Conditions: Dermatitis, Atopic
Keywords: atopic dermatitis skin barrier moisturiser emollient
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 50
Healthy volunteers: no

Brief summary:
Atopic dermatitis (AD) is among the most common chronic types of inflammatory skin disease and it is characterised by exacerbations or relapses over years. The patients have a genetically impaired skin barrier that can be evaluated by measuring the transepidermal water loss (TEWL), which is increased in both dry skin and clinically normal skin in AD patients. Moisturisers are first line treatment for AD patients and moisturisers are the most prescribed products in dermatology. The use of moisturisers have been found to reduce the need for steroids.

The newly developed moisturizing cream 1107.57 is intended for people with dry skin symptoms, such as dryness, itching, and flaking. As most people with dry skin of different origin have an impaired skin barrier function, it is important to investigate the possible influence on the skin barrier after long-term (several weeks') treatment. It is of utmost importance to evaluate different moisturisers head-to-head in order to facilitate an evidence-based choice of moisturiser.

The primary objective of the trial is to determine whether applying the test cream 1107.57 for 4 weeks is superior in terms of skin barrier strengthening, when compared with (1) no treatment and (2) two reference creams in adults with a predisposition to a skin barrier defect. Secondary objectives are to determine whether there is a difference between 1107.57 and (1) no treatment and (2) the two reference creams in skin moisturization, tolerability, cream consumption and safety.

Participants will treat their lower volar forearms for 28 days with three different creams (test cream and two reference creams) and leave one area untreated as a control. Each forearm will have two different treatment areas and treatment allocation will be randomized. One Finger Tip Unit (FTU) of each cream will be applied twice daily on the designated study area for 28 days. On day 1 and 29 the transepidermal water loss (TEWL) and skin capacitance is measured on their forearms to evaluate the effect on skin barrier function and skin hydration. Furthermore, on day 31, after challenge with 1 % sodium lauryl sulphate (SLS) on day 29, the susceptibility to irritation caused by SLS will be evaluated visually and by measuring TEWL on their forearms. Study participants will attend visits at the start of randomised therapy and on day 5, 15, 29 and 31. During the study period the participants will also grade and evaluate the tolerability of the different creams.

Detailed description:

Arms:
arm 1: Topical cream, 1 Finger Tip Unit per treatment area on the lower volar forearms twice daily for 28 days arm 2: Topical cream, 1 Finger Tip Unit per treatment area on the lower volar forearms twice daily for 28 days arm 3: Topical cream, 1 Finger Tip Unit per treatment area on the lower volar forearms twice daily for 28 days arm 4: Untreated skin area on the volar forearm

Interventions: intervention 1: 2% urea/20% glycerol cream intervention 2: Miniderm® 20% cream intervention 3: Diprobase® cream
Intervention descriptions: intervention 1: Moisturizing cream for topical application intervention 2: Moisturizing cream for topical application intervention 3: Emollient cream for topical application

Protocol document:
Prot_000.pdf: 
NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 1 of 65 
 
 
CLINICAL STUDY PROTOCOL 
 
 
A phase 2 randomised controlled trial of a NOVel moisturiser for 
Atopic dermatitis: effect on the skin barrier in adults with a 
predisposition to a skin barrier defect 
Short Title: 
NCT number: 
Date: 
A NOVel moisturiser for Atopic dermatitis: effect on the skin barrier 
NCT03901144 
2019-08-15 
 
 
 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 2 of 65 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
 
 
A phase 2 randomised controlled trial of a NOVel moisturiser for 
Atopic dermatitis: effect on the skin barrier in adults with a 
predisposition to a skin barrier defect 
Short Title: 
A NOVel moisturiser for Atopic dermatitis: effect on the skin barrier 
Acronym: 
NOVA – Skin Barrier 
IRAS number:    
251853 
Study code: 
Novum ACO-CT-2018-01 
Study development 
phase: 
Phase 2 
Amendment: 
Novum ACO-CT-2018-01-
V3(Amendment #2) 
Indication: 
Skin barrier 
strengthening 
EudraCT 
number: 
2018-002945-12 
Investigational 
product: 
Miniderm Novum 
Version: 
3.0 
Date: 
2019-08-15 
 
 
 
 
Principal Investigator: 
Professor Michael J Cork and Dr Simon Danby (Co-PI) 
Sponsor Signatory: 
Anneleen Spooren, PhD 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 3 of 65 
 
1 
SYNOPSIS 
Name of the Sponsor/Company: 
ACO Hud Nordic AB 
Study Code:  
Novum ACO-CT-2018-01 
Name of Investigational Product: 
Miniderm Novum 
EudraCT No.:  
2018-002945-12 
Development Phase of the Study: 
Phase 2 
Trial under an IND:  
Yes 
TITLE OF THE STUDY: 
A phase 2 randomised controlled trial of a NOVel moisturiser for Atopic dermatitis: effect on the skin 
barrier in adults with a predisposition to a skin barrier defect 
 
OBJECTIVES: 
OUTCOME MEASURES: 
Primary 
To determine whether applying 
a new moisturizing cream (the 
test cream) for 4 weeks is 
superior in terms of skin barrier 
strengthening, when compared 
with (1) no treatment and (2) two 
reference creams in adults with 
a predisposition to a skin barrier 
defect.  
1. Trans Epidermal Water Loss (TEWL) after 
induction of skin irritation 
2. Redness after induction of skin irritation 
Secondary 
To determine whether there is a 
difference between the new 
moisturising cream (the test 
cream) and (1) no treatment and 
(2) the two reference creams in: 
1. Resting skin barrier 
function  
2. Skin moisturisation 
3. Tolerability 
4. Cream consumption 
5. Safety 
 
1. TEWL after 4 weeks treatment  
2. Skin moisturisation: 
a. Capacitance measurements 
b. Skin surface dryness (3D skin 
images) 
c. NMF levels 
3. Tolerability properties: 
a. Participant tolerability scores by VAS  
b. Investigator visual scores for redness 
c. Objective erythema from 2D colour 
skin images 
4. Cream consumption (g) 
5. Number of adverse events 
Tertiary 
To investigate the number of 
participants with FLG loss-of-
function mutations and explore if 
there is any evidence of a 
1. Number of FLG loss-of-function mutation 
carriers 
2. Descriptive tabulations of TEWL by mutation 
status, if sufficient participants with mutation 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 4 of 65 
 
relationship to treatment effects 
are detected. 
TRIAL CONFIGURATION: 
A randomised, controlled, bilateral single centre trial. 
SETTING: 
Participants will be recruited from the general population by open advertisement and all trial related 
activities will be performed in the Skin Barrier Research Facility, operated by Sheffield Dermatology 
Research, based in the Royal Hallamshire Hospital, Sheffield. 
OVERALL STUDY DESIGN:  
Consenting volunteers with atopic dermatitis will be screened against the inclusion/exclusion criteria. 
Figure 1 and Table 1 illustrate the overall study design and the study flow-chart. Enrolled participants will 
be randomised to treat the lower or upper parts of the lower volar forearms (i.e. 4 treatment areas) with 
the new active emulsion (Miniderm Novum), the reference cream Miniderm 20% cream or the reference 
cream Diprobase cream. One area is left untreated as control. One Finger Tip Unit (FTU) of the creams 
will be applied twice daily for 28 (± 3) days. On day 1 and 29 (± 3) the transepidermal water loss (TEWL) 
and skin capacitance is measured on their forearms to evaluate the effect on skin barrier function and 
skin hydration. Furthermore, on day 31 (± 3), after challenge with 1 % sodium lauryl sulphate (SLS) on 
day 29 (± 3), the susceptibility to irritation caused by SLS will be evaluated visually and by measuring 
TEWL on their forearms. Study participants will attend visits at the start of randomised therapy and on 
day 5 (± 2), 15 (± 3), 29 (± 3) and 31 (± 3). During the study period the participants will also grade and 
evaluate the tolerability of the different creams.  
INVESTIGATIONAL 
PRODUCTS 
(dose, route, 
administration) 
Test product 
• 
Miniderm Novum cream (investigational product), 1 
FTU twice daily to the previously randomised volar 
forearm for 28 (± 3) days 
Comparator 
• 
Miniderm 20% cream (reference product), 1 FTU 
twice daily to the the previously randomised volar 
forearm for 28 (± 3) days 
• 
Diprobase cream (reference product), 1 FTU twice 
daily to the the previously randomised volar forearm 
for 28 (± 3) days 
DURATION OF TRIAL: 
31 (± 3) days - the primary end point of the trial will be measured on day 31. 
NUMBER OF PARTICIPANTS and statistical evaluation:  
50 participants will be recruited into the study.  This sample size is sufficient to provide more than 90% 
power to detect a difference (test treatment vs no treatment) of 3.5 in change in TEWL for the primary 
endpoint, if the data is suitable for a parametric analysis.  If the observed data is not suitable for a 
parametric analysis then the sample size would provide greater than 80% power in a non parametric 
analysis. 
INCLUSION AND EXCLUSION CRITERIA:  
Inclusion criteria: 
The participants have to meet all of the following criteria to be eligible to enter the study: 
• 
Willing and able to provide informed consent 
• 
Male or female and aged 18 years or above 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 5 of 65 
 
• 
Volunteers able to read and understand English  
• 
A personal history of atopic dermatitis  
Exclusion criteria: 
Participants meeting any of the following criteria will not be permitted to enter the study: 
• 
Eczema on the volar forearms requiring anti-inflammatory treatment 
• 
Possible allergy to ingredients in the study medications. 
• 
Any serious current medical condition which, in the opinion of the Investigator, may interfere with 
the evaluation of the results or may be contraindicated by the use of the test medications 
• 
Use of any concomitant medication that may interfere with the study related activities or 
assessment of efficacy, as judged by the Investigator 
• 
Use of any topical product, including cosmetic leave-on products on the volar forearms, within 1 
week prior to, and throughout the study 
• 
Female participant who, according to the participant, is pregnant or breast-feeding, or plans to 
become pregnant during the course of the study 
• 
Any participant-related factor suggesting potential poor compliance with study procedures (e.g. 
psychiatric disorders, history of alcohol or substance abuse), as judged by the Investigator 
• 
Enrolment in any interventional study or use of an investigational drug within 3 months prior to 
the screening visit 
• 
Volunteers judged by the PI to be inappropriate for the trial.  
STATISTICAL METHODS:  
The primary analysis will compare the test treatment to no treatment and to the two reference creams in 
terms of change in TEWL and redness between days 31 and 29 (after and before the induction of skin 
irritation). 
These analyses will be carried out on the FAS and PPS. 
Full details of the analyses to be carried out will be detailed in the SAP and will take account of both the 
distribution of the observed data and the matched nature of the data (4 treatment areas per subject).  
Where possible and appropriate the baseline value will be included as a covariate. The secondary 
analyses will be carried out on the FAS and will follow the same analysis plan as the primary analysis 
where baseline data is available (TEWL (baseline to day 19); skin moisturisation as measured by 
capacitance and skin surface dryness; tolerability properties as measured by investigator visual scores 
for redness and objective erythema from 2D colour skin images). 
Skin moisturisation as measured by NMF levels and patient tolerability scores will not be recorded prior 
to treatment and so will be summarised by timepoint and the treatments compared using an appropriate 
analysis, taking account of the distribution of the data and the ‘paired’ nature of the observations. 
STUDY PERIOD: 
First participant first visit is expected to be in Febuary 2019. 
Last participant last visit is expected to be in April 2019. 
 
 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 6 of 65 
 
Figure 1 
Trial flow chart 
 
Screening Visit
Visit 1 – Day 1
Baseline skin assessments
Visit 2
Treatment check
Visit 3 – Day 15
2-week skin assessments
Visit 4 – Day 29
4-week skin assessments
Remove patches (at 
home) – Day 30
Visit 5 – Day 31
Final skin assessments
2-weeks self 
treatment
2-weeks self 
treatment
Participant pathway
1-week washout
 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 7 of 65 
 
Table 1 
Schedule of events 
 
Screeninga 
Visit 1 
Baselinea,b 
Visit 2 
5 days b 
(+/- 2 
days) 
Visit 3 
15 days b 
(+/- 3 
days) 
Visit 4 
29 days b 
 (+/- 3 
days) 
30 days c  
(+/-3 
days) 
Visit 5 
31 days b  
(+/-3 
days) 
Screening & Enrolment: 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
Confirm eligibility  
X 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Screening (& admission) 
X 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
X 
 
 
Reconfirm ascent 
 
X 
X 
X 
X 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
 
X 
Adverse events 
X 
X 
X 
X 
X 
 
X 
Skin assessments: 
 
 
 
 
 
 
 
Acclimatize test sites 
 
X 
 
 
X 
 
X 
TEWL measurement 
 
X 
 
 
X 
 
Xd 
Capacitance measurement 
 
X 
 
 
X 
 
 
Image skin (2D – colour) 
 
X 
 
X 
X 
 
Xd 
Objective redness 
measurement 
 
 
 
 
X 
 
Xd 
Visual grading of redness 
 
 
 
 
X 
 
Xd 
Image skin (3D - roughness) 
 
X 
 
 
X 
 
 
Saliva sample collection 
 
Xe 
 
 
 
 
 
NMF sample collection 
 
 
 
 
X 
 
 
SLS application 
 
 
 
 
X 
 
 
SLS removal 
 
 
 
 
 
X 
 
Measurement of SLS-
exposed skin (TEWL and 
rednessd) 
 
 
 
 
 
 
Xd 
Treatment: 
 
 
 
 
 
 
 
Dispensation of investigative 
products and participant diary 
 
X 
 
 
 
 
 
Instructions to participants 
 
X 
 
 
 
 
 
Supervised product 
application 
 
X 
X 
X 
 
 
 
Review of participant diary 
and weigh treatments 
 
X 
X 
X 
X 
 
 
Collection of participant diary 
 
 
 
 
X 
 
 
Collection of investigational 
products 
 
 
 
 
X 
 
 
a 
The screening and baseline visit may be combined providing sufficient time is given to allow parents to properly 
consider the study.  
b 
Face-to-face meeting 
c  Participants removes SLS-patch after 24 hours and rinses with lukewarm water.  
d 
Measurement of skin irritation only 
e 
Saliva sample collection can be made at any visit 
 
 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 8 of 65 
 
2 
TABLE OF CONTENTS 
Section 
Page 
1 
SYNOPSIS .................................................................................................................... 3 
2 
TABLE OF CONTENTS ................................................................................................ 8 
3 
LIST OF ABBREVIATIONS ........................................................................................ 11 
4 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ............................ 12 
5 
INTRODUCTION ......................................................................................................... 14 
5.1 
Disease Background ........................................................................................ 14 
5.2 
Standard Treatment ......................................................................................... 14 
5.3 
Miniderm Novum .............................................................................................. 15 
5.4 
Study Rationale ................................................................................................ 15 
5.5 
Potential Risks and Benefits ........................................................................... 16 
5.5.1 
The potential risk associated with the intervention ........................... 16 
5.5.2 
The potential for physical and/or psychological harm to participants 17 
5.5.3 
The steps taken to avoid physical and/or psychological harm to 
participants ...................................................................................... 17 
6 
STUDY OBJECTIVES ................................................................................................ 19 
6.1 
Primary Objective ............................................................................................. 19 
6.2 
Secondary Objectives ...................................................................................... 19 
7 
STUDY DESIGN ......................................................................................................... 20 
7.1 
Study Design and Plan-Description ................................................................ 20 
7.2 
Trial Setting ...................................................................................................... 22 
7.3 
Recruitment Period .......................................................................................... 22 
7.4 
Study Period ..................................................................................................... 22 
7.5 
End of Study ..................................................................................................... 22 
8 
INVESTIGATIONAL PLAN ......................................................................................... 23 
8.1.1 
Schedule of events .......................................................................... 23 
8.1.2 
Recruitment ..................................................................................... 24 
8.1.3 
Informed Consent ............................................................................ 25 
8.1.4 
Study Visits ...................................................................................... 26 
8.1.4.1 
Visit 1 (Screening and baseline) ....................................................... 26 
8.1.4.2 
Visit 2 (Review of participant diary and weigh treatments, Day 5 (±3 
days)) ............................................................................................... 27 
8.1.4.3 
Visit 3 (Review of participant diary and weigh treatments, skin image, 
Day 15 (±3 days)) ............................................................................ 27 
8.1.4.4 
Visit 4 (Evaluation of TEWL change, start of SLS exposure, Day 29 
(±3 days)) ......................................................................................... 28 
8.1.4.5 
Visit 5  (Evaluation of TEWL change, Day 31 (±3 days)) .................. 28 
8.2 
Collection of human samples .......................................................................... 30 
8.2.1 
Stratum corneum samples ............................................................... 30 
8.2.2 
Saliva Samples ................................................................................ 30 
9 
SELECTION OF STUDY POPULATION ..................................................................... 31 
9.1 
Number of Participants .................................................................................... 31 
9.2 
Inclusion Criteria .............................................................................................. 31 
9.3 
Exclusion Criteria ............................................................................................. 31 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 9 of 65 
 
9.4 
Restrictions ...................................................................................................... 32 
9.5 
Screening failure .............................................................................................. 33 
9.6 
Removal of Participants from Treatment or Assessment ............................. 33 
9.7 
Premature Termination of the Study ............................................................... 33 
9.8 
Remuneration ................................................................................................... 34 
10 
TREATMENT OF PARTICIPANTS ............................................................................. 35 
10.1 Investigational Products .................................................................................. 35 
10.1.1 
Treatment Regimens........................................................................ 35 
10.1.2 
Identity of Investigational Products ................................................... 35 
10.1.3 
Packaging and Labelling of Investigational Products ........................ 35 
10.1.4 
Storage and Handling of Investigational Products ............................ 36 
10.2 Method of Assigning Participants to Treatment Groups ............................... 36 
10.3 Selection of Doses in the Study ...................................................................... 36 
10.4 Selection and Timing of Dose for Each Participant ....................................... 36 
10.5 Blinding............................................................................................................. 37 
10.6 Prior and Concomitant Therapy ...................................................................... 37 
10.7 Treatment Compliance ..................................................................................... 37 
10.8 Drug Accountability ......................................................................................... 38 
11 
STUDY ASSESSMENTS ............................................................................................ 39 
11.1 Primary and Secondary Endpoints ................................................................. 39 
11.2 Efficacy Variables and Assessments ............................................................. 40 
11.2.1 
Skin irritation testing ......................................................................... 40 
11.2.2 
Trans Epidermal Water Loss ............................................................ 41 
 
