Multicenter, Open Label, Uncontrolled Clinical Investigation on the Performance and Safety of DermoRelizema Ecofoam in the Management of Some Dermatitis in the Adult
Phase: NA
Conditions: Dermatitis
Sponsor: Relife S.r.l.

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MULTICENTER, OPEN LABEL, UNCONTROLLED CLINICAL INVESTIGATION ON 
THE PERFORMANCE AND SAFETY OF DERMORELIZEMA ECOFOAM IN THE 
MANAGEMENT OF SOME DERMATITIS IN THE ADULT 
 
Clinical Investigation Plan (CIP) code:   ReGl/20/Dec-Der/001 
Version 1.0, 06/11/2020 
 
 
Sponsor 
Relife S.r.l. 
 
Via dei Sette Santi 3  
50131 Florence, ITALY 
Phone: +39 055 56809345  
Fax: +39 055 56809346  
 
Coordinating Principal Investigator 
Prof. Gabriella Fabbrocini  
Unità Operativa Complessa di Dermatologia Clinica  
Azienda Ospedaliera Universitaria “Federico II” - Napoli 
Via Sergio Pansini 5, 80138 Napoli - Italy 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by law. In any event, persons to whom 
the information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to 
you which is indicated as privileged or confidential. 
 

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19/11/2020

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Investigator’s Approval Page 
 
I understand that all information concerning the product DermoRelizema ecofoam supplied by Relife 
Srl and/or Latis Srl in connection with this study protocol are confidential information. This information 
include: CIP, Case Report Form, product documents. 
 
I understand that any change in this study protocol must be approved in writing by Relife Srl the Co-
ordinating Investigator and the Ethics Committee before implementation, except where necessary to 
eliminate apparent immediate hazard to patients. 
 
I confirm that I will conduct the study according to this protocol (except when mutually agreed to in 
writing with Relife Srl or its delegate Latis Srl), the Good Clinical Practice (GCP), the UNI EN ISO 14155, 
the Declaration of Helsinki current edition and laws and regulations in the Country where the study is 
to be conducted. 
 
I confirm that I will record and report all adverse events occurring during the study, according to this 
protocol. 
I confirm that I am informed about the need of data records retention, according to current 
regulations and that no data can be destroyed without the written consent of Relife Srl. 
I confirm that I will transfer adequate ownership of my responsibilities for the clinical investigation and 
will inform the Sponsor, in case I retire from my PI role. 
I confirm that in case the Trial Center File is stolen or anyhow damaged, I will promptly inform the 
Sponsor and declare it to the Competent Authorities. 
 
 
Principal Investigator:  
……………………………………………………………………… 
 
………………………….. 
 
 
 
Signature & Date: _________________________________________________________ 
 
 

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General information 
 
Sponsor Representative 
Contact 
Martina Manni Study Medical Expert 
Phone. +39 055 56807184 
E-mail. mmanni@relifecompany.it 
 
Silvia Innocenti Head of Scientific Affairs 
Phone. +39 055 5680536 
E-mail. sinnocenti@relifecompany.it 
 
Lia Fabbri Clinical Trial Coordinator 
Phone. +39 055 56809528 
E-mail. lfabbri@relifecompany.it 
 
Manuela Chelo Study Safety Manager  
 
 
Phone. +39 055 56807111 
 
E-mail. mchelo@relifecompany.it 
 
Clinical CRO 
Latis Srl – Viale Sauli 39/5 – 16121 Genova 
Phone. +39 010 562234 
Fax. +39 010 540699 
E-mail. info@latiscro.it 
 
Contacts for safety reporting 
CRO Contact for Serious 
Adverse Events (SAEs) 
Latis Srl – Viale Sauli 39/5 – 16121 Genova 
Phone. +39 010 562234 
Fax. +39 010 540699 
Laura Michellini Scientific Director 
Mobile. +39 347 4785898 
E-mail. michellini@latiscro.it 
 
 
 
 

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TABLE OF CONTENTS 
1. 
SYNOPSIS OF THE CLINICAL INVESTIGATION PLAN ..................................................................................... 8 
2. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE ................................................... 15 
3. 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION.......................................................... 15 
4. 
RISK AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION ........................... 18 
5. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION ............................................................ 19 
5.1  
PRIMARY OBJECTIVE .................................................................................................................................... 19 
5.2  
SECONDARY OBJECTIVES ............................................................................................................................... 19 
5.3  
TOLERABILITY AND SAFETY OBJECTIVES ............................................................................................................ 19 
6. 
DESIGN OF THE CLINICAL INVESTIGATION ................................................................................................ 19 
6.1 
GENERAL .................................................................................................................................................... 19 
6.2 
INVESTIGATIONAL DEVICE .............................................................................................................................. 20 
6.2.1 
DermoRelizema ecofoam .................................................................................................................... 20 
6.2.1.1  
Packaging and labelling .............................................................................................................................. 21 
6.2.1.2 
Study device instructions for use ............................................................................................................... 21 
6.2.1.3 
Handling and storage ................................................................................................................................. 21 
6.2.1.4 
Study product accountability and compliance ........................................................................................... 22 
6.2.2 
Concomitant Medications/Treatments ............................................................................................... 23 
6.3 
SUBJECTS .................................................................................................................................................... 23 
6.3.1 
Inclusion criteria .................................................................................................................................. 23 
6.3.2 
Exclusion criteria ................................................................................................................................. 24 
6.4 
PROCEDURES .............................................................................................................................................. 25 
6.4.1 
Study Visits and Assessments .............................................................................................................. 25 
6.4.2 
IGA (Investigator’s Global Assessment) .............................................................................................. 27 
6.4.3 
EASI (Eczema Area and Severity Index) ............................................................................................... 27 
6.4.4 
DLQI (Dermatology Life Quality Index) – Appendix 2 .......................................................................... 28 
6.4.5 
Subject and Investigator Global Evaluation of Performance – Appendices 3 and 4 ........................... 28 
6.4.6 
Subject Overall Acceptability – Appendix 5 ......................................................................................... 29 
6.4.7 
VAS for pruritus, itching, pain and burning ......................................................................................... 29 
6.5 
MONITORING PLAN ..................................................................................................................................... 29 
7. 
STATISTICAL CONSIDERATIONS ................................................................................................................ 30 
7.1 
SAMPLE SIZE DETERMINATION ....................................................................................................................... 30 
7.2 
DEFINITION OF STUDY POPULATIONS FOR ANALYSIS .......................................................................................... 31 
7.3 
STATISTICAL ANALYSIS .................................................................................................................................. 31 
7.3.1 
Missing Data ....................................................................................................................................... 31 
7.3.2 
Multiplicity .......................................................................................................................................... 31 
7.3.3 
Covariates, Interactions and Subgroups ............................................................................................. 32 
7.3.4 
Analysis of Demographics and Baseline Variables .............................................................................. 32 
7.3.5 
Efficacy analysis .................................................................................................................................. 32 
7.3.5.1 
Primary endpoint ....................................................................................................................................... 32 
7.3.5.2 
Secondary endpoints ................................................................................................................................. 32 
7.3.6 
Safety Analysis .................................................................................................................................... 33 
7.4 
PLANNED INTERIM ANALYSIS ......................................................................................................................... 33 
8.        DATA MANAGEMENT ............................................................................................................................. 33 
9.        AMENDMENTS TO THE CIP ..................................................................................................................... 35 

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10. 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN............................................................................. 35 
11. 
DEVICE ACCOUNTABILITY ..................................................................................................................... 35 
12. 
STATEMENT OF COMPLIANCE .............................................................................................................. 36 
13. 
INFORMED CONSENT PROCESS ............................................................................................................ 36 
14. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICES DEFICIENCIES ........................................... 37 
14.1 
DEFINITIONS ............................................................................................................................................... 37 
14.2 
ADVERSE EVENT INTENSITY/CAUSALITY ........................................................................................................... 38 
14.3       ADVERSE EVENT, DEVICE DEFICIENCY, ADVERSE DEVICE EFFECT, REPORTING .......................................................... 39 
15. 
VULNERABLE POPULATION .................................................................................................................. 40 
16. 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION ................................. 40 
16.1  
STUDY DISCONTINUATION ............................................................................................................................. 40 
16.2  
STUDY INTERRUPTION .................................................................................................................................. 41 
17. 
PUBLICATION POLICY ........................................................................................................................... 41 
18. 
STUDY PROTOCOL PERSONAL DATA PROTECTION SECTION ................................................................. 42 
18.1  
GENERAL PRINCIPLES ON PERSONAL DATA COMPLIANCE .................................................................................... 42 
18.2 
ACKNOWLEDGMENT ..................................................................................................................................... 42 
18.3 
DATA CONTROLLERS AND DATA PROCESSORS ................................................................................................... 43 
18.4 
DUTIES OF THE PARTIES INVOLVED IN THE PERFORMANCE OF THE STUDY ............................................................... 43 
18.5 
ARCHIVING OF THE CLINICAL TRIAL MASTER FILE AND CODE PAIRING LIST ............................................................. 45 
18.6 
DATA BREACH ............................................................................................................................................. 46 
18.7 
INFORMATION NOTICE ON PERSONAL DATA PROTECTION AND PSEUDONYMISATION ............................................... 48 
18.8 
TRANSFER OF PATIENTS’ DATA OUTSIDE THE EUROPEAN UNION .......................................................................... 48 
18.9 
EXERCISE OF PATIENTS’ DATA PRIVACY RIGHTS ................................................................................................... 48 
19. 
BIBLIOGRAPHY ..................................................................................................................................... 50 
Appendix 1 ................................................................................................................................................................ 52 
Appendix 2 ................................................................................................................................................................ 53 
Appendix 3 ................................................................................................................................................................ 55 
Appendix 4 ................................................................................................................................................................ 56 
Appendix 5 ................................................................................................................................................................ 57 
Appendix 6 ................................................................................................................................................................ 58 
 
 
 
 

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1. 
SYNOPSIS OF THE CLINICAL INVESTIGATION PLAN 
 
Study Title 
MULTICENTER, OPEN LABEL, UNCONTROLLED CLINICAL INVESTIGATION 
ON THE PERFORMANCE AND SAFETY OF DERMORELIZEMA ECOFOAM IN 
THE MANAGEMENT OF SOME DERMATITIS IN THE ADULT 
Study Code  
ReGl/20/Dec-Der/001 
Study Acronym 
NA 
Study type and design 
Multicenter, open label, uncontrolled, single arm, post-market clinical 
follow-up study. 
Pre/post Marketing 
study 
Post Marketing Study 
Version/Date  
1.0 - 06/11/2020  
Sponsor 
RELIFE S.r.l. 
Countries and Sites 
Unità Operativa Complessa di Dermatologia Clinica - Azienda Ospedaliera 
Universitaria “Federico II” – Napoli 
Coordinating PI - Prof. Gabriella Fabbrocini 
 
Unità Operativa di Dermatologia - Azienda Ospedaliero-Universitaria 
Sant’Andrea – Roma 
PI - Prof. Severino Persechino 
Indication 
Some types of dermatitis, including atopic dermatitis (AD), contact 
dermatitis (CD), or dermatitis caused by solar radiation. 
Objectives  
Primary objective 
 
The primary objective of this clinical investigation is to evaluate and 
confirm the performance of the DermoRelizema ecofoam in the 
improvement 
of 
the 
dermatitis 
severity, 
by 
alleviating 
the 
symptomatology. 
The disease severity will be clinically measured through the Investigator 
Global Assessment (IGA) after 28 days of treatment. 
 
Secondary objectives 
▪ 
To evaluate the performance of the DermoRelizema ecofoam in the 
improvement of dermatitis severity (IGA) after 14 and 42 days of 
treatment. 
▪ 
To evaluate the eczema improvement through the EASI (Eczema 

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Area and Severity Index) score; 
▪ 
To evaluate itching, burning, pain and pruritus improvement as 
reported by the subject at visits by VAS; 
▪ 
To evaluate the improvement in the Quality of Life (QoL) of the 
subject 
related 
to 
his/her 
dermatitis, 
through 
the 
DLQI 
(Dermatology Life Quality Index) questionnaire; 
▪ 
To evaluate the subject’s adherence to treatment. 
▪ 
To evaluate the subject’s and Investigator’s global evaluation of 
performance of DermoRelizema ecofoam; 
▪ 
To evaluate the subject’s overall acceptability of the treatment.
 
