A Multicenter, Double Blind, Randomized, Vehiclecontrolled Clinical Study Evaluate the Efficacy and Safety of Relizema Cream in the Management of Atopic Dermatitis in Paediatric Patients.
Phase: NA
Conditions: Atopic Dermatitis
Sponsor: Relife S.r.l.

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
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Clinical Investigation Report 
 
Investigational device:   
RELIZEMATM CREAM 
 
Sponsor:  
 
 
 
Relife S.r.l.  
Via dei Sette Santi 3 - 50131 Florence, ITALY 
 
Sponsor’s representative:  
Silvia Innocenti, MD - Head of Scientific Affairs 
 
CIP identification:        
 
Version no. 1.1 – 31st October 2022 
 
Coordinating investigator:  
Prof. Luca Stingeni 
Dermatology Unit  
Santa Maria della Misericordia Hospital 
P.le Menghini, 3 - 06129 Perugia, ITALY  
 
CRO:   
 
 
 
Latis S.r.l 
Viale Sauli, 39/5 
16121 Genova, ITALY 
 
CRO’s representative:   
Laura Michellini, BSc – Scientific Director 
 
Biostatistician:  
 
 
Camilla Palermiti, DSc 
 
Date of report:  
 
 
20th November, 2023 
 
Author of report:   
 
Laura Michellini - Latis Srl 
 
 
 
 
 
The clinical investigation was performed in accordance with ISO 14155:2020, MDR, the ethical principles 
of the current version of the Declaration of Helsinki and GCP and any other applicable guidelines and 
regulations. 
 
 
A MULTICENTER, DOUBLE BLIND, RANDOMIZED, VEHICLE-
CONTROLLED CLINICAL STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF RELIZEMATM CREAM IN THE MANAGEMENT OF 
ATOPIC DERMATITIS IN PAEDIATRIC PATIENTS 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
Page 2 of 60 
 
Table of contents 
1. Summary .............................................................................................................. 4 
2. Introduction ........................................................................................................ 13 
2.1 
Rationale ............................................................................................................... 14 
3. Investigational device and methods ................................................................... 16 
3.1 
Investigational device description .......................................................................... 16 
3.1.1 
Description of the investigational device and comparator .............................. 16 
3.1.2 
Intended use of the investigational device ..................................................... 17 
3.1.3 
Previous intended use or indication for use, if relevant ................................... 17 
3.1.4 
Changes to the investigational device during the clinical investigation or any 
change from the IB ....................................................................................................... 17 
3.2 
Clinical investigation plan (CIP) ............................................................................. 17 
3.2.1 
Clinical investigation objectives ...................................................................... 17 
3.2.2 
Clinical investigation design ........................................................................... 22 
3.2.3 
Ethical considerations .................................................................................... 23 
3.2.4 
Data quality assurance ................................................................................... 24 
3.2.5 
Subject population for the clinical investigation .............................................. 24 
3.2.6 
Treatment and treatment allocation schedule ................................................. 26 
3.2.7 
Concomitant medications/treatments ............................................................. 26 
3.2.8 
Duration of follow-up ...................................................................................... 27 
3.2.9 
Statistical design, analysis and justifications .................................................. 29 
4. Results ............................................................................................................... 33 
4.1 
Clinical investigation initiation date ........................................................................ 33 
4.2 
Clinical investigation completion/suspension date ................................................. 34 
4.3 
Disposal of subjects and investigational devices ................................................... 34 
4.4 
Subject demographics ........................................................................................... 35 
4.5 
CIP compliance ..................................................................................................... 36 
4.6 
Analysis ................................................................................................................. 36 
4.6.1 
Primary endpoint performance analysis ......................................................... 37 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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4.6.2 
Secondary endpoints performance analysis ................................................... 41 
4.6.3 
Safety analysis ............................................................................................... 43 
5. Discussion and overall conclusions ................................................................... 48 
6. Abbreviated terms and definitions ...................................................................... 52 
7. Ethics ................................................................................................................. 54 
8. Investigators and administrative structure of clinical investigation ..................... 55 
9. Signature page ................................................................................................... 57 
10. Annexes to the report ......................................................................................... 58 
 
