Clinical trial NCT02925793
Conditions: Atopic Dermatitis
Sponsor: DS Biopharma
Start date: 2016-12-01; Completion date: 2018-07-01
Enrollment: 327 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this randomized, double blind, placebo controlled, parallel group study is to compare the safety and efficacy of topically applied DS107 cream (1% and 5%) versus vehicle cream, in the treatment of adult patients with mild to moderate Atopic Dermatitis (AD).

Detailed description:
This was a randomized, vehicle-controlled, double-blind, parallel-group, multicenter, Phase 2b study to investigate the safety and efficacy of topically administered DS107 cream and the dose-response relationship between DS107 cream and vehicle cream in patients 18 years and older with mild to moderate AD.

Approximately 300 patients (100 per treatment group), with mild to moderate AD were to be included in this study. All patients signed the patient information sheet (PIS)/informed consent form (ICF) and underwent screening for study eligibility. Eligible patients were randomized (1:1:1) to receive 1% DS107 cream, 5% DS107 cream or, vehicle cream:

Treatment Group A: 1% DS107 cream Treatment Group B: 5% DS107 cream Treatment Group C: Vehicle cream Study cream was to be applied topically to all affected or commonly affected areas twice daily (BID) for 8 weeks. To maintain the double-blind conditions, the DS107 and vehicle creams were identical in appearance. During their participation, patients were to come to the clinic on 7 occasions: Screening, Baseline, and at Weeks 2, 4, 6, 8 (end of treatment), and 10 (follow-up).

At the start of the study, areas for treatment were defined, DS107 or vehicle cream was then applied to those areas (and any newly affected areas) throughout the 8-week treatment period. Patients were instructed to apply the study cream liberally to the affected area in the morning and the evening. Emollients could be applied to other areas of dry skin that were not in the defined treatment area. On the days of clinic visits, patients were instructed to abstain from applying study cream for 6 hours prior to the visit and then to apply study cream as soon as possible after the clinic visit.

Once enrolled, patients were restricted from using any other treatment for AD. Any medication (prescription and over-the-counter \[OTC\] drugs) or therapeutic intervention deemed necessary for the patient, and which in the opinion of the investigator did not interfere with the safety and efficacy evaluations, could be continued unless they were included in the prohibited list of medications and therapeutic regimens.

Arms: arm 1: Vehicle cream applied topically to all affected or commonly affected areas twice-daily for 8 weeks arm 2: 1% DS107 cream applied topically to all affected or commonly affected areas twice-daily for 8 weeks arm 3: 5% DS107 cream applied topically to all affected or commonly affected areas twice-daily for 8 weeks
Interventions: intervention 1: DS107 intervention 2: Vehicle cream
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
Confidential / Clinical Study Protocol No. DS107E-06 Version 5.0 
 
 
 
Page 1 of 85 
 
 
 
 
 
A Randomised, Double-blind, Vehicle-Controlled, Phase IIb 
Study to Assess the Efficacy and Safety of Topically Applied 
DS107 Cream to Adults with Mild to Moderate Atopic Dermatitis  
 
 
 
 
Protocol Number # DS107E-06 
 
Version 5.0 
Amendment 4 
29 September 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 Tel. Canada: +1-888-902-5717 
Toll Free Tel. US: +1-800-879-8146 
Toll Free Tel. 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 
PROTOCOL SYNOPSIS ................................................................................................................................... 8 
LIST OF ABBREVIATIONS .......................................................................................................................... 14 
INTRODUCTION ............................................................................................................................................ 16 
1.1 
THERAPEUTIC AREA AND DISEASE BACKGROUND ............................................................................... 16 
1.2 
STANDARD TREATMENT ....................................................................................................................... 17 
1.3 
DRUG CLASS ........................................................................................................................................ 18 
1.4 
PRECLINICAL PHARMACOLOGY ............................................................................................................ 18 
1.5 
TOXICOLOGY ........................................................................................................................................ 19 
1.6 
PREVIOUS CLINICAL STUDIES WITH DS107 .......................................................................................... 20 
2 
RISK BENEFIT ASSESSMENT ............................................................................................................ 24 
3 
RATIONALE FOR THE STUDY .......................................................................................................... 25 
4 
STUDY OBJECTIVES ............................................................................................................................ 26 
5 
STUDY ENDPOINTS .............................................................................................................................. 27 
5.1 
PRIMARY ENDPOINT ............................................................................................................................. 27 
5.2 
SECONDARY ENDPOINTS ...................................................................................................................... 27 
5.3 
EXPLORATORY ENDPOINTS .................................................................................................................. 27 
6 
STUDY DESIGN ...................................................................................................................................... 28 
6.1 
GENERAL .............................................................................................................................................. 28 
7 
PATIENTS AND SCREENING ............................................................................................................. 30 
7.1 
SOURCE OF PATIENTS ........................................................................................................................... 30 
7.2 
INCLUSION CRITERIA ............................................................................................................................ 30 
7.3 
EXCLUSION CRITERIA ........................................................................................................................... 31 
7.4 
SCREENING AND CONSENT ................................................................................................................... 32 
7.5 
WITHDRAWAL OF PATIENTS ................................................................................................................. 33 
7.5.1 
Complete Withdrawal .................................................................................................................... 34 
7.5.2 
Withdrawals from IMP .................................................................................................................. 34 
7.6 
PATIENT REPLACEMENT ....................................................................................................................... 34 
7.7 
PROTOCOL VIOLATIONS ....................................................................................................................... 34 
8 
STUDY CONDUCT ................................................................................................................................. 35 
8.1 
STUDY SCHEDULE ................................................................................................................................ 35 
8.2 
CLINIC VISITS ....................................................................................................................................... 35 
8.2.1 
Screening Visit (Visit 1) ................................................................................................................. 35 
8.2.2 
Treatment Period ............................................................................................................................ 36 
8.2.3 
Baseline (Visit 2) ........................................................................................................................... 37 
8.2.4 
Week 2 (Visit 3) ............................................................................................................................. 38 
8.2.5 
Week 4 (Visit 4) ............................................................................................................................. 40 
8.2.6 
Week 6 (Visit 5) ............................................................................................................................. 41 
8.2.7 
Week 8 (Visit 6) / End of Treatment or Early Termination ........................................................... 42 
8.2.8 
Week 10 (Visit 7) / Follow up ........................................................................................................ 44 
9 
ASSESSMENTS ....................................................................................................................................... 45 
9.1 
EFFICACY ASSESSMENTS ...................................................................................................................... 45 
9.1.1 
Investigator Global Assessment (IGA) .......................................................................................... 45 
9.1.2 
Eczema Area and Severity Index (EASI) ....................................................................................... 45 
9.1.3 
Numerical Rating Scale (NRS) for Pruritus ................................................................................... 45 


 
 
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9.1.4 
Body Surface Area (BSA) .............................................................................................................. 46 
9.1.5 
Dermatology Life Quality Index (DLQI) Questionnaire ................................................................ 46 
9.1.6 
Patient Orientated Eczema Measure (POEM) ................................................................................ 46 
9.1.7 
Patient Global Impression of Severity (PGI-S) .............................................................................. 46 
9.1.8 
Patient Global Impression of Change (PGI-C) ............................................................................... 47 
9.2 
SAFETY ASSESSMENTS ......................................................................................................................... 47 
9.2.1 
Medical History .............................................................................................................................. 47 
9.2.2 
Physical Examination ..................................................................................................................... 47 
9.2.3 
Vital Signs ...................................................................................................................................... 47 
9.2.4 
Clinical Laboratory Safety Tests: Haematology, Serum Biochemistry, and Urinalysis ................. 48 
9.2.5 
Pregnancy Test ............................................................................................................................... 49 
9.2.6 
Biomarker Sampling ...................................................................................................................... 49 
9.2.7 
Sample Storage, Handling and Shipping ........................................................................................ 49 
9.2.8 
Adverse Event Assessment ............................................................................................................ 49 
9.2.9 
Concomitant Medication ................................................................................................................ 49 
9.2.10 Restrictions..................................................................................................................................... 51 
10 
INVESTIGATIONAL MEDICINAL PRODUCT / INVESTIGATIONAL DRUG .......................... 52 
10.1 
IMP ...................................................................................................................................................... 52 
10.2 
SUPPLY, PACKAGING, LABELLING, HANDLING AND STORAGE ............................................................. 54 
10.3 
DOSAGE AND ADMINISTRATION ........................................................................................................... 54 
10.4 
DURATION OF TREATMENT................................................................................................................... 55 
10.5 
METHODS FOR ASSIGNING PATIENTS TO TREATMENTS ........................................................................ 55 
10.6 
DRUG ACCOUNTABILITY ...................................................................................................................... 56 
11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................................... 57 
11.1 
DEFINITIONS OF ADVERSE EVENTS ...................................................................................................... 57 
11.1.1 Seriousness ..................................................................................................................................... 57 
11.1.2 Severity .......................................................................................................................................... 58 
11.1.3 Relationship to IMP ....................................................................................................................... 58 
11.1.4 Reporting of AEs and SAEs ........................................................................................................... 58 
11.2 
SERIOUS ADVERSE REACTIONS AND UNEXPECTED ADVERSE REACTIONS ........................................... 59 
11.2.1 Definitions ...................................................................................................................................... 59 
11.2.2 Reporting of suspected unexpected serious adverse reactions ....................................................... 60 
11.3 
DIFFERENTIATION OF TREATMENT FAILURE AND AE ........................................................................... 60 
11.4 
PREGNANCY REPORTING ...................................................................................................................... 60 
12 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT .................................................. 62 
12.1 
STUDY DESIGN ..................................................................................................................................... 62 
12.2 
RANDOMISATION .................................................................................................................................. 62 
12.3 
ESTIMATION OF SAMPLE SIZE ............................................................................................................... 63 
12.4 
BLINDING AND CODE BREAKING INSTRUCTIONS .................................................................................. 64 
12.5 
INTERIM ANALYSIS .............................................................................................................................. 64 
12.6 
DATA ANALYSIS ................................................................................................................................... 64 
12.7 
ANALYSIS POPULATIONS ...................................................................................................................... 64 
12.8 
SAFETY ANALYSIS................................................................................................................................ 65 
12.9 
STATISTICAL ANALYSIS PLAN .............................................................................................................. 66 
12.9.1 Primary Variables .......................................................................................................................... 66 
12.9.2 Secondary variables ....................................................................................................................... 67 
12.9.3 Safety variables .............................................................................................................................. 67 
12.10 DATA COLLECTION / CASE REPORT FORMS .......................................................................................... 68 
12.11 DATA MANAGEMENT ........................................................................................................................... 68 
12.12 PROTOCOL DEVIATIONS ....................................................................................................................... 69 
13 
REGULATORY AND ADMINISTRATIVE PROCEDURES ............................................................ 69 
13.1 
INSTITUTIONAL REVIEW ....................................................................................................................... 69 
13.2 
GOOD CLINICAL PRACTICE (GCP) ....................................................................................................... 69 
13.3 
ESSENTIAL DOCUMENTS....................................................................................................................... 70 
13.4 
RECORD RETENTION............................................................................................................................. 70 


 
 
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13.5 
MONITORING / QUALITY CONTROL ...................................................................................................... 70 
13.6 
QUALITY ASSURANCE .......................................................................................................................... 70 
13.7 
INSURANCE AND LIABILITY .................................................................................................................. 71 
13.8 
END OF TRIAL ....................................................................................................................................... 71 
13.9 
CONFIDENTIALITY ................................................................................................................................ 71 
13.10 REPORT AND PUBLICATION .................................................................................................................. 71 
14 
REFERENCES ......................................................................................................................................... 72 
15 
APPENDICES .......................................................................................................................................... 76 
15.1 
APPENDIX 1: STUDY FLOW-CHART ...................................................................................................... 76 
15.2 
APPENDIX 2: DIAGNOSTIC FEATURES OF AD (HANIFIN AND RAJKA CRITERIA) ................................... 77 
15.3 
APPENDIX 3: INVESTIGATOR’S GLOBAL ASSESSMENT (IGA) ............................................................... 78 
15.4 
APPENDIX 4: ECZEMA AREA AND SEVERITY INDEX (EASI) ................................................................. 79 
15.5 
APPENDIX 5: NUMERICAL RATING SCALE FOR ASSESSMENT OF PRURITUS ........................................... 80 
15.6 
APPENDIX 6: DERMATOLOGY LIFE QUALITY INDEX (DLQI) ................................................................ 81 
15.7 
APPENDIX 7: PATIENT ORIENTATED ECZEMA MEASURE ...................................................................... 83 
15.8 
APPENDIX 8: PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) ..................................................... 84 
15.9 
APPENDIX 9: PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) ....................................................... 85 
 
 
LIST OF FIGURES 
Figure 1: Structure of DS107 cream ......................................................................................... 18 
Figure 2: Study Outline ............................................................................................................. 28 
 
LIST OF TABLES 
Table 1: Summary of DS107 Cream Use in Human Healthy Volunteers/Patients ................... 20 
Table 2: Clinical Laboratory Safety Tests ................................................................................ 48 
Table 3: Total Blood Volume drawn ........................................................................................ 48 
Table 4: DS107 Cream Non-Medicinal Ingredients ................................................................. 52 
Table 5: Vehicle Non-Medicianl Ingredients ........................................................................... 53 
Table 6. Sample Size Calculation ............................................................................................. 63 
 
 


 
 
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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 Investigator’s name, address, qualifications and 
extent of involvement. 
 