Safety objectives 
▪ 
To evaluate the local and general tolerability of DermoRelizema 
ecofoam. 
Study Treatment 
DermoRelizema ecofoam 
Study Duration  
For each subject the investigation will be of 1,5 month (42 days ±1). 
The recruitment phase will be of 3 months. 
The overall project duration (from “First Subject In” to “Last Subject 
Out”) will be of about 4,5 months.  
Number of Patients  
40 
Target Study Population 
Adult outpatients of both sexes, affected by mild to moderate dermatitis, 
like atopic or contact dermatitis. 
 
Selection Criteria 
Inclusion Criteria: 
1. Subject’s written informed consent obtained prior to any study-
related procedures; 
2. Generally healthy male and female aged ≥ 18 years; 
3. Presence of dermatitis of any typology, including atopic 
dermatitis (AD), irritant contact dermatitis (ICD) or allergic 
contact dermatitis (ACD), of mild-moderate severity:  
§ 
IGA score 2 (=mild) or 3 (=moderate);  
4. Dermatitis affecting one or more body areas (face, legs, arms, 
etc.); 
5. Subjects with cooperative attitude, able to comprehend the full 
nature and the purpose of the investigation, including possible 
risks and side effects, and able to comply with the requirements 
of the entire investigation (including ability to attend the planned 

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visits according to the time limits), based on Investigator’s 
judgement. 
 
Exclusion criteria: 
1. Severe dermatitis at inclusion; 
2. Pregnant and breastfeeding women; 
3. Concomitant other skin disorders including skin infections; 
4. Currently or previously diagnosed or treated (chemotherapy 
and/or radiotherapy) for cancer in the past 5 years; 
5. History of previous skin cancer (history of non-metastatic 
squamous or basal cell carcinoma of the skin is allowed); 
6. Active infections or use of antibiotics in the past 7 days; 
7. Diabetic subjects; 
8. History of congenital or acquired immunodepression; 
9. Immunologic or infectious disease (e.g. hepatitis, tuberculosis, 
HIV or AIDS, any typology of lupus, rheumatoid arthritis) which 
could place the subject at risk or interfere with study results; 
10. Use of any topic medication for dermatitis in the past 14 days; 
11. Use of any topic product for dermatitis in the 2 days before study 
treatment start; 
12. Any systemic treatment or procedure that could influence 
dermatitis activity within the past 30 days (or 5 half-lives); 
13. Use of any corticosteroids, immunosuppressant drugs or 
immunotherapy within the past 30 days (or 5 half-lives); 
14. Use of oral antihistamines and antidepressants in the past 30 
days; 
15. Subjects with any other clinically significant or unstable 
concurrent disease or skin condition or general condition that, in 
the Investigator’s opinion, might interfere with the study 
evaluations; 
16. Allergy, sensitivity or intolerance to the components of the 
investigational device formulations ingredients; 
17. Concomitant or previous participation in other interventional 
clinical study in the past 3 months; 
18. Subjects planning sun exposure or tanning booths or UV sources 
throughout the course of the study. 
 
Concomitant 
Non-permitted treatments: 

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Treatments 
§ any topic product for dermatitis  
§ oral antihistamines and antidepressants 
§ corticosteroids (by any route) 
§ antibiotics 
§ immunosuppressant drugs and immunotherapies 
§ any systemic treatment or procedure that could influence 
dermatitis  
§ chemo and radiotherapies 
§ sun exposure or tanning booths or UV sources. 
 
Primary study endpoint 
Change in dermatitis severity from baseline (Visit 1) to 28 days of 
treatment (Visit 3) in the IGA (Investigator Global Assessment) score.  
Secondary study 
endpoints 
Performance endpoints  
1. Change in dermatitis severity from baseline (Visit 1) to 14 and 42 
days of treatment (Visit 2 and 4) in the IGA (Investigator Global 
Assessment) score  
2. Change from baseline (Visit 1) to 14, 28 and 42 days of treatment 
(Visit 2, 3 and 4) in the EASI score 
3. Change from baseline (Visit 1) to 14, 28 and 42 days of treatment 
(Visit 2, 3, 4) of treatment in the itching, burning, pain and 
pruritus severity as reported by the subject on VAS scale, 
administered at visits 
4. Change from baseline (Visit 1) to 14, 28 and 42 days of treatment 
(Visit 2, 3, 4) of treatment in the DLQI questionnaire 
5. Adherence to treatment, evaluated by counting the applications 
reported on the subject’s diary and the product accountability 
6. Subject’s and Investigator’s global evaluation on performance of 
the study product performed by means of a 7-items scale (where 
1 = very much improved, 2 = improved, 3 = minimally improved, 4 
= no change, 5 = minimally worse, 6 = worse, 7 = very much 
worse) at the end of the study (Visit 4)  
7. Subject’s evaluation of overall acceptability with treatment 
(which takes into account pleasant or unpleasant feeling with the 
product and the ease of use), performed by means of a 5-item 
scale (where 1 = very much satisfied, 2 = satisfied, 3 = neither 
satisfied nor dissatisfied, 4 = dissatisfied, 5 = very much 
dissatisfied) at the end of the study (Visit 4). 
 

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Safety endpoints 
1. Number and type of adverse events (AEs) occurring during the 
study (seriousness, severity, and relation to study treatment). 
2. Local tolerability at the site of administration. 
Sample size 
determination  
An exact binomial test with a nominal 5% two-sided significance level will 
have 80% power to detect the difference between the Null hypothesis 
proportion, π₀ of 0.5 (i.e., 50% of patients with treatment success) and 
the Alternative proportion, π₁, of 0.75 (i.e., 75% of patients with 
treatment success) when the sample size is 30 subjects. Assuming a 
possible 25% dropout rate, 40 subjects will be enrolled. 
 
Statistical Analysis  
Descriptive statistical analysis of all relevant variables will be performed. 
Continuous variables will be summarized by the number of patients (N), 
mean, standard deviation, median, minimum, maximum. Categorical 
variables will be summarized by number (N) and proportion of patients 
(%). The significance level of statistical tests will be set at 0.05. 
Parametric tests will be used to analyze continuous variables; when 
continuous variables are not normally distributed, the corresponding 
non-parametric tests will also be performed.  
Statistical Analysis – 
Primary performance 
endpoint 
Wilcoxon signed rank-sum test will be used to assess a significant change 
in IGA from baseline to day 28. IGA will be also dichotomized in terms of 
treatment success (decrease in IGA ≥ 1) or treatment failure (no 
decrease in IGA). The proportion of treatment successes will be 
compared to a referent proportion (50%, Null hypothesis proportion) 
using the exact binomial test. 
Statistical Analysis – 
Secondary performance 
endpoints 
Wilcoxon signed rank-sum test will be used to assess significant changes 
in IGA from baseline to day 14 and 42. IGA will be also dichotomized in 
terms of treatment success (decrease in IGA ≥ 1) or treatment failure (no 
decrease in IGA) and described using number (N) and the proportion of 
patients (%). 
Changes from baseline (Visit 1) to 14 days (Visit 2), 28 days (Visit 3) and 
42 days (Visit 4) of treatment in EASI score, DLQI questionnaire and 
pruritus, itching, burning and pain severity will be analyzed using paired 
t-test.  
The number of applications reported on the subject’s diary and the 
product accountability will be summarized to evaluate adherence to 
treatment.  
Subject’s and Investigator’s global evaluation on performance of the 

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study product performed at the end of the study (Visit 4) will be 
summarized through number (N) and proportion of patients (%) for each 
item. The variable will be also dichotomized in terms of improved/not 
improved. 
Subject’s evaluation of overall acceptability with treatment, performed 
by means of a 5-item scale will be summarized through number (N) and 
proportion of patients (%) for each item.  
Statistical Analysis – 
Safety endpoints 
AEs and ADEs will be tabulated by System Organ Class (SOC) and 
Preferred Term (PT) after medical coding using the Medical Dictionary 
for Regulatory Activities (MedDRA). An overview of AEs and ADEs will be 
prepared showing the number of AEs and ADEs and the number of 
patients with any AEs or ADEs, serious AEs or ADEs, severity of AEs or 
ADEs and AEs or ADEs leading to withdrawal.  
Summary tables showing the number of patients with at least one AE or 
ADE and event counts by SOC and PT (Preferred Term) will be prepared. 
Local tolerability at the site of administration will be summarized. 
 
Population 
The following populations are defined for this investigation: 
•Safety analysis set (SAF): all patients enrolled who sign informed 
consent and receive at least one administration of the investigational 
device. 
•Full analysis set (FAS): all patients of the SAF who have performed the 
baseline assessments and have at least one post-baseline assessment of 
any performance endpoint.  
•Per-Protocol analysis set (PPAS): all patients of the FAS who meet all 
inclusion/exclusion criteria and who do not have any major protocol 
deviation. 
The analysis of safety endpoints will be performed in the Safety 
population (SAF). Analysis of performance endpoints will be performed 
on the FAS population. The analysis of primary endpoint will be repeated 
in the PPAS. 
 
 
 
 

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Table 1: Study Flow-Chart  
 
Visit 1 
Visit 2 
Visit 3 
Visit 4* 
Day 1 
Day 14 ± 1 
Day 28 ± 1 
Day 42 ± 2 
Screening 
Baseline 
Treatment start 
Follow-up  
visit 
Follow-up  
visit 
End of 
treatment End 
of study 
Written informed consent 
ü 
 
 
 
Demographic data 
ü 
 
 
 
Medical and surgical history 
ü 
 
 
 
Physical examination (focused on skin 
examination) 
ü 
ü 
ü 
ü 
IGA  
ü 
ü 
ü 
ü 
EASI 
ü 
ü 
ü 
ü 
Concomitant medications/treatments 
ü 
ü 
ü 
ü 
Inclusion and exclusion criteria 
ü 
 
 
 
Study product dispensed 
ü 
ü 
ü 
 
Study product administration 
→ (twice daily) 
Study product returned 
 
ü 
ü 
ü 
Diary dispensed 
ü 
ü 
ü 
 
Study treatment recording on the diary 
→ (daily) 
VAS administration for pain, itching, burning, 
pruritus 
ü 
ü 
ü 
ü 
Diary returned 
 
ü 
ü 
ü 
DLQI questionnaire  
ü 
ü 
ü 
ü 
Global evaluation of performance1 
 
 
 
ü 
Global evaluation of product acceptability2 
 
 
 
ü 
Treatment compliance 
 
ü 
ü 
ü 
Local and general adverse events 
 
ü 
ü 
ü 
 
*Or Early termination Visit 
1To be evaluated by both the subject and the Investigator 
2To be evaluated by the subject  
 
 
 
 

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2. 
Identification and Description of the Investigational Device 
DermoRelizema ecofoam is a topical compact mousse indicated for treatment of the signs and 
symptoms associated with all types of dermatitis (including atopic, contact dermatitis, dermatitis 
caused by radiotherapy and by sun radiations) and erythema. The mechanism of action of 
DermoRelizema ecofoam is based on the creation of a protective thin layer on the skin, which protects 
the skin against external irritants without hindering normal transpiration. It helps reducing skin 
redness and its derma-protective action it helps maintaining and restoring the physiological skin 
barrier. 
Thanks to its light texture, it can be easily applied on wide areas.   
DermoRelizema ecofoam is a CE marked medical device class IIa, manufactured by Relife Srl, that is the 
Sponsor of this post-market clinical follow-up investigation.  
In this clinical investigation DermoRelizema ecofoam will be used to treat and alleviate dermatitis 
severity and symptoms as perceived by the patients, in compliance with its Instructions for Use (IFU). 
Different typologies of skin conditions will be treated like atopic dermatitis, irritant dermatitis, contact 
dermatitis, as they have common symptomatology and they all could benefit from the treatment with 
the topic product under investigation. 
 
 
3. 
Justification for the Design of the Clinical Investigation 
Dermatitis is a skin inflammatory disease commonly spreading in a limited area of the body and 
characterized by reddening, itching and skin dryness of the affected epidermis [1]. Dermatitis is a 
condition that can interfere with social function, sleep and employment. Its persistence and 
accompanying pruritus may be stressful and frustrating for patients.  
The most common types of dermatitis are contact dermatitis (CD) and atopic dermatitis (AD), also 
referred as atopic eczema, but also dermatitis caused by radiotherapy or solar radiations can occur. 
Only atopic dermatitis and contact dermatitis will be included in this clinical investigation.   
 