2D .................................................................................................... 41 
11.2.3 
Skin Imaging of erythema ................................................................ 41 
11.2.4 
Visual scoring of skin redness .......................................................... 41 
11.2.5 
Objective skin redness ..................................................................... 42 
11.2.6 
Skin capacitance .............................................................................. 42 
11.2.7 
3D Skin Imaging of surface dryness (roughness) ............................. 42 
11.2.8 
Natural Moisturizing Factors (NMF) .................................................. 42 
11.2.9 
Filaggrin mutations ........................................................................... 43 
11.2.10 
Cream Consumption ........................................................................ 43 
11.2.11 
Tolerability ....................................................................................... 43 
11.3 Demographic and Other Baseline Characteristics......................................... 44 
11.3.1 
Demographic and Baseline Data ...................................................... 44 
11.3.2 
Medical History ................................................................................ 44 
11.3.3 
Prior and Concomitant Medication and Therapy ............................... 44 
11.4 Safety Assessments ........................................................................................ 45 
11.5 Appropriateness of Measurements ................................................................. 45 
12 
ADVERSE EVENTS .................................................................................................... 47 
12.1 Definitions ........................................................................................................ 47 
12.1.1 
Adverse Event.................................................................................. 47 
12.1.2 
Adverse Reaction ............................................................................. 47 
12.1.3 
Unexpected Adverse Reaction ......................................................... 47 
12.1.4 
Serious Adverse Event ..................................................................... 47 
12.2 Reporting of Adverse Events .......................................................................... 48 
12.3 Reporting of Serious Adverse Events ............................................................ 50 
12.4 Pregnancy ......................................................................................................... 50 
12.5 Responsibilities ................................................................................................ 51 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 10 of 65 
 
13 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................... 53 
13.1 Statistical and Analytical Plans ....................................................................... 53 
13.1.1 
Data Sets to be Analysed ................................................................. 53 
13.1.2 
Statistical Issues .............................................................................. 53 
13.1.3 
Summary Statistics .......................................................................... 53 
13.1.4 
Primary Efficacy Analysis ................................................................. 54 
13.1.5 
Secondary Efficacy Analyses ........................................................... 54 
13.1.6 
Other Analyses ................................................................................ 54 
13.1.7 
Demographic and Other Baseline Characteristics ............................ 54 
13.1.8 
Exposure to Treatment and Treatment Compliance ......................... 55 
13.1.9 
Adverse Events ................................................................................ 55 
13.2 Determination of Sample Size ......................................................................... 55 
13.3 Procedures for Reporting any Deviation(s) from the Original Statistical 
Analysis plan .................................................................................................... 56 
14 
INVESTIGATOR/SPONSOR RESPONSIBILITIES ..................................................... 57 
14.1 Ethics ................................................................................................................ 57 
14.1.1 
Independent Ethics Committee (IEC) ............................................... 57 
14.1.2 
Ethical Conduct of the Study ............................................................ 57 
14.1.3 
Participant Information and Consent ................................................ 57 
14.2 Participant Records and Source Data............................................................. 57 
14.3 Access to Source Data and Documentation................................................... 58 
14.4 Monitoring ........................................................................................................ 59 
14.5 Data Management ............................................................................................ 59 
14.6 Quality Assurance and Audit .......................................................................... 60 
14.7 Record Retention ............................................................................................. 60 
14.8 Protocol Deviations.......................................................................................... 60 
14.9 Insurance .......................................................................................................... 60 
14.10 Report and Publication .................................................................................... 60 
15 
REFERENCE LIST ..................................................................................................... 62 
16 
SIGNATURES .................................................... ERROR! BOOKMARK NOT DEFINED. 
17 
CLINICAL STUDY PROTOCOL AGREEMENT FORM....... ERROR! BOOKMARK NOT 
DEFINED. 
18 
APPENDICES ............................................................................................................. 65 
 
LIST OF TABLES 
Table 1 
Schedule of events ............................................................................................... 7 
Table 2 
Schedule of events ............................................................................................. 24 
 
LIST OF FIGURES 
Figure 1 
Trial flow chart ...................................................................................................... 6 
Figure 2 
Overall Study Design ....................................................................................... 21 
 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 11 of 65 
 
3 
LIST OF ABBREVIATIONS  
AD 
Atopic Dermatitis 
AE 
AR 
Adverse Event 
Adverse Reaction 
CA 
Competent Authority 
CRF 
CRO 
Case Report Form 
Contract Research Organisation 
FAS 
EudraCT 
Full Analysis Set 
European Clinical Trials Database 
GCP 
IB 
ICF 
Good Clinical Practice 
Investigator Brochure 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
NMF 
PI 
PIS 
Independent Ethics Committee 
Natural Moisturising Factor 
Principal Investigator 
Patient Information Sheet 
PPS 
Per Protocol Set 
QoL 
PPS 
REC 
Quality of Life 
Per-Protocol Set 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAP 
SLS 
Statistical Analysis Plan 
Sodium Lauryl Sulfate 
SOP 
Standard Operating Procedure 
TEWL 
Transepidermal Water Loss 
 
 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 12 of 65 
 
4 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
PRINCIPAL INVESTIGATORS 
Name: 
Professor Michael J Cork, Professor of Dermatology at the University of Sheffield, 
Consultant Pediatric Dermatologist at the Sheffield Children’s Hospital NHS Trust 
and Consultant Dermatologist at the Sheffield Teaching Hospitals NHS 
Foundation Trust  
Address: 
The University of Sheffield Medical School (K125),  
 
Beech Hill Road,  
 
Sheffield S10 2RX 
Phone: 
0114 2712933 
E-mail: 
m.j.cork@sheffield.ac.uk 
 
 
Name: 
Dr Simon Danby BSc (Hon) PhD, Independent Research Fellow  
Address: 
The University of Sheffield Medical School (K123),  
Beech Hill Road,  
Sheffield S10 2RX 
Phone: 
0114 2159563 
E-mail: 
s.danby@sheffield.ac.uk 
 
SPONSOR’S STUDY DIRECTOR 
Name: 
Anneleen Spooren, PhD, Director R&D & Innovation CHCI 
Address: 
Perrigo 
 
Venecoweg 26 
 
B-9810 Nazareth 
 
Belgium 
 
Phone: 
+32 494 40 30 00 
E-mail: 
anneleen.spooren@perrigo.com 
 
CLINICAL RESEARCH FACILITY 
Name: 
Dermatology Research CRF, The University of Sheffield 
Address: 
The Royal Hallamshire Hospital, B Road, Sheffield S10 2RX 
Phone: 
0114 2159563 
E-mail:  
s.danby@sheffield.ac.uk, dermatologyresearch@sheffield.ac.uk 
 
 
CONTRACT RESEARCH ORGANISATION 
Name: 
TFS Develop 
Address: 
Brook House, 54A, Cowley Mill Road, Uxbridge, Middlesex, UB8 2QE 
Phone: 
07584 778 388 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 13 of 65 
 
 
 
BIOSTATISTICIAN 
Name: 
Rosie Taylor MSc CStat, Principal Consultant 
Address: 
The Statistical Services Unit, University of Sheffield, Hicks Building, Hounsfield 
Road, Sheffield, S3 7RH 
Phone: 
+44 (0)114 222 3900 
E-mail: 
r.n.taylor@sheffield.ac.uk 
 
PROTOCOL AUTHOR 
Name: 
Tina Holm, PhD, Innovation Manager 
Address: 
Perrigo Nordic  
 
Kistagangen 20B 
 
S-164 07 Kista 
 
Sweden 
 
Phone: 
+46 (0)732 744 113 
E-mail: 
 tina.holm@perrigo.com 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 14 of 65 
 
5 
INTRODUCTION 
5.1 
Disease Background 
Atopic dermatitis (AD) is among the most common chronic types of inflammatory skin disease. 
AD is a relapsing and remitting disease characterised by exacerbations or relapses over years. 
The symptoms, e.g. pruritus, erythema, scaling, vesiculation, weeping, crusting, and 
lichenification have considerable impact on the patient’s quality of life (QoL) (1). The disease 
predominantly affects children (2).  
AD is a multifactorial disease that is influenced by inheritance as well as the environment. The 
patients have a genetically impaired stratum corneum barrier (3). The skin barrier integrity can 
be evaluated by measuring the transepidermal water loss (TEWL), which is increased in both dry 
skin and clinically normal skin in AD patients (4, 5). A major predisposing factor for the disease 
is mutations in the filaggrin gene (6-8). 
Increased TEWL has been suggested to induce pathological effects by over-stimulating 
cytokines in the skin. The immunological response may result in flare-ups; red, scaly, itching, 
and inflamed patches (9, 10). Elevation of TEWL may therefore be regarded as a risk factor for 
developing flare-ups/eczema. Consequently the improvement of the defect barrier function is 
likely to prevent persistent dermatitis by mitigating the cytokine cascade (10). 
 
5.2 
Standard Treatment 
Moisturising creams are the most prescribed products in dermatology and the market is still 
increasing. The use of moisturisers in AD is almost instinctive and is emphasised by healthcare 
personnel, also when the eczema is cleared (11). Moisturiser therapy is suggested to prolong 
the clinical improvement after discontinuation with anti-inflammatory treatment (12) and to 
enhance degree of clearance of the eczema in AD (13, 14) i.e. moisturizers were found to be 
steroid-sparing (15). 
A reduced risk of AD relapse may be expected by strengthening of an impaired barrier function, 
since an abnormal stratum corneum has been suggested to be the primary exacerbant of 
inflammatory skin diseases. However, differences among moisturisers have been noted and 
three different patterns are noted in skin barrier disorders:  
1. The elevated TEWL level may remain unchanged (i.e. no influence of the barrier) (16, 
17) 
2. TEWL could increase further (i.e. weakening of the barrier) (18, 19) 
3. TEWL could decrease towards normal values (i.e. improvement of the barrier) (20) 
Therefore, the benefit of a general use of moisturisers has been questioned (21) and finding the 
most suitable product for an individual is currently a matter of trial and error. Furthermore, when 
applying creams on impaired skin, the patients may experience local side effects like stinging 
and burning sensations (22, 23). These side effects may negatively affect compliance to 
treatment. Hence, the influence on moisturisers is far from elucidated and more clinical studies 
are considered indispensable. 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 15 of 65 
 
The influence on moisturisers is far from elucidated and more clinical studies are considered 
necessary to investigate the influence of the skin barrier function. 
The investigational product is an oil-in-water emulsion with two active ingredients, urea 
(carbamide) at 2 % and glycerol (glycerine) at 20 %. In addition, it consists of a mixture of oils 
and waxes that have a documented beneficial emollient effect on the skin including the 
hydrogenated canola oil.   
Several studies have shown that urea-containing creams relieve clinical signs of dryness (24, 
25). Previous studies have shown that application of an emulsion with 5% urea improves skin 
barrier function to water, (i.e. reduces TEWL) (26-29) on atopic skin as well as normal skin and 
reduces skin susceptibility to surfactant-induced irritation (20, 29).  
These findings suggest a reduced risk for the recurrence of AD by daily treatment with a 
moisturiser. This was later confirmed in two clinical trials: 
• Treatment with 5% urea emulsion in patients with clear/almost clear AD resulted in 
significantly longer time to relapse vs untreated control group (30) 
• Treatment with 5% urea emulsion in patients with clear/almost clear resulted in 
significantly lower risk of relapse and significantly longer time to relapse vs reference 
cream with no humectants (31)  
Moreover, the 5% urea emulsion was well-tolerated in patients with atopic dermatitis. All patients 
in this relapse prevention study was above 18 years old.  
Several studies on glycerol-containing creams suggest that the creams increase skin hydration 
(32, 33) and relieve clinical signs of dryness (24). Furthermore, a recent systematic Cochrane 
meta-analysis concluded that there is moderate to high quality evidence that glycerol-containing 
moisturizers are more effective than ’vehicle’ or placebo (34). 
5.3 
Miniderm Novum 
The investigational product is an oil-in-water emulsion with two active ingredients, urea 
(carbamide) at 2 % and glycerol (glycerine) at 20 %, giving the product water binding properties.  
5.4 
Study Rationale 
The product is intended for people with dry skin symptoms, such as dryness (xerosis), itching 
(pruritus), and flaking in people with dry skin of different origin, e.g.: atopic dermatitis, contact 
dermatitis and psoriasis. The target population is infants and children but may also be a 
treatment option for adults, when relevant.  
As most people with dry skin of different origin have an impaired skin barrier function, it is 
important to investigate the possible influence on the skin barrier after long-term (several 
weeks’) treatment.  
This study is the first step in a sequence of studies investigating the effect of the newly 
developed moisturising emulsion Miniderm Novum. The primary objective of this study is to 
investigate the skin barrier strengthening effect and the tolerability of Miniderm Novum in adults, 
before continuing to investigate the potential of Miniderm Novum in children. Clinical trials 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 16 of 65 
 
following the trial presented in this protocol will be performed on children (relapse prevention 
study) and high-risk infants (primary prevention study). 
The comparator creams are Minderm 20% cream and Diprobase cream. Miniderm 20% cream 
contains commonly used cream ingredients and the humectant glycerol. It has been shown to 
neither improve nor impair the skin barrier function in patients with AD (35). The reference 
product Diprobase cream contains commonly used cream ingredients (cetomacrogol, cetostearyl 
alcohol, liquid paraffin, white soft paraffin), but no humectant. It was used in the pilot study by 
Simpson et al (36) showing that emollient enhancement of the skin barrier from birth offers 
effective atopic dermatitis prevention, and is one of the creams in the ongoing NIHR Health 
Technology Assessment (HTA) Barrier Enhancement Eczema Prevention (BEEP) study 
(https://www.nottingham.ac.uk/research/groups/cebd/projects/1eczema/beep-maintrial.aspx).  
It is of utmost importance to evaluate different moisturisers head-to-head in order to facilitate an 
evidence-based choice of moisturiser. 
5.5 
Potential Risks and Benefits 
The overall risks for the participants participating in the study are considered to be negligible. 
The potential benefits come from the development of an emollient with skin barrier strengthening 
effect but reduced risk of stinging sensation that might impact compliance.  
5.5.1 The potential risk associated with the intervention 
Adverse effects commonly reported after treatment with moisturising products are local 
sensations of burning and heat. It is well known that topical preparations may cause transient 
disagreeable sensations immediately after application.  
The study involves the repeated use of a topical skin care product that is not currently marketed. 
The product has been formulated using only ingredients already regarded as safe for topical use 
in humans. The formulation of the test product has also been reviewed independently for safety 
and is considered safe for human testing. The actives, urea and glycerol, have a long history of 
use in emollients and the reported use concentrations in cosmetics are up to 10% and 79%, 
respectively. The concentration of urea and glycerol in Miniderm Novum is 2% and 20%, 
respectively. All ingredients, except two, have a long history of safe use and are used in other 
licensed medicinal emollients marketed by ACO Hud Nordic on the Nordic market, i.e. 
Canoderm, Miniderm, Hyderm and Fenuril. The two new ingredients are panthenol and triacetin. 
Panthenol is added for its soothing function and it is commonly used in emollients targeted for 
children, i.e. Bepanthen. Triacetin is added to stabilize the urea and it is only present at 1%. 
Both ingredients have been evaluated in the Investigator’s Brochure and are regarded as safe to 
use. Whilst the risk is therefore minimal there is always a chance that someone may experience 
an adverse reaction to a topically applied product. The risk of this occurring will be minimized by 
excluding individuals who have previously reacted to products containing any of the ingredients 
in the test products (or similar complete formulations). The first product application will be made 
by the research team on site so that they can monitor any adverse skin changes. A 
Dermatologist is on-call throughout the study to treat any serious adverse reactions. 
The study team includes medically qualified clinical researchers, who will be available 
throughout the trial. Due to the low risk of the intervention and the mechanistic design of the 
study involving volunteers from the general population (participants are not selected based upon 
their use of NHS services) the PI may delegate activities, including informed consent and 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 17 of 65 
 
medical history taking (facilitated using the medical history form), to non-medically qualified and 
otherwise appropriately trained researchers. Because not all participants will be undergoing 
treatment for their eczema, and because the intervention is not herein being used 
therapeutically, GP’s will not ordinarily be contacted about the study unless the PI determines 
they need to be made aware of an adverse event. For this reason, GP contact details will be 
collected upon enrollment. 
 