 
 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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1. 
Summary 
Title of the clinical investigation - summary information 
Brief Study Title 
YOUNG 
Full Study Title 
A MULTICENTER, DOUBLE BLIND, RANDOMIZED, VEHICLE-
CONTROLLED CLINICAL STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF RELIZEMATM CREAM IN THE MANAGEMENT OF ATOPIC 
DERMATITIS IN PAEDIATRIC PATIENTS 
Study Code  
ReGl/21/Rcr-Dpe/001 
Dates of Investigation 
First Patient In – 27/10/2022 
Last Patient Out - 09/06/2023 
Location(s) 
The clinical investigation was conducted in Italy: 
Site 01 - Dermatology Unit, Santa Maria della Misericordia Hospital, P.le 
Menghini, 3 - 06129 Perugia. PI Prof. Luca Stingeni 
Site 02 – Dermatology Unit, Presidio Ospedaliero Gaspare Rodolico, 
AOU Policlinico “G. Rodolico-San Marco”, Via S. Sofia, 78 - 95123 
Catania. PI Prof. Giuseppe Micali 
Site 03 - Dermatology Unit, A.O.U "Federico II" di Napoli, Via Sergio 
Pansini, 5 - 80131 Napoli. PI Prof. Massimiliano Scalvenzi 
If relevant, reason for 
temporary halt or early 
termination 
No temporary halt or early conclusion occurred.  
A total of 60 subjects were planned and 50 were enrolled. The enrolment 
started in October 2022 and its conclusion was planned 3 months after. 
The deadline was significantly postponed until end of April 2023. After 
that, no further timing extension was allowed in order to avoid the study 
conduction during summertime, that could generate bias, being well 
known that AD spontaneously improves thanks to sun exposition. 
 
Purpose of the clinical investigation 
RelizemaTM cream is a dermatological cream for topical use indicated for the treatment of itching, and 
flushing associated with dermatitis, including atopic and contact dermatitis and/or erythema. Thanks 
to its derma-protective action it helps maintaining and restoring the physiological skin barrier. 
RelizemaTM cream is a CE marked medical device class IIa, manufactured by RELIFE Srl, that was 
the Sponsor of this pre-market clinical investigation, aimed to test the device in a pediatric population.  
 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
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Atopic dermatitis (AD) is a long-term (chronic) cutaneous inflammatory disease, very common 
condition in babies and children, affecting up to 25% of children. Depending on the severity of the 
disease, symptoms can include erythema, dry, scaly skin, itching, redness and swelling, thickened 
skin, pale skin on the face, small-raised bumps that may become crusty and leak fluid if scratched, 
rough bumps on the face, upper arms, and thighs, darkened skin, lichenification etc. Importantly, the 
disease can cause significant sleep disruption and impact the quality of life of patients and families. 
Since there is no curative etiological therapy for AD, the aim of all therapeutic interventions is the 
control and relief of symptoms and prevention of flare-ups.  
Currently available pharmacologic treatments for dermatitis management include the topical 
corticosteroids or immunosuppressants, which have a significant efficacy but are also associated with 
high incidence of transient skin reactions and, for this reason, are generally not recommended for the 
young children. 
There is strong evidence that the use of topical moisturizers, emollients and protective agents can 
reduce the need for pharmacologic intervention to treat AD symptoms and are particularly 
recommended in young patients. Among moisturizers, humectants are substances that attract water 
when applied to the skin and improve hydration of the stratum corneum with a physical mode of action. 
Glycerin together with hyaluronic acid (HA) are the most popular humectants and are both contained 
in RelizemaTM cream, together with furfuryl palmitate which has antioxidant properties, vitamin E with 
antioxidant and skin conditioning properties, ethylhexylglycerin with skin conditioning function. 
This pre-market clinical investigation was aimed to evaluate the clinical benefit of RelizemaTM cream 
in infants, children and adolescents suffering for AD symptoms. To assess in objective way the effects 
of RelizemaTM cream in the relief of AD symptoms, it was compared to placebo (vehicle) in this double-
blind designed study. 
 
Description of the investigational device, clinical investigation, and methods used 
Description of 
participants 
Infants from 6 months of age up to adolescents of 16 years inclusive, of 
both sexes, affected by mild to moderate atopic dermatitis. 
Inclusion criteria: 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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1. Release of the written informed consent obtained prior to any study-
related procedures, by both the parents/the guardian; 
2. Male and female infants, children, adolescent aged between 6 months 
and 16 years, inclusive; 
3. Presence of atopic dermatitis (AD) of mild-moderate severity:  
- 
IGA score 2 (=mild) or  
- 
IGA score 3 (=moderate) 
4. Patients with a baseline score for itch at least 4 on the NRS  
5. Patients/parents/guardian able to comprehend the full nature and the 
purpose of the investigation, 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. 
 