The most common and best characterized type of eczema, atopic dermatitis (AD), appears to be 
increasing in incidence [2]. AD pathogenesis is not completely known, even though the disease seems 
to be the result of genetic susceptibility, immune dysfunction and epidermal barrier dysfunction [3]: it 
has been hypothesized that patients with eczema have defects in the skin barrier that allows antigens 
to enter and trigger the stimulation of inflammatory cytokines [4,5]. AD is characterized by a red and 

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itchy rash most commonly located where the skin flexes (e.g. inside the elbows, behind the knees and 
the front of the neck). 
Other common eczematous dermatoses are contact dermatitis (CD), particularly allergic contact 
dermatitis (ACD) and irritant contact dermatitis (ICD). 
 
Contact dermatitis (CD) is a rash that occurs on areas of the body that have come into contact with 
substances that either irritate the skin or cause an allergic reaction. CD can be irritant contact 
dermatitis (ICD) or allergic contact dermatitis (ACD). ICD is provoked by handling water, detergents, 
solvents or harsh chemicals and by friction, while ACD is due to skin contact with substances that most 
people don't react to (most commonly nickel, perfume, rubber, hair dye or preservatives). CD is 
commonly characterized by skin becoming red, blistered, dry, scaly and cracked. 
The first precaution in ICD and ACD is to avoid or limit the contact with substances that are irritant or 
generate the allergic reaction.  
 
Although the above-mentioned types of dermatitis are characterized by different etiological factors, a 
key issue of the clinical condition is the dysfunction of the epidermal barrier. An altered skin barrier is 
the initial step that starts the so-called “vicious circle” of atopic dermatitis, characterized by dryness, 
tendency to itching and scratching, risk of superinfections, inflammation, pain and sleep disturbances. 
 
In order to support the resolution of epidermis damage in the case of any dermatitis, the principal 
approach is the induction and enhancement of skin barrier repair.  
Some of the currently available treatments for dermatitis management forecast the topical application 
of drugs - such as corticosteroids or immunosuppressants - acting at reducing the underlying 
inflammation and hypersensitization of the epidermis, though they are related to some side effects 
resulting from the topical application [7,8,9,10, 11].   
On the other hand, to effectively heal the skin barrier, TEWL (Trans Epidermal Water Loss) must be 
minimized and the skin must be protected from further contact with irritants, allergens and infectious 
organisms [12].  
A number of clinical trials have shown that moisturizers lessen symptoms and signs of dermatitis, 
including pruritus, erythema and fissuring [13-15]. Most of the time, rash and itching are successfully 
treated within three weeks [16]. It is now widely accepted that the application of topical moisturizers, 
emollients and protective agents should be an integral part of the treatment of patients with atopic 
and contact dermatitis, and there is strong evidence that their use can reduce the need for 
pharmacologic intervention to treat disease flare-ups.  

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Moisturizers - including petrolatum, physiological lipid mixtures, and ceramide-dominant triple-
physiolosic lipid (ceramide:cholesterol:free fatty acids at a 3:1:1 molar ratio) - play critical roles in 
dermatitis management [17]. Their daily use is now universally recommended to improve clinical 
symptoms and enhance skin barrier function. Moreover, the barrier improvement deriving from the 
prolonged use of these products is particularly relevant, given that the long-term topical application of 
corticosteroids is not well-tolerated and also reduces skin barrier function and increases TEWL [18].  
Moisturizers are generally composed of substances capable to restore the ability of the intercellular 
lipid bilayers to retain and redistribute water [19, 20]. Moisturizers contain three main properties, 
which are the occlusive, humectant, and emollient effects.      
The occlusive ingredients physically block TEWL by forming a hydrophobic film on the skin surface and 
within the superficial interstitium between corneocytes [21].  
The second property of moisturizers is the emollient effect, which smoothes skin by filling space 
between skin flakes with a droplet of oil [22].  
The other property of moisturizers is to be also humectant. Humectants are substances that attract 
water from the external environment when applied to the skin and theoretically improve hydration of 
the stratum corneum with a physical mode of action [23]. Glycerin, together with panthenol and 
hyaluronic acid, is the most popular of all humectants used in personal care products. All these three 
ingredients are contained in DermoRelizema ecofoam.  
Hyaluronic acid (HA) is a widely available, biocompatible, polysaccharide with distinguishing 
physiochemical properties, which inspire its application throughout several fields of medicine. HA is 
also a naturally-occurring molecule, one of the major components of the extracellular matrix of the 
skin. It is produced by fibroblasts and keratinocytes, and is present in all layers of the epidermis and 
the dermis. HA binds a large number of water molecules, improving tissue hydration and resistance to 
mechanical damage, especially in aesthetic dermatology. Moreover, HA is used in the treatment of 
skin damage that manifests during radiation therapy for the treatment of solid tumors, in particular 
breast, head and neck, thorax and abdomen cancers; since 1997, it has demonstrated to be effective 
and safe when applied topically for the prevention of radioepithelitis [24]. In addition, DermoRelizema 
ecofoam contains Sodium Butyroyl Formoyl Hyaluronate (sodium hyaluronate butyrate and formate). 
Sodium Butyroyl Formoyl Hyaluronate is a hyaluronan derivative in which hydroxylic functions of the 
polysaccharide are substituted by butyric acid. The substitution positively affects the stability of the 
molecule, because esterification of sodium hyaluronate with butyric acid reduces the rate of enzymatic 
degradation.  

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DermoRelizema ecofoam also contains glycerol, which is a well-known cosmetic ingredient and acts as 
humectant [25]. Glycerol-containing moisturizers produce long-lasting moisturization by binding and 
holding water, thus minimizing water loss.  
 
DermoRelizema ecofoam (DLP034) CE mark was supported by literature research. In order to allow the 
Manufacturer, Relife Srl, to review and confirm the clinical performance and safety of the medical 
device DermoRelizema ecofoam in the post-market phase, this post-market clinical follow-up 
investigation was designed and is going to be conducted in adult males and females affected by mild to 
moderate dermatoses, like AD, ICD or ACD. 
 
 
4. 
Risk and Benefits of the Investigational Device and Clinical Investigation 
To date a large variety of products for the treatment of eczematous dermatoses are available.  
DermoRelizema ecofoam is a medical device that is CE marked and already in use to treat dermatitis 
symptoms such as itching, flushing and erythema. In this clinical investigation DermoRelizema ecofoam 
will be used in adult subjects with mild to moderate dermatitis, of any origin, and erythema, according 
its IFU.  
DermoRelizema ecofoam will be recommended twice daily for 42 days (±2). The product’s components 
are known to be safe and well tolerated, therefore no risk seems to be associated to DermoRelizema 
ecofoam use.   
The only precaution for users is to avoid contact of the product with eyes and mucous membranes (if 
contact does occur rinse immediately with plenty of water). 
Within the clinical investigation the subject will be provided with instructions on the personal hygiene 
to follow, in order to further improve skin care and safety.   
No tests or invasive examinations are foreseen in this study that can increase the risk for participants. 
In the light of the above, no additional risk arising from the participation to this clinical investigation 
can be envisioned. 
 
 

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5. 
Objectives and Hypotheses of the Clinical Investigation 
5.1  
Primary Objective 
The primary objective of this clinical investigation is to evaluate and confirm the performance of the 
DermoRelizema ecofoam medical device in the improvement of the dermatitis severity, by alleviating 
the symptomatology. 
The disease severity will be clinically measured through the Investigator Global Assessment (IGA) for 
dermatitis after 28 days of treatment. 
 
5.2  
Secondary Objectives 
The secondary objectives of this clinical investigation are: 
- 
to evaluate the performance of the DermoRelizema ecofoam in the improvement of dermatitis 
severity (IGA) after 14 and 42 days of treatment; 
- 
to evaluate the eczema improvement through the EASI (Eczema Area and Severity Index) 
score; 
- 
to evaluate the improvement in itching, burning, pain and pruritus at visits, as reported by the 
subject at visits by VAS; 
- 
to evaluate improvement in the Quality of Life (QoL) of the subject related to his/her 
dermatitis, through the DLQI (Dermatology Life Quality Index) questionnaire; 
- 
to evaluate the subject’s adherence to treatment. 
- 
to evaluate the subject’s and Investigator’s global evaluation of performance of 
DermoRelizema ecofoam; 
- 
to evaluate the subject’s overall acceptability of the treatment. 
 
5.3  
Tolerability and Safety Objectives 
To evaluate the local and general tolerability of DermoRelizema ecofoam. 
 
 
6. 
Design of the Clinical Investigation 
6.1 
General 
This is a multicenter, open label, uncontrolled, post-market clinical follow-up investigation. 
All the subjects will be allocated to the following treatment group: 

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- 
DermoRelizema ecofoam, topically applied twice a day in all the affected areas for 42 
consecutive days. 
The subject will start treatment on the first day of study and will go on until 42 days after the first 
application. The treatment could be prolonged or shortened of maximum 2 days, in the case 
intermediate and/or final visits are delayed.  
Each subject for whom written consent is obtained will be identified during the study by a “Subject 
Code”, automatically generated and assigned by the e-CRF.   
All screened subjects will receive the Code regardless of whether they receive the treatment or not. If 
a subject discontinues from the study at any time, the Code will not be re-used. 
All subjects who will sign the informed consent and receive the Subject Code will be entered into a 
Subject’s Register, containing the name and surname of the patients and their Subject Codes. The 
Subject’s Register will be accessible for source data verification but will be preserved only at clinical 
site. 
Once eligibility of a patient is established (see Inclusion/Exclusion Criteria) the study treatment will be 
assigned. 
The Investigator will keep record of all enrolled patients in the Subject’s Screening/Enrolment Log: the 
Subject Code, the date of consent, the treatment assigned to the patient, if applicable, or the reason 
for not actively entering the study will be recorded. 
 
6.2 
Investigational device  
6.2.1 DermoRelizema ecofoam 
The product under investigation is DermoRelizema ecofoam. 
 
Manufacturer:   
 
Relife Srl, Via dei Sette Santi 3 - 50131 Firenze (FI) - Italy 
Device Name:   
 
DLP034 
Trade Name:   
 
DermoRelizema ecofoam  
Formulation:   
 
ecofoam 
Route of administration:  
topical application on breached/compromised skin 
 
Composition:   
 
aqua, peg-40 hydrogenated castor oil, glycerin, betaine, pullulan, 
capryloyl/ caproyl methyl glucamide, sodium cocoyl glycinate, 
ethylhexylglycerin, panthenol, propylene glycol, tocopheryl acetate, 
lauroyl/ myristoyl methyl glucamide, glyceryl caprylate, chondrus 
crispus powder, sodium butyroyl/formoyl hyaluronate, sodium 

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hyaluronate, hexamidine diisethionate, biotin, caprylhydroxamic acid, 
citric acid. 
 
 
 
 
It is formulated without fragrances, paraben, alcohol and gas. Nickel, 
antimony, arsenic, cadmium, cobalt, chrome, mercury and lead tested. 
 
DermoRelizema ecofoam is a CE marked, Class IIa medical device, dermatological compact mousse for 
topical use indicated for symptomatic treatment of all types of dermatitis (including atopic dermatitis, 
contact dermatitis, or dermatitis caused by radiotherapy and solar radiation) and erythema. It forms a 
thin protective layer on the skin which protects against external irritants, without hindering normal 
perspiration, and helps reduce redness. Additionally, due to its light texture, it can also be easily applied 
to large areas.  
 
6.2.1.1  Packaging and labelling 
DermoRelizema ecofoam will be provided for the study by the Sponsor of this clinical investigation. 
The study product shipment to the study sites will be done only after the completion of all Ethics and 
Administrative procedures. 
The product will be labeled as experimental treatment in accordance with applicable Good 
Manufacturing Practice (GMP, Annex 13). 
The primary package is a 70 ml labelled canister with pump. Each subject will receive a total of no. 3 
canisters and he/she will use a variable amount of cream depending on the extent of the area/s 
affected by dermatitis to be treated. Occasionally, if the subject needs further treatment (beyond the 
3 canisters received), the Investigator will be able to provide further amount of treatment. Additional 
canisters provided to the subject will be recorded in the CRF. 
 