 
 
 


 
 
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PROTOCOL SYNOPSIS 
STUDY TITLE: 
A Randomised, Double-blind, Vehicle-Controlled, Phase IIb 
Study to Assess the Efficacy and Safety of Topically Applied 
DS107 Cream to Adults with Mild to Moderate Atopic 
Dermatitis 
 
SHORT TITLE: 
Safety and Efficacy Study of Topically Applied DS107 Cream in 
Mild to Moderate Atopic Dermatitis Patients 
 
PHASE: 
IIb 
STUDY DURATION: 
10 weeks (Treatment Duration: 8 weeks) 
INVESTIGATIONAL 
PRODUCT: 
DS107 Cream   
 
Vehicle Cream 
 
OBJECTIVE:  
Efficacy Objective: 
 
 To compare the efficacy of topically applied DS107 cream 
(1% & 5%) versus vehicle, in the treatment of adult patients 
with mild to moderate Atopic Dermatitis (AD). 
 
Safety Objective: 
  
 To compare the safety of topically applied DS107 cream 
(1% & 5%) versus vehicle, in the treatment of adult patients 
with mild to moderate AD.  
 
PRIMARY ENDPOINTS: 
Primary Endpoint 
 
 
Change from baseline in Numeric Rating Scale (NRS) for 
Pruritus in treated population compared to vehicle 
population at Week 8. 
 
Co-Primary Endpoint 
 
 Change from baseline in Eczema Area and Severity Index 
(EASI) in treated population compared to vehicle population 
at Week 8.  
 
SECONDARY 
ENDPOINTS: 
 Change from baseline in NRS for Pruritus in treated 
population compared to vehicle population at Weeks 2, 4, 6 
and 10.   
 
 Proportion of patients achieving a decrease of at least 2.7 
points in NRS in treated population compared to vehicle 
population from baseline to Week 2, 4, 6, 8 and 10. 
 
 Change from baseline in EASI in treated population 
compared to vehicle population at Weeks 2, 4, 6 and 10.   
 
 Proportion of patients achieving an IGA score of 0 (clear) or 


 
 
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1 (almost clear) and a decrease of at least 2 points in IGA in 
treated population compared to vehicle population from 
baseline to Week 2, 4, 6, 8 and 10. 
 
 Proportion of patients achieving a decrease of at least 2 
points in IGA in treated population compared to vehicle 
population from baseline to Week 2, 4, 6, 8 and 10. 
 Change from baseline in IGA score in treated population 
compared to vehicle population at Weeks 2, 4, 6, 8 and 10.   
 
EXPLORATORY 
ENDPOINTS: 
 Change from baseline in the Dermatology Life Quality 
Index (DLQI) score in treated population compared to 
vehicle 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 
vehicle 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 
vehicle 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 
vehicle population at Week 2, 4, 6, 8 and 10. 
 
 
Determination of AD biomarkers in treated population 
compared to vehicle population at Baseline/Day 0 and Week 
8/Early Termination (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, urinalysis). 
 
 Clinical 
safety 
examinations 
(vital 
signs, 
physical 
examination). 
 
STUDY DESIGN: 
Approximately 300 patients with mild to moderate AD will be 
included in this multicenter, double-blind, vehicle controlled, 3-
arm, Phase IIb 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 5% DS107 cream, 1% DS107 
cream or vehicle cream twice daily for 8 weeks.  
 
During the 8 weeks of treatment patients will have to liberally 


 
 
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apply their assigned treatment topically to all affected or 
commonly affected areas twice daily (morning and evening).  
 
Patients will come to the clinic on 7 occasions: at Screening, 
Baseline, 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. 
TOTAL NUMBER OF 
RANDOMISED 
PATIENTS: 
300 
 
 
STUDY POPULATION: 
INCLUSION CRITERIA:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Patients with a clinically confirmed diagnosis of active AD 
according to Hanifin and Rajka criteria. 
  
2. Patients with mild to moderate AD at baseline as defined by 
an IGA score of 3 or 2 at baseline visit. Patients who are 
classified as having moderate AD should also have an EASI 
score of  ≥12 at the baseline visit. 
 
3. Patients with AD covering a minimum 5% of the body 
surface area at baseline. 
 
4. Patients whose pre-study clinical laboratory findings do not 
interfere with their participation in the study, in the opinion 
of the Investigator. 
5. Patients who are able and willing to stop current treatments 
for AD, including the use of emollients on the affected skin, 
throughout the study. 
 
6. Male or female patients aged 18 years and older on the day 
of signing the informed consent form (ICF). 
 
7. 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. 
 
8. 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 


 
 
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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, 
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 who have had excessive sun exposure, have used 
tanning booths or other ultraviolet (UV) light sources four 
weeks prior to baseline (Day 0) and/or are planning a trip 
to a sunny climate or to use tanning booths or other UV 
sources between screening and follow-up visits. 
7. Patients who have a history of hypersensitivity to any 
substance in DS107 or vehicle cream. 
8. Patients who have a white cell count outside of the normal 
reference range at screening, which cannot be justified by 
the investigator. 
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, 


 
 
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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 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. 
TEST PRODUCT, DOSE 
AND MODE OF 
ADMINISTRATION: 
DS107 cream will be provided as a cream containing either 5% 
or 1% DS107. 
Vehicle will be provided as a matching cream. 
This study will involve two dose levels of DS107 for 8 weeks 
(5% DS107 cream BD or 1% DS107 cream BD) and a vehicle 
control BD. 
EVALUATION CRITERIA: 
SAFETY 
 
 Physical examination 
 Vital signs, including blood pressure (BP), pulse and 
temperature 
 Clinical laboratory tests (haematology, biochemistry, and 
urinalysis) 
 Pregnancy test for females of child bearing potential 
 AEs 
 Concomitant medications (CMs) 


 
 
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BEHAVIOURAL 
RESTRICTIONS 
 Patients will be asked to refrain from any travel to sunny 
climates or use of tanning equipment, saunas and swimming 
throughout the duration of the study. 
 
 Extensive UV exposure or UV-B devices within four weeks 
of the trial and during the trial. 
OTHER RESTRICTIONS 
 Patients will be asked to refrain from the application of all 
emollients and creams to any area of skin impacted by AD 
during the course of this study. 
STATISTICAL ANALYSIS  
The primary analysis will be conducted in the full analysis set 
(FAS) population. 
Final analyses will be conducted using exact two-sided 97.4% 
confidence intervals for each DS107 dose minus vehicle 
difference; this strategy (Dunnett’s procedure) preserves the 
overall two-sided 5% Type I error. This allows either DS dose 
(1% and 5%) to be separately tested. 
A hierarchical testing sequence will be adopted, giving a pre-
defined testing order for multiple efficacy endpoints. 
A generalised linear mixed model (GLMM) will be used to 
separately analyze the continuous primary and co-primary 
efficacy endpoints at Week 8. The models will include 
Treatment Arm as a factor and respective baseline value as a 
covariate, with the treatment-by-visit interaction term as a 
random effect to account for missing data at Week 8. In addition, 
IGA-response will be analysed using a longitudinal mixed model 
for binary outcomes (GENMOD). 
Change from baseline for secondary and exploratory endpoints 
(IGA, DLQI, POEM, PGI-S and PGI-C) will be analysed using 
mixed model with repeated measures (MMRM) with Treatment 
Arm as a factor and respective baseline value as a covariate, with 
the treatment-by-visit interaction term as a random effect to 
account for missing data at Week 8. 
Sensitivity analyses will be performed to assess the robustness of 
the Missing at Random (MAR) assumptions that support the 
GLMM methods above for imputing missing data. 
SPONSOR: 
DS Biopharma 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
15-HETrE 
15-hydroxyeicosatrienoic acid 
AD 
Atopic Dermatitis 
AE 
Adverse Event 
BD 
Bis Die (Twice daily) 
BP 
Blood Pressure 
BPM 
CM 
COX 
Beats Per Minute 
Concomitant Medication 
Cyclooxygenase 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organisation 
CRF 
Case Report Form 
CsA 
Cyclosporin A 
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 
GLP 
GLMM 
Good Clinical Practice 
Good Laboratory Practice 
Generalised Linear Mixed Model  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IGA 
IgE 
Investigator’s Global Assessment 
Imunnoglobulin E 
IMP 
Investigational Medicinal Product 


 
 
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ISF 
Investigator Site File 
ITT 
Intention-To-Treat 
IWRS 
Interactive Web Response System 
MedDRA 
MMRM 
NOAEL 
NRS 
Medical Dictionary for Regulatory Activities 
Mixed Model with Repeated Measures 
No Observed Adverse Event Limit 
Numeric Rating Scale 
OTC 
Over The Counter 
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 Set 
PUVA 
Psoralen & Ultraviolet A 
PV CRO 
Pharmacovigilance Contract Research Organisation 
SAE 
Serious Adverse Event 
SAS 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SCORAD 
SCORing AD 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
SPC 
Summary of Products Characteristics 
SUSAR 
Th 
Suspected Unexpected Serious Adverse Reaction 
T helper cell 
TNF-α 
Tumor Necrosis Factor-Alpha 
UV-A/B 
Ultraviolet-A/B 
VAS 
Visual Analogue Scale 
 
 
 


 
 
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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 & Hanifin, 2013).  
 
AD progresses with erratic and often unpredictable flare-ups/exacerbations and is characterized by 
extremely dry, itchy skin which leads to scratching, resulting in further irritation and inflammation. 
As the skin loses moisture from the epidermal layer, it becomes increasingly dry and may begin to 
crack, weep, crust, and scale. This damage to the integrity of the skin renders it less protective and 
more prone to infection and environment influences (allergens and irritants). 
 
AD demonstrates specific age-dependent manifestations. Adult patients in the chronic phase 
demonstrate lichenified lesions which are associated with dryness, erythema and pruritus. The lesions 
most commonly occur on flexural folds, the face, the neck, the upper arms and back, and the dorsa of 
the hands, feet, fingers and toes. Adult patients may also develop exudation and crusting as a result of 
bacterial infections (Schultz-Larsen & Hanifin, 2002).  
 
In all stages of AD, pruritus that continues throughout the day and worsens at night, causes sleep loss, 
irritability and generalised stress, which substantially impairs the patient's quality of life (Simpson 
2010, Suarez et al. 2012). 
 
The mechanisms underlying the pathogenesis of AD remain unclear. Many studies have demonstrated 
the involvement of genetic predisposition, immune dysfunction, emotional and environmental stimuli 
and epidermal barrier dysfunction in its development and progression. It is well recognised however 
that IgE-mediated reactions (Bos et al. 1994) and elevated eosinophil levels (Kapp 1993) are involved 
in causing inflammation associated with AD. Additionally the overactivation 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 cream, a bioactive lipid containing >95% pure dihomo-γ-linolenic 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  DS107 cream has been 


 
 
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shown to improve the signs and symptoms of AD including pruritus and patient quality of life in a 
previous proof-of-concept Phase IIa study.  
 
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 severe 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) associated with the use of corticosteroids mean they can only be used as a short-term 
therapy.  
 
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, 
INF-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).  
 