Risk category 
Justification 
Type A: No higher risk than the risk of 
standard medical care 
The intervention comprises active substances 
(urea at 2 % and glycerol at 20 %) part of other 
medicinal products licenced in the EU. 
Reduction in risk from Type B is justified based 
upon the extensive clinical and cosmetic use of 
the product ingredients and there is no reason 
to suspect a different safety profile in this study 
population 
 
5.5.2 The potential for physical and/or psychological harm to participants 
This study involves a series of harmless procedures to test the properties of the skin. All types of 
procedures to test the skin are non-invasive and have been used safely in previous clinical 
studies, and so the risks of harm are minimal. 
Patch testing is performed using the standard skin irritant sodium lauryl sulfate (SLS). This is 
done to assess the sensitivity of the skin, and a mild irritant reaction is expected to evolve that 
will pass in a few days. The level of reaction, ranging from barely perceptible to prominent 
redness, varies between individuals. The test is routine in dermatology clinics. SLS is a common 
ingredient in cosmetic and household wash products such as shampoo and toothpaste. The 
patched site may become dry and require the use of a moisturizer. 
The risk of psychological distress is also low. Our questions are limited to the collection of basic 
demographic information, information about the participants skin history and details of any 
medical conditions and current treatments for safety monitoring purposes. We have limited the 
test sites to the forearms and clearly specify the test sites in the participant information. If at any 
point a participant becomes uncomfortable or distressed (however unlikely) we will cease 
procedures immediately and will only resume the study with the participant’s assent once they 
are comfortable/relaxed (which may be at a later date if possible within the bounds of the study). 
We will not enroll/continue to include participants who remain visibly uncomfortable or 
distressed. 
5.5.3 The steps taken to avoid physical and/or psychological harm to participants 
The following steps will be taken to protect participants from physical and/or psychological harm: 
• 
Informed consent will be performed, and we will make it clear to all participants that 
participation is entirely voluntary and that they are free to withdraw at any time. 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 18 of 65 
 
• 
Participants will be notified in advance of the anatomical locations we are interested in 
(forearms only) and encouraged to wear appropriate clothing. 
• 
Experienced members of staff who have received appropriate training will conduct all of 
the test procedures.  
• 
The equipment regularly undergoes biomedical engineering testing for safety. 
• 
Individual procedures will only be performed with participant assent (in addition to 
consent), and where participants feel discomfort we will cease the procedures and offer a 
break – we would then only continue with assent. 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 19 of 65 
 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
The primary objective is to determine whether applying a new moisturizing cream (the test cream) for 4 
weeks is superior in terms of skin barrier strengthening, when compared with (1) no treatment and (2) two 
reference creams in adults with a predisposition to a skin barrier defect.  
• 
TEWL after induction of skin irritation 
• 
Redness after induction of skin irritation 
 
The hypotheses for the study are provided below in order of importance: 
a) Skin irritation, indicated by elevated TEWL and redness, will be reduced following treatment with the  
test cream compared to the untreated control. 
b) Skin irritation, indicated by elevated TEWL and redness, will be reduced following treatment with the 
test cream compared to the reference creams, Miniderm 20% cream and Diprobase cream. 
 
6.2 
Secondary Objectives 
Secondary objectives: To determine whether there is a difference between the new moisturising cream 
(the test cream) and (1) no treatment and (2) the two reference creams in: 
• 
Resting skin barrier function  
• 
Skin moisturisation 
• 
Tolerability 
• 
Cream consumption 
• 
Safety 
 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 20 of 65 
 
7 
STUDY DESIGN 
7.1 
Study Design and Plan-Description 
A prospective phase 2 within-subject multilateral randomised controlled trial to determine the 
superiority of the test treatment at strengthening the skin barrier compared to no treatment and 
two reference treatments in adults with a predisposition to a skin barrier defect. 
Participants will treat their lower volar forearms for 28 days with three different creams (Miniderm 
Novum (test cream), Miniderm 20% cream or Diprobase cream) and leave one area untreated 
as a control. Each forearm will have two different treatment areas and treatment allocation will 
be randomized (right arm upper, right arm lower, left arm upper, left arm lower). One Finger Tip 
Unit (FTU) of each cream will be applied twice daily on the designated study area. As such there 
will be four treatment conditions (with each participant undertaking all 4 treatment conditions): 
1. No treatment (control), 
2. Miniderm Novum (test cream),  
3. Miniderm 20% cream or  
4. Diprobase cream 
 
Study overview: 
 
 
The participants will record details of cream application frequency, as well as participant 
tolerability in a diary. At each study visit, concomitant medication and any AEs are noted in the 
Case Report Form (CRF). The study medication will be collected and weighed in order to 
estimate cream consumption. 
Participants will attend 5 clinic visits during the study: 
• 
Visit 1 (screening) will be performed at baseline  
• 
Visit 2 will be performed after 5 days of treatment  
SIT
SIT
SIT
SIT
No treatment
Diprobase cream
Day:
1
5
31
V1
V4
8
15
22
29
V5
V2
V3
Visit:
Miniderm Novum (test cream)
Miniderm 20% cream
BLUE
Left lower 
forearm
___________
RED
Left upper 
forearm
___________
PURPLE
Right lower 
forearm
___________
GREEN
Right upper 
forearm
___________
Your 
Left
Your 
Right
Randomized site allocation
*SIT, Skin Irritation Test of skin barrier strength


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 21 of 65 
 
• 
Visit 3 will be performed after 15 days of treatment  
• 
Visit 4 will be performed after 29 days of treatment  
• 
Visit 5 will be performed 1 day after SLS-patch removal (Day 31 after start of treatment) 
The study design is visualised in Figure 2. 
 
Figure 2 
Overall Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Visit
Visit 1 – Day 1
Baseline skin assessments
Visit 2
Treatment check
Visit 3 – Day 15
2-week skin assessments
Visit 4 – Day 29
4-week skin assessments
Remove patches (at 
home) – Day 30
Visit 5 – Day 31
Final skin assessments
2-weeks self 
treatment
2-weeks self 
treatment
Participant pathway
1-week washout


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 22 of 65 
 
7.2 
Trial Setting 
This single-centre trial will be conducted The Sheffield Dermatology Research Clinical Research 
Facility. 
Sheffield Dermatology Research,  
The University of Sheffield,  
The Royal Hallamshire Hospital, B-Road,  
Sheffield S10 2TN 
Phone: 0114 2159563 
Email: s.danby@sheffield.ac.uk, dermatologyresearch@sheffield.ac.uk 
7.3 
Recruitment Period 
The expected recruitment period is 3 months. This is calculated to be sufficient to include 50 
participants with a mean accrual rate of 3.3 participants per week.  
7.4 
Study Period 
First participant first visit is expected to be in February 2019.  
Last participant last visit is expected to be in April 2019. 
7.5 
End of Study 
The end of study is defined as the date of the last participant’s last visit.  
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 23 of 65 
 
8 
INVESTIGATIONAL PLAN 
8.1.1 Schedule of events 
The schedule of events for the study is shown in Error! Reference source not found..  


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 24 of 65 
 
Table 2 
Schedule of events 
 
Screeninga 
Visit 1 
Baselinea,b 
Visit 2 
5 days b 
(+/- 2 
days) 
Visit 3 
15 days b 
(+/- 3 
days) 
Visit 4 
29 days b 
 (+/- 3 
days) 
30 days c  
(+/-3 
days) 
Visit 5 
31 days b  
(+/-3 
days) 
Screening & Enrolment: 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
Confirm eligibility  
X 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Screening (& admission) 
X 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
X 
 
 
Reconfirm ascent 
 
X 
X 
X 
X 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
 
X 
Adverse events 
X 
X 
X 
X 
X 
 
X 
Skin assessments: 
 
 
 
 
 
 
 
Acclimatize test sites 
 
X 
 
 
X 
 
X 
TEWL measurement 
 
X 
 
 
X 
 
Xd 
Capacitance measurement 
 
X 
 
 
X 
 
 
Image skin (2D – colour) 
 
X 
 
X 
X 
 
Xd 
Objective redness 
measurement 
 
 
 
 
X 
 
Xd 
Visual grading of redness 
 
 
 
 
X 
 
Xd 
Image skin (3D - roughness) 
 
X 
 
 
X 
 
 
Saliva sample collection 
 
X 
 
 
 
 
 
NMF sample collection 
 
 
 
 
X 
 
 
SLS application 
 
 
 
 
X 
 
 
SLS removal 
 
 
 
 
 
X 
 
Measurement of SLS-
exposed skin (TEWL and 
rednessd) 
 
 
 
 
 
 
Xd 
Treatment: 
 
 
 
 
 
 
 
Dispensation of investigative 
products and participant diary 
 
X 
 
 
 
 
 
Instructions to participants 
 
X 
 
 
 
 
 
Supervised product 
application 
 
X 
X 
X 
X 
 
 
Review of participant diary 
and weigh treatments 
 
X 
X 
X 
X 
 
 
Collection of participant diary 
 
 
 
 
X 
 
 
Collection of investigational 
products 
 
 
 
 
X 
 
 
a 
The screening and baseline visit may be combined providing sufficient time is given to allow parents to properly 
consider the study.  
b 
Face-to-face meeting 
c  Participants removes SLS-patch after 24 hours and rinses with lukewarm water.  
d 
Measurement of skin irritation only 
 
8.1.2 Recruitment 
Recruitment will be conducted in several ways: 


NOVA - Skin Barrier Clinical Study Protocol 
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Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
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Confidential 
Page 25 of 65 
 
1. General advertisement using posters (see attached PosterAdvert and AltMediaAdvert). 
The poster contains telephone and email contact details for the study team. Posters (see 
attached) will be displayed at: 
a. The University of Sheffield premises, including the Medical School 
b. Sheffield Hallam University (SHU) premises, with permission 
c. Online, on the University of Sheffield website, SHU website (student portal), 
Facebook, Twitter, including @Shef_Derm Twitter pages 
2. Email lists. An email, containing the information in the *Advert (and a copy of the 
Participant Information sheet, PIS), will be distributed to:  
a. an email list of people who have either expressed an interest in or have taken 
part in our research projects previously (where consent has been provided to do 
this)  
b. staff and students at the University of Sheffield, and SHU using the appropriate 
moderated email lists at each institution. 
The study office will handle all expressions of interest. Participants responding to our 
adverts/letters by phone/email will be asked to complete a registration form/expression of 
interest form (this may be done by phone/email/post).  
 
8.1.3 Informed Consent 
People responding to study advertisements will be provided with a Participant Information Sheet 
(PIS) and a study Registration Form.  
 
A member of the study team will then contact interested volunteers to arrange a screening visit 
at the test centre. While it is preferable to conduct the screening visit in person, it can be 
conducted by telephone at the participants request.  
 
A screening number will be assigned using the SDR Subject Screening Log at the point of first 
contact to record approaches. 
 
At the start of the screening visit (at least 24 hours after provision of the PIS), a study researcher 
(as delegated by the PI), trained in informed consent taking, will conduct the informed consent 
process. All participants will be provided with a Consent Form to sign, of which they will be 
provided a copy to keep.  
 
Following Informed Consent, we will complete the study Registration Form (if not already 
complete), the Background Information Form (includes medical history), together with the NESS 
Body Map form, and determine whether the participant meets the inclusion/exclusion criteria 
detailed on the Admission Form.  
 
Upon successful screening, all study appointments will be arranged such that participants have 
undergone a 1-week wash-out period for any topical products (excludes wash products) they 
may use on the skin of their test sites.  
 


NOVA - Skin Barrier Clinical Study Protocol 
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Version: Version 3.0 
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Date: 15 August 2019 
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Confidential 
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A screening number will be assigned using the Screening, Enrolment and Completion Log at the 
point of first contact to record approaches. 
 
The Enrolment Log will be completed and all enrolled participants assigned a unique study ID.  
 
Note for remote screening sessions: Where the screening is conducted by telephone the 
participants will be notified of the inclusion and exclusion criteria and asked to confirm whether 
they think they meet the criteria or not without further discussion or collection of the participants 
medical history. This will help minimise the number of volunteers who are invited to the test site 
who are then found to be unsuitable upon completion of screening, whilst also protecting the 
participants privacy. Under these circumstances Consent, Screening, and completion of the 
Background Information Form will need to be undertaken at the start of Visit 1.  
 
8.1.4 Study Visits 
The study assessments described in the sections below are presented in detail in Section 11.2 
(efficacy assessments), Section 11.3 (demographic data and baseline characteristics) and 
Section 11.4 (safety assessments). Recording and reporting of AEs are described in detail in 
Section 12. 
The timing of all study events is shown in Error! Reference source not found. in Section 8.1.1. 
 
8.1.4.1 Visit 1 (Screening and baseline) 
Before any study specific procedures are performed, the participants will sign the informed 
consent form. After written informed consent has been obtained, the following assessments and 
activities will be performed: 
• 
History of AD will be diagnosed according to UK working party criteria (37) (see also 
Section 9.2) 
o According to the UK working party diagnostic criteria (37), eczema is defined as 
exhibiting an itchy skin condition in the past 12 months plus 3 or more of: 
▪ 
History of involvement of the skin creases 
▪ 
Personal history of asthma or hay fever 
▪ 
History of generally dry skin in past year 
▪ 
Visible flexural dermatitis 
▪ 
Onset below age 2 
• 
Demographic data and baseline characteristics will be recorded (sex, date of birth, race)  
• 
Medical history will be recorded 
• 
Prior (see section 8.3 for details) and concomitant medication will be recorded 
• 
Inclusion and exclusion criteria will be evaluated 
• 
Eligible participants will be given a participant number 


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• 
Participant randomization 
• 
AE recording will start 
• 
The test sites will be acclimatized to the room conditions for ≥20 minutes 
• 
Baseline measurements will be performed 
o Measurement of Trans Epidermal Water Loss (TEWL) 
o Measurement of skin capacitance 
o 3D skin images captured (roughness evaluation) 
o 2D skin images captured (colour evaluation) 
• 
Collect a saliva sample for genotyping 
• 
Study creams (weighed) will be dispensed 
• 
Diary will be handed out (for recording cream application and tolerability) 
• 
The researcher will provide instructions to the participant 
• 
The participant will be asked to perform the first treatment applications under supervision 
• 
The first patient-orientated skin tolerability assessment will be recorded in the diary buy 
the participant 
The participants will start applying the creams on the same day as Visit 1 is performed.  
Before leaving the clinic, the participants will be informed about the restriction criteria and they 
will be instructed to return to the clinic 29 days (±3 days) later for measurement of TEWL and 
skin capacitance. The participant will also be instructed how to fill out the diary and to bring the 
investigational products to the last visit. 
 
8.1.4.2 Visit 2 (Review of participant diary and weigh treatments, Day 5 (±3 days)) 
At Visit 2, the following assessments and activities will be performed: 
• 
Review of participant diary 
• 
Weigh test and reference products 
• 
AEs recorded 
• 
Concomitant medications will be recorded  
• 
Remind the participant to complete the second patient-orientated skin tolerability 
assessment in the diary  
 
8.1.4.3 Visit 3 (Review of participant diary and weigh treatments, skin image, Day 15 (±3 
days)) 
At Visit 3, the following assessments and activities will be performed: 
• 
Review of participant diary 


NOVA - Skin Barrier Clinical Study Protocol 
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• 
Weigh test and reference products 
• 
Image analysis of the skin  
• 
AEs recorded 
• 
Concomitant medications will be recorded 
• 
2D skin images captured (colour evaluation) 
 
8.1.4.4 Visit 4 (Evaluation of TEWL change, start of SLS exposure, Day 29 (±3 days)) 
At Visit 4, the following assessments and activities will be performed: 
• 
Diary will be collected and reviewed 
• 
Ensure the participant has completed the third patient-orientated skin tolerability 
assessment in the diary  
• 
Collect and weigh test and reference products 
• 
Concomitant medications will be recorded 
• 
AEs recorded 
• 
Restriction criteria will be evaluated 
• 
The test sites will be acclimatized to the room conditions for ≥20 minutes 
• 
Skin measurements will be performed 
o Measurement of Trans Epidermal Water Loss (TEWL) 
o Measurement of skin capacitance 
o 3D skin images captured (roughness evaluation) 
o 2D skin images captured (colour evaluation) 
o Objective skin redness will be measured using the Mexameter 
o Visual scoring of redness  
• 
Collect NMF samples  
• 
SLS application 
• 
The researcher will provide instructions to the participant 
 
8.1.4.5 Visit 5  (Evaluation of TEWL change, Day 31 (±3 days)) 
At Day 30, the SLS-patch will be removed by the participant at home and the skin will be left to 
recover for 24 h.  
At Visit 5, the following assessments and activities will be performed: 
• 
Concomitant medications will be recorded 
• 
Restriction criteria will be evaluated 


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• 
The test sites will be acclimatized to the room conditions for ≥20 minutes 
• 
Skin measurements will be performed 
o Measurement of Trans Epidermal Water Loss (TEWL) 
o 2D skin images captured (colour evaluation) 
o Objective skin redness will be measured using the Mexameter 
o Visual scoring of redness  
• 
AEs recorded 
 


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8.2 
Collection of human samples 
The following types of human tissue/biological material will be collected as part of this study: 
1. Stratum corneum samples for quantification of Natural Moisturising Factor (NMF) levels 
2. Saliva Samples to obtain genomic DNA for the determination of FLG gene status. 
The samples will be stored in linked-anonymised form, meaning that they will be labelled with a 
participant ID and participant initials for identification (and not personal identifiable information, 
PII). The link between the participant ID and PII will be kept in the site file and only be accessible 
to the direct study team.  
The samples will be stored at the test site under the custodianship of the PI. All samples, except 
the extracted DNA, will be destroyed within 1 year following the last participants last visit. 
Extracted genomic DNA will be kept under the custodianship of the PI for use in future research 
project, unless specific consent for this is not obtained (separately specified on the ICF). 
8.2.1 Stratum corneum samples 
Superficial skin samples are collected by tape stripping. Tape stripping is a painless procedure 
that removes the dead cells (denucleated corneocytes) from the surface of the skin that will 
eventually be lost/shed as a result of normal desquamation. It can cause some discomfort and 
redness, but any redness usually dissipates in a matter of hours/days. No dressings are 
required. The only skin preparation required before tape stripping is the removal of visible 
contaminants by dry wipe if necessary.  
 
The samples collected by tape-stripping described herein do not meet the definition of relevant 
material under the Human Tissue Act because they contain no viable human cells (corneocytes 
are non-viable terminally differentiated/dead cells). 
8.2.2 Saliva Samples 
A saliva sample will be collected from the inside of the participants cheek during visit 1 in order 
to obtain a sample of genomic DNA. It can be easily collected by the participant themselves. 
Extracted genomic DNA will be genotyped for the 5 most common FLG gene mutations. The 
filaggrin gene (FLG) encodes proteins that are key to the normal barrier function of the skin. Null 
mutations in FLG are associated with an increased risk of eczema. Understanding how these 
mutations affect the responses to topical treatment is therefore of interest. 
 