6.2.1.2 Study device instructions for use 
Patients will be instructed to use DermoRelizema ecofoam two times daily: the first application in the 
morning and the second in the evening before bedtime, for 42 consecutive days.  
At the first use of the product the patient should be instructed to press the valve two or three times to 
activate the pump mechanism. After this, the subject should press the valve gently to obtain one or 
more doses of the product to apply on the selected area and massage. 
 
6.2.1.3 Handling and storage 
It is the Investigator/Institution’s responsibility to set up a system for handling the clinical investigation 
treatment, so as to ensure that:  

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· 
deliveries of product supply from the Sponsor are correctly received 
· 
products are handled and stored safely and properly in a secured area 
· 
treatments are only dispensed to study subjects in accordance with the clinical investigation plan 
· 
any unused, used, partially used product is returned to the Investigator (including empty 
canisters). 
The study product shall be carefully stored at the study site, in a safe area and separately from other 
devices/drugs/products. It shall be stored in a dry and cool place, away from direct sunlight or heat. 
The pharmacist and/or the Investigator shall maintain records of the study products receipt by the 
study site and an updated inventory of the study product.  
Treatments will be dispensed to the subjects enrolled in this clinical investigation only by authorized 
personnel.  
After study conclusion, all unused study product shall be returned to the Sponsor or destroyed at site 
after written Sponsor approval. 
 
6.2.1.4 Study product accountability and compliance 
The Investigator is responsible for ensuring the accountability of the study product. 
Accountability records will include: 
· 
confirmation of product delivery and receipt to/at the clinical site 
· 
records concerning the product delivery to each subject and the return from each subject 
· 
the return to the Sponsor or alternative disposition of unused products. 
The Investigator should maintain records that adequately document: 
· 
that the subjects were provided with the quantities specified by the clinical investigation 
plan/amendment(s) 
· 
that all study products provided by the Sponsor were fully reconciled. 
Unused products must not be discarded or used for any purpose other than the present clinical 
investigation.  
Products that have been allocated to one subject must not be re-dispensed to a different patient.  
Subjects will be reminded of the importance of strictly complying with the instructions received from 
the Investigator and to return all unused treatment or empty canisters to the Investigator.  
The Investigator will check and register when subjects are bringing back to the site the used/unused 
products. Compliance to the treatment will be done with subject’s diary information. 
 

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6.2.2 Concomitant Medications/Treatments 
Any medications (other than those excluded by the clinical investigation plan) that were considered 
necessary for the patients’ well-being and do not interfere with the study product can be given at the 
Investigator’s discretion. 
According to exclusion criteria, the following prior and concomitant medications are prohibited: 
§ 
any topic product for dermatitis  
§ 
oral antihistamines and antidepressants 
§ 
corticosteroids (by any route) 
§ 
antibiotics 
§ 
immunosuppressant drugs and immunotherapies 
§ 
any systemic treatment or procedure that could influence dermatitis  
§ 
chemo and radiotherapies 
§ 
sun exposure or tanning booths or UV sources. 
The subject will be recommended not to use any other product for the personal hygiene than the one 
provided by the Investigator. 
Any concomitant medication/treatment shall be recorded in the appropriate section of the CRF. 
 
6.3 
Subjects 
In this clinical investigation 40 subjects will be enrolled fulfilling the following eligibility criteria. 
 
6.3.1 Inclusion criteria 
1. 
Subject’s written informed consent obtained prior to any study-related procedures; 
2. 
Generally healthy male and female aged ≥ 18 years; 
3. 
Presence of dermatitis of any typology, including atopic dermatitis (AD), irritant contact 
dermatitis (ICD) or allergic contact dermatitis (ACD), of mild-moderate severity:  
§ 
IGA score 2 (=mild) or 3 (=moderate)  
4. 
Dermatitis affecting one or more body areas (face, legs, arms, etc.); 
5. 
Subjects with cooperative attitude, able to comprehend the full nature and the purpose of 
the investigation, including possible risks and side effects, and able to comply with the 
requirements of the entire investigation (including ability to attend the planned visits 
according to the time limits), based on Investigator’s judgement. 
 

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6.3.2 Exclusion criteria 
1. 
Severe dermatitis at inclusion; 
2. 
Pregnant and breastfeeding women; 
3. 
Concomitant other skin disorders including skin infections; 
4. 
Currently or previously diagnosed or treated (chemotherapy and/or radiotherapy) for 
cancer in the past 5 years; 
5. 
History of previous skin cancer (history of non-metastatic squamous or basal cell 
carcinoma of the skin is allowed); 
6. 
Active infections or use of antibiotics in the past 7 days; 
7. 
Diabetic subjects; 
8. 
History of congenital or acquired immunodepression; 
9. 
Immunologic or infectious disease (e.g. hepatitis, tuberculosis, HIV or AIDS, any typology 
of lupus, rheumatoid arthritis) which could place the subject at risk or interfere with study 
results; 
10. 
Use of any topic medication for dermatitis in the past 14 days; 
11. 
Use of any topic product for dermatitis in the 2 days before study treatment start; 
12. 
Any systemic treatment or procedure that could influence dermatitis activity within the 
past 30 days (or 5 half-lives); 
13. 
Use of any corticosteroids, immunosuppressant drugs or immunotherapy within the past 
30 days (or 5 half-lives); 
14. 
Use of oral antihistamines and antidepressants in the past 30 days; 
15. 
Subjects with any other clinically significant or unstable concurrent disease or skin 
condition or general condition that, in the Investigator’s opinion, might interfere with the 
study evaluations; 
16. 
Allergy, sensitivity or intolerance to the components of the investigational device 
formulations ingredients; 
17. 
Concomitant or previous participation in other interventional clinical study in the past 3 
months; 
18. 
Subjects planning sun exposure or tanning booths or UV sources throughout the course of 
the study. 
 

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6.4 
Procedures 
6.4.1 Study Visits and Assessments 
Visit 1 screening – baseline- treatment start (day 1):  
Subjects will be evaluated with regard to the inclusion and exclusion criteria that will allow their 
participation into the study. 
Before any study specific evaluation is carried out, subjects will receive all the information about the 
study by the Investigators and will sign an informed consent form. 
 
The following activities will be performed:  
§ 
Collection of information about demography  
§ 
Medical and surgical history  
§ 
Physical examination, focused on skin examination  
§ 
IGA on dermatitis  
§ 
EASI Score  
§ 
Previous (in the 30 days before) and concomitant medications/treatments 
recording 
§ 
Inclusion/exclusion criteria assessment 
§ 
VAS for pain, itching, burning, pruritus 
§ 
DLQI questionnaire 
§ 
Study product delivery to subject and instructions on how to use it 
§ 
Recommendations for personal hygiene to follow  
§ 
Diary dispensation and explanations on how to fill it in. 
 
Diary: on the diary each subject will record, at the end of each day, the study product applications 
performed.  
 
Recommendations for personal hygiene to follow: throughout the treatment phase subjects will be 
required to avoid soap and use only the product DermoRelizema liporestitutive cleanser, particularly 
indicated for dry and sensitive skin, provided by the Investigator for bathing and showering (bathing 
should be once a daily, with warm water, for approximately 5 to 10 minutes).  
 
DermoRelizema ecofoam application: to apply the study product on the affected body areas twice per 
day, once in the morning and once in the evening before bedtime. No additional creams, moisturizers, 
lotions or cleansers other than the product provided by the Investigator will be permitted. 
   

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Visit 2 (Day 14 ± 1) and Visit 3 (Day 28 ± 1) – follow-up visits:  
The following activities will be done at Visit 2 and Visit 3: 
§ 
Physical examination, focused on skin examination   
§ 
IGA on dermatitis  
§ 
EASI Score  
§ 
Change in concomitant medications/treatments recording  
§ 
VAS for itching, burning, pain, pruritus 
§ 
DQLI questionnaire  
§ 
Diary compilation check with the subject for treatment adherence and collection 
§ 
New diary delivery 
§ 
Study product collection and accountability 
§ 
New product delivery 
§ 
Adverse events (occurred since previous visit) recording. 
 
If Visit 2 is anticipated of one day (Day 13) or postponed of 1 day (Day 15), any attempt will be done to 
fix the following Visit 3 so that 28 days of study and treatment are respected (i.e. if Visit 2 is on Day 13, 
then Visit 3 will be 15 days after Visit 2).  
 
Visit 4 – End of treatment and end of study (Day 42 ±2):  
The following activities will be done at Visit 4: 
§ 
Physical examination, focused on skin examination   
§ 
IGA on dermatitis  
§ 
EASI Score  
§ 
Change in concomitant medications/treatments recording  
§ 
VAS for itching, burning, pain, pruritus 
§ 
DQLI questionnaire  
§ 
Diary compilation check with the subject for treatment adherence and collection 
§ 
Study product collection and accountability 
§ 
Subject global evaluation of performance  
§ 
Investigator global evaluation of performance  
§ 
Subject global acceptability evaluation on the study product 
§ 
Adverse events (occurred since previous visit) recording. 
Any attempt will be done to fix the Visit 4 so that the study and treatment days are as minimum 40 
and as maximum 42.  

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6.4.2 IGA (Investigator’s Global Assessment)  
IGA is a tool used in the clinical routine to define the dermatitis severity. The Investigator’s Global 
Assessment is based on a six-point scale: 
0 = clear 
1 = almost clear 
2 = mild 
3= moderate  
4 = severe 
5 = very severe. 
The IGA will be filled in by the Investigator at each visit. 
 
6.4.3 EASI (Eczema Area and Severity Index)    
The EASI score is a tool used to measure the extent (area) and severity of eczema.  
Four body regions are considered: head and neck, trunk (including genital area), upper limbs, lower 
limbs (including buttocks). The percentage of skin affected by eczema in each region is correlated to an 
area score (0 = 0: no eczema in this region; 1 = 1-9%; 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; 
6 = 90-100%: the entire region is affected by eczema).  
A severity score (0 =none, 1 = mild), 2 =moderate or 3 = severe) is then recorded for each of the four 
regions identified for the following four signs: 
1. Redness (erythema, inflammation); 
2. Thickness (induration, papulation, swelling—acute eczema); 
3. Scratching (excoriation); 
4. Lichenification (lined skin, prurigo nodules—chronic eczema). 
 
 
 

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EASI score calculation: 
 
 
Body region 
Erythema 
Edema/ 
papulation 
Excoriation 
Lichenification 
Area score 
Multiplier 
Score 
Head/neck 
(          + 
+ 
+ 
) 
X 
x 0.1 
 
Trunk 
(          + 
+ 
+ 
) 
X 
x 0.3 
 
Upper extremities 
(          + 
+ 
+ 
) 
X 
x 0.2 
 
Lower extremities 
(          + 
+ 
+ 
) 
X 
x 0.4 
 
 
The final EASI score is the sum of the 4 region scores 
 
 
(0-72) 
 
Severity strata for the EASI are as follows: 0 = clear; 01-1.0 = almost clear; 1.1-7.0 = mild; 7.1-21.0 = 
moderate; 21.1-50.0 = severe; 50.1-72.0 = very severe. 
The EASI score will be filled in by the Investigator at each visit. 
 
6.4.4 DLQI (Dermatology Life Quality Index) – Appendix 2 
DLQI is a questionnaire used to measure the impact of skin disease on the quality of life of an affected 
person. There are 10 questions, covering the following topics: symptoms, embarrassment, shopping 
and home care, clothes, social and leisure, sport, work or study, close relationships, sex, treatment. 
Each question refers to the impact of the skin disease on the patient’s life over the previous week. 
Each question is scored from 0 to 3, giving a possible score range from 0 (meaning no impact of skin 
disease on quality of life) to 30 (meaning maximum impact on quality of life). 
Global score:  
0-1 = No effect on patient’s life 
2-5 = Small effect 
6-10 = Moderate effect  
11-20 = Very large effect  
21-30 = Extremely large effect. 
The DQLI will be compiled by the subject at each visit. 
 
6.4.5 Subject and Investigator Global Evaluation of Performance – Appendices 3 and 4 
Subjects’ and Investigator’s global evaluation of the performance of DermoRelizema ecofoam will be 
performed by means of the 7-item scale, where 1 = very much improved, 2 = improved, 3 = minimally 

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improved, 4 = no change, 5 = minimally worse, 6 = worse, 7 = very much worse at the end of the study 
(Visit 4). 
 