 
 
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A multi-therapeutic approach that incorporates short-term management of flares and longer-term 
strategies to prolong the time between flares is needed for the treatment of AD. Therefore there is an 
unmet medical need for more effective well tolerated AD therapies that can be used safely in the long 
term.  
1.3 
Drug Class 
 
DS107 cream contains the active pharmaceutical ingredient DGLA, a long-chain polyunsaturated 
fatty acid endogenously present in the body.  
 
Figure 1: Structure of DS107 cream 
 
 
 
1.4 
Preclinical Pharmacology 
Numerous preclinical studies have been performed to determine the mechanism of actions of DS107 
in inflammatory skin disease 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 
monocytes.  Both IL-1β and IL-8 play an important role in the pathogenesis of AD. Inhibition of these 
pro-inflammatory pathways with DS107 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, Amagi 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).   


 
 
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DGLA has been reported to supress acute and chronic inflammation in whole animal preclinical 
studies, when administered in the diet. Oral administration of up to 600 mg/kg DGLA has shown dose 
dependent improvements in the severity of skin lesions in animal models of AD. DGLA treatment is 
correlated with decreased plasma IgE concentrations which may contribute to resolving the AD 
lesions.  
In the same study DGLA was shown to also significantly decreases the number of scratch events and 
duration of scratching in animal models of AD (Kawashima et al. 2008; Amagi 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 
 
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. Reaction was 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. The microscopic 
findings 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.  
 
Oral Toxicology 
A 13-week oral study in rats using Oral DS107 did not show any significant treatment-related effect 
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 Oral DS107 at levels found in this product 
is unlikely to cause adverse effects (Kawashima et al. 2009). 
 


 
 
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Mutagenicity 
Previously, DS107 exhibited no mutagenicity in an Ames test regardless of the presence or absence of 
S9 mix  (Kawashima et al. 2009). A recent DS Biopharma sponsored Ames test showed no substantial 
increases in revertant colony numbers with any of the tester strains following exposure to DS107, at 
any dose level, in the presence or absence of S9 mix. Therefore, DS107 was considered to be negative 
for the induction of mutagenicity in this in vitro assay when tested in accordance with regulatory 
guidelines. Furthermore, in a mouse lymphoma assay sponsored by the company, DS107 was not 
associated with genotoxicity in the presence or absence of metabolic activation. 
 
Conclusion 
Overall in these non-clinical safety studies it was concluded that DS107 is well tolerated and safe. 
1.6 
Previous Clinical Studies with DS107 
DS107 cream has been administered to date in 294 healthy volunteers/patients during the course of 
one Phase I trial (DS107E-01) and four Phase II trials (DS107E-02, DS107E-03, DS107E-04 and 
DS107E-05) for Acne Vulgaris (AV) and AD. Up to 5% DS107 cream is well tolerated in healthy 
volunteers and patients with AD. Below are a list of the completed and on-going trials which utilise 
DS107 cream. 
 
Table 1: Summary of DS107 Cream Use in Human Healthy Volunteers/Patients 
 
DS107E-01 
A Randomised, Double Blind, Vehicle Controlled, Multiple Ascending Dose Phase I Study to 
Investigate the Local Tolerability of Topical DGLA 
Phase 
Duration 
Indication 
IMP 
Conc. 
# Healthy 
Volunteers Status 
I 
(safety) 
2 weeks 
Healthy Volunteers 
0.1% 
0.5% 
1% 
2.5% 
5%  
30 
Completed 
DS107E-02 
A Randomised, Double-blind, Vehicle-Controlled, Phase II Study to Assess the Efficacy and Safety 
of Topically Applied DGLA Cream in Patients with Mild to Moderate AD 
Phase 
Duration 
Indication 
IMP 
Conc. 
# Patients 
Status 
IIa 
(safety & efficacy) 
4 weeks 
Mild to Moderate AD 
0.1% 
1% 
5%  
203 
Completed 
DS107E-03 
A Randomised, Double-blind, Vehicle-Controlled, Phase II Study to Assess the Efficacy and Safety 
of Topically Applied DGLA Cream in Patients with Mild to Moderate Acne Vulgaris 
Phase 
Duration 
Indication 
IMP 
# Patients 
Status 


 
 
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Conc. 
IIa 
(safety & efficacy) 
12 weeks 
AV 
1% 
5%  
154 
Completed 
DS107E-04 
A Prospective, Randomised, Vehicle-controlled, Double-blind, Exploratory Clinical Trial to Assess 
the Efficacy and Steroid Sparing Potential of DGLA Cream Topically Applied to Patients with 
Moderate to Severe AD 
Phase 
Duration 
Indication 
IMP 
Conc. 
# Patients 
Status 
Exploratory 
(safety & efficacy) 
5 weeks 
Moderate to Severe 
AD 
5%  
40 
(planned) 
On-going 
DS107E-05 
A Prospective, Randomised, Vehicle-controlled, Double-blind, Exploratory Clinical Trial to Assess 
the Efficacy and Steroid Sparing Potential of DGLA Cream Topically Applied to Childhood Patients 
with Moderate to Severe AD 
Phase 
Duration 
Indication 
IMP 
Conc. 
# Patients 
Status 
Exploratory 
(safety & efficacy) 
9 weeks 
Moderate to Severe 
AD 
1%  
40 
(planned) 
On-going 
 
 
DS107 Cream Phase I Study (DS107E-01) 
 
In this 2 week study, DS107 cream was administered topically to healthy human volunteers twice 
daily for 14 days. The safety margins concerning systemic safety risks and local tolerability following 
topical drug application were addressed and the safety margin calculated for the trial highlighted the 
lack of any systemic safety risks for humans exposed to DS107 cream when applied topically. The 
healthy volunteers were randomised to 5 cohorts and applied either 0.1%, 0.5%, 1%, 2.5% or 5% 
DS107 cream to one arm and the vehicle cream to the other arm. No clinically relevant dermal 
reactions were observed in this study as a result of topical application of DS107 cream. 
 
DS107 Cream Phase IIa Study in AD (DS107E-02) 
The study was a randomized, vehicle-controlled, double-blind, multi-centre Phase IIa trial to 
investigate the efficacy, safety, tolerability and bioavailability of three topically applied DS107 cream 
concentrations (0.1%, 1% and 5%) versus a matching vehicle in adult patients with mild to moderate 
AD. For all efficacy variables (change in mEASI, IGA, VAS, POEM and DLQI), there was a 
consistent trend of improvement from baseline over the study period (day 0 to day 28) for the 1% and 
5% DS107 cream treatment groups. This trend of improvement displayed no evidence of treatment 
plateau, suggesting that greater and clinically significant improvement from baseline may be expected 
if treatment was to be continued for a longer time period. No SAEs were observed throughout the 
course of this study. The DS107 cream treatment groups were similar to the vehicle groups in terms of 
number of adverse events and event severity. No deaths or other SAEs occurred during the study. 


 
 
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Other than one strongly elevated CPK value in one patient (reported as not drug related AE) at the last 
visit in the 5% DS107 group, no clinically relevant treatment differences were seen in any of the 
laboratory parameter. In the vital signs parameters, the mean values were stable across treatment 
groups. Overall, DS107 cream appears safe and well tolerated, with a profile similar to vehicle. 
 
 
DS107 Cream Phase IIa Study in Acne Vulgaris (DS107E-03) 
This 12 week study was a randomized, vehicle-controlled, double-blind, multi-centre proof of concept 
Phase IIa trial to investigate the efficacy, and safety of topically applied DS107 cream in patients with 
mild to moderate AV. This vehicle-controlled trial involved topical application of DS107 cream to all 
affected areas of the skin at dose strengths of 1% and 5% DS107 cream. 
All treatment groups displayed clinical significance in the improvement in the symptoms of AV after 
12 weeks of treatment with 1% DS107 cream, 5% DS107 cream or the vehicle cream. DS107 cream 
did not show statistically significant differences regarding efficacy over vehicle cream. Sixty (39.0%) 
patients experienced an adverse event (AE) during the study. All AEs were mild in severity and 
resolved without intervention. The number of patients experiencing an AE was comparable between 
the treatment groups. The results of the laboratory and vital sign assessments did not reveal any safety 
concerns during the study for any treatment group.  
 
DS107 Cream Exploratory Phase II Study in Adults with AD (DS107E-04) 
The 5 week exploratory Phase II study is designed to evaluate the efficacy and steroid sparing 
potential of 5% DS107 cream. Adult patients with moderate to severe AD will be treated with a potent 
glucocorticosteroid (mometasone furoate) for one week. Patients will then apply 5% DS107 cream 
twice daily as a maintenance therapy to prevent relapse. Efficacy and safety of DS107 following one 
week treatment with mometasone furoate will be compared to vehicle cream following one week 
treatment with mometasone furoate. The primary efficacy endpoint is defined as the change in EASI 
at Week 5 compared to vehicle. This trial is on-going. 
 
DS107 Cream Exploratory Phase II Study in toddlers with AD (DS107E-05) 
The 9 week exploratory Phase II study is designed to evaluate the efficacy and steroid sparing 
potential of 1% DS107 cream in infant patients with moderate to severe AD. Toddlers between the 
age of 3-12 months with moderate to severe AD will be treated with a 0.1% hydrocortisone butyrate 
cream once daily (morning) and DS107 cream once daily (evening) for one week. Patients’ 


 
 
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parents/guardians will then apply either 1% DS107 cream or vehicle cream twice daily as a 
maintenance therapy for the following 8 weeks to prevent relapse. Efficacy and safety of DS107 
cream will be assessed over time. The primary efficacy endpoints are defined as the change in IGA 
score from baseline to Week 9 and the SCORAD change from baseline to Week 9. This trial is on-
going. 


 
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2 
RISK BENEFIT ASSESSMENT 
To date, DS107 cream has been administered to 294 healthy volunteers/patients during the 
course of one Phase I trial and four Phase II trials for AD and AV. DS107 cream at a 
concentration of up to 5% was well tolerated in healthy volunteers and patients with AD and 
AV with no SAEs reported over a dosing period of up to 12 weeks. Oral DS107 has also been 
administered orally in two well controlled clinical trials in healthy volunteers (Phase 1) and 
patients with moderate to severe AD (Phase IIa). There were no drug related SAEs on either 
study. Furthermore there were no drug related AEs associated with safety lab results, physical 
exams or vital signs. All AEs were mild to moderate in severity and resolved without 
interevention. Overall orally administered DS107 was well tolerated at concentrations up to 4 
g. 
 
Based on both the favourable safety profile and the therapeutic potential of DS107 cream 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 cream for the treatment 
of mild to moderate AD. 
 
 


 
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3 
RATIONALE FOR THE STUDY 
 
The previous clinical studies indicate that DS107 cream is well tolerated and safe in both 
healthy volunteers and patients with AD and AV. The proof-of-concept Phase IIa study 
(DS107E-02) demonstrated that both 1% and 5% DS107 cream has a clinically relevant effect 
adult patients with mild to moderate AD. These results illustrate a clear rationale for the 
development of DS107 as a topical agent for the treatment of AD. 
 
No plateau in treatment efficacy was observed during the Phase IIa study within a 4 week 
treatment period with topical DS107 cream which indicates that the maximum efficacy may 
not yet have been determined and should be further evaluated by optimizing the dosing 
duration and/or concentration. Therefore, the goal for this dose-finding study is to examine 
the efficacy of 5% DS107 cream BD and 1% DS107 cream BD for a treatment period of 8 
weeks in patients with mild to moderate AD.  
 
The design of the current study is a randomised, vehicle-controlled, and double-blinded 
parallel group comparison in which the efficacy and safety of an 8 week treatment with 
DS107 cream is assessed in patients with mild to moderate AD. The design of the study was 
selected to minimise potential bias during the safety and efficacy assessments.  
The novel mechanism of action and safety profile of DS107 cream offer a potential benefit to 
AD patients and may represent a new class of medicine for this disease. 
 
Based on the afore-mentioned preclinical studies demonstrating the efficacy of DS107 in 
animal models of AD and the positive signals in the Phase IIa study in patients, there is a 
clear rationale for the further development of  DS107 cream as a treatment for patients with 
mild to moderate AD.  
 
 
 


 
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4 
STUDY OBJECTIVES 
Efficacy Objective: 
 
 
To compare the efficacy of topically applied DS107 cream (1% & 5%) versus 
vehicle, in the treatment of adult patients with mild to moderate AD. 
 
Safety Objective: 
  
 
To compare the safety of topically applied DS107 cream (1% & 5%) versus vehicle, 
in the treatment of adult patients with mild to moderate AD.  
 