Exclusion criteria: 
1. Severe dermatitis at inclusion; 
2. Pregnant and breastfeeding patients; 
3. Concomitant other skin disorders including skin infections; 
4. Use of antibiotics in the past 7 days; 
5. History of congenital or acquired immunodepression; 
6. Immunologic or infectious disease (e.g. hepatitis, tuberculosis, HIV or 
AIDS, any typology of lupus, rheumatoid arthritis) which could place 
the patient at risk or interfere with study results; 
7. Use of any topic or systemic drug for dermatitis in the past 10 days; 
8. Use of any topic emollient product for dermatitis in the 2 days before 
study treatment start; 
9. Any systemic treatment or procedure that could influence dermatitis 
activity within the past 30 days (or 5 half-lives); 
10. Use 
of 
any 
corticosteroids, 
immunosuppressant 
drugs 
or 
immunotherapy within the past 30 days (or 5 half-lives); 
11. Use of oral antihistamines and antidepressants in the past 30 days; 
12. Patients 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; 
13. Allergy, sensitivity or intolerance to the components of the 
investigational device formulations ingredients; 
14. Concomitant or previous participation in other interventional clinical 
study in the past 3 months; 
15. Patients planning sun exposure or tanning booths or UV sources 
throughout the course of the study. 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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Description of the 
device and comparator 
RelizemaTM cream is a CE marked medical device, class IIa, 
manufactured by RELIFE Srl. RelizemaTM cream is a dermatological 
cream for topical use indicated for the treatment of itching, and flushing 
associated with dermatitis, including atopic and contact dermatitis and/or 
erythema.  
The mechanism of action of the product is based on the creation of a sheer 
physical barrier that separates the skin from the surrounding environment, 
useful for generating favorable conditions for the maintenance and/or 
recovery of the physiological cutaneous layer in case of dermatitis. It 
improves dry skin by keeping it hydrated. Its formulation protects and 
moisturizes the skin with a soothing effect. 
Its main functional components are: 
- Hyaluronic acid, with a humectant function, generates a protective film 
that helps to retain the aqueous content of the skin, keeping it hydrated 
- Furfuryl palmitate has antioxidant properties 
- Vitamin E has antioxidant and skin conditioning properties 
- Glycerin with humectant function 
- Ethylhexylglycerin with skin conditioning function. 
 
As comparator, a placebo was used, constituted by the vehicle alone. 
Description of 
procedures to use the 
device 
RelizemaTM cream / vehicle were used two times daily: the first application 
in the morning and the second in the evening before bedtime, for three 
cycles of 13 (±2 days). The study treatment started on the day after initial 
visit (Visit 1) and was suspended for 1 day only on the visit days. 
Study design 
Multicenter, double blind, randomized, vehicle-controlled, pre-market 
clinical follow-up study. 
Objectives and 
endpoints 
The primary objective of this clinical investigation was to evaluate and 
confirm the performance of the RelizemaTM cream in the improvement of 
the dermatitis severity, assessed through a clinical parameter, the 
Investigator’s Global Assessment (IGA) at baseline and at Visit 3, 
compared to vehicle. 
The primary endpoint was the responder rate in active treatment group 
and placebo group assessed according to the decrease in the Investigator 
Global Assessment (IGA) score evaluated at Visit 3, from baseline. 
Patients were considered responders when the IGA (Investigator Global 
Assessment) score decreases of at least one point. 
 
Secondary objectives of this clinical investigation were: 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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Page 8 of 60 
 