6.4.6 Subject Overall Acceptability – Appendix 5 
Subjects’ evaluation of overall acceptability with the study treatment, which takes into account the 
pleasant or unpleasant feeling with the product and the ease of use, will be performed by means of a 
5-item scale, where 1 = very much satisfied, 2 = satisfied, 3 = neither satisfied nor dissatisfied, 4 = 
dissatisfied, 5= very much dissatisfied.  
Global acceptability evaluation by the subject will be assessed at the end of the treatment (Visit 4).  
 
6.4.7 VAS for pruritus, itching, pain and burning 
The subject will be requested to indicate at each visit his/her pruritus, itching, burning and pain by 
placing a vertical mark along a 100 mm VAS (Visual Analogue Scale). The rating will be recorded as a 
distance from the left side of the scale (0 mm) to the mark made by the patient. 
Example:  
 
Rating (mm): |__|__|__| 
A VAS scale for each of the 4 symptoms will be completed by the subject at each visit. 
 
6.5 
Monitoring Plan 
The study will be monitored on a regular basis by the CRO’s adequately qualified and trained clinical 
Monitors throughout the study period to ensure the proper conduct of the clinical Investigation.  
The purposes of study monitoring are to verify that the rights and well-being of study subjects are 
protected, that the reported study data are accurate, complete and verifiable against the source 
documents, and that the study is conducted in accordance with the current clinical investigation plan, 
Good Clinical Practice guideline (UNI EN ISO 14155) and applicable regulatory requirements. 
During the monitoring visits, Monitors will verify the following, including but not limited to: subject 
informed consent, subject’s eligibility, safety data and reporting, quality of source documents and CRF 
data against subject’s medical records. If inconsistencies are found, the corresponding corrections to 
the CRF data will have to be made by the Investigator or designated person. Monitors will also check 
subject compliance, accrual, study product handling, including dispensing procedures and 
No 
pruritus 
 
 
 
 
 
 
 
 
 
 
Worst possible pruritus 
 
 
 
 
 
 
 
 
 
 

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accountability logs, delegation of responsibilities within the Investigator’s team, relevant 
communications with family doctors, if any, ancillary equipment and facilities, etc. The Investigator 
and other site staff involved in the study must allocate enough time to the Monitor at these visits. 
Given the current COVID-19 pandemic situation also proper approaches will be implemented remotely 
to allow the performance of the monitoring activities, in line with applicable guidelines of competent 
authorities and best practices. 
Upon request by the Sponsor, on-site study audits may be conducted in order to ensure the study is in 
compliance with GCP, applicable regulatory requirements, and the clinical investigation plan. The 
auditing activities may also be conducted after study completion. 
The Investigator agrees to allow Sponsor/auditors/CRO monitors to have direct access to his/her study 
records for review, being understood that they are bound by professional secrecy, and as such will not 
disclose any personal identity or personal medical information. 
Regulatory Authorities may wish to conduct on-site inspections (during the study or after its 
completion). If a Regulatory Authority notifies the Investigator of an inspection or visits the site 
unannounced for purposes of conducting an inspection, the Investigator must inform the Sponsor and 
CRO immediately. The Investigator will make all efforts to facilitate the conduct of the audits and 
inspections giving access to all necessary facilities, data and documents. 
Any result or information arising from the inspection will be immediately communicated by the 
Investigator to the Sponsor. The Investigator will take all appropriate measures required by the 
Sponsor to implement corrective actions for all problems found during audits or inspections. 
 
 
7. 
Statistical Considerations 
This section summarizes the statistical principles and methods planned to analyze the data for this 
clinical investigation. 
 
7.1 
Sample Size Determination 
An exact binomial test with a nominal 5% two-sided significance level will have 80% power to detect 
the difference between the Null hypothesis proportion, π₀ of 0.5 (i.e., 50% of patients with treatment 
success) and the alternative proportion, π₁, of 0.75 (i.e., 75% of patients with treatment success) when 
the sample size is 30 subjects. Assuming a possible 25% dropout rate, 40 subjects will be enrolled.  
 

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7.2 
Definition of Study Populations for Analysis 
The following populations are defined for this investigation: 
• 
Safety analysis set (SAF): all patients enrolled who sign informed consent and receive at least 
one administration of the investigational device. 
• 
Full analysis set (FAS): all patients of the SAF who have performed the baseline assessments 
and have at least one post-baseline assessment of any performance endpoint (primary or secondary).  
• 
Per-Protocol analysis set (PPAS): all patients of the FAS who also meet all inclusion/exclusion 
criteria and who do not have any major protocol deviation (i.e. wrong inclusion, use of forbidden 
concomitant medications, etc.). 
The analysis of safety endpoints will be performed in the Safety population (SAF). Analysis of 
performance endpoints will be performed on the FAS population. The analysis of primary endpoint will 
be repeated in the PPAS 
 
7.3 
Statistical Analysis 
Descriptive statistical analysis of all relevant variables will be performed. Continuous variables will be 
summarized by the number of patients (N), mean, standard deviation, median, minimum, maximum. 
Categorical variables will be summarized by the number (N) and the proportion of patients (%). Where 
appropriate, 95% confidence intervals for the target variables will be estimated. 
The significance level of statistical tests will be set at 0.05. Parametric tests (e.g., paired t-test) will be 
used to analyze continuous variables; when continuous variables are not normally distributed, the 
corresponding non-parametric tests (e.g. Wilcoxon signed-sum rank test) will also be performed. 
Details of statistical analysis are provided in the following paragraphs. 
The statistical analysis will be performed using SAS 9.4 for Windows (SAS Institute Inc., Cary, NC, USA). 
 
7.3.1 Missing Data 
Missing data will not be replaced in any statistical analysis. 
 
7.3.2 Multiplicity 
This is a single-arm clinical investigation and no adjustment for multiplicity will be used.  
 

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7.3.3 Covariates, Interactions and Subgroups 
This is a single-arm clinical investigation. No covariates or interaction analysis will be performed. 
Subgroup analyses could be performed to better describe the performance and safety of the study 
device. 
 
7.3.4 Analysis of Demographics and Baseline Variables 
Demographic (gender, age) and baseline characteristics will be summarized using mean, median, 
standard deviation, minimum and maximum for continuous variables and frequencies and percentages 
for categorical variables.   
 
7.3.5 Efficacy analysis 
7.3.5.1 Primary endpoint 
Wilcoxon signed rank-sum test will be used to assess a significant change in IGA from baseline to day 
28.  
The assessment will be also dichotomized in terms of treatment success (decrease in IGA between 
baseline and day 28 ≥ 1) or treatment failure (no decrease in IGA, i.e. IGA at day 28 equal to or higher 
than IGA at baseline) and described using number (N) and the proportion of patients (%). The 
proportion of treatment successes will be compared to a referent proportion (50%, Null hypothesis 
proportion) using the exact binomial test. 
 
7.3.5.2 Secondary endpoints 
Wilcoxon signed rank-sum test will be used to assess significant changes in IGA from baseline to day 14 
and 42. IGA will be also dichotomized in terms of treatment success (score decrease ≥ 1) or treatment 
failure (no score decrease) and described using number (N) and the proportion of patients (%). 
Changes from baseline (Visit 1) to 14 days (Visit 2), 28 days (Visit 3) and 42 days (Visit 4) of treatment 
in EASI score, DLQI questionnaire and VAS for pruritus, itching, burning and pain severity will be 
analyzed using paired t-test.  
The number of applications reported on the subject’s diary will be summarized to evaluate adherence 
to treatment.  
Subject’s and Investigator’s global evaluation on performance of the study product performed at the 
end of the study (Visit 4), by means of a 7-items scale, will be summarized through number (N) and 
proportion of patients (%) for each item. The variable will be also dichotomized in terms of 
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Subject’s evaluation of overall acceptability with treatment, performed by means of a 5-item scale will 
be summarized through number (N) and proportion of patients (%) for each item. 
 
7.3.6 Safety Analysis 
All enrolled subjects receiving at least one treatment application will be included in the safety analysis. 
Adverse events (AEs) and Adverse Device Events (ADEs) will be coded using the last updated version of 
the Medical Dictionary for Regulatory Activities (MedDRA) dictionary to give a preferred term (PT) and 
a system/organ class term (SOC) for each event. The number of subjects who experienced at least one 
AE or ADE, study product-related AE or ADE, serious AE or ADE, severe AE or ADE and the number of 
subjects withdrawn due to AE will be summarized. 
For each SOC and preferred term, summaries will be made with respect to the proportion of subjects 
having at least one occurrence of that event during the study and the total number of events. The 
incidence of AEs and ADEs will be presented overall, by SOC and preferred term, and additional 
grouping by severity and relationship to the study treatment.  
Local tolerability at the site of administration (e.g. skin increased itching or redness or irritation) will be 
reported and summarized. 
 
7.4     Planned Interim Analysis 
No interim analysis is planned. 
 
 
8.        Data Management 
During each study visit, the study Investigator (or designee) will collect and report study data in the 
relevant patient’s chart, documenting all significant observations. 
Any contact with the patient via telephone or other means that provides significant clinical 
information shall be documented in the source data. 
An Electronic Case Report Form (e-CRF) will be used to record subject’s study data.  
All data relating to the study will be documented in the electronic CRF (e-CRF). This CRF is developed 
to record the data requested by the protocol.  
The Investigator will maintain a list of all persons authorized to make entries and/or corrections on the 
e-CRFs. Each authorized person will be provided with a user-specific ID protected by a renewable 
password. Data entries and corrections will be made only by the authorized persons. The e-CRF system 
will record date and time of any entry and /or correction and the user ID of the person making the 

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entry/correction. The system will keep track of all old and new values (audit trail). It is the 
responsibility of the Investigator to ensure that the CRFs are properly and completely filled in. The 
CRFs must be completed for all subjects who have been included in the study. The Investigator will 
review all CRFs and electronically sign and date them for each subject, verifying that the information is 
complete, true and correct. All fields on the CRF must be completed as applicable. 
Checks to assist during the data entry and to assess the appropriateness and consistency of data will 
be developed on the e-CRF system. E-CRF pages will be reviewed both on site by the monitor of the 
center and remotely, by the data management staff of the CRO. Data Clarification Sheets (DCS) will be 
generated through the e-CRF system, both automatically, through edit checks, and manually, by CRAs 
and/or data managers, and the Investigator will have to check and solve them. The Investigator is 
responsible for the review and approval of all query resolutions. 
Subject’s diaries will be dispensed at each Visit; the diary will have to be filled daily by the subject 
during treatment period. It is responsibility of the Investigator’s to instruct the participants on how to 
fill in the diaries in a clear way and preferably in black ball-point pen. The diary is anonymous, the 
subject is identified through the Subject Code. Diaries data will be reported on the e-CRF by the 
Investigator (or designee). Diaries will be considered source data. 
Subjects will be provided with paper questionnaires. Such documents will be filled by the subjects 
during the study visits, to record data concerning their QoL with respect to dermatitis condition and to 
report the symptoms severity.  
It is responsibility of the Investigators to instruct the study participants on how to fill in questionnaires 
in a clear way and preferably in black ball-point pen. The questionnaires will be anonymous, each 
subject is identified through the Subject Code. Questionnaires data will be reported on the e-CRF by 
the Investigator (or designee). Questionnaires will be considered source data, too. 
 
At the beginning of the trial, a Study Master File will be established according to Sponsor or Latis SOPs, 
in order to maintain the trial documents as specified in the UNI EN ISO 14155 Guideline and as 
required by the applicable regulatory requirements. Latis will take measures to prevent accidental or 
premature destruction of these documents. 
Clinical sites will permit trial-related monitoring, audits, and regulatory inspection providing direct 
access to source data / documents. 
Essential documents of the clinical investigation, including the subject identification list, source data 
and case report forms will be retained for 10 years after the completion or discontinuation of the trial 

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at clinical sites. The sponsor will retain the trial master file for 10 years after the Marketing 
Authorisation for the study product has been discontinued in all countries. 
 