 
 


 
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5 
STUDY ENDPOINTS 
5.1 
Primary Endpoints 
 
Primary Endpoint 
 
 Change from baseline in Numeric Rating Scale (NRS) for Pruritus in treated population 
compared to vehicle population at Week 8. 
 
Co-Primary Endpoint 
 
 Change from baseline in Eczema Area and Severity Index (EASI) in treated population 
compared to vehicle population at Week 8.  
5.2 
Secondary Endpoints 
 
 Change from baseline in NRS for Pruritus in treated population compared to vehicle 
population at Weeks 2, 4, 6 and 10.   
 
 Proportion of patients achieving a decrease of at least 2.7 points in NRS in treated 
population compared to vehicle population from baseline to Weeks 2, 4, 6, 8 and 10. 
 
 Change from baseline in EASI in treated population compared to vehicle population at 
Weeks 2, 4, 6 and 10.   
 
 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 vehicle population 
from baseline to Weeks 2, 4, 6, 8 and 10. 
 
 Proportion of patients achieving a decrease of at least 2 points in IGA in treated 
population compared to vehicle population from baseline to Weeks 2, 4, 6, 8 and 10. 
 
 Change from baseline in IGA score in treated population compared to vehicle population 
at Weeks 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 vehicle population at Weeks 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Orientated Eczema Measure (POEM) score in treated 
population compared to vehicle population at Weeks 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Global Impression of Severity (PGI-S) score in 
treated population compared to vehicle population at Weeks 2, 4, 6, 8 and 10. 
 
 
Change from baseline in the Patient Global Impression of Change (PGI-C) score in 
treated population compared to vehicle population at Weeks 2, 4, 6, 8 and 10. 
 
 
Determination of AD biomarkers in treated population compared to vehicle population at 
Baseline/Day 0 and Week 8/Early Termination (samples to be retained for the potential 
analysis at a later date). 
 


 
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6 
STUDY DESIGN 
6.1 
General 
This is a randomised, vehicle-controlled, double-blind, parallel group, multi-centre Phase IIb 
study to investigate the efficacy of topically administered DS107 cream and the dose-response 
relationship between DS107 cream and vehicle cream in AD patients 18 years and older. 
It is planned that approximately 300 patients, 100 patients per treatment group, with mild to 
moderate 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 5% DS107 cream, 1% DS107 cream or vehicle cream twice 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, 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.   
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. 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 9.2.9). 


 
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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: 
 
Treatment group A: 1% DS107 cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks  
 
 
Treatment group B: 5% DS107 cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks  
 
 
Treatment group C: Vehicle cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks 
 
To maintain the double-blind conditions, the DS107 cream and vehicle cream will be identical 
in appearance. 
An area for treatment will be defined at the start of the study and DS107 or vehicle cream will 
be applied to that area (and any newly affected areas) for the complete 8 week duration. 
Emollients can be applied to other areas of dry skin not in the defined treatment area.  Patients 
will be instructed to apply the IMP/vehicle cream liberally to the affected area, after breakfast 
and dinner respectively for 8 weeks (except on the days of clinic visits when patients will be 
instructed to abstain from applying IMP/vehicle cream for 6 hours prior to the visit and to 
apply IMP/vehicle cream as soon as possible after the clinic visit).  
 
 
 


 
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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 (see section 7.2) and must not meet any of the following exclusion criteria (see section 
7.3). Inclusion in the trial starts with the informed consent signature. The inclusion and 
exclusion criteria are to be verified at the screening visit (Visit 1) and at the start of 
treatment/baseline visit (Visit 2). 
7.1 
Source of Patients 
The study population will consist of male and female patients with confirmed diagnosis of 
AD aged between 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 mild to moderate AD at baseline as defined by an IGA score of 3 or 2 at 
baseline visit. Patients who are classified as having moderate AD should also have an 
EASI score of  ≥12 at the baseline visit. 
 
3. Patients with AD covering a minimum 5% of the body surface area at baseline. 
 
4. Patients whose pre-study clinical laboratory findings do not interfere with their 
participation in the study, in the opinion of the Investigator. 
5. Patients who are able and willing to stop current treatments for AD, including the use of 
emollients on the affected skin, throughout the study. 
 
6. Male or female patients aged 18 years and older on the day of signing the informed 
consent form (ICF). 
 
7. 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. 


 
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8. 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 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. 
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 who have had excessive sun exposure, have used tanning booths or other 
ultraviolet (UV) light sources four weeks prior to baseline (Day 0) and/or are planning a 
trip to a sunny climate or to use tanning booths or other UV sources between screening 
and follow-up visits. 
7. Patients who have a history of hypersensitivity to any substance in DS107 or vehicle 
cream. 
8. Patients who have a white cell count outside of the normal reference range at screening, 
which cannot be justified by the investigator. 
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.  


 
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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 
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. 
 
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 of 
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 


 
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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 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 


 
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assessments listed at Week 10/Visit 7. 
 
There will be two main categories for withdrawals from the study: “complete withdrawal” 
and “withdrawals from Investigational Medicinal Product (IMP)”. 
7.5.1 
Complete Withdrawal 
Discontinuation of IMP and all efficacy and safety evaluations. Standard reasons for 
withdrawing from further participation in the study and from the follow-up visits may be: 
 
Patient’s decision (withdrawal of consent to participate) 
 
Patients lost to follow-up (drop-out) 
 
7.5.2 
Withdrawals from IMP 
Discontinuation of IMP, but continued follow-up visits, including efficacy and safety 
evaluations. Standard reasons for withdrawing from taking further IMP, 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. Patients who withdraw from the study due to a lack of efficacy after four 
weeks of treatment will not 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 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, 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. 
 
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, or from taking new or not previously prescribed anti-histamines or 
any antimicrobial medication. 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. Emollients can be applied to other areas of dry skin not in the defined treatment 
area.  A list of ‘medications and therapeutic regimens excluded from the study’ is defined 
below (Section 9.2.9).  
8.2 
Clinic Visits 
 
A tabulated flow chart of the study is presented in Appendix 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/events will occur: 
 
Demographic data 
 
Medical 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]) 


 
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 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, 
urinalysis and FSH levels 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) 
 
Investigator’s Global Assessment (IGA) (as detailed in Section 9.1.1) 
 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
 
Body Surface Area (BSA) (as detailed in Section 9.1.4) 
 
NRS pruritus assessment (as detailed in Section 9.1.3) 
 
Concomitant medication assessment (as detailed in Section 9.2.9) 
 
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. 
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 apply DS107 cream or vehicle cream in the morning and in the 
evening (except on the mornings of clinic visits when patients will be instructed to abstain 
from applying DS107/vehicle cream prior to the visit. They will apply DS107/vehicle cream 
as soon as all of the efficacy assessments are complete during the clinic visit). 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.  


 
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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) 
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 Section Appendix 2 (15.2)) 
 
Patient randomisation (as detailed in Section 10.5) 
 
Samples for clinical laboratory safety tests (haematology, urinalysis and serum 
biochemistry as detailed in Section 9.2.4) 
 
Biomarker sampling (as detailed in Section 9.2.6) 
 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3) 
 
Physical examination (as detailed in Section 9.2.2) 
 
Dispense study drug  
 
Dispense patient compliance log 
 
Study drug administration (on site) (as detailed in Section 10.3) 
 
Investigator’s Global Assessment  (IGA) (as detailed in Section 9.1.1) 
 
Body Surface Area (BSA) (as detailed in Section 9.1.4) 
 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
 
NRS pruritus assessment (as detailed in Section 9.1.3) 
 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
 
Patient Orientated Eczema Measure (POEM) (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire (PGI-S) (as detailed in Section 
9.1.7) 
 
Patient Global Impression of Change Questionnaire (PGI-C) (as detailed in Section 
9.1.8)  
 
Concomitant medication assessment (as detailed in Section 9.2.9) 
 
If all study entry criteria are satisfied the Investigator will randomize the patient and provide 
the patient with six tubes of the designated DS107 or vehicle cream from one of the patient 
treatment packs available at the site (allocated via the central randomization). 


 
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The first application of DS107 or vehicle cream will be carried out at site once all baseline 
assessments have been completed. The patient will carry out their second application of 
DS107 or vehicle cream in the evening of Day 0.  
 
Patients will be given a compliance log to document application of the DS107 or vehicle 
cream. Clinical staff will explain to the patient how to use the compliance log to document 
IMP application compliance. 
 
All dispensed DS107 cream and vehicle cream should be weighed (tube only, without the 
outer carton but including the tube lid) upon dispensing.  
 
An NRS for the assessment of pruritus will be captured on a daily basis from baseline through 
to the follow up visit.  
 
Collection of AEs will begin after the first application 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 bring with them the unused DS107/vehicle cream, the used 
DS107/vehicle cream, and the patient compliance log. Patients should not apply DS107 or 
vehicle cream on the morning of their return site visit (Visit 3). 
 
8.2.4 
Week 2 (Visit 3) 
Patients will return to the investigational site at Week 2/Visit 3. Patients should not apply 
DS107 or vehicle cream on the morning of Visit 3. 
 
For accountability purposes, patients will be required to bring both the used and unused 
DS107/vehicle cream 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  


 
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 
Dispense patient compliance log  
 
Collect and review patient compliance log  
 
IMP accountability (as detailed in Section 10.6) 
 
Study drug administration (on site) (as detailed in Section 10.3) 
 
Investigator’s Global Assessment (IGA) (as detailed in Section 9.1.1) 
 
Body Surface Area (BSA) (as detailed in Section 9.1.4) 
 
Eczema Area and Severity Index (EASI) (as detailed in Section9.1.2) 
 
NRS pruritus assessment (as detailed in Section 9.1.3) 
 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section9.1.5) 
 
Patient Orientated Eczema Measure (POEM) (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire (PGI-S) (as detailed in Section 
9.1.7) 
 
Patient Global Impression of Change Questionnaire (PGI-C) (as detailed in Section 
9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.9) 
 
AE assessment (as detailed in Section 11) 
 
The DS107 or vehicle cream will be returned and six tubes of DS107 or vehicle cream will be 
supplied to the patient. The cream will continue to be applied twice-daily. The patient 
compliance log will be provided to the patient who will be instructed to complete this as 
before.  
 
All dispensed DS107 cream and vehicle cream should be weighed (tube only, without the 
outer carton but including the tub lid) upon dispensing and again upon return of 
product. 
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
baseline to the follow up visit.  
 
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/vehicle cream, the 
used DS107/vehicle cream, and the patient compliance log. Patients should not apply DS107 
or vehicle cream on the morning of their return site visit (Visit 4). 
 


 
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8.2.5 
Week 4 (Visit 4) 
Patients will return to the investigational site at Week 4/Visit 4. Patients should not apply 
DS107 or vehicle cream on the morning of Visit 4.  
 
For accountability purposes, patients will be required to bring both the used and unused 
DS107/vehicle cream supplied at Visit 3. 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) 
 
Study drug administration (on site) (as detailed in Section 10.3) 
 
Investigator’s Global Assessment (IGA) (as detailed in Section 9.1.1) 
 
Body Surface Area (BSA) (as detailed in Section 9.1.4) 
 
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 Section9.1.5) 
 
Patient Orientated Eczema Measure (POEM) (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire (PGI-S) (as detailed in Section 
9.1.7) 
 
Patient Global Impression of Change Questionnaire (PGI-C) (as detailed in Section 
9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.9) 
 
AE assessment (as detailed in Section 11) 
 
The DS107 or vehicle cream will be returned and six tubes of DS107 or vehicle cream will be 
supplied to the patient. The cream will continue to be applied twice-daily. The patient 
compliance log will be provided to the patient who will be instructed to complete this as 
before.  


 
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All dispensed DS107 cream and vehicle cream should be weighed (tube only, without the 
outer carton but including the tube lid) upon dispensing and again upon return of 
product. 
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
baseline to the follow up visit.  
 
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/vehicle cream, the 
used DS107/vehicle cream, and the patient compliance log. Patient should not apply DS107 
or vehicle cream on the morning of their return site visit (Visit 5). 
 
8.2.6 
Week 6 (Visit 5) 
Patients will return to the investigational site at Week 6/Visit 5. Patients should not apply 
DS107 or vehicle cream on the morning of Visit 5. 
 
