate model will 
be done for the change from baseline to Week 10, using the same PROC 
MIXED code.    
 
As NRS is a daily assessment, the analysis of NRS will be performed 
using the daily average at each visit. At each visit, the average of the NRS 
values since the previous visit will be computed. Missing values for any 


 
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day will be ignored and the between-visit daily average will be computed 
using non-missing values only. The baseline value will be the average 
computed during the screening period. This analysis of change from 
baseline in NRS will be performed the same as the analysis of change 
from baseline in EASI, with CFB_NRS and B_NRS representing the 
change from baseline in NRS and the baseline NRS, respectively.  
 
 
2.2.12.3 
Exploratory Endpoints  
 
•    Time to response by Week 8.  A Kaplan-Meier lifetable will be 
constructed using nominal visits.  A Wilcoxon-Gehan test will be used to 
compare all treatments; p-values will also be computed for each of the 
three treatment pairs for the primary endpoint using the FAS population. 
This will be a graph. 
 
•    Probability of being in response (PBIR) between Weeks 2 and 8.  The 
PBIR will be computed as a descriptive statistic for the primary endpoint 
using the FAS population. Each visit will be equally weighted in this 
analysis. This will be a graph. 
 
•    Sustained efficacy between Weeks 8 and 10.  This analysis will be 
endpoint-specific.   Binary endpoints will be evaluated using logistic 
regression (PROC LOGISTIC) controlling for baseline IGA score and 
baseline AD severity while continuous endpoints will be analyzed using 
proc GLM controlling for the same factors. A shift table will be created 
presenting the number and frequencies of subjects in response and the 
shift from Week 8  to Week 10 for the primary endpoint analysis for both 
the FAS and PPS populations.    
 
•  Change from baseline in the Dermatology Life Quality Index 
(DLQI) score in treated population compared to placebo population 
at Week 2, 4, 6, 8 and 10 and from Week 8 to Week 10 and change 
from baseline to subject’s last treatment visit. 
 
 
DLQI is a set of 10 questions, scored 0=Not at all, 1=A little, 2=A 
lot, or 3=Very much, or 0=Not relevant, except for Questions 1 and 
2 that do not include a response of ‘Not Relevant’. Missing 
responses are assigned ‘0’. The DLQI total score is calculated by 
summing the score of each question resulting in a maximum of 30 
and a minimum of 0.  The higher the score, the more quality of life 


 
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is impaired.   This scoring will be done by the data management 
group and provided to CTDS in the SDTM datasets.     
 
Mean DLQI will be computed as the Total DLQI divided by the 
number of questions with non-missing responses. The scoring 
instructions for DLQI specify that if 2 or more questions are not 
answered, then the questionnaire will not be scored; this approach is 
not taken here with Mean DLQI computed instead. Summary 
statistics for Total DLQI and Mean DLQI will be presented. The 
analysis of change from baseline in Mean DLQI will be performed 
the same as the analysis of change from baseline in EASI, with 
appropriate changes in the variables for change from baseline and 
Mean DLQI at baseline.  
 
Summary statistics as continuous data and change from baseline 
will be presented by treatment group and visit for the totals for the 4 
sub-scales: 
Symptoms and feelings 
  
Questions 1 and 2 
Daily Activities 
 
 
Questions 3 and 4 
Leisure 
 
 
 
Questions 5 and 6 
Personal relationships  
 
Questions 8 and 9 
 
•  Change from baseline in the Patient Orientated Eczema Measure 
(POEM) score in treated population compared to placebo population at 
Week 2, 4, 6, 8 and 10 and from Week 8 to Week 10 and change from 
baseline to subject’s last treatment visit. 
 
POEM is a set of 7 questions regarding the frequency of conditions related 
to eczema, with responses of 0 = no days. 1 = 1-2 days, 2 = 3-4 days, 3 = 
5-6 days, or 4 = every day. The sum of the scores for the 7 questions is the 
Total POEM. 
 
Mean POEM is the Total POEM divided by the number of questions 
with non-missing responses. The scoring instructions for POEM 
specify that if response to one question is missing, the response for 
that question will be equated to 0, and if the responses to more than 
one question are missing, then the questionnaire is not scored; this 
approach is not taken here with Mean POEM for questions with 
non-missing responses computed instead. The analysis of change 
from baseline in Mean POEM will be performed the same as the 
analysis of change from baseline in EASI, with appropriate changes 
in the variables for change from baseline and Mean POEM at 
baseline. 


 
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Summary statistics (counts and frequencies) will be presented by 
treatment group and visit for categories based on Total POEM of  
Clear or almost clear = 0 to 2; 
Mild eczema = 3 to 7; 
Moderate eczema = 8 to 16; 
Severe eczema = 17 to 24; 
Very severe = 25 to 28. 
 