 
 


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9 
SELECTION OF STUDY POPULATION 
9.1 
Number of Participants 
It is estimated that 50 evaluable participants will be needed (see Section 13.2 for sample size 
calculation).  
9.2 
Inclusion Criteria 
The participants have to meet all of the following criteria to be eligible to enter the study: 
1) Willing and able to provide informed consent 
2) Male or female and aged 18 years or above 
3) Volunteers able to read and understand English  
4) A personal history of atopic dermatitis  
The diagnosis of AD history will be set according to UK working party 1994 (37). 
9.3 
Exclusion Criteria 
Participants meeting any of the following criteria will not be permitted to enter the study: 
1) Eczema on the volar forearms requiring anti-inflammatory treatment 
2) Possible allergy to ingredients in the study medications. 
3) Any serious current medical condition which, in the opinion of the Investigator, may interfere 
with the evaluation of the results or may be contraindicated by the use of the test 
medications 
4) Use of any concomitant medication that may interfere with the study related activities or 
assessment of efficacy, as judged by the Investigator 
5) Use of any topical product, including cosmetic leave-on products on the volar forearms, 
within 1 week prior to, and throughout the study 
6) Female participant who, according to the participant, is pregnant or breast-feeding, or plans 
to become pregnant during the course of the study 
7) Any participant-related factor suggesting potential poor compliance with study procedures 
(e.g. psychiatric disorders, history of alcohol or substance abuse), as judged by the 
Investigator 
8) Enrolment in any interventional study or use of an investigational drug within 3 months prior 
to the screening visit. Cosmetic studies on emollient use are allowed and the wash out 
period is 7 days, as with any emollient used 
9) Volunteers judged by the PI to be inappropriate for the trial.  


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9.4 
Restrictions 
• 
Medications Prohibited >28 Days Prior to Baseline/Day 1 and throughout the study 
o Use of systemic (oral, parenteral) corticosteroids prohibited less than 3 months prior 
to baseline/day 1 and throughout the study 
• 
Medications Prohibited 28 Days Prior to Baseline/Day 1 and throughout the study 
o Use of TCS, or TCI, anywhere on the body. 
o Inhaled glucocorticoids of low to moderate doses for treatment of asthma are allowed 
o Use of systemic immunosuppressive agents, including but not limited to, 
methotrexate, ciclosporin, azathioprine, hydroxychloroquine, and mycophenolate 
mofetil. 
o Tanning bed use, or light therapy Ultraviolet (UV), Ultraviolet B (UV-B), psoralen–UV-
A [PUVA]). 
o Use of topical retinoids. 
• 
Medications Prohibited 14 Days Prior to Baseline/Day 1 and throughout the study 
o Use of systemic antibiotics. 
o Use of topical antihistamines anywhere on the body. 
• 
Medications Prohibited 7 Days Prior to Baseline/Day 1 and throughout the study 
o Use of topical antibacterial medications or products, including antibacterial soaps, 
bleach baths, topical sodium hypochlorite-based products anywhere on the body. 
o Systemic sedating antihistamines (eg, hydroxyzine or diphenhydramine or other 
sedating antihistamines). 
o Use of systemic non-sedating antihistamines in a nonstable (eg, escalating or 
decreasing, or as needed) regimen. Subjects on a stable non-sedating systemic 
antihistamine regimen with ≤7 days of consistent use prior to Visit 1 are permitted to 
continue but must not alter or stop their regimen during the study. 
o Use of bland (non-medicated) emollients, moisturisers or sunscreen on the test 
areas, within 7 days prior to Visit 1. Use of bland (non-medicated) emollient(s) is 
permitted during the study to manage dry skin in areas surrounding but not on or 
overlapping the test areas. 
• 
Medications prohibited from Baseline/Day 1 and throughout the study 
o Use of vasoactive drugs in a non-stable (eg, escalating or decreasing, or as needed) 
regimen including: metaraminol, adrenaline/epinephrine, 
noradrenaline/norepinephrine, phenylephrine, dobutamine, dopamine, dopexamine, 
oxymetazoline. 
o Peroral anti-fungal medication 
o Topical anti-fungal creams on the test areas 


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9.5 
Screening failure 
All individuals who sign the consent form and either (1) withdraw their participation before the 
first assessment/procedure, (2) fail to meet all of the eligibility criteria and/or (3) for technical or 
logistical reasons do not participate in the first assessment session will be considered a 
“screening failure.” 
9.6 
Removal of Participants from Treatment or Assessment 
Participants are free to discontinue their participation in the study at any time. Withdrawal from 
the study will not affect or prejudice the participant’s further care or treatment. Participants may 
be withdrawn from study treatment and assessments at any time, if deemed necessary by the 
Investigator. 
Potential reasons for withdrawal of participants from this study are: 
• 
If a participant decides to withdraw from the study (including if the participant withdraws 
informed consent) 
• 
Intercurrent illness 
• 
If the participant uses any prohibited concomitant medication or treatments listed in 
Section 9.4, at the discretion of the Investigator 
• 
If the participant experiences an unacceptable AE 
• 
If the participant is lost to follow-up 
The reason and date the participant is withdrawn from the study will be documented in the CRF 
(e.g. lost to follow-up, consent withdrawn, incorrect enrolment, AEs, etc.). If a participant is 
withdrawn from further treatment with the investigational creams, the Investigator should 
complete the study termination page of the CRF. All AEs should be followed up in accordance 
with Section 12.2. 
If a participant is withdrawn from the study, all data collected until the time of withdrawal will be 
used in the analyses. 
9.7 
Premature Termination of the Study 
The Investigator or the Sponsor may terminate this study prematurely for any reasonable cause. 
The Independent Ethics Committee(s) (IECs) and Competent Authority(ies) (CAs) should be 
informed promptly.  
Conditions that may warrant termination include, but are not limited to: 
• 
The discovery of an unexpected, significant, or unacceptable risk to the participants 
enrolled in the study, or potential study participants 
If the CA obtains information that raises doubts about the safety or scientific validity of the 
clinical study, the CA can suspend or prohibit the study. Before the CA reaches its decision, it 
shall, except where there is imminent risk, ask the Sponsor and/or the Investigator for their 
opinion, to be delivered within one week (Directive 2001/20/EC, Article 12, Section 1). 


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If the study is prematurely terminated or suspended for any reason, the Investigator/institution 
should promptly inform the study participants and should assure appropriate therapy and follow-
up for the participants. 
9.8 
Remuneration 
All participants enrolled onto the study will be compensated for their time. A payment in Amazon 
Vouchers will be made as follows: 
• 
£100 for completing the study 
This is based upon a rate of £20 per visit to our test site. 
Participants who fail to complete the study, for whatever reason, may claim a proportion of the 
remuneration commensurate with the extent of their participation.  
Travel to and from the test site by taxi will be additionally arranged at our expense (not taken out 
of the remuneration). 


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10 TREATMENT OF PARTICIPANTS 
10.1 
Investigational Products 
10.1.1 Treatment Regimens 
The participants will apply 3 different creams on their lower volar forearms and the treatment 
area will be randomized. One randomized area will be left untreated. One FTU of the creams will 
be applied twice daily for 28 (± 3 days). 
 
10.1.2 Identity of Investigational Products 
The following creams will be used:  
• 
Test cream: Miniderm Novum, moisturising cream containing 2% urea and 20% glycerol 
(no marketing authorization, Investigator´s brochure provided with the protocol) 
• 
Reference cream: Miniderm 20% cream, moisturising cream containing 20% glycerol 
(marketing authorization in Sweden, Norway and Finland, SmPC provided with the 
protocol) 
• 
Reference cream: Diprobase cream (no pharmacologically active component), paraffin 
based cream (marketing authorization, SmPC provided with the protocol) 
 
10.1.3 Packaging and Labelling of Investigational Products 
The test cream will be produced by Pharmavize NV Kleimoer 4, 9030 Mariakerke, Belgium.  
Miniderm 20% cream will be produced by Medgenix Benelux, Vilegveld 21, 8560 Wevelgem, 
Belgium.  
Miniderm Novum and Miniderm 20% cream will be filled in identical plastic tubes of 100 mL at 
Pharmavize.  
Diprobase cream will be used in its original tube of 50 g and labelled as the other products.   
 
The products will be labelled with: 
• 
Name, address and telephone number of the sponsor 
• 
pharmaceutical dosage form, route of administration, quantity of dosage units and the 
identifier of the product 
• 
batch number 
• 
trial reference code 
• 
trial subject identification number 
• 
name of Investigator 


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• 
name of Sponsor 
• 
“directions for use, please see patient diary” 
• 
“For clinical trial use only” 
• 
Storage conditions 
• 
Expiry date in month/year format 
• 
“keep out of reach of children” 
• 
Randomized application site (upper left arm, lower left arm, upper right arm or lower right 
arm) 
 
10.1.4 Storage and Handling of Investigational Products 
All creams in the study should be stored in a locked cupboard below 25°C and out of reach of 
children. Temperature logs throughout the study will be kept. Only personnel authorised by the 
principal investigator should dispense the study medication, and the accountability is the 
responsibility of investigator. The investigator/study nurse/pharmacist must complete and return 
the study medication supply form verifying the receipt of study medication to the study monitor. 
A study medication inventory (dispensing records) for all medication dispensed must be 
maintained at all times and always kept current.  
For application of the creams, please refer to Section 10.4.  
 
10.2 
Method of Assigning Participants to Treatment Groups 
Randomisation (allocation of the treatments to the test sites) will be performed according to a 
randomisation list with balanced allocation to the 4 different test areas (to avoid site-dependent 
effects). Participants eligible for the study will be provided with a participant ID number at Visit 1.   
 
10.3 
Selection of Doses in the Study 
The doses of the creams will be 1 FTU of cream per treatment area. 
 
10.4 
Selection and Timing of Dose for Each Participant 
The creams should be applied morning and evening according to the randomisation for 28 days 
(± 3 days). 
 


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10.5 
Blinding 
The Investigator should keep the randomisation key and the numbering of the products in a 
secure, limited-access location to prevent inadvertent breaking of the blind. In an emergency 
requiring information about the study treatment, the appropriate envelope may be opened and 
the date, time and reason should be recorded and signed by the Investigator or his/her delegate. 
If the code should be broken without prior announcement to the Sponsor, the person who breaks 
the code should inform the Sponsor immediately. 
Data will be collected and entered into the database on an ongoing basis. A clean file 
declaration will take place when all data have been entered and cleaned, and the database will 
then be locked before starting the analyses. 
All study personnel at the clinic, as well as the CRO and Sponsor staff will remain blinded to the 
individual treatments during the study. Miniderm Novum and Miniderm will be packed in identical 
tubes and therefore blinded to both participants and study personnel. Diprobase cream will be 
provided in its original tube and thus not blinded. A product code will be indicated on the label to 
enable identification of the different treatments. The products are labelled upon arrival to the 
clinical research facility and therefore none of the study personnel can discriminate Miniderm 
Novum from Miniderm.  
 
10.6 
Prior and Concomitant Therapy 
The concomitant medication and therapies listed in Section 9.4 should be avoided during the 
study. 
Medication, which is considered necessary for the participants safety and well-being, may be 
given at the discretion of the Investigator. However, concomitant medication administered during 
the study may lead to withdrawal of the participant from the study (see Section 9.6). 
 
10.7 
Treatment Compliance 
Compliance will be noted in the participant diaries. Use of creams will be recorded daily by the 
participants. 
The test and reference creams will also be weighed before dispensing of the creams to the 
participants, during the study at day 5 and 15, and after return of the creams. Cream 
consumption (test or reference creams) based on weight will be calculated in order to analyse 
exposure to treatment. Patients that apply treatment on less than 75% of the days in the study 
period are considered to be violating the protocol and will be excluded from the per protocol 
population. 
 


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10.8 
Drug Accountability 
All study medications supplied for this study should be stored in a secure place. The Investigator 
or designated person at the study site will keep a record of the inventory and dispensing of all 
study medications. The Investigator is responsible for the product accountability.  


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11 STUDY ASSESSMENTS 
11.1 
Primary and Secondary Endpoints 
 
Objectives 
Outcome measures 
Primary 
To determine whether applying 
a new moisturizing cream (the 
test cream) for 4 weeks is 
superior in terms of skin barrier 
strengthening, when compared 
with (1) no treatment and (2) 
two reference creams in adults 
with a predisposition to a skin 
barrier defect.  
1. Trans Epidermal Water Loss (TEWL) after 
induction of skin irritation (TEWL on day 31 – 
TEWL on day 29) 
2. Redness after induction of skin irritation 
(redness on day 31 – TEWL on day 29) 
Secondary 
To determine whether there is 
a difference between the new 
moisturising cream (the test 
cream) and (1) no treatment 
and (2) the two reference 
creams in: 
1. Resting skin barrier 
function  
2. Skin moisturisation 
3. Tolerability 
4. Cream consumption 
5. Safety 
 
1. TEWL after 4 weeks treatment (day 29-
baseline) 
2. Skin moisturisation: 
a. Capacitance measurements (day 29-
baseline)  
b. Skin surface dryness (3D skin images, 
day 29-baseline) 
c. NMF levels on day 29 
3. Tolerability properties: 
a. Participant tolerability scores by VAS 
on day 1, day 5 and day 29  
b. Investigator visual scores for redness 
(day 15 – baseline and day 29 – 
baseline) 
c. Objective erythema from 2D colour 
skin images (day 15 – baseline and 
day 29 – baseline) 
4. Cream consumption after 28 days of treatment 
(g) 
5. Number of adverse events 
Tertiary 
To investigate the number of 
participants with FLG loss-of-
function mutations and 
investigate and relationshhip 
with  treatment effects 
1. Number of FLG loss-of-function mutation 
carriers 
2. Descriptive tabulations of TEWL by mutation 
status, if sufficient participants with mutation 
are detected 
 


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11.2 
Efficacy Variables and Assessments 
Unless otherwise indicated all procedures will be conducted by the investigative team, 
comprising experienced skin/dermatology researchers delegated duties by the PI, at the 
Sheffield Dermatology Research CRF. All assessments will be conducted at each of the 4 
treatment sites in each participant unless otherwise indicated. None of the procedures listed 
would be routinely performed as part of standard clinical care. 
11.2.1 Skin irritation testing 
This test is a previously published method for determining skin sensitivity. It is based upon the 
skin’s response to the standard irritant sodium lauryl sulphate (SLS). Exposure to 1% SLS for 24 
hr under occlusion is followed by evaluation of redness and TEWL readings of the transient 
irritation. The procedure is summarised below: 
1. Demarcate the test sites; upper volar forearms – both sides, 2 patches each (refer to 
“Test Sites”). 
2. Score visible redness for the test sites using the scales provided 
3. Capture skin site images as described above (for determination of erythema index) 
4. Measure objective skin redness (mexameter) and TEWL (as described above) at each 
patch site 
5. Apply Finn Chambers (12mm aluminium chambers on Scanpor tape) containing a filter 
insert and 50μL 1% SLS to designated test sites. Record the time of patch application. 
6. Cover all test sites with a waterproof adhesive membrane (Patch Protect). 
7. Instruct the participants to: 
a. Wash as normal – the dressings are water proof 
b. Contact us if the patches come away before the 24hr period is complete 
c. Remove the patches themselves in 24hrs (day 30) 
d. Wash the skin of their forearms with water after removing the patches, and then 
avoid washing the sites until after the next visit  
e. Not to apply any products to the patch test sites 
8. 24 ± 2 hours after patch removal (48 ± 2 hours after patch application), remark the test 
sites where necessary 
9. Locate/demarcate the test sites 
10. Repeat the visual scoring, image capture and objective assessments of redness, and 
TEWL. 
The procedure is conducted over 49 hours, and involves 60 minutes to conduct the baseline 
assessments, 40 minutes to apply the patches, 10 minutes to remove them 24 hours later and a 
further 60 minutes to evaluate the results.  
 
Quantification of skin irritation will support the two primary efficacy outcomes (further details on 
these variables are provided below): 
1. 
Trans Epidermal Water Loss (TEWL) after induction of skin irritation (TEWL on day 31 – 
TEWL on day 29) 
2. 
Redness after induction of skin irritation (redness on day 31 – TEWL on day 29). 
Redness is measured using the following techniques (described in more detail below): 


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a. 
Visual scoring by the investigator 
b. 
Measurement of skin redness objectively using the Mexameter 
c. 
Determination of the erythema index from 2D skin images 
 
11.2.2 Trans Epidermal Water Loss 
Skin barrier function will be evaluated by measuring the Trans Epidermal Water Loss (TEWL) of 
the untreated area and the areas treated with creams, before and after treatment (secondary 
outcome). TEWL will also be measured before and after induction of skin irritation by application 
of SLS (see “induction of skin irritation”) as a means of quantifying skin irritation (primary 
outcome). TEWL measurements, recorded in g/m2/h, will be performed using an AquaFlux 
AF200 condensing chamber probe (Biox Systems Ltd., London, UK).  
Three repeat TEWL measurements, taking ~2 minutes each, will be collected at each site. 
Measurements will be repeated if an anomaly occurs during measurement (i.e. deviation from a 
typical bell shaped TEWL curve), which can occur if a participant becomes uncomfortable, or if 
the reading appears abnormally low or high. In either event the measurement will not be taken 
until at least 4 minutes has passed from the collection of the first measurement to permit 
restoration of normal TEWL. If TEWL was retaken due to a measurement anomaly the first 
reading will be discarded. If the reading was repeated for any other reason both measurements 
will be recorded the average of all readings will be used for subsequent analysis. After use in 
each participant the probe will be decontaminated with a 70% alcohol wipe.  
All assessments will be performed in a room maintained at 21 ± 2 ° C and 38–50% relative 
humidity according to published guidelines (38). All test sites will be acclimatized to room 
conditions for 20-30 min before assessment. 
 