1. To evaluate the performance of the RelizemaTM cream, compared to 
placebo, in the improvement of dermatitis severity (IGA) at Visit 2 and 
Visit 4. 
2. To evaluate the eczema improvement through the EASI (Eczema Area 
and Severity Index) score at each time point, in the two treatment 
groups; 
3. To 
evaluate 
itching 
improvement 
as 
reported 
by 
the 
patient/parents/guardian at visits by the Numerical Rating Scale 
(NRS), in the two treatment groups; 
4. To evaluate the QoL improvement of the patient related to his/her 
dermatitis, through the Children Dermatology Life Quality Index 
(CDLQI) in the two treatment groups; 
5. To evaluate the patient’s adherence to treatment; 
6. To evaluate the need of a rescue treatment (as indicated by the 
Investigator) to manage AD flare; 
7. To evaluate the patient’s and Investigator’s global evaluation of 
performance of RelizemaTM cream, compared to placebo. 
Secondary endpoints were: 
1. The percentage of responders, evaluated according to the IGA score 
decrease as above described, assessed at Visit 2 and 4, compared to 
baseline (Visit 1);  
2. The change in the EASI score (0-72) for the four key signs of AD 
(erythema, induration/papulation, excoriation and lichenification) 
assessed at Visit 2, 3 and 4, compared to baseline (Visit 1); 
3. The change in NRS scale at Visit 2, 3 and 4, compared to baseline 
(Visit 1); 
4. The change in the CDLQI questionnaire answers at (Visit 2, 3 and 4, 
compared to baseline (Visit 1); 
5. The adherence to treatment, evaluated by counting the applications 
reported on the patient’s diary; 
6. The use of a rescue medication, as prescribed by the Investigator; 
7. The patient’s/parents’/guardian’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). 
 
Safety objectives was to evaluate the local and general tolerability of 
RelizemaTM cream compared to placebo. 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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Safety endpoints were: 
1. The number and type of adverse events (AEs) occurring during 
the study (seriousness, severity, and relation to study treatment). 
2. The local tolerability at the site of administration. 
Sample size 
It was estimated that the percentage of patients improved at Visit 3 was 
equal to 26% in the placebo arm and 80% in the test medical device arm. 
With a 0.05 two-sided significance level, a sample size of 48 patients in 
each arm had 90% power to detect the above estimated difference 
between groups. Estimating a rate of non-evaluable patients up to 20%, 
the randomization of 60 patients was thought to allow the replacement of 
non-evaluable patients for any reason. 
Randomisation and 
blinding 
The study treatment was assigned through electronic randomization 
process (eCRF). The randomization list was generated by the CRO using 
the PROC PLAN of SAS 9.4 for Windows (SAS Institute Inc., Cary, NC, 
USA).  
The blind was maintained during the study using the following methods:  
- 
indistinguishable test device and placebo 
- 
random treatment assignment  
- 
blinded assessments. 
Follow up duration 
Each patient was followed in the study for 42 (±2) days. The study 
product application was ended on the evening before last visit. 
Concomitant 
treatments 
The following treatments were not permitted during the study: 
- 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  
- sun exposure or tanning booths or UV sources. 
Statistical analysis 
methods 
Descriptive statistical analysis of all relevant variables was performed. 
Continuous variables were summarized by the number of patients (N), 
mean, standard deviation, median, minimum, maximum. Categorical 
variables were summarized by number (N) and percentage of patients 
(%). The significance level of statistical tests was set at 0.05. Parametric 
tests were used to analyze continuous variables; when continuous 
variables were not normally distributed, the corresponding non-parametric 
tests were also performed. 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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Substantial 
modifications 
No relevant changes were made to the clinical investigation plan during 
the study.  
One non substantial amendment dated 31.10.2022 was notified to ECs 
(Ethics Committees) and CA (Competent Authority), in order to better 
specify that two different EASI scales were in use, one for children < 8 
years and one for children ≥ 8 years of age. 
One substantial amendment was also issued for the change of the PI at 
clinical site no.3 (Napoli). 
 
Results of the investigation 
Participant flow 
Fifty patients were enrolled and randomized: 25 to RelizemaTM cream and 
25 to placebo. 
Three patients withdrew prematurely, 1 in RelizemaTM cream group (lost 
to follow-up after Visit 1) and 2 in placebo group (one for consent 
withdrawal and one for SAE, both after Visit 2). 
 