 
9.        Amendments to the CIP 
Changes to the clinical investigation plan may only be made by means of a written amendment, which 
has to be approved and signed by the authorized representatives of the Sponsor, and by the 
Investigator. 
Exhaustive justifications that motivate the amendment to the clinical investigation plan should clearly 
be addressed in the document.  
All substantial Clinical Investigation Plan amendments must be submitted for approval to IEC and 
notified to the Regulatory Authority. In case of non-substantial amendment the IEC and the Regulatory 
Authority (when applicable) will be only notified of the amendment without the request to review and 
approve it. 
The Investigator, the Sponsor and IEC, separately or together, should decide whether the subject’s 
informed consent form needs to be changed. 
 
 
10. 
Deviations from Clinical Investigation Plan 
The Investigator is to conduct the study in accordance with the relevant, current clinical investigation 
plan and will only deviate when necessary to protect the safety, rights and welfare of the subjects. In 
the event that an isolated, unforeseen instance occurs resulting in a clinical investigation plan 
deviation, the Investigator is to document this deviation and notify the CRO or the Sponsor as soon as 
possible. In no instance should this increase the subject’s risk or affect the validity of the study. 
 
 
11. 
Device Accountability 
The Investigator is responsible of ensuring accountability of the study product, including reconciliation 
of study product and maintenance of records. 
Upon receipt of the study product, the Investigator (or designee) will check the contents and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the Sponsor 
and returning it to the Sponsor. A copy will be retained in the Investigator File. 

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The dispensing of the study product will be carefully recorded on the appropriate accountability forms 
provided by the Sponsor and an accurate accounting will be available for verification by the Study 
Monitor at each monitoring visit. 
Study product accountability records will include: 
· Confirmation of study product receipt at the clinical site. 
· The inventory at the site of study product provided by the Sponsor. 
· The tubes delivery to each subject. 
· The tubes return from each subject. 
· The return to the Sponsor or alternative disposition of unused study product. 
The Investigator should maintain records that adequately document: 
· That the subjects were provided with the quantities specified by the Clinical Investigation 
Plan/amendment(s), and 
· That all study products provided by the Sponsor were fully reconciled. 
Unused study product must not be discarded or used for any purpose other than the present study. 
Study product that has been dispensed to a subject must not be re-dispensed to a different subject. 
The Study Monitor will periodically collect the study product accountability forms and will check all 
returns (both unused and used containers) before arranging for their return to the Sponsor or 
authorizing their destruction by the clinical site. 
 
 
12. 
Statement of Compliance 
The study will be conducted in compliance with the current version of the Declaration of Helsinki 
(Appendix 6), with the clinical investigation plan, the UNI EN ISO 14155, the Italian laws in force and 
the principles of the Good Clinical Practice.  
The clinical investigation will start at clinical site only after obtaining the approval of the relevant Ethics 
Committee. 
  
 
13. 
Informed Consent Process 
The Investigator is responsible for and will obtain informed consent from each subject in the study, in 
accordance with the UNI EN ISO 14155, and the current version of the Declaration of Helsinki.  

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All subjects invited to participate in the study are entitled to make their voluntary decision based on all 
current available information provided to them by the Investigator/designee. In addition, they will be 
given a document in native language written in clear concise lay language for review and 
consideration. The document will previously have been approved by the relevant independent Ethics 
Committee (IEC) and may further be updated as new important information becomes available that 
may affect subject’s willingness to participate or continue in the study. 
The subject must be made aware that he/she may refuse to join the study or may withdraw his/her 
consent at any time without prejudicing further medical care and that he/she is covered by the 
Sponsor's indemnity insurance in the event of a study related injury. Subjects must also know that 
their personal medical records may be reviewed in confidence by the Sponsor's staff or 
representatives and by Regulatory Authority and IEC and that personal information will be collected 
and retained in a confidential database. Consent will always be given in writing after the subject has 
had adequate time to review the information and ask questions, if need be. 
 
14. 
Adverse Events, Adverse Device Effects and Devices Deficiencies 
14.1 Definitions 
Adverse Event (AE) 
Any undesirable experience occurring to a subject, whether or not it is considered causally related to 
the investigational medical device. An AE may be a clinical finding, a clinical laboratory abnormality or 
a symptomatic complaint which is considered by the Investigator to be outside the normal variation 
for that parameter. 
 
Adverse Device Effect (ADE) 
Any untoward and unintended response to a medical device. This includes any event resulting from 
insufficiencies or inadequacies in the instructions for use or the deployment of the device and any 
event that is a result of a user error. 
 
Device Deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, safety or performance 
(included malfunctions, use errors and inadequate labelling). 
 
Serious Adverse Event (SAE) 

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A serious adverse event (SAE) could be any event that suggests a significant hazard, contraindication, 
side effect, or precaution. The seriousness of an AE relates to its clinical significance and its potential 
impact on health.  
An AE will be considered as serious when: 
Lead to death 
Lead to serious deterioration in the health of the subject, that either results in: 
a. a life-threatening illness or injury, or 
b. a permanent impairment of a body structure or a body function, or 
c. in-patient or prolonged hospitalization, or 
d. medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function 
Lead to foetal distress, foetal death or a congenital abnormality or birth defect. 
 
Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event or that might have led to any of these consequences if suitable action had not been taken or 
intervention had not been made or if circumstances had been less opportune. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect that by its nature, incidence, severity or outcome has not been identified 
in the risk analysis report. 
 
Incident 
Any malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any lack of labelling or instructions for use which, directly or indirectly, may cause or have 
caused death or serious deterioration in the health of the patient or of a user or of other persons. 
 
14.2 Adverse Event Intensity/Causality 
The Investigator, based on his direct observation or on subjects' report, will record the event according 
to the current version of CTCAE: 
Description 
Definition 
Grade 1 (Mild): 
asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 

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Grade 2 (Moderate):   
 
minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental daily life activities. 
Grade 3 (Severe):  
 
 
medically 
significant 
but 
not 
immediately 
life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self -care daily life activities. 
Grade 4 (Life-threatening 
consequences):  
urgent intervention indicated. 
Grade 5: 
death related to AE 
 
The relationship of any AE to the product will be classified by the Investigator as follows: 
Description 
Definition 
Certain 
The AE is clearly related to the study product  
Probable 
The AE is likely related to the study product 
Possible 
The AE may be related to the study product 
Doubtful 
The AE is unlikely related to the study product 
None 
The AE is clearly not related to the study product 
Unknown 
Causality is not assessable, for one reason or another, e.g. because of 
insufficient evidence, conflicting data or poor documentation 
 
14.3 Adverse Event, Device Deficiency, Adverse Device Effect, reporting 
The Investigator will record any AEs, Device Deficiency and ADEs occurring during the study. He/She 
will also co-operate with the Sponsor in connection with the reporting of any SAE/SADE, Serious 
Incident to the Competent Authority and to the Independent EC, if applicable.  
All AEs regardless of severity occurring between recruitment and completion of the study by a subject 
must be recorded on the AE form provided with the e-CRF. 
If there is a significant worsening of a medical condition that was present before starting the study, 
this should be considered as a new AE and a complete evaluation recorded. 
Signs and symptoms considered as lack of efficacy and occurring during the study will not be recorded 
on the AEs Section of the e-CRF except on the condition that, in the Investigator’s opinion, these signs 
and symptoms are caused by any reason different from lack of efficacy of the study product or meet 
the definition of serious AE. 
 
In the event of a SADE/SAE, Serious Incident the Investigator has to: 

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▪ 
Complete the relevant CRF pages and a reporting form with all the available initial information, 
▪ 
Immediately inform the Sponsor or the CRO by telephone,  
▪ 
Fax the completed report form to the contact person at the Sponsor or the CRO as soon as 
possible. 
SAE/SADE, Serious Incidents reporting contacts are on page 5 of this Clinical Investigation Plan.
The Investigator is responsible for ensuring the follow-up of any subject who experiences an 
SAE/SADE/ Serious Incident during the study. The investigator must re-examine the subject at regular 
intervals until the symptoms have completely disappeared or stabilized. 
The Sponsor or its delegate will be responsible for reporting the SAE/SADE/Serious Incident to the 
appropriate Authorities and EC, according to the local regulations. 
 
 
15. 
Vulnerable Population 
This section is not applicable, since no subject belonging to any vulnerable population will be recruited 
for participating in this study. 
 
 
16. 
Suspension or Premature Termination of the Clinical Investigation 
Unless premature interruption occurs, the end of the study will be the last closure visit at clinical sites. 
 
16.1  Study Discontinuation 
Subjects may be discontinued at any time from the study for any of the following reasons: 
Ø 
An AE occurs that, in the opinion of the Investigator, makes it unsafe for the subject to continue 
in the study 
Ø 
Lack of compliance of the subject to the study treatment or assessments 
Ø 
The subject needs to use a medication/treatment not allowed for a disease or for a flare of the 
dermatitis  
Ø 
The subject is lost to follow-up 
Ø 
The subject dies 
Ø 
The subject withdraws consent 
Ø 
The Investigator, for any reason, terminates the entire study, or terminates the study for that 
subject or the attending physician requests that the subject be withdrawn for any medical 
reason 

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Ø 
The Sponsor or the Regulatory Authority or the Ethics Committee, for any reason, terminates 
the entire study or terminates the study for this site or for a particular subject. 
If a subject is discontinued from the study, the Investigator will, as far as possible, complete the end of 
study visit (Visit 4) e-CRF fields. The Investigator should try to ascertain the reason(s) for withdrawal, 
while fully respecting the subject’s rights. 
 
16.2  Study Interruption 
The Sponsor may consider study closure at the clinical site if the following occurs: 
Ø serious and/or persistent non-compliance with the Clinical Investigation Plan 
Ø inadequate collaboration of site personnel with CRO/Sponsor 
Ø administrative reasons 
Ø non-compliance with GCP, SOPs or regulatory requirements 
Ø lack of confidentiality and/or non-compliance with the contract spread with the Sponsor. 
 
 
17. 
Publication Policy 
All information obtained as a result of the study will be regarded as confidential. 
The results of the clinical study will be documented in an integrated clinical study report according to 
UNI EN ISO 14155. 
The Sponsor and the Investigator(s) agree that no publications presenting or discussing data and/or 
results from this clinical study sponsored by Relife Srl will take place until the participating centers 
have completed the study, the data have been interpreted, and the final report has been issued. 
As a rule, the Sponsor is free to use the data collected in the sponsored study for world-wide scientific 
product documentation, and for publication. 
In general, the Sponsor has no objections if the Investigators publish the results of the study. However, 
the Investigators are requested to provide the Sponsor with a copy of the manuscript for review 
before submitting it to the publisher with a cover letter informing the Sponsor about the intention to 
publish the study results. When permission for presentation or for publication is granted, 
Investigators, prior to submission of a manuscript or abstract to the publisher, shall forward a copy of 
said manuscript or abstract to the Sponsor who shall have 90 days to request any reasonable 
amendment thereto, which shall be taken into due account and consideration by the Investigators. 
The Sponsor is entitled to include as authors of the publication all Sponsor’s personnel who 
contributed substantially to the theoretical or experimental work and also to take part in the decision 

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that establishes the order in which the authors’ names will be given. Costs for publication must be 
regulated by written agreement between the parties.  
If publication of the results of the study, either in part or in full, is prepared by the Sponsor, the 
Investigators will be provided with a copy of the manuscript before the submission to the publisher 
and asked to give approval of the document. The Investigators will be asked in writing if they accept to 
be included as author of the publication. Answers should be sent in writing to the Sponsor within a 
reasonable time limit (30 days). If no answer is received, it is assumed that the Investigators agree to 
the Sponsor’s proposal. 
 
 
18. 
Study Protocol Personal Data Protection Section 
18.1  General Principles on Personal Data Compliance 
All clinical trial information shall be recorded, processed, handled, and stored in such a way that it can 
be accurately reported, interpreted and verified; at the same time, the confidentiality of records and 
of the personal data of the patients  shall remain protected in accordance with the applicable law on 
personal data protection such as the EU General Data Protection Regulation 679/2016 and the EU 
Regulation on clinical trials on medical device product  745/2017. 
This section defines the appropriate technical and organisational measures that shall be implemented 
to protect information and personal data processed against unauthorised or unlawful access, 
disclosure, dissemination, alteration, or destruction or accidental loss as well as to assure the 
fulfilment of patients’ privacy rights. 
 