11.2.3 2D Skin Imaging of erythema 
A single close-up (50x magnification) image of each skin site will be captured using the c-cube 
camera with glass lens (Pixience, France). Each image takes approximately 5 minutes to 
capture. A 16x12mm area of the test site skin is imaged therefore there are no data 
confidentiality concerns. Captured 2D images are analysed to determine the skin erythema 
index (degree of redness, arbitrary numerical value) for the region of interest. This quantitative 
metric supports the primary outcome and the secondary tolerability outcome. The images are 
stored by the c-cube clinical database software within a protocol specific folder locally and on 
the server within the study specific folder.  
 
11.2.4 Visual scoring of skin redness 
Visual redness will be scored by an experienced grader using the scale below to assess both 
tolerability (secondary outcome) and skin irritation following patch/irritation testing (primary 
outcome). The assessment takes no more than 2 minutes. 
 
Table 9.3: Visual assessment scale for erythema 
Score 
Description 
0 
No reaction. 


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0.5 / + Slight, patchy erythema – barely perceptible 
1 
Slight uniform erythema – mild erythema 
2 
Moderate, uniform erythema – Moderate erythema 
3 
Strong erythema – Marked erythema 
 
11.2.5 Objective skin redness 
Skin redness will be measured 3 times within each patch test site using a C&K Mexameter probe 
to quantify SLS-induced skin irritation (primary outcome measure). All 3 measurements (arbitrary 
numerical scale) will be recorded. A fourth measurement should be collected if the variation is 
deemed to be too great (at the discretion of the Investigator), under which circumstance all 4 
measurements will be recorded (no measurement is discarded). After use in each participant the 
probe will be decontaminated with a sanitation/detergent wipe. It takes approximately 5 minutes 
per test site to perform this procedure (20 minutes in total) 
 
11.2.6 Skin capacitance 
Capacitance, an indirect measure of skin water content, will be measured using a Corneometer 
CM825 (CK electronic GmbH, Cologne, Germany). Three repeats will be taken from each test 
site. Between every treatment site the probe head should be cleaned and dried to prevent cross-
over contamination. All 3 measurements will be recorded. A fourth measurement should be 
collected if the variation is deemed to be too great (at the discretion of the Investigator), under 
which circumstance all 4 measurements will be recorded (no measurement is discarded). 
Capacitance units are reported using an arbitrary scale from 0 to 130, where values below 30 
indicate very dry skin and values above 45 indicate sufficiently moisturised skin. It takes 
approximately 5 minutes per test site to perform this procedure (20 minutes in total) 
 
 
11.2.7 3D Skin Imaging of surface dryness (roughness) 
A close-up (50x magnification) image of each skin site will be captured using the c-cube camera 
(Pixience, France) without glass lens. Each image takes approximately 6 minutes to capture. A 
16x12mm area of the test site skin is imaged therefore there are no data confidentiality 
concerns. Captured images are analysed for topographical changes (skin surface roughness in 
this case as a parameter associated with surface dryness). The images are stored by the c-cube 
clinical database software within a protocol specific folder locally and on the server within the 
study specific folder. An arbitrary quantitative metric for surface roughness is derived from the 
images with the c-cube software. 
 
 
11.2.8 Natural Moisturizing Factors (NMF) 
Samples for analysis of stratum corneum NMF levels (including urocanic acid and pyrrolidine 
carboxylic acid) will be collected by tape stripping 


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Tape-stripping involves the repeated application and removal of D-Squame cutaneous stripping 
discs (CuDerm cooperation, Dallas, USA) to/from the skin in a standardised manner.42,46 A 
specially designed plunger is used to exert a standardised pressure (225g/cm2) to each disc. 
Approximately 3 corneocyte layers (incomplete layers/uneven coverage) are removed per disc, 
depending on the participant and the treatment conditions. The amount of stratum 
corneum/corneocytes collected, and the associated depth through the stratum corneum 
sampled, is determined by measuring the amount of corneotypes removed by each disc using 
the SquameScan Device. 
In this case the application and removal of 3 consecutive D-squame discs to a single site 
constitutes a single sample. Two samples will be collected from each sampling site (each of the 
4 treatment areas), comprising tape-strips/discs 1-3 and 4-6, representing different depths 
through the stratum corneum. Samples will be stored at -20oC before extraction and HPLC 
analysis. A quantitative value for the NMF components urocanic acid and pyrrolidine carboxylic 
acid will be obtained. It takes approximately 10 minutes to collect all samples from all 4 
treatment sites.  
 
11.2.9 Filaggrin mutations 
A single saliva sample will be collected from each enrolled participant at Visit 1 to obtain 
genomic DNA for determination of participant FLG gene status. It takes no more than 5 minutes 
to collect the sample, which is done by the participant themselves using a passive spit or 
facilitated swab technique. FLG loss-of-function mutations are a risk factor for AD and 
predispose to more severe disease. Samples will undergo DNA extraction and genotyping at the 
University of Sheffield for the 5 common European loss-of-function FLG mutations that have 
been reported to confer increased AD risk. 
 
11.2.10 
Cream Consumption 
Cream consumption will be based on the weight of the reference and test creams before 
(Visit 1), during (Visit 2 and 3) and after use (Visit 4). The study team will weigh the treatments at 
each visit. 
 
11.2.11 
Tolerability 
The participants will be asked to score the degree of smarting/burning sensation (a sharp, local, 
superficial effect which can be experienced during contact with for example acidic solutions) 
using a VAS scale, at the start of treatment, after 5 days and again after 4 weeks of treatment. 
These participant assessments will be recorded in the treatment diary. The assessments can be 
made at the test site or at the participants home. 
 


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11.3 
Demographic and Other Baseline Characteristics 
The following information will be collected by the investigative team, comprising experienced 
skin/dermatology researchers delegated duties by the PI, at the Sheffield Dermatology Research 
CRF. 
11.3.1 Demographic and Baseline Data 
The following demographic and baseline data will be collected at Visit 1 by the study team as 
part of a guided ‘background information’ questionnaire taking approximately 30 minutes to 
complete: 
• 
Sex 
• 
Date of birth 
• 
Race/ethnicity 
• 
Time since AD diagnosis (at Visit 1) 
• 
Investigator global assessment (IGA) of AD severity 
• 
Time since last flare/episode of AD (according to the participant) 
• 
Number of relapses during last 12 months (at Visit 1) 
 
11.3.2 Medical History 
Medical history according to the participant will be recorded at the screening visit. Changes in 
medical history from the screening visit will be recorded at Visit 1. Medical history will be 
captured as part of the background information questionnaire (above). 
Relevant medical history includes, but is not limited to, asthma and allergy, other skin diseases 
and all chronic conditions. 
 
11.3.3 Prior and Concomitant Medication and Therapy 
Medications and therapies will be recorded on the concomitant medication form. 
At Visit 1, all prior medications (oral and topical) used within 3 weeks prior to screening, as well 
as any topical products or ultraviolet light therapy used on the eczematous areas within 3 weeks 
prior to screening, will be recorded. This will take an average of 15 minutes depending upon the 
number of medications and involve completion of the Concomitant Medication Form. 
During the treatment phase, participants will be asked to fill in any concomitant medication or 
therapy in the diaries. At Visits 4 and 5, information about concomitant medication and therapies 
used will be entered into the concomitant medication form. This is anticipated to take an average 
of 5 minutes per participant per visit. 
 


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11.4 
Safety Assessments 
The safety assessments are limited to recording of AEs. 
AEs will be recorded from Visit 1 to the completion of Visit 5. During the treatment phase, 
participants will record AEs in their diaries. Information about AEs will then be entered into the 
CRF at Visits 4 and 5. An average of 10 minutes has been allocated for AE reporting per 
participant per visit. 
For further information about definitions and reporting of AEs and Serious Adverse Events 
(SAEs), see Section 12 below.  
11.5 
Appropriateness of Measurements 
Instrumental assessment of the skin condition will be used to evaluate the skin barrier function 
as well as skin hydration.  
 
Two instruments to be used, the AquaFlux and the Corneometer, measure the water 
evaporation through the stratum corneum (TEWL) and the surface capacitance, respectively. 
TEWL is elevated when the skin barrier function is disturbed (39). Therefore, in atopic 
participants with active dermatitis, both TEWL and percutaneous absorption of hydrocortisone 
are elevated (40). Also the unaffected skin of atopic participants show increased levels of TEWL 
(4, 5, 41). Measurements of TEWL are considered valuable to demonstrate treatment effects in 
damaged skin. Furthermore, measurements of TEWL are often used to detect irritant effects 
from topical treatment. Induction of skin irritation using the model irritant sodium lauryl sulphate 
(SLS) is a well established method (42). This method is utilized in this protocol to evaluate if the 
creams provide protection from irritation, which is an indication of a skin barrier strengthening 
effect. A protective effect is shown if the TEWL of the area treated with cream is lower after 
induction of irritation, compared with the untreated area. TEWL measurement is a highly 
sensitive and precise measure of SLS irritant effects on skin with dose-effect relationship easily 
demonstrated in the concentration ranges normally used in provocative testing (42).  
 
Data from skin surface capacitance measurements with a Corneometer is though less easy to 
interpret. Corneometer measurements is claimed to reflect the hydration status of the skin. 
However, the reading can be influence by other agents than water, for instance by body hair and 
cream residues (43, 44). The active ingredients in the tested creams, such as urea, can also 
induce changes in keratin dipole orientation by virtue of its protein denaturant properties and 
thereby affect the electrical properties of the skin. Therefore, data from Corneometer 
measurements need careful interpretation. 
 
TEWL measurements will be performed using an AquaFlux AF200 condensing chamber probe 
(Biox Systems Ltd, London, U.K.). Skin surface capacitance will be measured using a 
Corneometer CM825 (CK electronic GmbH, Cologne, Germany). All assessments will be 
performed in a room maintained at 21 ± 2 °C and 38–50% relative humidity according to 
published guidelines.   
 
Invisible skin reactions to topically applied drugs and cosmetics are a common problem among 
subjects who consider their skin as sensitive. The reactions are often purely sensory 
phenomena without clinical expression, making dermatologist or instrumental evaluation 


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impossible. One test method for evaluation of smarting / stinging potential is the grading by the 
subjects themselves (45). The participants are asked to mark in their diary on a 10 cm visual 
analogue scale (VAS) the degree of subjective discomfort following the use of the test creams. 0 
cm represents no discomfort at all and 10 cm the worst possible state. It is considered more 
appropriate that the grading is performed at the participants’ home rather than during the clinical 
visit since the participant will probably give a more accurate rating in conjunction to the 
application of the creams. The degree of discomfort will be graded and evaluated in the 
beginning, after 5 days and at the end of the study. 
 
The criteria used to describe response are widely used and considered to be reliable. 


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12 ADVERSE EVENTS 
12.1 
Definitions 
12.1.1 Adverse Event 
Any untoward medical occurrence in a participant or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. 
Comment: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not considered related to the investigational 
medicinal product. 
If eczema appears on a study area or the untreated control area, the participant should note the 
date in the diary and immediately contact the Investigator in order to have the eczema 
investigated. The participant should continue to treat the eczema with the randomised cream 
until he/she has seen the Investigator. The Investigator judges if the eczema should be 
documented as an AE and if the participant will continue in the study. The participant will then be 
instructed to continue his/her treatment with the randomised cream or discontinue the study. 
12.1.2 Adverse Reaction 
All untoward and unintended responses to an investigational medicinal product related to any 
dose administered. 
Comment: All AEs judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is evidence or 
argument to suggest a causal relationship. 
12.1.3 Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator's Brochure for an unauthorised investigational product or Summary 
of Product Characteristics for an authorised product). 
Comment: When the outcome of the adverse reaction is not consistent with the applicable 
product information this adverse reaction should be considered as unexpected. 
12.1.4 Serious Adverse Event 
Any untoward medicinal occurrence or effect that at any dose: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 


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Comments: Life-threatening in the definition of a serious adverse event (SAE) or serious 
adverse reaction refers to an event in which the participant was at risk of death at the time of 
event; it does not refer to an event which hypothetically might have caused death if it was more 
severe. 
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious in other situations. Important adverse events/reactions that are not immediately life-
threatening or do not result in death or hospitalisation but may jeopardise the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above, should 
also be considered serious. 
12.1.5 Serious Adverse Drug Reaction 
A Serious adverse Drug Reaction (SADR) is an adverse drug reaction which results in death, is 
life-threatening, requires hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, causes a congenital anomaly/birth defect in 
offspring. 
12.1.6 Unexpected Serious Adverse Reaction 
An unexpected serious adverse Drug Reaction is an adverse which complies with the definition 
of a serious adverse reaction and, at the same time, that of an unexpected adverse reaction. 
12.1.7 Suspected Unexpected Serious Adverse Reaction (SUSAR)  
A SUSAR is an adverse reaction that is both unexpected (not consistent with the applicable 
product information) and meets the definition of a Serious Adverse Event in a causal relationship 
with the investigational medicinal product. 
 
12.2 
Reporting of Adverse Events 
All study participants will be carefully monitored for the occurrence of AEs during the study 
period from Visit 1 to the completion of Visit 3. During the treatment phase, the participants will 
record all AEs in their diaries. At each visit, the researcher will then transfer AEs recorded in the 
diaries to the CRF. The Investigator will also collect AEs using a non-leading question such as 
“have you experienced any new health problems or worsening of existing conditions”, as well as 
report any AEs directly observed. 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. 
All AEs including but not limited to events reported by the participant, or reported in answer to an 
open question by the Investigator or member of this team, which fall into any of the above 
definitions must be recorded as an AE in the CRF and should include the following information: 
• 
Brief description of the event (diagnosis) 
• 
Start date (and time, if relevant) 
• 
Stop date (and time, if relevant) (or resolution) 
• 
Severity 


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• 
Action taken regarding study drug 
• 
Opinion on causality 
• 
Seriousness 
• 
Outcome 
Severity 
Severity describes the intensity of an event, and will be assessed as: 
Mild 
The AE does not interfere in a significant manner with the participant’s normal functioning level. 
It may be an annoyance. 
Moderate 
The AE produces some impairment of function but not hazardous to health. It is uncomfortable 
and/or an embarrassment. 
Severe 
The AE produces significant impairment of functioning or incapacitation and/or it is a hazard to 
the participant. 
If an AE changes in severity, the worst severity should be reported. 
Causality 
Causality will be assessed as: 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfil this definition. 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, but which could also be explained by concurrent disease or other 
drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
Unlikely 
A clinical event, including laboratory test abnormality, with a temporal relationship to drug 
administration which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 
Follow-up of Participants after Adverse Events 
Any AE that is ongoing when the participant is withdrawn from the study should be followed up 
until the AE is resolved or the Investigator decides that the AE is stable and needs no further 


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follow-up. The date when the Investigator considers one of these outcomes to have occurred for 
the last ongoing AE for a participant will be considered the last visit for this participant, and the 
outcome should be recorded in the CRF. 
12.3 
Reporting of Serious Adverse Events 
The Investigator is responsible for ensuring that all SAEs are reported to the Sponsor 
immediately, but in any event no later than 24 hours of any site staff becoming aware of the 
event. Initial reports should be followed as soon as possible by detailed written reports. The 
initial and follow-up reports should identify participants by unique code numbers assigned in the 
study rather than by the participants’ names, personal identification numbers, and/or addresses. 
The following information is mandatory for the initial report: 
• 
Participant study ID 
• 
Study treatment (blinded, if applicable) 
• 
Start date (time, if relevant) of the study treatment 
• 
Brief description of the event (diagnosis) 
• 
Start date (time, if relevant) of the event 
• 
Seriousness criteria 
• 
Causality assessment 
All Serious or Unexpected Adverse Events must be reported by e-mail within 24 hours to the 
Sponsor, CHCIGlobalSafety@perrigo.com. Where appropriate, hospitalisation or autopsy 
reports should be made available.  
The sponsor shall ensure that all relevant information about suspected serious unexpected 
adverse reactions that are fatal or life-threatening is recorded and reported as soon as possible 
to the competent authorities in all the Member States concerned, and to the Ethics Committee, 
and in any case no later than seven days after knowledge by the sponsor of such a case, and 
that relevant follow-up information is subsequently communicated within an additional eight 
days.  
All other suspected serious unexpected adverse reactions shall be reported to the competent 
authorities concerned and to the Ethics Committee concerned as soon as possible but within a 
maximum of 15 days of first knowledge by the sponsor. All Serious Adverse Events will be 
followed up until resolution (i.e. asymptomatic, stabilisation or death). 
12.4 
Pregnancy 
Female participants will be instructed to notify the Investigator immediately if they become 
pregnant during the study, but they will not be withdrawn from study treatment. The participants 
will also be instructed to report pregnancies discovered after the last visit, if they believe that 
conception occurred during their participation in the study. 
A pregnancy as such is not an AE, unless there is a possibility that the investigational product 
has interfered with the efficiency of any contraceptive measures. However, the Investigator 


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should report pregnancies according to the procedures and timelines described for reporting of 
SAEs (Section 12.3). Pregnancies do not need to be followed up. 
 
12.5 
Responsibilities 
The following section details the responsibilities for reporting and reviewing AE’s by each party. 
Principal Investigator (PI):  
Checking for AEs and ARs when participants attend for treatment / follow-up. 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in assigning seriousness, causality and whether the 
event/reaction was anticipated using the Reference Safety Information approved for the 
trial. 
3. Ensuring that all SAEs are recorded and reported to the sponsor within 24 hours of 
becoming aware of the event and provide further follow-up information as soon as 
available. Ensuring that SAEs are chased with Sponsor if a record of receipt is not 
received within 2 working days of initial reporting.  
4. Ensuring that AEs and ARs are recorded and reported to the sponsor in line with the 
requirements of the protocol.  
 
Sponsor: (NB where relevant these can be delegated to the CRO) 
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs 
according to the trial protocol onto a database.  
2. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System coding 
to all SAEs and SARs. 
3. Expedited reporting of SUSARs to the Competent Authority (MHRA in UK) and REC 
within required timelines. 
4. The unblinding of a participant for the purpose of expedited SUSAR reporting. In the 
case of SUSAR, the appropriate envelope may be opened and the date, time and reason 
should be recorded and signed by the Investigator or his/her delegate. If the code should 
be broken without prior announcement to the Sponsor, the person who breaks the code 
should inform the Sponsor immediately. 
5. Checking for (annually) and notifying PIs of updates to the Reference Safety Information 
for the trial. 
6. Preparing and final sign off of the Development Safety Update Report (DSUR) as 
required and ensuring timely submission to the MHRA and REC. 
 