 
Primary and secondary performance endpoints were analyzed on the Full 
Analysis Set (FAS) population: 49 patients in total, 24 in RelizemaTM 
cream group (patient ID 03-009 was excluded because no data was 
available after initial visit) and 25 in Placebo group. 
Additionally, the primary endpoint was analyzed on the Per-Protocol 
Analysis set (PPAS) made of 46 patients: 
- 
patient ID 03-009 randomized to RelizemaTM cream was excluded 
from PPAS because no data was available after initial visit;  

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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- patients ID 02-004, 02-006 randomized to Placebo were excluded 
because they drop out from the study after second visit;  
- 
patient ID 01-020 randomized to Placebo was excluded because of 
poor treatment compliance (<80%).  
Safety endpoints were analyzed on the Safety Analysis Set (SAF) 
population (i.e 50 patients).   
Baseline demographic 
and clinical 
characteristics 
Of the enrolled patients, 19 were female and 31 were male: in RelizemaTM 
cream group 10 patients (40.0%) were female and 15 patients (60.0%) 
were male; in Placebo group 9 patients (36.0%) were female and 16 
patients (64.0%) were male.  
Mean age was 6.72 (SD=4.97) years in RelizemaTM cream group and 6.62 
(SD=4.45) years in Placebo group. 
Patients were also distributed into three age categories: from 6 months to 
2 years, from 3 to 11 years and from 12 to 16 years and the age categories 
were homogeneous between groups. 
The body areas most affected by atopic dermatitis were “Face, Legs, 
Arms, Trunk”: 15 patients (60.0%) in RelizemaTM cream group and 16 
patients (64.0%) in Placebo group. The remaining 19 patients were evenly 
distributed among the other body area.  
Only 2 patients (8.0%) in Placebo group had at least one significant 
medical condition (food allergy and milk allergy) in the medical history and 
only 1 patient (4.0%) in Placebo group underwent surgery (orchidopexy) 
in the past.  
No statistically significant difference was detected for gender, age, body 
areas affected by dermatitis and medical/surgical history between groups. 
Outcome of the 
intervention 
The proportion of responder (decrease in IGA >= 1) at Visit 3 (i.e. after 28 
days of treatment) was the primary performance endpoint. The 70.8% of 
patients in RelizemaTM cream group was responders while only the 60.0% 
in Placebo group was. The analysis repeated on PPAS showed the same 
result, with the 70.8% of patients in in RelizemaTM cream group and the 
59.1% in Placebo group responders. The difference between treatment 
groups was not statistically significant (Table 2.1.1 and 2.1.2) but the 
within group analysis showed that RelizemaTM cream has a pronounced 
and statistically significant clinical performance (proportion of responders 
p value=0.0412*). 
Also, the proportion of responders analysed at Visit 2 and Visit 4 (i.e. after 
2 and 6 weeks of treatment) showed the 50.0% of responders in 
RelizemaTM cream group and the 40.0% in Placebo group at Visit 2 (Table 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
Page 12 of 60 
 
2.2.1) and the 75.0% in RelizemaTM cream group and 56.0% in Placebo 
group at Visit 4 (Table 2.2.2). No statistically significant difference 
between groups was observable but the within groups analysis evidenced 
the marked and statistically significant clinical performance of RelizemaTM 
cream, at Visit 4 (proportion of responders: p value=0.0143*). 
 
EASI score decreased in both treatment groups in similar way and with 
statistical significance: mean changes from baseline to, respectively 14, 
28 and 42 days of treatment were of -3.13 (SD=4.70), -4.30 (SD=5.51) 
and -5.45 (SD=6.62) in RelizemaTM cream group and -3.32 (SD=5.54), -
4.64 (6.04) and -4.31 (6.26), in Placebo group. No statistically significant 
difference between groups was observable (Table 2.2.3). 
 
Mean itching rating decreased in both treatment groups from baseline to, 
respectively 14, 28 and 42 days of treatment: mean changes were -0.96 
(SD=1.16), -1.58 (SD=1.21) and -2.42 (SD=1.67) in RelizemaTM cream 
group and -0.50 (SD=1.25), -1.26 (SD=1.66) and -1.83 (SD=1.86), in 
Placebo group. The RelizemaTM cream performance was statistically 
significant at each time point while the one of Placebo was only at Visit 3 
and 4. In any case, no statistically relevant difference was observed 
between the two groups at each time point of the study (Table 2.2.4). 
As well, mean worst itching rating decreased in both treatment groups 
from baseline to, respectively 14, 28 and 42 days of treatment, always 
with statistical significance within each treatment group: mean changes 
were -1.21 (SD=1.41), -1.96 (SD=1.49) and -2.63 (SD=2.34) in 
RelizemaTM cream group and -0.63 (SD=1.17), -1.65 (SD=1.40) and -2.00 
(SD=1.62) in Placebo group. No statistically significant difference between 
groups was observable (Table 2.2.4).  
 