18.2 Acknowledgment 
The Sites, the Principal investigator, the CRO as well as their appointed staff and service providers 
acknowledge that:  
(a) 
the performance of the study will imply processing of sensitive personal data; 
(b) 
personal data processing is regulated by the applicable European (i.e. the EU General Data 
Protection Regulation 679/2016 and the EU Regulation on clinical trials on medical device product  
745/2017 ) and local laws (i.e. the laws of the country where the study is conducted) as well as by the 
Sponsor’s national legislation.  In particular, it is hereby acknowledged that being the Sponsor a 
company incorporated under Italian law, it has to mandatorily comply with Italian legal provisions on 
data protection: therefore the Sites, the Principal investigator, the CRO  shall cooperate with the 
Sponsor to allow the fulfillment of such obligations; 

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(c) 
strict compliance with the applicable data protection laws and this section of the protocol is 
deemed by the Sponsor as an essential condition of collaboration with the Sites, the Principal 
investigator, the CRO. 
 
18.3 Data Controllers and Data Processors 
The  Sponsor, the Sites, the Principal investigator and  the CRO  acknowledge that according to the 
applicable privacy laws, Sponsor and Sites will act as independent data controllers while CRO and the 
Principal investigator will act as data processors respectively of the Sponsor and of Sites. Before the 
beginning of the study, the Sites will instruct in writing Principal Investigator as its data processor1.  
However, if specific local laws or regulations mandate a different definition of the privacy roles, the 
Sponsor,  the Sites, the Principal investigator and  the CRO   will implement the relevant legal 
instruments (e.g. if pursuant to the local laws  the Site is a data processor of the Sponsor, a Data 
Processing Agreement will be finalised; if  pursuant to the local laws Sponsor and Site are join 
controllers, a Joint Controllership Agreement will be finalised). 
 
18.4 Duties of the Parties Involved in the Performance of the Study 
Collection and use of patients’  personal data (i.e. subjects' data), will be carried out in full respect of 
the provisions of the information notices submitted to patients, as well as  the privacy rights, the 
fundamental freedoms and the dignity of data subjects. All the parties involved in this study undertake 
to adopt adequate measures to warrant that data will always be processed securely and in compliance 
with privacy laws. 
The Sites, the Principal investigator, the Sponsor, the CRO  as well as their appointed staff and service 
providers, each in its respective remit and within the limits of their specific role in the study-, shall 
implement the following safety measures (physical, logical, organizational, technical, electronic, I.T. 
etc) to ensure adequate protection of the personal data of the patients involved in the study. In 
particular: 
(i) 
DATA SAFETY. The Sites and/or the Principal Investigator   shall adopt all the necessary 
measures to prevent or minimise the risks of theft, fire, flooding, partial or total loss, accidental 
disclosure or illegal/unauthorised access to patient’s data or Sponsor’s proprietary confidential 
information; to this extent, before the beginning of the study, the Sites and/or the Principal 
 
1 For clinical trials where the Principal Investigators are the owners of the Site, this provision may not apply. In such 
cases, the Principal Investigator might be considered as a Data Controller. 

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Investigator shall ensure that the actual measures they have implemented are fit-for-purpose and law-
compliant, and in particular: 
- in order to minimise the risk of unauthorized access and theft, the hardware on which patients’ 
personal data are stored shall be placed in a restricted-access area, accessible only to those 
individuals who need to retrieve the patients’ personal data included in the database for 
professional purposes; the same safeguards shall be put in place for non-electronic databases;
- any electronic database containing the patients’ personal data shall be password-protected by 
means of a strong password. Systems shall be set so that passwords must be updated at least every 
two months  and feature at least 8 characters, with upper-case and lower-case recognition, 
containing "special" characters, such as upper case letters [A-Z], lower case letters [a-z], numbers 
[0-9], symbols [!, #, $, etc.] or other special characters [Á, ë, ö etc.]. Passwords shall not include 
elements which may easily be associated with the assignee or information regarding him/her , such 
as name and year of birth (e.g. “johnbrown80”) or easily predictable strings of characters (e.g. 
“qwerty”, “12345”, “admin”, “user”, etc.);  
- adequate cryptographic protection measures shall be put in place for data “at rest” and “in transit” 
(these include, for example, file system or database cryptography, or any other equivalent IT 
measure which renders data unintelligible to those who are not authorised to access them);  
- high level security measures shall be implemented also on the files or databases which contain the 
“key” to match the patients’ personal data (i.e. name, surname, etc.) with their respective “Patient 
IDs” (as defined at point (iv) below); 
- Backup processes and other measures that ensure rapid restoration of business critical systems 
shall be implemented; 
- Updated Antivirus and firewall programs shall be installed on the IT devices. 
The Sites shall, regularly test and update the measures listed above.  
The Sites shall, upon request from the Sponsor and/or the CRO, provide detailed written information 
about the measures listed above.  
The CRO shall ensure that the selected sites for the study have implemented the above listed 
measures.  
(ii) TRANSMISSION OF DATA. All the parties that transfer data through internet and/or to the 
centralised database(s) used to process study’s  data or to generate statistical analyses shall 
implement secure protocols based on cryptographic standards which make data unintelligible to 
unauthorized individuals. 

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(iii) 
SECURITY OF THE CENTRALISED DATA BASE. The centralised database held by the Sponsor shall 
have the following safeguards in place:  
- 
appropriate authentication methods, which differentiate between different users according to 
their respective roles so as to ensure that access to a specific set of subjects' data is permitted 
exclusively to those for whom access to such data is essential in the context of their work for the 
study; 
- 
appropriate measures to ensure that the authentication credentials are periodically updated 
(i.e.  password change); 
(iv) 
PSEUDONYMIZATION. All personal data that may allow identification of the patients involved 
in the study shall be adequately dissociated from the other data pertaining to the study 
(“pseudonymisation” process). The Principal investigator  shall adequately dissociate the identification 
data of patients from the data pertaining to the study by linking results to a an alphanumerical code 
[“Patient ID”], whose format shall not make it possible to identify the patient directly or indirectly, so 
as to ensure that only anonymous data are transmitted to the Sponsor, and /or the CRO. 
Sites/Principal Investigator shall securely store a separate list (e.g: identification log) with the 
identification code, together with all signed informed consents, in accordance with the security 
measures as defined above.  
(v) 
TRAINING. The parties shall ensure that any personnel involved in the study have received 
proper training on data protection issues. 
All actions related to the implementation of the afore mentioned measures shall be provided by the 
Sponsor, the Sites and/or the CRO to the competent authorities (including data protection authorities) 
and Ethics Committees if and when requested. If such authorities or the Sponsor consider the 
implementation of the afore mentioned measures insufficient to guarantee an adequate level of 
protection of the patients’ personal data, The Sites, the Principal investigator,  the CRO   undertake to 
adopt all the necessary activities to overcome such remarks to assure the full compliance with the data 
protection laws.  
 
18.5 Archiving of the Clinical Trial Master File and Code Pairing List 
Unless other EU laws require archiving for a longer period, the Sponsor the Sites and the Principal 
Investigator  shall archive the content of the clinical trial master file, including the relevant patients’ 
personal data, for at least 25 years after the end of the clinical trial. However, medical records shall be 
archived in accordance with the national laws of the country where the study is performed. The 

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patient code pairing list (i.e. the list that where the Patient ID is linked to the patients’ identification 
data such as name and surname), shall be archived care of the Principal Investigator. 
 The content of the clinical trial master file shall be archived in a way that ensures that it is readily 
available and accessible, upon request, to the competent authorities. 
Any transfer of ownership of the content of the clinical trial master file shall be documented. The new 
owner shall undertake the responsibilities set out in this protocol. 
Once mandatory data retention time for the clinical trial master file has elapsed, the Centre/Principal 
Investigator shall seek the authorisation of the Sponsor to destroy the clinical trial master file. 
 
18.6 Data Breach!
Data Breach is an incident regarding personal data security and leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, stored 
or otherwise processed. In particular: destruction of personal data is where the data no longer exists, 
or no longer exists in a form that is of any use to the Sites, sponsor, CRO, Principal Investigator etc.; 
data loss is when the data may still exist, but the Sites, sponsor, CRO, Principal Investigator etc. has 
lost control or access to it, or no longer has it in its possession; damage is where personal data has 
been altered, corrupted, or is no longer complete; data unavailability is where, following a data 
incident  (such as a network outage, a natural or man-made disaster, etc.), personal data become 
temporarily inaccessible to the Sites, sponsor, CRO, Principal Investigator etc. 
Anomalous Event is an event that is not part of the standard operational scope of an infrastructure, 
network or service and which affects, or is likely to affect, personal data; this may include theft or loss 
of IT devices and other physical events (e.g. an unauthorised access to a locked storage room 
containing paper files with personal data), and/or electronic/IT anomalies (e.g. cyber-attacks, default 
or hacking of cloud services), which may in any way entail loss, unavailability, alteration, theft, copy or 
dissemination of personal data.   
Whoever becomes aware in any way of an Anomalous Event and/or of a Data Breach (see definitions 
above) affecting the patients’ personal data and/or personal data collected in the context of the study, 
shall, as appropriate, immediately (and in any case no later than 24 hours from the knowledge of an 
Anomalous Event and/or of a Data Breach) inform the SME, the sponsor’s Data Protection Officer, who 
may be contacted at DPO contact details: dpo@menarini.com, the Sites and the CRO  responsible 
persons for data breach incidents management at dpo@latiscro.it and shall provide the following 
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(i) Anomalous  Event  / Data Breach  Type  (e.g. data loss, unauthorized access, loss of company device, 
etc.);  
(ii) Person or source that first reported the Anomalous Event/ Data Breach; 
(iii) Date and Time when the person who first reported the Anomalous Event / Data Breach became 
aware of it; 
(iv) Anomalous Event / Data Breach Date and Time (actual or presumed); 
(v) Place (specify if actual or alleged) where the Anomalous Event / Data Breach occurred; 
(vi) Anomalous Event / Data Breach Description;  
(vii) Indicate the source of the Anomalous Event / Data Breach (e.g. I.P. source) - (if relevant); 
(viii) Indicate the affected infrastructure / system / application / cloud/ software / hardware / database 
and their location; 
(ix) List or describe the processing/storage systems affected by the Anomalous Event/Data Breach (if 
relevant); 
(x) Number of data subjects involved (if known); 
(xi) Amount of allegedly breached data  
(xii) Other relevant information 
Once all the above information has been provided, the Sponsor and/or the Sites should have a 
reasonable degree of certainty that a security incident has occurred that has led to personal data being 
compromised.  
Then, as appropriate, Sponsor and Sites, each one in its respective remit, shall manage the Data Breach 
in accordance with the applicable data protection regulations. 
For Data Breach affecting personal data of patients enrolled within the European Union, Sponsor and 
Sites autonomously or jointly-depending on the circumstances and their privacy responsibilities as 
defined by the Regulation 679/2016- shall:  
1. Collect the necessary evidence and information; 
2. Categorise the breach; 
3. Determine the risk probability and level to the rights and freedom of the concerned patients; 
4. Identify and put in place appropriate remedies to minimise the impact of the Data Breach 
5. Determine the notification and communication duties vis à vis the competent supervisory authority 
and/or the concerned patients. 
 

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18.7 Information Notice on Personal Data Protection and Pseudonymisation 
Prior to patients’ enrolment in the study, the Principal Investigator and/or the Sites   (including their 
personnel) shall provide each patient with adequate, law-compliant “information notices and consent 
forms to process personal data” as included in the ICF (or, as the case may be, through a separate, 
specific form) provided by the Sponsor or delegated CRO and shall collect his/her written consent to 
the processing of personal data according to the actual performance conditions in which the study is 
carried out. The Principal Investigator is responsible to archive the signed ICF in accordance with the 
security measures described above. 
Among other things, the ICF (or the separate form) shall inform patients about:  
(i) the applicable data protection legislation 
(ii) the kind of data that shall be collected during the study listing them in detail or by category; 
(iii) the purpose of data processing (eg. vigilance, post market surveillance data) and the legal basis; 
(iv) whether granting the consent(s) to process personal data is a necessary or an optional condition to 
take part in the study (if the processing relies on consent as a legal basis);  
 (v) the pseudonymisation procedure and scope; 
(vi) who can access patients’ data and under what circumstances eg. Principal Investigator, Site, 
Sponsor, regulatory authorities, CRO; 
(vii) the period of data retention/storage as defined in paragraph 8;  
(viii) patients’ data protection rights as defined by the EU General Data Protection Regulation 
679/2016. 
(ix) Data Controllers / Data Processors and the relevant contact details 
(x) Sponsor’s Data Protection Officer contacts (DPO).  
 