For accountability purposes, patients will be required to bring both the used and unused 
DS107/vehicle cream 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) 
 
Study drug administration (on site) (as detailed in Section 10.3) 
 
Investigator’s Global Assessment (IGA) (as detailed in Section 9.1.1) 
 
Body Surface Area (BSA) (as detailed in Section 9.1.4) 
 
Eczema Area and Severity Index (EASI) (as detailed in Section9.1.2) 
 
NRS pruritus assessment (as detailed in Section 9.1.3) 


 
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 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
 
Patient Orientated Eczema Measure (POEM) (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire (PGI-S) (as detailed in Section 
9.1.7) 
 
Patient Global Impression of Change Questionnaire (PGI-C) (as detailed in Section 
9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.9) 
 
AE assessment (as detailed in Section 11) 
 
The DS107 or vehicle cream will be returned and six tubes of DS107 or vehicle cream will be 
supplied to the patient. The cream will continue to be applied twice-daily. The patient 
compliance log will be provided to the patient who will be instructed to complete this as 
before.  
 
All dispensed DS107 cream and vehicle cream should be weighed (tube only, without the 
outer carton but including the tube lid) upon dispensing and again upon return of 
product. 
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
baseline to the follow up visit.  
 
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/vehicle cream, the 
used DS107/vehicle cream, and the patient compliance log. Patients should not apply DS107 
or vehicle cream on the morning of their return site visit (Visit 6). 
8.2.7 
Week 8 (Visit 6) / End of Treatment or Early Termination 
Patients will return to the investigational site at Visit 8. The last administration of 
DS107/vehicle cream should be made the evening before Visit 6. 
 
For accountability purposes, patients will be required to bring both the used and unused 
DS107/vehicle cream supplied at Visit 5. Patients will be required to provide the patient 
compliance log for confirmation of compliance.  
 
The following procedures/assessments will occur: 


 
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 
Samples for clinical laboratory safety tests (haematology, urinalysis and serum 
biochemistry as detailed in Section 9.2.4) 
 
Biomarker sampling (as detailed in Section 9.2.6) 
 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3)  
 
Physical examination (as detailed in Section 9.2.2) 
 
Collect study drug  
 
Collect and review patient compliance log  
 
IMP accountability (as detailed in Section 10.6) 
 
Investigator’s Global Assessment (IGA) (as detailed in Section 9.1.1) 
 
Body Surface Area (BSA) (as detailed in Section 9.1.4),  
 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
 
NRS pruritus assessment (as detailed in Section 9.1.3) 
 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
 
Patient Orientated Eczema Measure (POEM) (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire (PGI-S) (as detailed in Section 
9.1.7) 
 
Patient Global Impression of Change Questionnaire (PGI-C) (as detailed in Section 
9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.9) 
 
AE assessment (as detailed in Section 11) 
 
The DS107 or vehicle cream will be returned. No further DS107 or vehicle cream or patient 
compliance log will be issued. Following completion of the study assessments at this visit, 
there will be continued study restrictions in line with those described in section 9.2.9 and 
9.2.10.  
 
An NRS for the assessment of pruritus will continue to be captured on a daily basis from 
baseline to the follow up visit.  
 
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.  


 
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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, urinalysis and serum 
biochemistry as detailed in Section 9.2.4) - Only if clinically significant change from 
baseline in safety lab results at Week 8 / Visit 6 
 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 
9.2.3) 
 
Physical examination (as detailed in Section 9.2.2) 
 
Investigator’s Global Assessment (IGA) (as detailed in Section 9.1.1) 
 
Body Surface Area (BSA) (as detailed in Section 9.1.4) 
 
Eczema Area and Severity Index (EASI) (as detailed in Section 9.1.2) 
 
NRS pruritus assessment (as detailed in Section 9.1.3) 
 
Dermatology Life Quality Index (DLQI) Questionnaire (as detailed in Section 9.1.5) 
 
Patient Orientated Eczema Measure (POEM) (as detailed in Section 9.1.6) 
 
Patient Global Impression of Severity Questionnaire (PGI-S) (as detailed in Section 
9.1.7) 
 
Patient Global Impression of Change Questionnaire (PGI-C) (as detailed in Section 
9.1.8) 
 
Concomitant medication assessment (as detailed in Section 9.2.9) 
 
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 and Severity Index (EASI) 
The 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 
Numerical Rating Scale (NRS) for Pruritus 
 
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 experienced at its 
worst over the previous 24 hours. The NRS for pruritus 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 once at screening 
and then daily starting at baseline through to the last study visit.  
 


 
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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.  
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  
 
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. 2004 (Appendix 7) is a self-assessment of disease severity by the patient. 
POEM has a maximum value of twenty eight based on the patient’s response to seven 
questions scored according to the following scale: 
- 
No days = 0 
- 
1-2 days = 1 
- 
3-4 days = 2 
- 
5-6 days = 3 
- 
Everyday = 4 
9.1.7 
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 


 
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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 patients 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 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 all visits in accordance with local practices. This examination will be 
symptom-directed, i.e., a standard panel of body systems will not be assessed unless indicated 
by patient. For example should the patient report to the Investigator the presence of ‘rash’ 
then the skin would be evaluated. It is not required that additional body systems are assessed 
unless clinically warranted. Any clinically significant abnormal results should be recorded in 
the CRF. Changes in findings of the physical examination compared with the baseline 
examination should be recorded as an AE. 
9.2.3 
Vital Signs 
Vital 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) 


 
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- 
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. 
Serum biochemistry: 
Creatinine, uric acid , alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), lactate dehydrogenase (LDH), creatine 
phosphokinase (CPK), albumin, cholesterol, triglycerides, glucose. 
Urinalysis: 
pH, protein, glucose, blood. 
 
Table 3: Total Blood Volume drawn 
Test 
Number of 
Samples 
Volume per 
sample (ml) 
Total (ml) 
Haematology/Biochemistry 4* 
9 
36 
Biomarkers 
2 
3 
6 
Total volume 
 
 
42 
*Sample at Visit 7/Follow up will only be taken if a laboratory AE was recorded at Week 8 
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 initialled and signed by the Investigator before insertion in 
the CRF.  
 
Additional blood may be required for repeats of safety laboratory test. 
 


 
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9.2.5 
Pregnancy Test 
For female patients of childbearing potential, a pregnancy test will be carried out at screening, 
as per the study flow chart (Appendix 1). 
 
9.2.6 
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. 
9.2.7 
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. 
9.2.8 
Adverse Event Assessment 
See Section 11. 
9.2.9 
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, does 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.  
 


 
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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 IMP during the entire period of the study.  
 
9.2.9.1 
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 basline/ Day 0 
and continues to use the same agent everyday throughout the study 
 
Inhaled and intranasal corticosteroids for stable medical conditions are allowed.  
 
9.2.9.2 
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 
 
calcineurin inhibitors 
 
tars 
 
bleach 
 
antimicrobials 
 
bleach baths 
 
Any topical product containing urea, ceramides or hyaluronic acid 
 
Emollients within the test area (may be applied to areas of dry skin outside of the test 
area and must be in use for 4 weeks prior to initiation of trial) 
 
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  
 
UVA or UVB 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 


 
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9.2.10 Restrictions 
Behavioural 
Patients will be asked to refrain from any travel to sunny climates or use of tanning 
equipment, saunas and swimming throughout the duration of the study. 
 
Extensive UV exposure or UV-B devices within 4 weeks of the trial and during the trial. 
 
Other 
Patients will be asked to refrain from the application of all emollients and creams to any area 
of skin impacted by AD during the course of this study. 
 
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.  
 
 


 
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10 
INVESTIGATIONAL MEDICINAL PRODUCT / 
INVESTIGATIONAL DRUG 
 
10.1 IMP  
The following medication supplies will be used in the study:  
 
DS107 cream:  
DS107 cream contains DS107 as an active ingredient.  
DS107 cream will be supplied in two concentrations: 5% and 1%.  
 
DS107 cream is formulated as a white to off white-cream for topical application. 
 
DS107 Cream Medicinal Ingredients: 
DGLA (Di-hommo-gamma-linolenic acid) 
 
DS107 Cream Non-Medicinal Ingredients: 
Table 4: DS107 Cream Non-Medicinal Ingredients 
Excipient 
Function 
Status 
Steareth-2 
Primary Emulsifier 
Ph.Eur 
Steareth-21 
Primary Emulsifier 
Manufacturer’s In-house Specification 
Cetyl Alcohol 
Co-emulsifier 
Ph.Eur 
L(+)Ascorbyl Palmitate 
Anti-oxidant 
Ph.Eur 
all-rac-α-Tocopherol 
Anti-oxidant 
Ph.Eur 
Medium Chain 
Triglycerides 
Emollient 
Ph.Eur 
Myristyl Myristate 
Co-emulsifier, 
Emollient 
Manufacturer’s In-House Specification 
Isopropyl Palmitate 
Emollient 
Ph.Eur 
Glycerol, Anhydrous 
Humectant 
Ph.Eur 
Methyl 4-Hydroxybenoate 
Preservative 
Ph.Eur 
Ethyl 4-Hydroxybenzoate 
Preservative 
Ph.Eur 
Propyl 4-Hydroxybenzoate 
Preservative 
Ph.Eur 
Bronopol 
Preservative 
Manufacturer’s In-House Specification 
Ascorbic Acid 
Antioxidant 
Ph.Eur 
Carbomer 
Viscosity Modifier 
NF 
Xanthan Gum 
Thickener 
Ph.Eur 
Soy Lecithin 
Stabilizing Agent 
Manufacturer’s In-house Specification 
Potassium Hydroxide 
pH adjustment 
Ph.Eur 
Mild Care 345 
Fragrance 
Manufacturer’s In-house Specification 


 
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Water For Irrigation 
Solvent 
Ph.Eur 
 
Vehicle cream:  
A matching vehicle cream is also supplied. This is identical in composition to the DS107 
cream formulation minus active drug substance. The vehicle formulation is based on the 
formulation of the investigational medicinal product with additional water for irrigation being 
used to compensate for the absence of active pharmaceutical ingredient in the formulation.  
 
Vehicle Cream Medicinal Ingredients: 
None 
 
Vehicle Cream Non-Medicinal Ingredients: 
Table 5: Vehicle Non-Medicianl Ingredients 
Excipient 
Function 
Status 
Steareth-2 
Primary Emulsifier 
Ph.Eur 
Steareth-21 
Primary Emulsifier 
Manufacturer’s In-house Specification 
Cetyl Alcohol 
Co-emulsifier 
Ph.Eur 
L(+)Ascorbyl Palmitate 
Anti-oxidant 
Ph.Eur 
all-rac-α-Tocopherol 
Anti-oxidant 
Ph.Eur 
Medium Chain 
Triglycerides 
Emollient 
Ph.Eur 
Myristyl Myristate 
Co-emulsifier, 
Emollient 
Manufacturer’s In-House Specification 
Isopropyl Palmitate 
Emollient 
Ph.Eur 
Glycerol, Anhydrous 
Humectant 
Ph.Eur 
Methyl 4-Hydroxybenoate 
Preservative 
Ph.Eur 
Ethyl 4-Hydroxybenzoate 
Preservative 
Ph.Eur 
Propyl 4-Hydroxybenzoate 
Preservative 
Ph.Eur 
Bronopol 
Preservative 
Manufacturer’s In-House Specification 
Ascorbic Acid 
Antioxidant 
Ph.Eur 
Carbomer 
Viscosity Modifier 
NF 
Xanthan Gum 
Thickener 
Ph.Eur 
Soy Lecithin 
Stabilizing Agent 
Manufacturer’s In-house Specification 
Potassium Hydroxide 
pH adjustment 
Ph.Eur 
Mild Care 345 
Fragrance 
Manufacturer’s In-house Specification 
Water For Irrigation 
Solvent 
Ph.Eur 
 
 
Drug bulk product and vehicle are manufactured by C.P.M. ContractPharma GmbH & Co., 
Germany and packaged by Anderson Brecon Limited, UK. Labelled DS107 cream and 


 
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matching vehicle cream will be supplied by Anderson Brecon Limited to a central distribution 
facility as a cream formulation in aluminium tubes packed in cartons with tamper evident 
seals.  
IMPs will be stored at ambient condition (i.e. up to 25°C) and should be used within the 
assigned expiry date. 
 