CDLQI score decreased (meaning an improvement in the QoL) in both 
treatment from baseline to, respectively 14, 28 and 42 days of treatment, 
always with statistical significance within each treatment group: mean 
changes were -2.29 (SD=2.52), -3.86 (SD=4.33) and -5.29 (SD=4.73) in 
RelizemaTM cream group and -1.28 (SD=2.22), -2.56 (SD=2.94) and -3.53 
(SD=4.00) in Placebo group. No statistically significant difference between 
groups was observable (Table 2.2.5). 
 
Finally, the Investigators evaluated that at the end of treatment (6 weeks) 
there was an improvement respect to initial condition in the 79.1% of 
patients treated with RelizemaTM cream and in the 70.8% of patients 
treated with Placebo.  

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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Page 13 of 60 
 
The patients (parents/guardian) opinion was more likely to find it 
RelizemaTM cream satisfactory (87.5%) than Placebo (66.6%). 
In both cases, no statistically significant difference between groups was 
observable (Table 2.2.8). 
Safety outcomes 
Only 2 adverse events to 2 patients occurred during the study, none of 
them was evaluated as related to the study treatment, by the Investigator. 
One of the two events was serious and leading to study premature 
discontinuation: patient ID 02-004, randomized to placebo, had a bacterial 
gastroenteritis requiring hospitalization. 
The second event was of mild intensity and not related to study treatment:  
patient ID 01-002, randomized to RelizemaTM cream, had a limb injury. 
The patient continued the study. 
Deviations to clinical 
investigation plan 
A total of 60 protocol deviations occurred during the study, 31 in 
RelizemaTM cream group and 29 in Placebo group.  
All deviations were evaluated as minor (Table 1.2) therefore no protocol 
deviation caused the exclusion of any subject from the study populations 
for analyses. 
The majority of protocol deviations were related to treatment compliance 
(90.3% and 93.1% respectively in RelizemaTM cream and Placebo groups) 
and a minority were related to delay in scheduled visits (6.5% and 6.9% 
respectively in RelizemaTM cream and Placebo groups). 
 
Conclusions of the clinical investigation 
Data analysis showed a consistent improvement of the AD condition and symptoms with the 
progression of both treatments, RelizemaTM cream and Placebo, without statistically significant 
difference between the two treatments. However, looking to all the performance endpoints, the 
improvement of the AD condition and symptoms resulted always more relevant within the RelizemaTM 
cream group than within the Placebo group. 
Also, it must be noticed that the Placebo used in this study was a vehicle with hydrating properties (a 
real inert placebo could have not been used mainly for ethical reasons), therefore the comparison in 
this study was between two creams with very close compositions and properties. In light of this it is 
understandable and justified that no statistically significant difference emerged from data analysis. 
The relevant result of this clinical investigation is that, from statistical and clinical point of view, the 
RelizemaTM cream has shown to be effective and absolutely safe in the relief of AD symptoms in 
young patients, from 6 months of age. 
 
 

 
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Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
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Page 14 of 60 
 
2. 
Introduction 
RelizemaTM cream is a dermatological cream for topical use indicated for the treatment of 
itching, and flushing associated with dermatitis, including atopic and contact dermatitis and/or 
erythema. Thanks to its derma-protective action it helps maintaining and restoring the 
physiological skin barrier. 
RelizemaTM cream is a CE marked medical device class IIa, manufactured by RELIFE Srl, that 
was the Sponsor of this pre-market clinical investigation.  
The mechanism of action of the product is based on the creation of a sheer physical barrier 
that separates the skin from the surrounding environment, useful for generating favorable 
conditions for the maintenance and/or recovery of the physiological cutaneous layer in case of 
dermatitis. It improves dry skin by keeping it hydrated. Its formulation protects and moisturizes 
the skin with a soothing effect. 
In this clinical investigation RelizemaTM cream was used to treat and alleviate atopic dermatitis 
symptoms in infants over 6 months of age, children and adolescents. The IFU of the device do 
not specify the use in children, which was the reason why the study was conceived as pre-
market. 
 