18.8 Transfer of Patients’ Data Outside the European Union 
The study performance does not entail transferring patients’ personal data (coded data) outside the 
EU. 
 
18.9 Exercise of patients’ data privacy rights 
Each study patient has the right to contact the Sponsor, the Sites, the Principal investigator, the CRO  
to exercise the rights afforded to the patient by the law, including those afforded under articles 15 to 
22 of Regulation (EU) 2016/679, namely: knowing whether or not any data referring to his/her is being 
processed in the context of the study; access his/her data; verify the data’s content, origin, exactness, 
location (including, where applicable, the non EU countries where the data might be); obtain a copy of 

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the data including their transmission to another entity indicated by the patient; ask that the data are 
supplemented, updated, amended; in the circumstances set forth by the law, ask that the processing 
of data is restricted, that data are anonymised or frozen; oppose to the processing of his/her data for 
legitimate reasons.  Each patient has the right to lodge a complaint with his/her local supervisory 
authority and/or to notify to the Data Protection Officer any use of his/her personal data the patient 
regards as inappropriate. 
Each study patient is free to withdraw at any time from the study. In such case, each study patient may 
ask the Sponsor, the Sites, the Principal investigator, the CRO to destroy/delete his/her personal data 
thus preventing any further processing or analysis of his/her data. However, data and results of tests 
that may have been used to determine the results of the study shall not be deleted, to avoid altering 
or impairing altogether the results of the study.  
If the Sites, the Principal investigator, the CRO receive a request for data privacy rights exercise, the 
concerned recipient shall immediately inform the Sponsor DPO by email at DPO contact details: 
dpo@menarini.com. 
The request shall be fulfilled within the term set forth by the applicable privacy laws (normally 30 
days).  The Sponsor, the Sites, the Principal investigator, the CRO shall implement adequate 
organisational measures to reply to patients within the above mentioned deadline. 
 
 
 
 

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19. 
Bibliography 
1. Smith SM, Nedorost ST. "Dermatitis" defined. Dermatitis. 2010 Sep-Oct;21(5):248-50. 
 
2.  Zug KA, McKay M. Eczematous dermatitis: a practical review. Am Fam Physician. 1996 Sep 
15;54(4):1243-50, 1253-4. Review. Erratum in: Am Fam Physician 1997 Feb 1;55(2):448.  
 
3. http://www.aafp.org/afp/1999/0915/p1191.html 
 
4. http://www.dermnetnz.org/topics/causes-of-atopic-dermatitis/ 
 
5. http://www.skindermatologists.com/eczema.html 
 
6. Lamb JH, Shelmire B, Cooper Z, Morgan RJ, Keaty C. Solar dermatitis. Arch Derm Syphilol. 1950 
Jul;62(1):1-27. 
 
7. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic 
dermatitis: section 2. management and treatment of atopic dermatitis with topical therapies. J 
Am Acad Dermatol. 2014; 71:116-132.     
 
8. Werfel T. Topical use of pimecrolimus in atopic dermatitis: update on the safety and efficacy. J 
Dtsch Dermatol Ges. 2009;7:739-742.   
    
9. Takahashi-Ando N, Jones MA, Fujisawa S, et al. Patient-reported outcomes after 
discontinuation of long-term topical corticosteroid treatment for atopic dermatitis: a targeted 
cross-sectional survey. Drug Healthc Patient Saf. 2015;7:57-62. 
 
10. Coondoo A, Phiske M, Verma S, Lahiri K. Side-effects of topical steroids: A long overdue revisit. 
Indian Dermatol Online J. 2014 Oct;5(4):416-25.    
 
11. Kempers S, Boguniewicz M, Carter E, et al. A randomized investigator-blinded study comparing 
pimecrolimus cream 1% with tacrolimus ointment 0.03% in the treatment of pediatric patients 
with moderate atopic dermatitis. J Am Acad Dermatol 2004; 51: 515–25. 
 
12. Chamlin SL, Kao J, Frieden IJ, Sheu MY, Fowler AJ, Fluhr JW, et al. Ceramide-dominant barrier 
repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a 
sensitive indicator of disease activity. J Am Acad Dermatol 2002;47:198-208. 
 
13. Ex 8 Rawlings AV, Canestrari DA, Dobkowski B. Moisturizer technology versus clinical 
performance. Dermatol Ther 2004;17(Suppl):49-56. 
 

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14. Breternitz M, Kowatzki D, Langenauer M, Elsner P, Fluhr JW. Placebo-controlled, double-blind, 
randomized, prospective study of a glycerol-based emollient on eczematous skin in atopic 
dermatitis: biophysical and clinical evaluation. Skin Pharmacol Physiol 2008; 21:39-45.  
 
15. Peris K, Valeri P, Altobelli E, Fargnoli MC, Carrozzo AM, Chimenti S. Efficacy evaluation of an 
oil-in-water emulsion (Dermoflan) in atopic dermatitis. Acta Derm Venereol 2002; 82:465-6. 
 
16. http://www.webmd.com/skin-problems-and-treatments/eczema/tc/atopic-dermatitis 
treatment-overview 
 
17. Kim BE, Leung DYM. Significance of Skin Barrier Dysfunction in Atopic Dermatitis. Allergy 
Asthma Immunol Res. 2018 May;10(3):207-215. 
 
18. Kao JS, Fluhr JW, Man MQ, Fowler AJ, Hachem JP, et al. Short-term glucocorticoid treatment 
compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition 
of epidermal lipid synthesis accounts for functional abnormalities. J Invest Dermatol 2003; 120: 
456-464. 
 
19. Moncrieff G, Cork M, Lawton S, Kokiet S, Daly C, Clark C. Use of emollients in dry-skin 
conditions: consensus statement. Clin Exp Dermatol. 2013;38:231–238.   
 
20. Kraft JN, Lynde CW. Moisturizers: what they are and a practical approach to product selection. 
Skin Therapy Lett. 2005;10:1–8. 
 
21. Del Rosso JQ. Moisturizers: Function, formulation and clinical applications. In: Draelos Z, Dover 
JS, Alam M, editors. Cosmeceuticals. 2nd ed. China: Saunders Elsevier; 2009. pp. 97–102. 
 
22. Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet. 2012 Jan 28; 379(9813):361-72. 
 
23. Verdier-Sévrain S, Bonté F. Skin hydration: a review on its molecular mechanisms. J Cosmet 
Dermatol. 2007 Jun;6(2):75-82. 
 
24. Liguori V, Guillemin C, Pesce GF, Mirimanoff RO, Bernier J. Double-blind, randomized clinical 
study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy. 
Radiother Oncol 1997;42:155-61. 
 
25. Rawlings AV, Canestrari DA, Dobkowski B. Moisturizer technology versus clinical performance. 
Dermatol Ther. 2004;17 Suppl 1:49-56. 
 
26. Chren MM, Lasek RJ, Sahay AP, Sands LP. Measurement properties of Skindex-16: a brief 
quality-of-life measure for patients with skin diseases. J Cutan Med Surg. 2001;5:105-110. 
 
 
 

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Appendix 1  
 
List of Abbreviations   
 
 
ACD 
Allergic Contact Dermatitis 
AD 
Atopic Dermatitis 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
CD 
Contact Dermatitis 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
CRO 
Contract Research Organization  
CTCAE 
Common Terminology Criteria for Adverse Events 
DLQI 
Dermatology Life Quality Index questionnaire 
EASI 
Eczema Area and Severity Index 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIV 
Human Immunodeficiency Virus 
ICD 
Irritant Contact Dermatitis 
ICH  
International Conference on Harmonization 
IFU 
Instructions For Use 
IGA 
Investigator Global Assessment 
IEC 
Indipendent Ethics Committee 
MedDRA 
Medical Dictionary for Regulatory Activities 
PI 
Principal Investigator 
PPAS 
Per-Protocol Analysis Set 
PT 
Preferred Term 
ml 
Milliliters 
N 
Number 
SADE 
Serious Adverse Device Effect 
SAF 
Safety Analysis Set 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEWL 
Trans Epidermal Water Loss 
USADE 
Unanticipated Serious Adverse Device Effect 
UV 
Ultraviolet 
VAS 
Visual Analogue Scale 
 
 

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Appendix 2  
 
 
 

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Appendix 3  
 
Questionario per la valutazione, da parte del Paziente, della 
prestazione 
 
Codice Soggetto: |___|___| 
 
Data di compilazione del questionario: |___|___| |___|___| |___|___|___|___| 
      
 
                                                            giorno         mese                   anno 
 
 
Come valuta complessivamente la Sua dermatite rispetto a prima del trattamento con il 
prodotto DermoRelizema ecofoam? 
 
¨ Molto migliorata/o  
¨ Migliorata/o 
¨ Solo leggermente migliorata/o 
¨ Nessuna variazione rispetto a prima 
¨ Leggermente peggiorata/o 
¨ Peggiorata/o 
¨ Molto peggiorata/o 
  
 
 
 
 
 
 

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Appendix 4 
 
Questionario per la valutazione, da parte dello Sperimentatore, della 
prestazione 
 
Codice Soggetto: |___|___| 
 
Data di compilazione del questionario: |___|___| |___|___| |___|___|___|___| 
      
 
                                                            giorno         mese                   anno 
 
 
Come valuta complessivamente la dermatite del Suo/della Sua paziente, rispetto a prima del 
trattamento con DermoRelizema ecofoam? 
 
¨ Molto migliorata  
¨ Migliorata 
¨ Solo leggermente migliorata 
¨ Nessuna variazione rispetto a prima 
¨ Leggermente peggiorata 
¨ Peggiorata 
¨ Molto peggiorata 
  
 
 
 
 
 
 
 

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Appendix 5 
 
Questionario per la valutazione della accettabilità da parte del 
paziente 
 
 
Codice Soggetto: |___|___| 
 
Data del questionario: |___|___| |___|___| |___|___|___|___| 
      
 
                                              giorno         mese                   anno 
 
Relativamente alla sensazione di gradevolezza sulla pelle del prodotto DermoRelizema 
ecofoam, Le chiediamo di esprimere il suo grado di soddisfazione 
¨ Molto soddisfatto  
¨ Soddisfatto 
¨ Né soddisfatto né insoddisfatto 
¨ Non soddisfatto 
¨ Decisamente non soddisfatto 
 
 
Relativamente alla facilità di utilizzo (spalmabilità) del prodotto DermoRelizema ecofoam, Le 
chiediamo di esprimere il suo grado di soddisfazione 
¨ Molto soddisfatto  
¨ Soddisfatto 
¨ Né soddisfatto né insoddisfatto 
¨ Non soddisfatto 
¨ Decisamente non soddisfatto 
  
 

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Appendix 6 
 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving human 
subjects. 

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6.         The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality.
7.         Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. The responsibility for the protection of research subjects must always rest with the 
physician or other health care professionals and never with the research subjects, even though they 
have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other 
health care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
Risks, Burdens and Benefits  

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16.       In medical practice and in medical research, most interventions involve risks and burdens. 
           Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
           Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.            
 
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable 
group. In addition, this group should stand to benefit from the knowledge, practices or interventions 
that result from the research. 
 
Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 

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information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating subjects 
who are harmed as a consequence of participation in the research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and approval 
to the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations of 
the country or countries in which the research is to be performed as well as applicable international 
norms and standards but these must not be allowed to reduce or eliminate any of the protections for 
research subjects set forth in this Declaration.  
           The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After 
the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.  
 
Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent  
25.       Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any possible 
conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, post-study provisions and any other relevant 

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aspects of the study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the methods used 
to deliver the information. 
           After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed.       
           All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be 
performed with persons capable of providing informed consent, and the research entails only minimal 
risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is able 
to give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorised representative. The potential subject’s dissent should 
be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research  group. In such circumstances the 
physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 

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31.       The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from 
the study must never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
           Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive any 
intervention less effective than the best proven one, placebo, or no intervention will not be subject to 
additional risks of serious or irreversible harm as a result of not receiving the best proven 
intervention.  
           Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent 
process. 
 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 

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completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise 
made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be 
declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorised representative, may use an unproven intervention if in 
the physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. 
This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available.