Trial Steering Committee (TSC):  


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Due to the mechanistic nature of the study, the short duration and the low risk posed by the 
intervention there will be no TSC for this study. 
 
Data Monitoring Committee (DMC): 
Due to the short duration of the study and the low risk posed by the intervention there will be no 
DMC for this study. 
  


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13 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
13.1 
Statistical and Analytical Plans 
Before the unblinding of the study data, a separate statistical analysis plan (SAP), which will 
provide the technical details of the statistical analysis outlined below, will be prepared and 
approved. 
13.1.1 Data Sets to be Analysed 
The participant population sets are defined as follows: 
Full analysis set (FAS): All participants who are diagnosed with a history of AD and who are 
randomised for the treatment. 
Per-protocol set (PPS): All participants who are deemed to have no major protocol violations 
that could interfere with the objectives of this study. This is a sub-population of the FAS. 
Note: Important violations of eligibility criteria and other deviations from the protocol will be 
assessed in cooperation with the Sponsor. Important deviations from the protocol may lead to 
exclusion of a participant from the PPS.  All deviations will be discussed and agreed prior to the 
unblinding of the data. 
Safety set: All randomised participants who receive at least 1 dose of test or reference cream. 
Although the primary analysis will be performed on both the FAS and the PPS, the FAS will be 
considered the primary analysis population.  Secondary analyses will be performed on the FAS 
only. 
Safety summaries will be performed on the safety set. 
13.1.2 Statistical Issues 
Handling of Drop-outs or Missing Data 
Missing data will not be replaced. The drop out rate will be calculated and analysed. Further 
details will be presented in the SAP. 
Blind Review 
Prior to code breaking, a blind review of the data will be performed. The objective of the review 
is to identify problems and to make decisions regarding data analytical issues under blind 
conditions.  
13.1.3 Summary Statistics 
Data will be summarised using appropriate descriptive statistics such as mean and standard 
deviation, minimum and maximum.  If appropriate, median and quartiles may be presented in 
place of the mean and standard deviation.  Further details will be given in the statistical analysis 
plan. 
Demographic and patient history data collected at screening and baseline visits will be 
summarised. 


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13.1.4 Primary Efficacy Analysis 
The primary analysis will compare the test treatment to no treatment and to the two reference 
creams in terms of change in TEWL and redness between days 31 and 29. 
The statistical analysis technique used must take account of the design of the study, such that 
each participant has four ‘matched’ treatment areas.  In addition, the choice of analysis must 
consider the distribution of the data, as it is likely that both TEWL and redness score will be 
skewed.  Therefore, both transformations combined with parametric tests and non-parametric 
tests which take account of the ‘matched’ nature of the data will be considered.  Where possible 
and appropriate the baseline values will be included as a covariate.  Further details will be 
outlined in the SAP. 
These analyses will be carried out on the FAS and PPS. 
13.1.5 Secondary Efficacy Analyses 
The secondary analyses will compare the test treatment to no treatment and to the two 
reference treatments in terms of change in TEWL and skin moisturisation as measured by 
capacitance and skin surface dryness from baseline to day 29.   
The analyses of these outcomes will follow the same plan as the primary analyses.   
Skin moisturisation as measured by NMF levels will not be recorded at baseline and therefore 
the analysis will compare the treatments in terms of the data observed at day 29 using a suitable 
analysis, taking account of the distribution of the data and the ‘matched’ nature of the 
observations. 
Patient tolerability scores will not be recorded prior to treatment and so will be summarised by 
timepoint (day 1, day 5 and day 29) and the treatments compared using a suitable analysis, 
taking account of the distribution of the data and the ‘paired’ nature of the observations. 
Tolerability properties as measured by investigator visual scores for redness and objective 
erythema from 2D colour skin images:  The change from baseline to day 15 and from baseline to 
day 31 will be compared between treatments using a suitable analysis, in a similar way to the 
primary analyses. 
The secondary analyses will be carried out on the FAS. 
13.1.6 Other Analyses 
The total consumption of the creams (test or reference cream), based on cream weight, will be 
calculated and tabulated descriptively.  If appropriate consideration will be given to including the 
cream consumption as a covariate in the model or in an exploratory analysis of the primary 
endpoints.  
The number of FLG loss-of-function mutation carriers will be summarised.  If sufficient 
participants with the mutation are detected then descriptive tabulations of TEWL by mutation 
status will be presented. 
13.1.7 Demographic and Other Baseline Characteristics 
Participant disposition, demographic and other baseline data will be presented using summary 
statistics. Both the FAS will be used for this presentation. 


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13.1.8 Exposure to Treatment and Treatment Compliance 
For exposure to treatment, the total consumption of the test and reference creams will be 
calculated. The FAS set will be used for this presentation. 
For treatment compliance, data from the participant diaries will be used. 
13.1.9 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities and tabulated by system 
organ class and by preferred term. 
The total number of participants with at least 1 AE and the total number of AEs will be 
presented. 
The number of participants and the number of AEs will be tabulated by system organ class and 
by preferred term. AEs will also be tabulated versus worst severity and worst relationship to 
treatment. Finally, for those AEs which are specifically recorded as related to one of the test 
sites the AEs will be summarised by test site.  A listing, by participant number, will also be 
produced which lists the AEs with worst severity and worst relationship to treatment.  
13.2 
Determination of Sample Size 
The sample size for this study is based on the primary end point, change in TEWL after 
induction of skin irritation (change between day 19 and day 21), with the primary comparison 
being between the test treatment and no treatment and the secondary comparison being 
between the test treatment and the two reference treatments. 
In a similar study the standard deviation of the difference in change in TEWL after induction of 
skin irritation was seen to be approximately 8 g/m2/h when comparing the no treatment group to 
an active treatment. (that is: standard deviation of {[Change after skin irritation in no treatment 
area]-[Change after skin irritation in active treatment area]}). 
When comparing the difference between the test treatment and one of the two reference 
treatments the standard deviation was approximately 3. 
If the assumptions of a paired t-test are found to be valid, for a sample of 40 participants this 
analysis would have >90% power to detect a difference (in change) of 3.5 g/mÇ.h between test 
treatment and no treatment.  The same sample size would also have >90% power to detect a 
difference (in change) of 2 g/mÇ.h between test treatment and active treatment.  If a parametric 
analysis is indicated then an analysis which includes the baseline as a covariate will be 
considered which, if there is variation at baseline may increase the power of the analysis further. 
If the assumptions of a paired t-test are not met (and a suitable transformation cannot be found) 
then a sign test (or a wilcoxon matched pairs test) may be used.  A power calculation can be 
carried out for the sign test (46) although this too makes some assumptions. This calculation 
shows that a sample size of N=40 would have >80% power to detect a difference such that the 
probability of X>0 (where X is the difference in change, as above) is approximately 0.7. This 
probability is not unrealistic given the data seen previously, and, if the clinically relevant 
difference detailed above is seen, the probability of X>0 may in fact be increased leading to 
higher power. To account for dropouts, 50 subjects will be recruited. 
 


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13.3 
Procedures for Reporting any Deviation(s) from the Original Statistical Analysis 
plan 
Any deviation(s) from the original statistical analysis plan (as described in the study protocol or 
in the SAP) will be described and justified in a revised SAP and in the final report, as 
appropriate. 


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14 INVESTIGATOR/SPONSOR RESPONSIBILITIES 
14.1 
Ethics 
14.1.1 Independent Ethics Committee (IEC) 
This protocol and any amendments will be submitted to a properly constituted IEC, in 
accordance with the International Conference on Harmonisation (ICH) guidelines, the applicable 
European Directives and local legal requirements, for approval of the study. Approval must be 
obtained in writing before the first participant can be recruited. 
14.1.2 Ethical Conduct of the Study 
The study will be conducted in compliance with the protocol, regulatory requirements, Good 
Clinical Practice (GCP) and the ethical principles of the latest revision of the Declaration of 
Helsinki as adopted by the World Medical Association. 
14.1.3 Participant Information and Consent 
All participants will receive written and verbal information regarding the study. This information 
will emphasise that participation in the study is voluntary and that the participant may withdraw 
from the study at any time and for any reason. All participants will be given the opportunity to ask 
questions about the study and will be given sufficient time to decide whether to participate in the 
study. 
Before any study-related procedures are performed at the first study visit, the informed consent 
form will be signed and personally dated by the participant (or their legally acceptable 
representative and/or witness, as applicable) and by the researcher who conducted the informed 
consent discussion. 
The consent includes information that data will be recorded, collected, and processed in 
accordance with the Regulation (EU) 2016/679 of the European Parliament and of the Council of 
27 April 2016 on the protection of natural persons with regard to the processing of personal data 
and on the free movement of such data, and repealing Directive 95/46/EC, the data will not 
identify any persons taking part in the study. 
A copy of the participant information including the signed consent form will be provided to the 
participant. 
The study team includes medically qualified clinical researchers, who will be available 
throughout the trial. Due to the low risk of the intervention and the mechanistic design of the 
study involving volunteers from the general population (participants are not selected based upon 
their use of NHS services) the PI may delegate activities, including informed consent and 
medical history taking (facilitated using the medical history form), to non-medically qualified and 
otherwise appropriately trained researchers. 
14.2 
Participant Records and Source Data 
All data will be collected during the conduct of the study. No patient notes will be accessed. The 
following documents will capture source data: 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
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• 
Medical History Form: Medical history according to the participant 
• 
Participant Diaries: Treatment compliance, adverse events and participant reported 
tolerability. The information in the diary will be transferred to an electronic CRF at each 
study visit. 
• 
Adverse Events Form.  
• 
Concomitant Medication Form: recent (Visit 1) and concomitant medication (Visits 2-5) 
according to the participant 
All other study information will be directly recorded into an electronic CRF. Completed electronic 
CRF’s will be printed, dated and signed (by the researcher) upon completion to verify them. 
Verified printed records of the eCRF’s will be kept in the site file. 
 
The following data may be recorded directly in the eCRF(s), which will then be considered as 
source data: 
• 
Race 
• 
Sex 
• 
Time since AD diagnosis (at Visit 1) 
• 
Number of relapses during last 12 months (at Visit 1) 
• 
Cream consumption (weight of creams) 
• 
TEWL measurements 
• 
Capacitance measurements (skin hydration) 
• 
Objective skin redness measurements 
 
Skin images will be captured directly in the Pixience clinical software database, stored by 
participant ID, visit number and anatomical site/test site. Colour and dryness measures 
determined from the images within the software will be directly reported in an annotated 
database.  
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility and timeliness 
of the data recorded in the CRFs. Data reported in the CRF that are derived from source 
documents should be consistent with the source documents or the discrepancies should be 
explained. Signed sections of CRFs will be monitored and collected on a regular basis. 
 
14.3 
Access to Source Data and Documentation 
Access to study information will be managed in the following ways: 
• 
Personal identifiable information (PII): Collected in order to conduct the study, this 
data will be accessible only to the direct study team at the site. PII collected on the 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 59 of 65 
 
registration form will be kept for up to 5 years in order to contact participants about future 
studies, pending specific informed consent is obtained for this, otherwise contact details 
will be destroyed at the end of the study. PII will be kept in paper form. Where 
participants consent to being contacted about future studies, their contact details will also 
be stored in the electronic volunteer register. The volunteer register is located on a 
secure server with access control in a separate location to the source data. 
• 
Source data: All source data will be in a pseudonymised fashion using a participant ID 
and participant initials to identify records. Patient ID’s will be generated upon enrolment 
using the enrolment log. The enrolment log will be kept in paper form in the study site file. 
Source data will be retained by the site under the custodianship of the Principle 
Investigator. The Investigator will guarantee access to source documents for the monitor 
and auditors as well as for inspection by appropriate regulatory agencies, and the IEC, if 
required. Source data in paper form will be stored in a locked cupboard in the study 
rooms, and electronic source data will be stored on a secure severed, with access 
control, managed by the University of Sheffield. 
• 
Study data (collated and verified by site): The collated and verified study data will 
have any PII removed and will be shared with the study Statistician and the Sponsor.  
14.4 
Monitoring 
The monitor will visit the study site on a regular basis to ensure that the study is conducted and 
documented in accordance with this protocol, ICH GCP guidelines, regulatory requirements and 
any study specific documents such as CRF completion guidelines. 
Monitoring visits will be conducted to confirm that e.g.: 
• 
The investigational team is adhering to the study protocol 
• 
Informed consent has been obtained from all participants 
• 
AEs have been reported as required 
• 
Data are being accurately recorded in the CRFs 
• 
The creams are being stored correctly and drug accountability is being performed on an 
ongoing basis 
• 
Facilities are, and remain, acceptable throughout the study 
• 
The Investigator and the site are receiving sufficient information and support throughout 
the study 
Moreover, during monitoring visits the data recorded in the CRFs, source documents and other 
study-related records will be compared against each other in order to ensure accurate data that 
reflect the actual existence of the participant in the study i.e. source data verification. 
14.5 
Data Management 
Data management and handling will be conducted according to the study specific Data 
Management Plan in accordance with ICH guidelines and Investigator’s standard operating 
procedures (SOPs). 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 60 of 65 
 
Data entry, validation, and data queries will be handled by the Investigator Data Management 
Team. The data will be subjected to validation according to Investigator SOPs in order to ensure 
accuracy in the collected CRF data. 
Before database closure a reconciliation will be performed between the SAEs entered in the 
safety database TrackWise and the study SAE forms after database closure. 
Any deviations, i.e. discrepancies and additions from the process defined in the Data 
Management Plan, will be described in a study specific Data Management Report. 
14.6 
Quality Assurance and Audit 
Audits or inspections, including source data verification, may be performed by representatives of 
the CRO, the Sponsor, a CA and/or an IEC. 
14.7 
Record Retention 
The Investigator/institution should maintain essential documents (as defined in ICH E6 GCP, 
Section 8) as required by the applicable regulatory requirement(s). The Investigator/institution 
should take measures to prevent accidental or premature destruction of the documents. 
The Investigator/institution shall retain all Clinical Trial records for a period of 25 years after Trial 
Completion. 
It is the responsibility of the Sponsor to inform the Investigator/institution in writing as to when 
the documents no longer need to be retained. 
14.8 
Protocol Deviations 
Deviations from the study protocol will be documented in a Protocol Deviation Log. 
The classification of participants into protocol violators will be made during a meeting before 
database lock. The classification will be mutually agreed between the Sponsor, the 
Investigators, the statistician and the CRO before breaking the randomisation codes.  
14.9 
Insurance 
The Sponsor must provide insurance or must indemnify (legal and financial coverage) the 
Investigator/the institution against claims arising from the study, except for claims that arise from 
malpractice, negligence or non-compliance with the protocol. 
14.10 Report and Publication 
After completion of the study, a clinical study report will be prepared according to the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3) by Sponsor in close 
collaboration with the Investigator. 
All publications and presentations must be based upon the clinical study report. 
All information supplied by the Sponsor in connection with this study will remain the sole 
property of the Sponsor and is to be considered confidential information. No confidential 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 61 of 65 
 
information will be disclosed to others without obtaining prior written consent from the Sponsor 
and will not be used except in the performance of this study. 
If the Investigator wishes to publish results from this clinical study, written permission to publish 
must be obtained from the Sponsor in advance. As some of the information regarding the 
investigational products and development activities at the Sponsor may be of a strictly 
confidential nature, the Sponsor must first review any publication manuscript prior to their 
submission to journals, meetings or conferences. 
The Sponsor may choose to publish or present data from this study. If an Investigator is offered 
authorship, he/she will be asked to critically review the article for important intellectual content 
and approve the version to be published. The Sponsor has the right to use the results for 
registration and internal presentation and for promotion of the Sponsor’s commercial interests. 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 62 of 65 
 
15 REFERENCE LIST 
1. 
Halvarsson K, Loden M. Increasing quality of life by improving the quality of skin in 
patients with atopic dermatitis. Int J Cosmet Sci. 2007;29(2):69-83. 
2. 
Flohr C, Mann J. New insights into the epidemiology of childhood atopic dermatitis. 
Allergy. 2014;69(1):3-16. 
3. 
Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, et al. 
New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment 
interactions. J Allergy Clin Immunol. 2006;118(1):3-21; quiz 2-3. 
4. 
Werner Y, Lindberg M. Transepidermal water loss in dry and clinically normal skin in 
patients with atopic dermatitis. Acta Derm Venereol. 1985;65(2):102-5. 
5. 
Loden M, Olsson H, Axell T, Linde YW. Friction, capacitance and transepidermal water 
loss (TEWL) in dry atopic and normal skin. Br J Dermatol. 1992;126(2):137-41. 
6. 
Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common 
loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor 
for atopic dermatitis. Nat Genet. 2006;38(4):441-6. 
7. 
Morar N, Cookson WO, Harper JI, Moffatt MF. Filaggrin mutations in children with severe 
atopic dermatitis. J Invest Dermatol. 2007;127(7):1667-72. 
8. 
Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-
function variations within the filaggrin gene predispose for atopic dermatitis with allergic 
sensitizations. J Allergy Clin Immunol. 2006;118(1):214-9. 
9. 
Loden M. The skin barrier and use of moisturizers in atopic dermatitis. Clin Dermatol. 
2003;21(2):145-57. 
10. 
Elias PM, Wood LC, Feingold KR. Epidermal pathogenesis of inflammatory dermatoses. 
American journal of contact dermatitis : official journal of the American Contact Dermatitis 
Society. 1999;10(3):119-26. 
11. 
Holden C, English J, Hoare C, Jordan A, Kownacki S, Turnbull R, et al. Advised best 
practice for the use of emollients in eczema and other dry skin conditions. J Dermatolog Treat. 
2002;13(3):103-6. 
12. 
Szczepanowska J, Reich A, Szepietowski JC. Emollients improve treatment results with 
topical corticosteroids in childhood atopic dermatitis: a randomized comparative study. Pediatr 
Allergy Immunol. 2008;19(7):614-8. 
13. 
Giordano-Labadie F, Cambazard F, Guillet G, Combemale P, Mengeaud V. Evaluation of 
a new moisturizer (Exomega milk) in children with atopic dermatitis. J Dermatolog Treat. 
2006;17(2):78-81. 
14. 
Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution 
duration. Cutis. 2008;81(1):87-91. 
15. 
Lucky AW, Leach AD, Laskarzewski P, Wenck H. Use of an emollient as a steroid-
sparing agent in the treatment of mild to moderate atopic dermatitis in children. Pediatr 
Dermatol. 1997;14(4):321-4. 
16. 
Halkier-Sorensen L, Thestrup-Pedersen K. The efficacy of a moisturizer (Locobase) 
among cleaners and kitchen assistants during everyday exposure to water and detergents. 
Contact Dermatitis. 1993;29(5):266-71. 
17. 
Vilaplana J, Coll J, Trullas C, Azon A, Pelejero C. Clinical and non-invasive evaluation of 
12% ammonium lactate emulsion for the treatment of dry skin in atopic and non-atopic subjects. 
Acta Derm Venereol. 1992;72(1):28-33. 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 63 of 65 
 