10.2 Supply, Packaging, Labelling, Handling and Storage 
DS107 cream and vehicle cream will be provided by the Sponsor. 
 
The DS107 cream and vehicle cream will be a white to off white-cream formulation supplied 
from the manufacturer to the central distribution facility. The central distribution facility will 
supply the IMP and vehicle to site where it will be handled by the site pharmacy or 
responsible personnel according to local Regulations. Patients who qualify for randomisation 
at Baseline/Visit 2 will be given IMP for 2 weeks/14 days at Baseline/Visit 2, Week 2/Visit 3, 
Week 4/Visit 4,  and Week 6/Visit 5.  
 
The DS107 cream and vehicle cream will be labelled with information according to local 
regulation.  
 
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. The DS107 cream and vehicle cream 
will be stored at a controlled room temperature of ambient condition (ie. Up to 25°C) in a 
secure area protected from unintended use and will only be supplied to patients in the trial 
under the supervision of the Investigator. 
 
10.3 Dosage and Administration 
IMP at dose strengths of 5% and 1% DS107 cream or vehicle cream will be topically applied 
liberally to all affected or commonly affected areas twice daily (morning and evening) by the 
patients. The last study drug application 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: 1% DS107 cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks  


 
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 
Treatment group B: 5% DS107 cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks  
 
Treatment group C: Vehicle cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks 
 
An area for treatment will be defined at study start and DS107 or vehicle cream will be 
applied to all that area (and any newly affected areas) for the complete 8 week duration. 
Emollients can be applied to other areas of dry skin not in the defined treatment area.  
 
DS107 or vehicle cream will not be applied on the morning of clinic visits 3, 4, 5, and 6 (will 
be applied as soon as all of the efficacy assessments are complete during the clinic visit). To 
maintain the blind throughout the study, the DS107 cream and vehicle cream will be identical 
in appearance. 
 
If a patient misses one application of the study product they should apply the study product as 
usual at the time of the next scheduled application. Patients should remember to note the 
missed application in the Patient Compliance Log. 
 
10.4 Duration of Treatment 
Patients will topically apply either DS107 cream or vehicle cream liberally to all affected or 
commonly affected areas twice 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: 1% DS107 cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks  
 
Treatment group B: 5% DS107 cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks  
 
Treatment group C: Vehicle cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks 
 


 
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A randomization list, permuted blocks and stratified by site will be generated by DS 
Biopharma or its designee. The randomization schedule with study drug assignments will be 
generated prior to the start of the study and will be known only to the individuals responsible 
for labelling the study drug, the statisticians generating the schedule and the IWRS team 
responsible for implementing the schedule. The IWRS will assign a medication kit number to 
each patient and the contents will be based on the randomization code.  
 
At the investigational site, each patient will be assigned a patient identifier number during 
screening that will be used on all patient documentation. The patient identifier number will 
contain the site number and the patient number assigned in numerical order at the screening 
visit (e.g.: 102-10 for the tenth patient screened at the site number 02). Patient numbers will 
be assigned in ascending order starting with 01. 
 
10.6 Drug Accountability 
All IMP supplied 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 tubes of IMP to the study site at every visit. Following compliance 
assessment the tubes 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 will 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 who has signed the ICF and 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 patients 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 SAE.  
A SAE (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):  


 
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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.  
 
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, a 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.  


 
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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 the 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 the 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).  
AEs should be reported for the entire study duration up to and including the follow up period. 
Following completion of the study, if the Investigator becomes aware of any AE that is 
potentially related to the IMP the Sponsor should be notified.  
 
11.2 Serious Adverse Reactions and Unexpected Adverse Reactions  
11.2.1 Definitions  
Adverse Reaction:  
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions.  
The phrase "responses to a medicinal product" means that a causal relationship between a 
medicinal product and an AE 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:  


 
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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 is 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 the 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 the 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 the 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 the 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 


 
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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, vehicle-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 vehicle 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 vehicle treatment. A full description of the study design is presented in Section 6 (above). 
12.2 Randomisation 
Approximately 300 patients will be randomized into double-blind treatment groups in a 1:1:1 
ratio as follows: 
 
Treatment group A: 1% DS107 cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks  
 
Treatment group B: 5% DS107 cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks  
 
Treatment group C: Vehicle cream applied topically to all affected or commonly 
affected areas twice-daily for 8 weeks. 
 
A randomization list, permuted blocks and stratified by site will be generated by DS 
Biopharma 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. 
 


 
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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 
The sample size for the topical DS107 Phase IIb study was informed from the post-hoc 
analysis of the Phase IIa study. NRS and EASI will be the primary and co-primary efficacy 
endpoints. The positive efficacy data over 4 weeks showed no sign of a plateau and suggests 
further improvements may be observed at week 8.  Dunnettt’s procedure will be used to allow 
simultaneous comparisons of each DS107 dose vs. vehicle control.  
 
The sample size was estimated from the Phase IIa results at week 4/exit; the mean 
improvement and corresponding standard deviation for vehicle subjects were used to perform 
the following calculations. As shown below, 100 patients per treatment arm (300 patients in 
total) will be required to detect mean advantages of 3.03 units for NRS (10 point scale) and 
6.6 units for EASI favoring DS107 vs. vehicle. This assumes a two-sided test with 80% power 
conducted at the 5% overall significance level with a Dunnettt’s adjustment for multiple 
doses. 
 
Table 6. Sample size calculation 
Two group Satterthwaite t-test: No Difference (unequal variances) (equal n's) 
 
NRS 
EASI 
Overall Dunnett’s Type I Error 
0.026 
0.026 
1 or 2 sided test? 
2 
2 
Target DS107 Mean Reduction, 1 
3.030 
6.600 
Expected Vehicle Mean Reduction, 2 
1.810 
4.000 
Mean Difference Goal, 1 - 2 
1.220 
2.600 
Phase IIa DS107 Standard Deviation, 1 
2.490 
4.450 
Phase IIa Vehicle Standard Deviation, 2 
3.040 
7.110 
Power (%) 
80 
80 
n per group 
100 
100 
 


 
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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 a pre-specified Interim 
Statistical Analysis Plan. 
 
 
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. Changes from baseline and 
percent changes from baseline will be evaluated for continuous endpoints. 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. 
 


 
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Randomised Population 
The Randomised Population consists of all patients who are randomised to the study. 
 
Safety Analysis Set (SAS) 
The SAF 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 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 PPS is the subset of FAS who completed the study without any major violations. Protocol 
violations will be assessed for each patient in a blinded fashion prior to database lock at a 
Blind Data Review Meeting (BDRM), and the PPS will also be finalised during this meeting. 
PPS is a supportive analysis population for efficacy endpoints. Analysis will be done 
according to the treatment patients were randomised to. 
 
12.8 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. 


 
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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 DS107E-06 will detail all analysis to be performed.  
12.9.1 Primary Variables 
The primary variable will be: 
 
The change from baseline in NRS for Pruritus in treated population compared to 
vehicle population at Week 8. 
The co-primary variable will be: 
 
The change from baseline in EASI in treated population compared to vehicle 
population at Week 8.  
 
The continuous primary and co-primary efficacy endpoints will be separately analyzed using 
a Generalized Linear Mixed Model (GLMM). The models will include Treatment Arm as a 
factor and respective baseline value as a covariate, with the treatment-by-visit interaction term 
as a random effect to account for missing data. The primary analysis will be based on the 
FAS, and repeated for the PPS as a supportive sensitivity analysis. The models will also allow 
the estimation of the mean changes from baseline at each on-study visit in addition to Week 8. 
The change from Week 8 to Week 10 will also be of interest to assess relapse once off study 
drug.   
 
Sensitivity analyses will be performed to assess the robustness of the Missing at Random 
(MAR) assumptions that support the GLMM methods above for imputing missing data. 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 
vehicle arm as the reference.  This is based on the assumption that patients who discontinue 


 
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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 vehicle group.  The sensitivity analyses for 
missing data will be performed on the FAS only. 
12.9.2 Secondary variables 
 
IGA-response will be analyzed using a longitudinal mixed model for binary outcomes 
(GENMOD). The model will include Treatment Arm as a factor and respective baseline value 
as a covariate, with the treatment-by-visit interaction term as a random effect to account for 
missing data. The primary analysis will be based on the FAS, and repeated for the PPS as a 
supportive sensitivity analysis. The models will also allow the estimation of the response 
percents at each on-study visit in addition to Week 8. The shift from Week 8 to Week 10 will 
also be of interest to assess relapse once off study drug.  
 
Change from baseline endpoints (IGA, DLQI, POEM, PGI-S and PGI-C) will be analyzed 
using mixed model with repeated measures (MMRM) with Treatment Arm as a factor and 
respective baseline value as a covariate, with the treatment-by-visit interaction term as the 
random effect to account for missing data. The secondary efficacy analyses will be based 
on the FAS only. 
 
In addition, a hierarchical testing sequence will be adopted, giving a  pre-defined 
testing order for multiple efficacy endpoints as follows: NRS, EASI, IGA, IGA 
response, PGI-S, PGI-C, DLQI and POEM. 
12.9.3 Safety variables 
The type and frequency of AEs 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 SAEs, AEs leading to withdrawal and 
AEs possibly or probably related to treatment will be summarized per treatment group. 
 
 


 
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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 patients meeting the 
eligibility criteria and being randomised in the study; 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 
Procedures (SOP). The handling of data, including data quality control, will comply with all 
applicable regulatory guidelines. 


 
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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. 
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 PIS/ICF will be approved by the relevant competent authorities (CA) and 
ethics committees (EC), 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 CA and EC 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 CA.  
SUSAR reports and Periodic Safety Reports will be sent to Competent Authorities and Ethics 
Committees according to local regulations.   
13.2 Good Clinical Practice (GCP) 
The study will be managed and conducted according to the latest ICH guidelines for 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). 


 
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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, drug accountability, compliance with regulatory requirements and continued 
adequacy of the investigational site and its facilities.  
Incorrect or missing entries in the CRFs will be queried and will be corrected appropriately. 
All clinical data will undergo quality control checks prior to clinical database lock. Edit 
checks will then be performed for appropriate databases as a validation routine using SAS ® 
to check for missing data, data inconsistencies, data ranges, etc. Each eCRF is reviewed and 
signed by the principal ivestigator (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 


 
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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. 
The data derived from this trial will be kept for 25 years as per the guidelines of the NNHPD 
(Natural and Non-prescription Health Products Directorate). 
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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‘Dihomo- γ -linolenic acid prevents the development of AD 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 AD: meta-
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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: 
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from the patients' perspective.’ Arch Dermatol; Dec;140(12) pp. 1513-9. Erratum in: 
Arch Dermatol. 2005 Mar;141(3) pp.381. 
 
 
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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 
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 
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, 
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‘Guidelines of care for the management of AD: section2. Management and treatment 
of AD 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 AD (AD) 
trials: Many options, no standards.’ J Am Acad Dermatol; 74(2), pp. 288 - 294. 
 
 
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 AD.’ 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 AD. EASI 
Evaluator Group.’ Exp Dermatol. Feb;10(1), pp. 11-8. 
 
 
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 AD--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 AD in NC/Nga Mice.’ Lipids; 43 (1), pp. 37-43. 
 


 
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 
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. 'AD.‘ Lancet; 361, pp. 151-160. 
 
 
Leung, DY & Guttman-Yassky, E 2014. ‘Deciphering the complexities of AD: 
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. 
 
 
Schultz-Larsen, FV & Haniﬁn, JM 2002. ‘Epidemiology of AD.’ 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 
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 
Simpson, EL 2010. ‘AD: A review of topical treatment options.’ Curr. Med Res 
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 
Suarez, AL, Feramisco, JD, Koo, J & Steinhoff, M 2012. ‘Psychoneuroimmunology 
of psychological stress and AD: 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 
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 
Williams, H & Flohr C 2006. ‘How epidemiology has challenged 3 prevailing 
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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 
Biomarker Sampling 
 
X 
 
 
 
X 
 
Pregnancy Test (-hCG if 
female of childbearing 
potential)  
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drug 
 
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 
 
Study Drug Administration 
(on site) 3 
 
X 
X 
X 
X 
 
 
IGA 
X 
X 
X 
X 
X 
X 
X 
BSA 
X 
X 
X 
X 
X 
X 
X 
EASI Assessment 
X 
X 
X 
X 
X 
X 
X 
NRS Pruritus Assessment 
X 
X------------------------------------------------------------------------------------------------------ 
DLQI Questionnaire 
 
X 
X 
X 
X 
X 
X 
POEM Questionnaire 
 
X 
X 
X 
X 
X 
X 
PGI-C Questionnaire 
 
X 
X 
X 
X 
X 
X 
PGI-S Questionnaire 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events4 
 
 
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. Patients will be instructed to take their last study drug dose the day preceding Week 8 visit. 
4. Collection of AE will start after the first study drug administration 
 


 
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15.2 Appendix 2: Diagnostic Features of AD (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  
 
 
 
 
 


 
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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  


 
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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  
10 
Over the last week, how much of a problem has the treatment for 
your skin been, for example by making your home messy, or by 
taking up time? 
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. 
 