Shift tables presenting the number and frequency of subjects in each 
eczema severity category at Week 8 and last treatment visit and Week 8 to 
Week 10 will be presented by treatment group. 
 
•  Change from baseline in the Patient Global Impression of Severity 
(PGI-S) score in treated population compared to placebo population at 
Week 2, 4, 6, 8 and 10 and from Week 8 to Week 10 and change from 
baseline to subject’s last treatment visit.  
 
The categories for the PGI-S are:  normal, mild, moderate or severe.   A 
Shift table will be created presenting the number and frequencies of 
subjects in each category and the shift from the follow-up visit to 
baseline.    
 
 
Patient Global Impression of Change (PGI-C) is captured at the follow-up 
visits and is a 7 –point scale assessing the overall status of the patient 
since the start of the study with responses of 1=very much improved, 
2=much improved, 3=minimally improved, 4= no change, 5=minimally 
worse, 6= much worse and 7=very much worse.  Summary statistics 
(count and frequencies) will be presented by treatment group and visit for 
the status categories.  A shift table presenting the number and frequency of 
subjects in each category at Week 8 to Week 10 will be presented by 
treatment group. 
•  Plasma DGLA concentrations in treated population compared to 
placebo population at Baseline/Day 0, Week4, Week 8 and Week 10: 
samples to be retained for the potential analysis at a later date.  Details of 
these analyses will be described in a separate document and the analyses 
will not be included with the analyses described herein. 
 


 
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• Determination of AD biomarkers in treated population compared to 
placebo population at Baseline/Day 0 and Week8/Early Termination 
(samples to be retained for the potential analysis at a later date). 
Details of these analyses will be described in a separate document and the 
analyses will not be included with the analyses described herein. 
 
 
2.2.13 Safety Analyses 
All subjects enrolled in the study who received at least one dose of the 
medication will be included in the safety analysis (i.e. Safety Analysis 
Set).     
 
2.2.13.1 
Extent of Exposure 
Treatment duration is defined as 8 weeks (Day 56  2 days).  The date of 
the first and last doses of study medication will be collected from 
information recorded on the study drug admin page of the eCRFs. Study 
medication is to be orally taken once daily.   
 
Extent of exposure to study medication will be tabulated by treatment 
group by 2 week intervals.  The number of doses of study medication will 
be summarized by treatment group by each 2 week interval only for those 
subjects who returned to the clinic for each interval.  The expected number 
of doses per 2 week intervals is 14, based on twice daily dosing. 
Compliance will be measured by calculating the number of doses/expected 
number of doses *100 and presented by treatment group for each interval.       
 
 
2.2.13.2 
Safety Endpoint(s) 
The safety objective is to compare the safety of orally administered DS107 
capsules (1g & 2g) versus placebo, in the treatment of adult patients with 
moderate to severe AD. Results will be pooled for 1g and 2g treatment 
groups as well. 
 
2.2.13.3 
Adverse Events 
Counts and percentages of subjects who experienced any of the following 
will be presented by treatment group, as well as a total DS107 treatment 
group that includes both the 1g and 2g DS107 subjects: any AE, any IMP 
related AE, any AE requiring modification of study medication dosing 
(dose reduced, drug interrupted), discontinuations of study participation 
due to an AE (drug withdrawn), any serious adverse events (SAE), deaths, 
or IMP related SAEs.   Only those adverse events determined to be 
treatment emergent (TEAE) will be presented (where Qlabel=”Treatment 


 
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Emergent” from the SUPPAE SDTM dataset).  Treatment emergent 
adverse events are those events with the date of AE onset being greater 
than or equal to the date of the first dose date of study drug. A two-sided 
Fisher Exact test will be utilized for an overall global test and for the pair-
wise comparisons of each treatment compared to placebo.   
Verbatim terms on the case report forms will be coded to preferred term 
(PT) and related system organ class (SOC) using MedDRA Coding 
Dictionary Version 19.1. The number and percentage of subjects who 
experience treatment-emergent adverse events (TEAE) will be tabulated 
by System Organ Class (SOC) and Preferred Term (PT) within each 
treatment group.  The number of events will be tabulated by System Organ 
Class (SOC) and Preferred Term (PT) within each treatment group.  In 
addition, a tabulation of adverse events that occur at a frequency of 2% or 
greater at the SOC or PT level will be prepared.  A two-sided Fisher Exact 
test will be performed on system organ class (SOC) with a 2% or greater 
frequency to facilitate evaluation of potential safety differences among 
treatments. 
 
Adverse events will be counted only once for a subject within each 
Preferred Term and System Organ Class; thus, since a subject may have 
more than one Preferred Term within an SOC, percentages of PT may not 
sum to the percentage in the SOC.  If a subject reports a Preferred Term 
multiple times with differing severities (mild, moderate or severe), only 
the most severe is counted but all events will be counted.  If a subject 
reports a Preferred Term multiple times with differing relationships to 
IMP, only the one that is related to IMP is counted. 
 