2.1 
Rationale 
Atopic dermatitis is a long-term (chronic) cutaneous inflammatory disease. It causes erythema, 
dry, itchy skin. It’s a very common condition in babies and children, affecting up to 25% of 
children [1]. It usually first appears during early childhood [2].  
The underlying etiopathogenesis is multifaceted with a central role played by the relationship 
between impaired skin barrier and dysregulated immune response [3,4]. The first step in AD 
progress seems to be the altered skin barrier where environmental factors irrupt, leading to 
inflammatory response [5,6,7]. 
The loss-of-function mutations in the structural protein filaggrin and other skin proteins induce 
perturbed barrier function, thus resulting in diminished epidermal defense mechanisms to 
allergens, microbes, and other environmental agents [8,9,10].  
Symptoms may come and go or occur most or all of the time. Any area of the body may be 
affected. In babies, symptoms usually affect the face, neck, scalp, elbows, and knees. In 
children and adolescents, symptoms usually affect the skin inside the elbows, on the back of 
the knees, the sides of the neck, around the mouth, and on the wrists, ankles, and hands. 
Depending on the severity of the disease, symptoms can include erythema, dry, scaly skin, 
itching, redness and swelling, thickened skin, pale skin on the face, small raised bumps that 

 
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may become crusty and leak fluid if scratched, rough bumps on the face, upper arms, and 
thighs, darkened skin, lichenification etc. 
Importantly, the disease can cause significant sleep disruption and impact the quality of life of 
patients and families [11]. 
 
Since there is no curative etiological therapy for AD, the aim of all therapeutic interventions is 
the is the control and relief of symptoms and prevention of infections [12].    
Some of the currently available treatments for dermatitis management include the topical 
application of corticosteroids or immunosuppressants, acting at reducing the underlying 
inflammation and hypersensitization of the epidermis. They have a significant efficacy but are 
also associated with high incidence of transient skin reactions [13,14,15,16,17] that make them 
not well accepted by the patient and generally not recommended for the young children. 
It is, instead, widely accepted that the application of non-steroidal topical moisturizers, 
emollients and protective agents should be an integral part of the treatment of young patients 
with AD, and there is strong evidence that their use can reduce the need for pharmacologic 
intervention to treat disease flare-ups.  
Moisturizers are recommended to improve clinical symptoms and enhance skin barrier 
function. Moisturizers are generally composed of substances capable to restore the ability of 
the intercellular lipid bilayers to retain and redistribute water [18,19]. Moisturizers contain three 
main properties, which are the occlusive, humectant, and emollient effects.      
Among moisturizers, humectants are substances that attract water when applied to the skin 
and improve hydration of the stratum corneum with a physical mode of action. Glycerin 
together with hyaluronic acid (HA) are the most popular of all humectants used in personal 
care products.  
 
Both ingredients are contained in RelizemaTM cream, together with furfuryl palmitate which has 
antioxidant properties, vitamin E with antioxidant and skin conditioning properties, 
ethylhexylglycerin with skin conditioning function. 
HA is a well-known component of the extracellular matrix of most connective tissue. It is 
especially abundant in the skin, where it has a protective, structure-stabilizing and shock-
absorbing role. Evidence is available supporting HA as treatment of AD [20]. 
On the other hand, studies conducted on glycerol-containing creams [21,22], showed the 
significant hydration and barrier-improving effect of such products when compared to glycerol-
free creams. 
In this pre-market clinical investigation RelizemaTM cream was tested in infants, children and 
adolescents to evaluate the effects on AD symptoms relief when compared to placebo 
(vehicle). 

 
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The clinical investigation was regularly submitted to the competent Ethics Committees and to 
the Italian Ministry of Health (Competent Authority), as for requirements in pre-market clinical 
investigations. 
The study was conducted in the full respect of the Helsinki Declaration, of the ISO 14155 and 
GDPR (General Data Protection Regulation 679/2016) prescriptions. 
 
3. 
Investigational device and methods 
3.1 
Investigational device description 
3.1.1 
Description of the investigational device and comparator 
The products under investigation were RelizemaTM cream and its comparator, the vehicle (or 
placebo). 
 