 
 


 
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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. 
 
 
 
 


 
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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 AD symptoms are now: 
 
 
(1) 
Normal skin 
 
(2) 
Mild 
 
(3) 
Moderate 
 
(4) 
Severe 
 
 
 
 


 
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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: B 
DS Biopharma DS107E-06 
 
 
Page 1 of 31 
 
 
 
 
  
 
DS Biopharma 
Protocol #: # DS107E-06 
A Randomised, Double-blind, Vehicle-Controlled, 
Phase IIb Study to Assess the Efficacy and Safety of 
Topically Applied DS107 Cream to Adults with 
Mild to Moderate Atopic Dermatitis 
 
Protocol Version 5.0/Amend. #4 
 
 
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 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: B 
DS Biopharma DS107E-06 
 
 
Page 2 of 31 
 
 
 
By signing the following, I agree to the contents in the Statistical Analysis Plan and its 
associated attachments. 
 
 
 
Approved by: 
 
 
 
 
Name 
Title 
Signature 
Date  
Phil Lavin, PhD 
Senior Biostatistical 
Consultant (for sponsor) 
 
 
 
Terri Sampo, MPH 
Principal Consultant, 
CTDS 
 
10/11/2017 
 
 
 
 
 
 
 
 
 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
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DS Biopharma DS107E-06 
 
 
Page 3 of 31 
 
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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            Statistical Analysis Plan 
 
 
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DS Biopharma DS107E-06 
 
 
Page 4 of 31 
 
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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DS Biopharma DS107E-06 
 
 
Page 5 of 31 
 
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 (SS) .................................................................................................................................. 13 
2.2.4.3 
Per-Protocol Analysis Set (PPS) ...................................................................................................................... 13 
2.2.4.4 
Subgroup Analyses .......................................................................................................................................... 14 
2.2.5 
Study Assessment Time Points ............................................................................................................. 14 
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 ..................................................................................................................... 16 
2.2.10 
Interim Analyses .................................................................................................................................. 16 
2.2.11 
Randomization/Unblinding .................................................................................................................. 17 
2.2.11.1 
Randomization Methodology ...................................................................................................................... 17 
2.2.11.2 
Unblinding ................................................................................................................................................... 17 
2.2.12 
Efficacy Analyses ................................................................................................................................. 18 
2.2.12.1 
Primary Endpoint ......................................................................................................................................... 18 
2.2.12.2 
Secondary Endpoints ................................................................................................................................... 19 
2.2.12.3 
Exploratory Endpoints ................................................................................................................................. 21 
2.2.13 
Safety Analyses .................................................................................................................................... 25 
2.2.13.1 
Extent of Exposure ...................................................................................................................................... 25 
2.2.13.2 
Safety Endpoint(s) ....................................................................................................................................... 25 
2.2.13.3 
Adverse Events ............................................................................................................................................ 26 
2.2.13.3.1 
Serious Adverse Events ............................................................................................................................ 26 
2.2.13.3.2 
Deaths ....................................................................................................................................................... 27 
2.2.13.3.3 
Interruptions or Discontinuations of Study Medication Due to an AE ..................................................... 27 
2.2.13.4 
Laboratory Data ........................................................................................................................................... 27 
2.2.13.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety ................................................. 27 
3 
DOCUMENT VERSION CONTROL ............................................................................................................. 29 
APPENDIX A - PROGRAMMING SPECIFICATIONS FOR TABLES AND LISTINGS ............................... 30 
 
 
 
 
 
 
 
 
 


 
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1 Protocol Summary 
 
Title 
A Randomised, Double-blind, Vehicle-Controlled, Phase IIb Study 
to Assess the Efficacy and Safety of Topically Applied DS107 
Cream to Adults with Mild to Moderate Atopic Dermatitis 
  
Study Objectives 
Efficacy Objective:  
To compare the efficacy of topically applied DS107 cream (1% & 
5%) versus vehicle in the treatment of adult patients with mild to 
moderate Atopic Dermatitis (AD).  
  
Safety Objective:   
To compare the safety of topically applied DS107 cream (1% & 
5%) versus vehicle in the treatment of adult patients with mild to 
moderate AD. 
 
Primary Endpoint 
Primary Endpoint 
 
 
Change from baseline in Numeric Rating Scale (NRS) for Pruritus in 
the treated DS107 dose populations compared to vehicle population 
at Week 8/exit. 
 
Co-Primary Endpoint 
 
 Change from baseline in Eczema Area and Severity Index (EASI) in 
the treated DS107 dose populations compared to vehicle population 
at Week 8/exit.  
 
Secondary Endpoint(s) 
Change from baseline in Numeric Rating Scale (NRS) for Pruritus 
in the treated DS107 dose populations compared to vehicle 
population at Weeks 2, 4, 6, 10, and last treatment visit. 
 
Proportion of patients achieving a decrease of at least 2.7 points in 
NRS in the treated DS107 dose populations compared to vehicle 
population from baseline to Week 2, 4, 6, 8 and 10. 
 
Change from baseline in Eczema Area and Severity Index (EASI) 
in the treated DS107 dose populations compared to vehicle 
population at Weeks 2, 4, 6, 10, and last treatment visit. 
 
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 the 
treated DS107 dose populations compared to vehicle population 
from baseline to Week 2, 4, 6, 8, 10, and last treatment visit. 


 
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Proportion of patients achieving a decrease of at least 2 points in 
IGA in the treated DS107 dose populations compared to vehicle 
population from baseline to Week 2, 4, 6, 8, 10, and last treatment 
visit. 
 
Change from baseline in IGA score in the DS107 dose treated 
populations compared to vehicle population at Weeks 2, 4, 6, 8, 
10, and last treatment visit. 
 
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 the DS107 dose treated populations compared to 
vehicle population at Week 2, 4, 6, 8, 10, and last treatment visit 
and from Week 8 to Week 10.  
  
• Change from baseline in the Patient Orientated Eczema Measure 
(POEM) score in the DS107 dose treated populations compared to 
vehicle population at Week 2, 4, 6, 8, 10, and last treatment visit 
and from Week 8 to Week 10.  
  
• Change from baseline in the Patient Global Impression of 
Severity (PGI-S) score in the DS107 dose treated populations 
compared to vehicle population at Week 2, 4, 6, 8, 10, and last 
treatment visit and from Week 8 to Week 10.  
  
• Change from baseline in the Patient Global Impression of 
Change (PGI-C) score in the DS107 treated populations compared 
to vehicle population at Week 2, 4, 6, 8, and 10, and last treatment 
visit and from Week 8 to Week 10.  
  
• Determination of AD biomarkers in the DS107 dose treated 
populations compared to vehicle 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.  


 
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• Safety laboratory parameters (haematology, clinical chemistry, 
urinalysis).  
  
• Clinical safety examinations (vital signs, physical examination). 
 
Test Product, Dose and 
Mode of Administration 
 
All study medication will be blinded.  DS107 cream will be 
provided as a cream containing either 5% or 1% DS107. Vehicle 
will be provided as a matching cream. This study will involve two 
dose levels of DS107 for 8 weeks (5% DS107 cream BD or 1% 
DS107 cream BD) and a vehicle control BD 
 
Study Design: 
Approximately 300 patients with mild to moderate AD will be 
included in this multicenter, double-blind, vehicle controlled, 3 
arm, 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 2.6% Type I error (to allow for 
each DS107 dose to be separately compared to vehicle control). 
  
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 5% DS107 cream, 1% DS107 cream or 
vehicle cream twice daily for 8 weeks.   
  
During the 8 weeks of treatment patients will have to liberally 
apply their assigned treatment topically to all affected or 
commonly affected areas twice daily (morning and evening).   
  
Patients will come to the clinic on 7 separate visits: Screening, 
Baseline (Day 0), 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 mild to moderate AD at baseline as defined by an 
IGA score of 3 or 2 at baseline visit. Patients who are classified as 
having moderate AD should also have an EASI score of ≥12 at the 
baseline visit.  
3. Patients with AD covering a minimum 5% of the body surface 
area at baseline.  


 
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4. Patients whose pre-study clinical laboratory findings do not 
interfere with their participation in the study, in the opinion of the 
Investigator.  
5. Patients who are able and willing to stop current treatments for 
AD, including the use of emollients on the affected skin, 
throughout the study.  
6. Male or female patients aged 18 years and older on the day of 
signing the informed consent form (ICF).  
7. 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.  
8. 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.  
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 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 


 
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climate or to use tanning booths or other UV sources between 
screening and follow-up visits.  
7. Patients who have a history of hypersensitivity to any substance 
in DS107 or vehicle cream.  
8. Patients who have a white cell count outside of the normal 
reference range at screening, which cannot be justified by the 
investigator.  
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 
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-blind Phase IIb study is to assess the efficacy and safety of 
topically applied DS107 Cream to adults with mild to moderate Atopic Dermatitis.   This 
study uses a randomized (1:1:1, Treatment group A: 1% DS107 cream, Treatment group 
B: 5% DS107 cream, Treatment group C: Vehicle cream), double-blind, vehicle-
controlled parallel group design.  Disposition, compliance, demographics, and primary 
and secondary efficacy results will be presented by treatment group separately for mild 
and moderate AD as well as for combined groups. Study medication will be applied twice 
daily to the designated Treatment Area 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 primary focus will be the separate comparisons of the two DS107 concentrations vs. 
vehicle control using a Dunnett’s correction (two-sided p=0.026) to reach statistical 
significance supported by the two-sided p-values and the two-sided 97.4% confidence 
intervals (Dunnett’s procedure).  Comparisons between the two active groups will be 
considered to be descriptive statistics.   
  
The following summary statistics will be reported for continuous data: number of 
subjects, mean, standard deviation, median, minimum and maximum.  For categorical 
data, the number and percentage of subjects within each treatment group will be reported.   
 


 
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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.  
 
 
2.2 
Subject Population 
 
2.2.1 Baseline Characteristics/Medical History 
 
Demographics - gender, age, race (years), ethnicity, country and baseline 
BSA will be summarized by treatment group for the Full analysis set 
(FAS) population.  Demographics will be displayed separately for the mild 
and moderate AD as well as overall.   
 
P-values will be provided for the overall global test and each vehicle pair 
and for descriptive comparison of 5% DS107 to 1% 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 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 mild and moderate AD as well as overall.  
 


 
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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. 
 
2.2.3 Dose Regimen 
 
The following three formulations have identical appearance:  1% DS107 cream, 
5% DS107 cream and Vehicle cream in a 1:1:1 ratio, respectively.  The 
medication assigned by randomization will be topically applied liberally by the 
patients to all affected or commonly affected areas twice daily (morning and 
evening) 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.   
 
 


 
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2.2.4.4 
Subgroup Analyses 
 
Subgroup analyses will be conducted on the primary and secondary 
endpoints stratifying by severity of atopic dermatitis (mild or moderate), 
defined as an IGA score of 2=mild or 3=moderate 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: 
 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 application of study medication will be carried out at the site once all 
baseline assessments have been completed. The patient will carry out 
their second application 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 8 weeks 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 
 


 
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The effects of missing efficacy data will be incorporated through the appropriate 
covariance structure from the GLMM.  This will apply to continuous as well as 
binary endpoints. 
 
A sensitivity analysis will be performed for Week 8/Exit outcome under the 
missing at not random (MNAR) assumption for the primary efficacy analyses 
using the FAS.  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 vehicle 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 vehicle group.  The sensitivity 
analyses for missing data will be performed on the FAS only. 
  
2.2.7 Safety Monitoring 
 
 
No safety monitoring committees are planned for the study.  
 