2.2.13.3.1 
Serious Adverse Events 
The number and percentage of subjects experiencing a Serious 
Adverse Event (SAE) will be tabulated by SOC and PT within 
each treatment group and overall.  SAEs will be counted only once 
for a subject within each PT and SOC.    
 
2.2.13.3.2 
Deaths 
A listing of subjects who die while on study will be prepared along 
with the adverse event associated with the cause of death. 
 
2.2.13.3.3 
Interruptions or Discontinuations of Study 
Medication Due to an AE 
A listing of subjects who have changes to their study medication 
dosing (dose reduced, interruptions or discontinuations) will be 
prepared.   


 
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2.2.13.4 
Laboratory Data  
Any laboratory test results considered to be clinically significant by the 
Investigator will be captured as an adverse event.   All clinical laboratory 
values (haematology and biochemistry) will not be tabulated but will be 
listed for each patient by treatment group and visit.  Values outside the 
laboratory normal ranges will be listed separately by patient and treatment 
group with associated comments as to their clinical significance.  
 
2.2.13.5 
Vital Signs, Physical Findings, and Other Observations Related 
to Safety   
Vital signs are collected at the screening, visit 2/baseline and the follow-
up visits.  Temperature (oC), systolic and diastolic blood pressure (mmHg) 
and heart rate (BPM) will be tabulated by treatment group using the 
baseline value (where baseline record flag= ‘Y’) and end of study (week 
10).  Change from end of study to baseline will be presented as descriptive 
statistics.    
 
Physical Examination Findings will be presented in the listings but not 
tabulated. 
 
Concomitant Medications will be coded per the WHO Drug dictionary 
(version effective March 2017 and provided to CTDS in the SDTM CM 
dataset.   Concomitant Medications will be tabulated by treatment group, 
Drug Class (pharmacological level, ATC3) and Drug Name (chemical 
substance level, ATC5).  These data will be provided in subject data 
listings along with the verbatim drug term and usage details. 
 
 
 
 
 
 
 
 


 
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3 Document Version Control 
 
Revision History: 
 
REVISION 
RELEASE 
DATE 
AUTHOR 
SUMMARY OF CHANGES 
A 
17Jul2017 
CTDS/P. Lavin 
Initial Version  
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix A - Programming Specifications for Tables and Listings 
 
The following specifications will be used in the production of tables and listings. 
 
1. Page Setup 
Unless otherwise noted, tables and listings will use landscape orientation.  Margins will be at 
least 1.5 inches on the bound side and at least 1 inch on the other three sides.   
The following header information should be included: 
  Upper left:  Sponsor name and protocol number 
  Center: CONFIDENTIAL 
  Upper right: Page number shown as Page n of N.  Page numbers should be sequential 
within a table or listing.   
 
The footer should include: 
  The name of the SAS program used to generate the output along with the run date/time 
and the words “by CTDS”.   
  For tables, the corresponding listing number(s). 
    
2. Footnotes 
Unless otherwise specified, footnotes should appear on all pages within the table. 
 
3. Font  
Font will be 8-point Arial, or smaller if needed for space constraints.  If possible, small tables 
should appear on one page.  If tables continue on to multiple pages, there should be a page 
break after an assessment so that all the statistics for an assessment appear on the same page.  
 
4. Tables 
Table titles should reflect the content of the table.  Under the main title, in parentheses, the 
name of the analysis population being summarized should appear.   
 
4.1 Summary Statistics - Continuous Data 
Unless otherwise noted, the mean and median and confidence interval (CI) of a set of 
values should be printed out to one decimal place more than the original value.  The 
standard deviation should be printed out to 2 decimal places more than the original 
value.   The number of subjects on whom the parameter is assessed should appear.  
Minimum and maximum should be consistent with the original value.  P-values will be 
expressed as 4 decimal places.   Any p-values that get calculated as 0.0000 should be 
expressed as p-value <0.0001. 
 
4.2 
Summary Statistics - Categorical Data 


 
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Numbers of subjects are reported as whole numbers.  Null counts are represented as 0.  
Table percentages should be reported to one decimal unless otherwise noted.  Null 
percentages should be reported as 0.0%. 
 
 
For all categories, the total number of subjects with data will be presented as N and the 
number of subjects with non-missing data will be used as the denominator for the 
calculation of the percentages, unless otherwise noted.    
 
 
5. Subjects Included in Listings 
In general, subject data listings should include all subjects who signed the informed consent.  If 
a listing includes a subset of subjects who meet a certain condition (eg, subjects with SAEs) 
then this should be clear from the title of the listing.  If there are no subjects who meet the 
condition (eg, no subjects with SAEs) for either the tables or the listings, then a page marker 
should appear stating that no subjects met the criteria.