18. 
Kolbe L, Kligman AM, Schreiner V, Stoudemayer T. Corticosteroid-induced atrophy and 
barrier impairment measured by non-invasive methods in human skin. Skin Res Technol. 
2001;7(2):73-7. 
19. 
Ganemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a 
double-blind study of four different cream formulations. Br J Dermatol. 1999;141(6):1027-32. 
20. 
Loden M, Andersson AC, Lindberg M. Improvement in skin barrier function in patients 
with atopic dermatitis after treatment with a moisturizing cream (Canoderm). Br J Dermatol. 
1999;140(2):264-7. 
21. 
Tsang M, Guy RH. Effect of Aqueous Cream BP on human stratum corneum in vivo. Br J 
Dermatol. 2010;163(5):954-8. 
22. 
Lonne-Rahm S, Berg M, Marin P, Nordlind K. Atopic dermatitis, stinging, and effects of 
chronic stress: a pathocausal study. J Am Acad Dermatol. 2004;51(6):899-905. 
23. 
An S, Lee E, Kim S, Nam G, Lee H, Moon S, et al. Comparison and correlation between 
stinging responses to lactic acid and bioengineering parameters. Contact Dermatitis. 
2007;57(3):158-62. 
24. 
Loden M, Andersson AC, Anderson C, Bergbrant IM, Frodin T, Ohman H, et al. A double-
blind study comparing the effect of glycerin and urea on dry, eczematous skin in atopic patients. 
Acta Derm Venereol. 2002;82(1):45-7. 
25. 
Serup J. A double-blind comparison of two creams containing urea as the active 
ingredient. Assessment of efficacy and side-effects by non-invasive techniques and a clinical 
scoring scheme. Acta Derm Venereol Suppl (Stockh). 1992;177:34-43. 
26. 
Andersson AC, Lindberg M, Lodén M. The effect of two urea-containing creams on dry, 
eczematous skin in atopic patients. I. Expert, patient and instrumental evaluation. Journal of 
Dermatological Treatment. 1999;10(3):165-9. 
27. 
Lodén M, Bárány E, Mandahl P, Wessman C. The Influence of Urea Treatment on Skin 
Susceptibility to Surfactant-Induced Irritation: A Placebo-Controlled and Randomized Study. 
Exog Dermatol. 2004;3(1):1-6. 
28. 
Loden M. Barrier recovery and influence of irritant stimuli in skin treated with a 
moisturizing cream. Contact Dermatitis. 1997;36(5):256-60. 
29. 
Buraczewska I, Berne B, Lindberg M, Torma H, Loden M. Changes in skin barrier 
function following long-term treatment with moisturizers, a randomized controlled trial. Br J 
Dermatol. 2007;156(3):492-8. 
30. 
Wiren K, Nohlgard C, Nyberg F, Holm L, Svensson M, Johannesson A, et al. Treatment 
with a barrier-strengthening moisturizing cream delays relapse of atopic dermatitis: a prospective 
and randomized controlled clinical trial. J Eur Acad Dermatol Venereol. 2009;23(11):1267-72. 
31. 
Akerstrom U, Reitamo S, Langeland T, Berg M, Rustad L, Korhonen L, et al. Comparison 
of Moisturizing Creams for the Prevention of Atopic Dermatitis Relapse: A Randomized Double-
blind Controlled Multicentre Clinical Trial. Acta Derm Venereol. 2015;95(5):587-92. 
32. 
Loden M, Wessman W. The influence of a cream containing 20% glycerin and its vehicle 
on skin barrier properties. Int J Cosmet Sci. 2001;23(2):115-9. 
33. 
Blichmann CW, Serup J, Winther A. Effects of single application of a moisturizer: 
evaporation of emulsion water, skin surface temperature, electrical conductance, electrical 
capacitance, and skin surface (emulsion) lipids. Acta Derm Venereol. 1989;69(4):327-30. 
34. 
van Zuuren EJ, Fedorowicz Z, Christensen R, Lavrijsen A, Arents BWM. Emollients and 
moisturisers for eczema. The Cochrane database of systematic reviews. 2017;2:CD012119. 
35. 
Loden M, Andersson AC, Andersson C, Frodin T, Oman H, Lindberg M. Instrumental and 
dermatologist evaluation of the effect of glycerine and urea on dry skin in atopic dermatitis. Skin 
Res Technol. 2001;7(4):209-13. 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 64 of 65 
 
36. 
Simpson EL, Chalmers JR, Hanifin JM, Thomas KS, Cork MJ, McLean WH, et al. 
Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. 
J Allergy Clin Immunol. 2014;134(4):818-23. 
37. 
Williams HC, Burney PG, Pembroke AC, Hay RJ. The U.K. Working Party's Diagnostic 
Criteria for Atopic Dermatitis. III. Independent hospital validation. Br J Dermatol. 
1994;131(3):406-16. 
38. 
Pinnagoda J, Tupker RA, Agner T, Serup J. Guidelines for transepidermal water loss 
(TEWL) measurement. A report from the Standardization Group of the European Society of 
Contact Dermatitis. Contact Dermatitis. 1990;22(3):164-78. 
39. 
Loden M. Biophysical methods of providing objective documentation of the effects of 
moisturizing creams. Skin Res Technol. 1995;1(3):101-8. 
40. 
Aalto-Korte K. Improvement of skin barrier function during treatment of atopic dermatitis. 
J Am Acad Dermatol. 1995;33(6):969-72. 
41. 
Watanabe M, Tagami H, Horii I, Takahashi M, Kligman AM. Functional analyses of the 
superficial stratum corneum in atopic xerosis. Arch Dermatol. 1991;127(11):1689-92. 
42. 
Tupker RA, Willis C, Berardesca E, Lee CH, Fartasch M, Agner T, et al. Guidelines on 
sodium lauryl sulfate (SLS) exposure tests. A report from the Standardization Group of the 
European Society of Contact Dermatitis. Contact Dermatitis. 1997;37(2):53-69. 
43. 
Loden M, Hagforsen E, Lindberg M. The presence of body hair influences the 
measurement of skin hydration with the Corneometer. Acta Derm Venereol. 1995;75(6):449-50. 
44. 
Loden M, Lindberg M. The influence of a single application of different moisturizers on 
the skin capacitance. Acta Derm Venereol. 1991;71(1):79-82. 
45. 
Sahlin A, Edlund F, Loden M. A double-blind and controlled study on the influence of the 
vehicle on the skin susceptibility to stinging from lactic acid. Int J Cosmet Sci. 2007;29(5):385-
90. 
46. 
Noether GE. Sample Size Determination for Some Common Nonparametric Tests. 
Journal of the American Statistical Association. 1987;82(398):645-7. 
 
 
 
 
 
 


NOVA - Skin Barrier Clinical Study Protocol 
Sponsor: ACO Hud Nordic AB 
Version: Version 3.0 
Study Code: Novum ACO-CT-2018-01 
Date: 15 August 2019 
EudraCT No.: 2018-002945-12 
Confidential 
Page 65 of 65 
 
16 APPENDICES 
Appendix A:  Supplementary files 
• 
Poster advert 
• 
Alternative media advert 
• 
Participant Information Sheet 
• 
Informed Consent Form 
• 
Registration Form 
• 
SDR Subject Screening Log 
• 
Background Information Form (includes medical history) 
• 
Admission Form 
• 
SDR Screening, Enrolment and Completion Log 
• 
SDR Concomitant medication Form 
• 
SDR Adverse Events Form 
• 
Serious Adverse Event and Pregnancy Report Form 
• 
Participant Diary 
• 
Skin Assessment Visit Case Record Forms 
• 
Compliance Monitoring Case Record Form 
• 
Substantial amendment no 1 table 
 
Appendix B:  Risk Assessment 
 
 

SAP_001.pdf: 
Nova – Skin Barrier Study 
 
Statistical Analysis Plan v1.0 
SSU2018/009  
 
4 November 2019 
 
 
 
Statistical Analysis Plan (SAP) 
 
 
A phase 2 randomised controlled trial of a NOVel moisturiser for Atopic 
dermatitis: effect on the skin barrier in adults with a predisposition to a skin 
barrier defect 
 
 
 
 
 
 
 
 
 


Nova – Skin Barrier Study 
 
Statistical Analysis Plan v1.0 
SSU2018/009  
 
4 November 2019 
 
 
Statistical Analysis Plan (SAP) 
 
 
A phase 2 randomised controlled trial of a NOVel moisturiser for Atopic 
dermatitis: effect on the skin barrier in adults with a predisposition to a skin 
barrier defect 
 
 
 
Date: 
 
R Taylor, Statistician 
Statistical Service Unit, The University of Sheffield 
 
 
 
 
 
 
 
 
 
Date: 
 
Principal Investigator 
 
 
 
 
 
 
 
 
 
Date: 
 
Sponsor Representative: Tina Holm,  
Sponsor Clinical Study Manager 
 
 
 
 
 
 
 
 
 


Nova – Skin Barrier Study 
 
Statistical Analysis Plan v1.0 
SSU2018/009  
 
4 November 2019 
 
Statistical Services Unit, The University of Sheffield 
Page 3 of 15 
Contents 
Abbreviations ............................................................................................................................................................... 4 
1. 
Introduction: ....................................................................................................................................................... 5 
2. 
Study Methods ................................................................................................................................................... 5 
2.1 
Study Design .................................................................................................................................................. 5 
2.2 
Randomisation .............................................................................................................................................. 6 
2.3 
Sample size: .................................................................................................................................................... 6 
2.4 
Timelines ......................................................................................................................................................... 7 
3. 
Data Collection: ................................................................................................................................................. 7 
4. 
Analysis Objectives: .......................................................................................................................................... 7 
4.1 
Primary objective: ........................................................................................................................................ 7 
4.2 
Secondary objective: .................................................................................................................................. 8 
4.3 
Tertiary objective: ........................................................................................................................................ 8 
5. 
Analysis Sets and Protocol Deviations ...................................................................................................... 8 
6. 
Endpoints and Covariates ............................................................................................................................. 9 
6.1 
Primary endpoints ....................................................................................................................................... 9 
6.2 
Secondary endpoints ................................................................................................................................. 9 
6.3 
Tertiary endpoints: ...................................................................................................................................... 9 
6.4 
Variables .......................................................................................................................................................... 9 
7. 
Statistical Analyses .......................................................................................................................................... 11 
7.1 
Primary Analysis ........................................................................................................................................... 11 
7.2 
Secondary Analyses .................................................................................................................................... 12 
7.3 
Tertiary Analysis .......................................................................................................................................... 12 
7.4 
Adverse event data: .................................................................................................................................... 13 
7.5 
Multiplicity considerations ...................................................................................................................... 13 
7.6 
Missing and unusual data ......................................................................................................................... 13 
7.7 
Interim Analysis: ........................................................................................................................................... 13 
7.8 
Data Monitoring Committee (DMC): .................................................................................................. 13 
7.9 
Changes From Protocol ............................................................................................................................ 13 
8. 
List of Tables, Figures and Listings ........................................................................................................... 14 
 
 
 


Nova – Skin Barrier Study 
 
Statistical Analysis Plan v1.0 
SSU2018/009  
 
4 November 2019 
 
Statistical Services Unit, The University of Sheffield 
Page 4 of 15 
Abbreviations 
 
AD 
Atopic Dermatitis 
ANCOVA 
Analysis of Covariance 
FAS 
Full Analysis Set 
FLG 
Filaggrin mutation 
FTU 
Finger Tip Unit 
PPS 
Per protocol Set 
NMF 
Natural Moisturising Factor 
SLS 
Sodium Lauryl Sulfate 
TEWL 
Trans Epidermal Water Loss 
 
 
 


Nova – Skin Barrier Study 
 
Statistical Analysis Plan v1.0 
SSU2018/009  
 
4 November 2019 
 
Statistical Services Unit, The University of Sheffield 
Page 5 of 15 
1. Introduction:  
This study is designed in order to evaluate the skin barrier strengthening effects of Miniderm 
Novum and the two reference creams compared to untreated. It is a randomised, controlled, 
blinded, four parallel group study. 
The participants will apply cream (1 FTU) twice daily on designated treatment areas on their 
volar forearms for 28 days. On day 5 and 15 the participants will visit the clinic where the test 
and reference products will be weighed and the diary reviewed. Skin imaging to analyse 
erythema will be performed on day 1, 15, 29 and 31. On the morning of day 29 the participants 
will wash their arms and not apply any product. They will visit the clinic and TEWL and skin 
capacitance will be measured. Small metal cups (Finn chambers) with SLS will be attached to 
the skin on the 4 treatment areas and the participants will be instructed to avoid showering 
or heavy exercise to avoid the patches getting wet. On day 30 the participants will remove 
the patch and leave the skin to recover for 24 hours. On day 31 the participants will visit the 
clinic and TEWL and skin capacitance will be measured again. 
2. Study Methods 
2.1 
Study Design 
It is planned to recruit 40 adults (male and female, aged 18 and above) with personal history 
of atopic dermatitis but no current eczema on the volar forearms and no possible allergy to 
the ingredients in the study medications. 
Four treatment sites on the lower volar forearms (two on the right and two on the left) will 
be randomised for each participant with one treatment to be applied to each of three sites 
and the fourth remaining untreated as a control. The four treatment groups are;  
• 
No treatment (control) 
• 
Miniderm Novum (test cream) 
• 
Miniderm 20% (reference cream) 
• 
Diprobase (reference cream) 
One Finger Tip Unit (FTU) of each cream will be applied twice daily on the designated study 
area. The participants will record details of cream application frequency, as well as 
participant tolerability in a diary. 
Subjects will remain in the study for 4-5 weeks. 
At each study visit, concomitant medication and any AEs are noted in the Case Report Form 
(CRF). The study medication will be collected and weighed in order to estimate cream 
consumption. 
Participants will attend 5 clinic visits during the study: 
• 
Visit 1 (screening) will be performed at baseline (Day 1) 
• 
Visit 2 will be performed after 5 days of treatment  
• 
Visit 3 will be performed after 15 days of treatment  


Nova – Skin Barrier Study 
 
Statistical Analysis Plan v1.0 
SSU2018/009  
 
4 November 2019 
 
Statistical Services Unit, The University of Sheffield 
Page 6 of 15 
• 
Visit 4 will be performed after 29 days of treatment  
• 
Visit 5 will be performed 1 day after SLS-patch removal (Day 31) 
Assessors will be blind to the treatment assigned to each site. Subjects will be blinded to the 
cream assigned to each study site – although the untreated site will remain unblinded.  
2.2 
Randomisation 
Screening will take place either before or at the same visit as Day 1. Those eligible to take 
part will be randomised on Day 1 with each subject testing all four treatments – one on each 
site of the left or right lower volar forearm.  
Miniderm Novum and Miniderm 20% will be packaged in identical 100mL plastic tubes by 
Pharmavize. Diprobase cream will be used in its original tube of 50 mg. The tube will be 
concealed with concealing tape and labelled as the other products. 
The Investigator will keep the randomisation key and the numbering of the products in a 
secure, limited-access location to prevent inadvertent breaking of the blind. In case of 
emergency, the blind may be broken. All unblinding events will be recorded. 
Full unblinding information will be provided to the statistician at the time of database lock. 
2.3 
Sample size: 
 
The sample size for this study is based on the primary end point, change in Trans Epidermal 
Water Loss (TEWL) after induction of skin irritation (change from day 29 to day 31), with the 
primary comparison being between the test treatment and no treatment and the secondary 
comparison being between the test treatment and the two reference treatments. 
In a similar study the standard deviation of the difference in change in TEWL after induction 
of skin irritation was seen to be approximately 8 g/mÇ.h when comparing the no treatment 
group to an active treatment. (that is: standard deviation of {[Change after skin irritation in 
no treatment area]-[Change after skin irritation in active treatment area]}). 
When comparing the difference between the test treatment and one of the two reference 
treatments the standard deviation was approximately 3. 
If the assumptions of a paired t-test are found to be valid, for a sample of 40 participants this 
analysis would have >90% power to detect a difference (in change) of 3.5 g/mÇ.h between 
test treatment and no treatment.  The same sample size would also have >90% power to 
detect a difference (in change) of 2 g/mÇ.h between test treatment and active treatment.  If 
a parametric analysis is indicated then an analysis which includes the baseline as a covariate 
will be considered which, if there is variation at baseline may increase the power of the 
analysis further. 
If the assumptions of a paired t-test are not met (and a suitable transformation cannot be 
found) then a sign test (or a wilcoxon matched pairs test) may be used.  A power calculation 


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can be carried out for the sign test1 although this too makes some assumptions.  This 
calculation shows that a sample size of N=40 would have >80% power to detect a difference 
such that the probability of X>0 (where X is the difference in change, as above) is 
approximately 0.7.  This probability is not unrealistic given the data seen previously, and, if 
the clinically relevant difference detailed above is seen, the probability of X>0 may in fact be 
increased leading to higher power. 
 