2.2.8 Statistical Hypotheses 
 
The original null hypothesis (H0) for each analysis is the equality of the means for 
the three treatment groups. A global test was to be performed across all three 
treatment groups.  The test will still be performed 
 
The revised primary focus will be the separate comparisons of the two DS107 
concentrations vs. vehicle control using a Dunnett’s correction (two-sided 97.4% 
confidence intervals and two-sided p=0.026) to reach statistical significance.  The 
null hypotheses are the pairwise comparisons of the equality of the two DS107 
concentrations vs. vehicle.  Dunnett’s procedure will be used to adjust for the 
multiple comparisons.  The overall 5% Type I error rate is controlled for by the 
Dunnett’s correction for multiple comparisons. 
  
Testing between the two active groups will be considered as descriptive statistics.  


 
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All statistical testing will be two-sided; global tests will be performed at the 0.05 
level while all pairwise DS107 comparisons vs vehicle will be performed at the 
0.026 level.   
 
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 Phase IIa study.  NRS and EASI will be the primary and 
co-primary efficacy endpoints.  The positive efficacy data over 4 weeks showed 
no sign of a plateau and suggests further improvements may be observed at Week 
8.  Dunnettt’s procedure will be used to allow simultaneous comparisons of each 
DS dose concentration vs. vehicle control.  
 
The sample size was estimated from the Phase IIa results at Week 4/exit; the 
mean improvement and corresponding standard deviation for vehicle subjects 
were used to perform the following calculations. As shown below, 100 patients 
per treatment arm (300 patients in total) will be required to detect mean 
advantages of 3.03 units for NRS (10-point scale) and 6.6 units for EASI favoring 
DS107 vs. vehicle.  This assumes a two-sided test with 80% power conducted at 
the 5% overall significance level with a Dunnettt’s adjustment for multiple doses. 
 
Table 1. Sample Size Calculation 
Two group Satterthwaite t-test: No Difference (unequal variances) (equal n's) 
 
NRS 
EASI 
Overall Dunnett’s Type I Error 
0.026 
0.026 
1 or 2 sided test? 
2 
2 
Target DS107 Mean Reduction, 1 
3.030 
6.600 
Expected Vehicle Mean Reduction, 2 
1.810 
4.000 
Mean Difference Goal, 1 - 2 
1.220 
2.600 
Phase 2a DS107 Standard Deviation, 1 
2.490 
4.450 
Phase 2a Vehicle Standard Deviation, 2 
3.040 
7.110 
Power (%) 
80 
80 
n per group 
100 
100 
 
2.2.10 Interim Analyses  
 
An interim analysis is planned to assess the primary and co-primary efficacy 
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sample size. 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 2.6% Type I error 
(to allow for each DS107 dose to be separately compared to vehicle control).    
 
2.2.11 Randomization/Unblinding 
 
2.2.11.1 
Randomization Methodology 
 
Approximately 300 patients will be randomized to the three blinded 
treatment groups in a 1:1:1 ratio as follows:  
 
• Treatment group A: 1% DS107 cream applied topically to all affected or 
commonly affected areas twice-daily for 8 weeks   
• Treatment group B: 5% DS107 cream applied topically to all affected or 
commonly affected areas twice-daily for 8 weeks   
• Treatment group C: Vehicle cream applied topically to all affected or 
commonly affected areas twice-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 unblinding. 
 


 
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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 mild and 
moderate AD as well as combined across mild and moderate AD strata.  
Models will include a baseline covariate for mild/moderate 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. 
 
2.2.12.1 
Primary Endpoint  
 
The primary efficacy variable is the change from baseline in Numeric 
Rating Scale (NRS) in the DS107 dose treated populations compared to 
vehicle population at week 8/exit.  
 
The change from baseline in NRS will be analyzed for the FAS with SAS 
PROC MIXED using code similar to the following, with CFB_NRS and 
B_NRS representing the change from baseline and the baseline NRS, 
respectively.  
 
proc mixed data= FAS;  
class trt  AD visit; 
model CFB_NRS= trt AD B_ NRS/CL alpha=0.052; 
lsmeans trt*visit / diff CL; 
run; 
 
where fas= Full Analysis Set (FAS).  The cl and alpha= option specifies 
that two-sided exact 97.4% confidence intervals will be provided.  The 
between-treatment effects are determined from the diff option of the 
LSMEANS statement. Results will be presented separately for mild and 
moderate AD.  The primary analysis will be based on the FAS and 
repeated for the PPS as a supportive analysis.    
 
Co-Primary Endpoint 
 
Change from baseline in Eczema Area and Severity Index (EASI) in the 
DS107 dose treated population compared to vehicle population at Week 


 
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8/exit. The change from baseline in EASI will be analyzed the same way 
as the primary endpoint. 
 
The study drug is to be considered effective when both of the primary 
endpoint and co-primary endpoint demonstrate an effect, i.e. reject the null 
hypothesis using the separate comparisons vs. vehicle control. 
 
2.2.12.2 
Secondary Endpoints 
 
The secondary endpoints are: 
•  Change from baseline in Numeric Rating Scale (NRS) in treated 
population compared to vehicle population at Weeks 2, 4, 6, 10 and 
subject’s last treatment.   These will be analyzed using PROC MIXED as 
described in the primary endpoints section. Three separate models will be 
done using the same PROC MIXED code, one for the change from 
baseline to Week 2, 4 and 6, one for the change from baseline to Week 10 
and the third for the change from baseline to last treatment visit. 
 
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 
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.  
 


 
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•  Proportion of patients achieving at a decrease of at least 2.7 points in 
NRS in treated population compared to vehicle population from baseline 
to Week 2, 4, 6, 8, 10, and last treatment visit.  These will be analyzed 
using PROC GENMOD using code similar to the following, with 
Outcome and B_NRS representing the outcome (whether or not achieved a 
decrease of at least 2 points) and the baseline NRS, respectively.   
 
PROC GENMOD data=FAS descending; 
        Class trt AD visit; 
        Outcome= trt AD B_NRS/dist=bin cl alpha=0.052; 
        Repeated subject=trt*visit/corr=un; 
        slice trt*visit / sliceby=visit ilink cl diff ; 
                                    run; 
 
Three separate models will be done using the same PROC GENMOD 
code, one for the change from baseline to Week 2, 4, 6 and 8, one for the 
change from baseline to Week 10 and the third for the change from 
baseline to last treatment visit. 
 
 
•  Change from baseline in Eczema Area and Severity Index (EASI) in 
treated population compared to vehicle population at Weeks 2, 4, 6 and 10 
and subject’s last treatment visit.   These will be analyzed using the similar 
PROC MIXED code as described in the primary endpoint section. Three 
separate models will be done using the same PROC MIXED code for the 
change from baseline to Week 2, 4 and 6, for the change from baseline to 
Week 10, and for the change from baseline to last treatment visit. 
 
•  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 vehicle population from baseline to Week 2, 4, 6, 8 and 10 
and change from baseline to subject’s last treatment visit.  These analyses 
will be performed using the same PROC GENMOD code described above. 
Three separate models will be done for the change from baseline to Week 
2, 4, 6 and 8, for the change from baseline to Week 10, and for the change 
from baseline to last treatment visit. 
 


 
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•  Proportion of patients achieving a decrease of at least 2 points in IGA 
in treated population compared to vehicle population from baseline to 
Week 2, 4, 6, 8, 10, and change from baseline to subject’s last treatment 
visit.  These analyses will be performed using the same PROC GENMOD 
code described above. Three separate models will be done using the same 
PROC GENMOD code for the change from baseline to Week 2, 4, 6 and 
8, for the change from baseline to Week 10 and for the change from 
baseline to last treatment visit. 
 
•  Change from baseline IGA in treated population compared to vehicle 
population at Weeks 2, 4, 6, 8 and 10 and subject’s last treatment visit.  
These will be analyzed using the same PROC MIXED using code similar 
to the following, with CFB_IGA and B_IGA representing the change from 
baseline and the baseline IGA, respectively. Method=ml is the maximum 
likelihood estimate. 
 
proc mixed method =ml data= FAS; 
class trt visit AD; 
model CFB_IGA= trt AD B_ IGA/CL alpha=0.052; 
lsmeans trt*visit / diff CL; 
run; 
 
Three separate models will be done using the same PROC MIXED 
code for the change from baseline to Week 2, 4, 6 and 8, for the 
change from baseline to Week 10 and for the change from baseline 
to last treatment visit. 
 
The method for controlling the Type I error rate is provided in 
Section 2.2.12.4. 
 
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. 
 


 
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•    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 vehicle 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. These analyses will be 
done using PROC MIXED similar to the code described above. 
 
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 
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 
 


 
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•  Change from baseline in the Patient Orientated Eczema Measure 
(POEM) score in treated population compared to vehicle 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. These analyses will be done 
using PROC MIXED similar to the code described above. 
 
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. 
 
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 vehicle 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. These analyses will be done 
using PROC MIXED similar to the code described above. 
 
The categories for the PGI-S are:  normal, mild, moderate or severe.   A 
Shift table will be created presenting the number and frequencies of 


 
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subjects in each category and the shift from the follow-up visit to 
baseline.    
 
•  Change from baseline in the Patient Global Impression of Change (PGI-
C) score in treated population compared to vehicle 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. 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. 
• Determination of AD biomarkers in treated population compared to 
vehicle 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.  
The method for controlling the Type I error rate is provided in 
Section 2.2.12.4. 
 
2.2.12.4 
Controlling Type I error 
 
Dunnett’s test will be used to provide for simultaneous comparisons of 
each DS107 dose vs. vehicle by allowing two-sided p=0.026 per dose 
comparison. 
 
No multiplicity adjustment is necessary for the primary and co-primary 
endpoints as the Type I error rate will not be affected because both must 
be met for study success. A hierarchical testing sequence methodology 
will be applied to the second and exploratory endpoints in order to control 
the overall type 1 error. Table 2 provides the order of testing for each 
active dose group compared to the vehicle group for the secondary and 
exploratory efficacy endpoints; these will each be global tests across all 
post-baseline outcomes excluding Week 10. Each of these tests will be at 
the 0.05 significance level. A test will be considered statistically 
significant only if the corresponding test has a p-value <0.05 and all 
previous tests (as determined by the testing order defined in Table 2) have 
a p-value <0.05. 
 
 


 
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Table 2. Hierarchical Testing Sequence for Secondary and Exploratory Endpoints 
Testing 
Order 
Endpoint 
Efficacy Endpoint 
1 
Secondary 
Change in NRS from baseline 
2 
Secondary 
Proportion achieving a reduction of at least 2.7 points in NRS 
3 
Secondary 
Change in EASI from baseline 
4 
Secondary 
Proportion achieving an IGA score of 0 or 1 and a decrease of at 
least 2 points in IGA 
5 
Secondary 
Proportion achieving a decrease of at least 2 points in IGA 
6 
Secondary 
Change in IGA from baseline 
7 
Exploratory Change in DLQI from baseline 
8 
Exploratory Change in POEM from baseline 
9 
Exploratory Change in PGI-S from baseline 
10 
Exploratory Change in PGI-C from baseline 
 
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 applications of study medication will be collected from 
information recorded on the study drug admin page of the eCRFs.  Study 
medication is to be applied twice daily.   
 
Extent of exposure to study medication will be tabulated by treatment 
group by 2-week intervals.  The number of applications 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 applications per 2-week intervals is 14, based on 
twice daily dosing. Compliance will be measured by calculating the 
number of applications/expected number of applications *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 topically applied DS107 
cream (1% & 5%) versus vehicle, in the treatment of adult patients with 
mild to moderate AD.  Results will be pooled for 1% and 5% as well.   


 
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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 1% and 5% 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 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 application 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 vehicle.   
 
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 Preferred Term is reported 
multiple times with differing severities (mild, moderate or severe), only 
the most severe is counted but all events will be counted.  If a Preferred 
Term is reported 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 
 


 
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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.   
 
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, biochemistry and urinalysis) 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, 


 
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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  
B 
11Oct2017 
CTDS/P. Lavin 
Updated SAP to reflect updated protocol 
version 5.0 
 
 
 
 
 
 
 
 
 


 
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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 


 
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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 
 
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 (e.g, subjects with SAEs) 
then this should be clear from the title of the listing.  If there are no subjects who meet the 
condition (e.g. no subjects with SAEs) for either the tables or the listings, then a page marker 
should appear stating that no subjects met the criteria.