2.4 
Timelines 
Analysis will take place once all participants have had their final assessment at Day 31 or have 
discontinued.   
Completion of the SAP, data cleaning and a blind review will take place prior to data base 
lock.  During blind review all decisions about protocol deviations (ITT and PP populations) 
and analyses (such as assumptions checking) will be made.  Once all these activities have 
taken place then the database will be locked and unblinded. 
 
3. Data Collection:  
Data is to be collected in excel format on a secure drive available only to the necessary study 
staff.  Data will be provided to the SSU as clean data files. 
Adverse event data is being collected in a separate study database and will also be provided 
to SSU as an excel file.  Coding of AEs will be carried out prior to delivery of the data to SSU. 
4. Analysis Objectives: 
4.1 
Primary objective: 
The primary objective is to determine whether applying a new moisturizing cream (the test 
cream) for 4 weeks is superior in terms of skin barrier strengthening, when compared with 
(1) no treatment and (2) two reference creams in adults with a predisposition to a skin 
barrier defect. 
The hypotheses for the study are provided below in order of importance: 
a) Skin irritation, indicated by elevated TEWL and redness, will be reduced following 
treatment with the  test cream compared to the untreated control. 
b) Skin irritation, indicated by elevated TEWL and redness, will be reduced following 
treatment with the test cream compared to the reference creams, Miniderm 20% cream 
and Diprobase cream. 
 
1 Sample Size Determination for Some Common Nonparametric Tests Gottfried E. Noether Journal of the 
American Statistical Association, Vol. 82, No. 398. (Jun., 1987), pp. 645-647 


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4.2 
Secondary objective: 
To determine whether there is a difference between the new moisturising cream (the test 
cream) and (1) no treatment and (2) the two reference creams in: 
• 
Resting skin barrier function  
• 
Skin moisturisation 
• 
Tolerability 
• 
Cream consumption 
• 
Safety 
 
 
4.3 
Tertiary objective: 
To investigate the number of participants with FLG loss-of-function mutations and to 
investigate any relationship with treatment effects. 
5. Analysis Sets and Protocol Deviations 
Full Analysis Set (FAS): All subjects who were diagnosed with a history of AD and were 
randomised into the study. 
Per-protocol set (PPS): All participants who are deemed to have no major protocol 
violations that could interfere with the objectives of this study. This is a sub-population of the 
FAS. 
Safety set: All randomised participants who receive at least 1 dose of test or reference 
cream. 
 
The primary analysis outcome summaries will be performed on both the FAS and the PPS, 
however the FAS will be considered the primary analysis population  .  Secondary analyses 
will be performed on the FAS only. 
 
Safety summaries will be performed on the safety set. 
 
Prior to code breaking, a blind review of the data will be performed. The objective of the 
review is to identify problems and to make decisions regarding data analytical issues under 
blind conditions.   Important violations of eligibility criteria and other deviations from the 
protocol will be assessed in cooperation with the Sponsor. Important deviations from the 
protocol may lead to exclusion of a participant from the PPS.  All deviations will be discussed 
and agreed prior to the unblinding of the data. 
In addition the blind data review will consider if the location of observations and the 
adherence of SLS patches has any impact on the data and if so how to allow for this in the 
analysis. 
 
 


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6. Endpoints and Covariates 
6.1 
Primary endpoints 
• 
Outcome relating to the strength of the skin barrier:  
o Change in TEWL post-induction of skin irritation after 4 weeks treatment (Day 
31 – Day 29)  
o Change in objective skin redness (visual scores and mexameter) post-
induction of skin irritation after 4 weeks treatment to (Day 31 – Day 29)  
6.2 
Secondary endpoints 
• 
Outcome relating to the resting strength of the skin barrier: 
o TEWL after 4 weeks treatment (Day 29 – Day 1) 
• 
Outcomes relating to the skin moisturisation:  
o Capacitance measurements (Day 29 – Day 1) 
o Skin surface dryness (3D skin images) (Day 29 – Day 1) 
o NMF levels (Day 29) 
• 
Outcomes relating to tolerability:  
o Participant tolerability scores by VAS (Day1, Day 5, Day 29) 
o Investigator visual scores for redness (Day 15 and Day 29, adjusted for Day 1) 
o Objective erythema from 2D colour skin images (Day 15 and Day 29, adjusted 
for Day1) 
• 
Outcome relating to cream consumption:  
o Cream consumption (g) (Day 1, Day 5, Day 15 & Day 29) 
• 
Outcome relating to safety:  
o Number of adverse events (Screening, Day 1, Day 5, Day 15, Day 29 and Day 31) 
6.3 
Tertiary endpoints:  
• 
Outcomes relating to FLG loss-of-function mutations: ▪  
o Number of FLG loss-of-function mutation carriers 
 
6.4 
Variables 
TEWL  
Triplicate measurements will be performed at each test site (upper part of the right and left 
lower volar forearm and lower part of the right and left lower volar forearm) at baseline 
(Day 1), after 4 weeks treatment (Day 29) and after skin irritation (Day 31) using an AquaFlux 
condensing chamber probe. A fourth measurement may be taken if the technician feels that 
one of the previous readings was abnormal. The average reading for each patient at each 
time point at each site will be used in the analysis.  
 
Redness  
Visual scoring of subject’s skin by an expert will take place at 4 weeks (Day 29) and after skin 
irritation (Day 31).   Scores will be on a scale from 0 to 3. 


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Objective scoring of the sites will also be measured using a mexameter.  Triplicate recordings 
will be made; the average reading for each patient at each time point at each site will be used 
in the analysis. 
Change will be calculated as post-irritation observation – 4 week observation (Day 31 – 
Day 29). 
Secondary endpoint: Erythema index from 2d imaging will be measured at baseline and on 
days 15, 29 and 31. 
 
Capacitance 
Triplicate measurements will be performed at each test site at baseline (Day 1) and after 
4 weeks of treatment (Day 29) using a corneometer. A fourth measurement may be taken if 
the technician feels that one of the previous readings was abnormal.  The average reading for 
each patient at each time point at each site will be used in the analysis. Capacitance units are 
reported using an arbitrary scale from 0 to 130, where values below 30 indicate very dry skin 
and values above 45 indicate sufficiently moisturised skin. 
 
Skin surface dryness (3D image)  
A close-up image of each skin site will be captured using the c-cube (Pixience, France) at 
baseline (Day 1), after 2 weeks treatment (Day 15), after 4 weeks treatment (Day 29) and 
after induction of skin irritation (Day 31). Images can be analysed at the end of the study to 
obtain quantitative values for dryness (roughness). 
 
2D Skin Imaging of Erythema 
A single close-up image of each skin site will be captured using the c-cube camera with glass 
lens (Pixience, France). Captured 2D images are analysed to determine the skin erythema 
index (degree of redness, arbitrary numerical value) for the region of interest.  
 
NMF levels  
Samples for analysis of stratum corneum NMF levels will be collected by tape stripping after 
4 weeks of treatment (single time point, Day 29). Two samples will be collected from each 
sampling site (tape-strips/discs 1-3 and 4-6), representing different depths through the 
stratum corneum.  The samples will be analysed separately. 
 
Participant tolerability VAS  
Participants will use a diary to record their VAS score of the degree of smarting at the start 
of treatment (Day 1), after 5 days (Day 15) and again after 4 weeks (Day 29). 
 


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Cream Consumption 
Cream consumption will be based on the weight of the reference and test creams before 
(Day 1), during (Days 5 and 15) and after use (Day 29). 
 
Adverse Events 
Participants will record AEs throughout the study in their diaries with the information 
transferred to the CRF at Day 29 and Day 31.   
 
FLG loss-of-function mutations 
Saliva samples will be collected at baseline (Day 1) to obtain genomic DNA for determination 
of participant FLG gene status. Samples will undergo DNA extraction and genotyping at the 
University of Sheffield for the 5 common European loss-of-function FLG mutations that have 
been reported to confer increased AD risk. 
7. Statistical Analyses 
Outcome and demographic data will be summarised at each time point using appropriate 
descriptive statistics such as N, mean, standard deviation, min, lower quartile, median, upper 
quartile, max.   
As noted in section 5 the data will be explored during the blind data review to assess if the 
proposed analysis methods needs to be updated to allow for the location or adherence of 
the SLS patches.   
7.1 
Primary Analysis 
 
The primary analyses will compare the test treatment to no treatment and to the two 
reference creams in terms of change in TEWL and redness (visual scoring and mexameter) 
between days 31 and 29. This will be done using Analysis of Covariance (ANCOVA) with 
change (Day 31 - Day 29) as the outcome, treatment as a factor, subject as a random effect 
and day 29 incuded as a covariate. Key group comparisons (Miniderm Novum Vs Control, 
Miniderm Novum Vs Miniderm 20% and Miniderm Novum Vs Diprobase) will be calculated 
directly from the ANCOVA model.  
 
These analyses will be carried out on both the FAS and the PPS, the analysis on the PPS will 
be considered supportive of the primary analysis carried out on the FAS. 
 
In both analyses, if the assumptions of the test are not met, transformations of the raw data 
or alternative tests will be considered, such as the Wilcoxon matched pairs or sign test, and 
the most appropriate solution applied. 
 
 


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7.2 
Secondary Analyses 
 
For each secondary analysis key group comparisons (Miniderm Novum Vs Control, Miniderm 
Novum Vs Miniderm 20% and Miniderm Novum Vs Diprobase) will be presented. These 
analyses will be carried out on the FAS only. 
 
In all analyses, if the assumptions of the test are not met, transformations of the raw data or 
alternative tests will be considered and the most appropriate solution applied. 
 
Skin Barrier: 
The secondary analyses will compare the test treatment to no treatment and to the two 
reference treatments in terms of change in TEWL from baseline (Day 1) to Day 29. This will 
be done using ANCOVA with change (Day 29 – Day 1) as the outcome, Day 1 TEWL as a 
covariate, treatment as a factor and subject as a random effect.  
 
Skin Moisturisation: 
Capacitance and skin surface dryness (Day 29-Day 1) will be analysed using an ANCOVA as 
described for TEWL above. 
 
The test treatment will be compared to no treatment and to the two reference treatments in 
terms of skin moisturisation (NMF) at Day 29. This will be done using ANOVA with Day 29 
NMF as the outcome, treatment as a factor and subject as a random effect.  The samples 
representing different depths will be analysed separately.  
 
Tolerability: 
Patient tolerability scores will not be recorded prior to treatment and so will be summarised 
by time point (Day 1, Day 5 and Day 29) and the treatments compared using repeated 
measures ANOVA with score as the outcome, visit (Day 1, Day 15 or Day 29) and treatment as 
factors and subject as a random effect. 
 
Tolerability scores as measured by investigator visual scores for redness and objective 
erythema from 2D colour skin images will be analysed including the observations from day 15 
and 29, adjusting for baseline as necessary.  This analysis will use a repeated measures 
ANOVA with change from baseline as the outcome, visit (Day 15 or Day 29) and treatment as 
factors, day 1 as a covariate and subject as a random effect. 
 
Consumption: 
The total consumption of the creams (test or reference cream), based on cream weight will 
be calculated and tabulated descriptively.  The planned dose is 0.5g per application (2 
applications per day), if consumption is twice or half that expected over the study this will be 
flagged.  If appropriate, consideration will be given to including the cream consumption as a 
covariate in the model or in an exploratory analysis of the primary endpoints.  
7.3 
Tertiary Analysis 
 
The number of FLG loss-of-function mutation carriers will be summarised. If sufficient 
participants with the mutation are detected then descriptive tabulations of TEWL by 
mutation status will be presented.  
 


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7.4 
Adverse event data: 
 
All Adverse Events will be summarized for all subjects enrolled in the study – both the 
number of participants with an AE and the total number of AEs. AEs will be tabulation by 
system organ class and by preferred term, as well as severity and relationship to treatment. 
Finally, those AEs which are specifically recorded as related to one of the test sites, the AEs 
will be summarised by test site. A listing, by participant number, will be produced to show 
the AEs with the worst severity and worst relationship to treatment. 
 
7.5 
Multiplicity considerations 
All analyses in this SAP will be carried out with a two sided 5% significance level.   
Secondary analyses are considered to be exploratory and so no adjustment will be made for 
multiplicity. 
7.6 
Missing and unusual data  
Missing data will not be replaced. If appropriate the drop out rate will be calculated and 
analysed.  
During data review (prior to data base lock and unblinding), readings that are incorrect, i.e. 
outside the equipment measurement range, will be removed. However, all readings that are 
possible, even if they are unusually low or high, will be kept in the analysis.  
7.7 
Interim Analysis: 
No interim analyses are planned for this trial. 
7.8 
Data Monitoring Committee (DMC): 
No DMCs are planned for this trial. 
7.9 
Changes From Protocol 
An additional exploratory analysis has been proposed for the blind data review to investigate 
any impact of the location or adherence of the SLS patches on the observed data at day 31.  
This is due to investigators noting that the patches may not adhere so well in different 
locations along the forearm and also that the skin may react differently depending on 
distance from wrist/elbow. 
 
 


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8. List of Tables, Figures and Listings  
 
Tables 
14.1.1 
Disposition  
14.1.2 
Important PDs (Full Analysis Set) 
14.1.3 
Patients excluded from analysis populations (Full Analysis Set)  
14.1.4 
Demographic data (Full Analysis Set) 
14.1.5 
Baseline eczema history (Full Analysis Set) 
14.1.6 
Medical History (Full Analysis Set) 
14.1.7 
Temperature and humidity during skin assessments  
14.2.1 
TEWL (g/m2h) 
14.2.1.1 
Change in TEWL (g/m2h)  post-induction of skin irritation after 4 weeks of 
treatment (Day 31 – Day 29)  
14.2.1.2 
Analysis of change in TEWL post induction of skin irritation (day31-Day29) 
14.2.1.3 
Change in TEWL (g/m2h) after 4 weeks of treatment ( Day 29- Day1)  
14.2.1.4 
Analysis of change in TEWL following 4 weeks of treatment 
14.2.2 
Investigator visual scores for redness 
14.2.2.1 
Change in visual score for redness  post-induction of skin irritation after 4 
weeks of treatment (Day 31 – Day 29)  
14.2.2.3 
Analysis of change in visual score for redness post induction of skin 
irritation (day31-Day29) 
14.2.2.4 
Analysis of visual score for redness at day 29. 
14.2.3 
Objective Erythema from 2D colour skin images 
14.2.3.1 
Change in Objective Erythema  post-induction of skin irritation after 4 
weeks of treatment (Day 31 – Day 29)  
14.2.3.2 
Analysis of change in Objective Erythema post induction of skin irritation 
(day31-Day29) 
14.2.3.3 
Change in Objective Erythema after 2 and 4 weeks of treatment   
14.2.3.4 
Analysis of Objective Erythema from baseline to day 15 and day 29. 
14.2.4 
Objective Redness (Mexameter) 
14.2.4.1 
Change in objective skin redness (Mexameter) after 4 weeks treatment to 
post-induction of skin irritation (Day 31 – Day 29)  
14.2.4.2 
Analysis of change in objective redness 
14.2.5 
Skin Capacitance measurements 
14.2.5.1 
Change in skin capacitance (Day 29 – Day 1) 
14.2.5.2 
Analysis of change in skin capacitance 
14.2.6 
Skin surface dryness (Sa (µm) 3D skin images) (Day 29 – Day 1) 
14.2.6.1 
Change in skin surface dryness, Sa (µm) (Day 29-Day1) 
14.2.6.2 
Analysis of change in dryness, Sa (µm) 
14.2.7 
Patient tolerability scores (VAS) 
14.2.7.1 
Analysis of patient tolerability scores (VAS) 
14.2.8 
Total Cream consumption 
14.2.9. 
NMF 
14.2.9.1 
Analysis of NMF scores 
14.2.10 
Summary of FLG 
14.3.1 
Number of patients experiencing AEs 
14.3.2 
Adverse Events by system organ class and preferred term 
14.3.x  
Adverse Events - further tables as appropriate 
Listings 


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16.2.1 
Discontinued patients 
16.2.2 
Protocol deviations 
16.2.3 
Patients excluded from analysis populations 
16.2.4.1 
Demographic data 
16.2.4.2 
Baseline eczema history 
16.2.4.3 
Medical history 
16.2.4.4 
Patient routine 
16.2.5 
Cream consumption 
16.2.6.1 
TEWL 
16.2.6.2 
Investigator visual scores for redness 
16.2.6.3 
Objective erythema 
16.2.6.4 
Objective Redness (Mexameter) 
16.2.6.5 
Skin Capacitance measurements 
16.2.6.6 
Skin surface dryness (3D skin images) (Day 29 – Day 1) 
16.2.6.7 
Patient tolerability scores (VAS) 
16.2.6.8 
Total Cream consumption 
16.2.6.9 
NMF 
16.2.6.10 
FLG 
16.2.7 
AEs 
 
Figures: 
Figure 14.2.1.1 
Change in TEWL (g.m2h) post induction of skin irritation (Day 31-Day 29) 
Figure 14.2.1.2 
Change in TEWL 9gm2h) after 4 weeks of treatment (Day29-Day1) 
Figure 14.2.2.1  
Change in visual score for redness  post-induction of skin irritation (Day 31 – 
Day 29) 
Figure 14.2.4.1 
Change in objective skin redness (mexameter) (Day 31 – Day 29) 
Figure 14.2.5.1 
Change in skin capacitance (Day 29 – Day 1) 
Figure 14.2.6.1 
Change in skin surface dryness, Sa (µm) (Day 29-Day1) 
Figure 14.2.9.1 
NMF levels at Day 29