RelizemaTM cream 
Manufacturer:  
 
RELIFE Srl, Via dei Sette Santi 3 - 50131 Firenze (FI) - Italy 
Device Name:  
 
DLP011 
Trade Name:   
 
RelizemaTM cream  
Formulation:   
 
cream  
Route of administration:  
topical application on breached/compromised skin  
Composition:  
aqua, 
hydrogenated 
polydecene, 
ethylhexyl 
palmitate, 
dimethicone, glycerin, glyceryl stearate, peg-100 stearate, 
cetearyl alcohol, magnesium stearate, ricinus communis seed 
oil, 
phenoxyethanol, ascorbyl 
palmitate, 
disodium 
edta, 
ethylhexylglycerin, furfuryl palmitate, ethyl linoleate, tocopheryl 
acetate, sodium hyaluronate, ethyl oleate, ethyl linoleate, propyl 
gallate, tocopherol, ethyl palmitate, ethyl stearate. 
It does not contain fragrance and parabens. It is nickel, antimony, arsenic, cadmium, cobalt, 
chrome, mercury and lead tested. 
 
 
Vehicle (placebo) 
Manufacturer:  
 
RELIFE Srl, Via dei Sette Santi 3 - 50131 Firenze (FI) - Italy 
Device Name:  
 
not applicable 
Trade Name:   
 
not applicable 
Formulation:   
 
cream  
Route of administration:  
topical application on breached/compromised skin  
Composition:  
aqua, 
hydrogenated 
polydecene, 
ethylhexyl 
palmitate, 
dimethicone, glyceryl stearate, peg-100 stearate, cetearyl 

 
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alcohol, magnesium stearate, ricinus communis seed oil, 
phenoxyethanol, 
disodium 
edta, 
ethylhexylglycerin, 
ethyl 
linoleate, sodium hyaluronate, ethyl oleate, ethyl linoleate, propyl 
gallate, ethyl palmitate, ethyl stearate. 
 
Test device and vehicle were indistinguishable by appearance, smell and possibly other 
parameters as far as necessary to reach the study objectives (double blind design) and 
technically feasible.  
 
3.1.2 
Intended use of the investigational device 
RelizemaTM cream is a CE marked, Class IIa medical device, dermatological cream for topical 
use indicated for symptomatic treatment of dermatitis and erythema. RelizemaTM cream is 
indicated for the treatment of itching and flushing associated with different types of dermatitis, 
including atopic dermatitis. Thanks to its derma-protective action it helps maintaining and 
restoring the physiological skin barrier. Its formulation protects and moisturizes the skin with a 
soothing effect. 
RelizemaTM cream creates a sheer physical barrier that separates the skin from the surrounding 
environment, useful for generating favorable conditions for the maintenance and/or recovery of 
the physiological cutaneous layer in case of dermatitis. It improves dry skin by keeping it 
hydrated. 
 
3.1.3 
Previous intended use or indication for use, if relevant 
The medical device RelizemaTM cream was intended only for adult population and this clinical 
investigation was conducted with the aim to extend the indication also to the pediatric 
population. No other previous intended use nor indication for use.  
 
3.1.4 
Changes to the investigational device during the clinical investigation 
or any change from the IB  
No changes to the medical device nor to the IB occurred during the clinical investigation. 
 
3.2 
Clinical investigation plan (CIP) 
3.2.1 
Clinical investigation objectives 
The primary objective of this clinical investigation was to evaluate and confirm the performance 
of the RelizemaTM cream in the improvement of the dermatitis severity, assessed through a 
clinical parameter, the Investigator’s Global Assessment (IGA) at baseline (Visit 1) and at Visit 
3, compared to vehicle (placebo). 

 
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The primary endpoint of this clinical investigation was the responder rate in active and placebo 
groups assessed according to the decrease in the Investigator Global Assessment (IGA) score 
evaluated at Visit 3 from baseline. 
Patients were considered responders when the IGA (Investigator Global Assessment) score 
decreased of at least one point. 
 
The secondary performance objectives of the clinical investigation were: 
- 
to evaluate the performance of the RelizemaTM cream, compared to placebo, in the 
improvement of dermatitis severity (IGA) at Visit 3 and 4; 
- 
to evaluate the eczema improvement through the EASI (Eczema Area and Severity 
Index) score at each time point, in the two treatment groups; 
- 
to evaluate itching improvement as reported by the patient/parents/guardian at visits 
by the Numerical Rating Scale (NRS), in the two treatment groups; 
- 
to evaluate the QoL improvement of the patient related to his/her dermatitis, through 
the Children Dermatology Life Quality Index (CDLQI), in the two treatment groups; 
- 
to evaluate the patient’s adherence to treatment; 
- 
to evaluate the need of a rescue treatment (as indicated by the Investigator) to manage 
AD flare; 
- 
to evaluate the patient’s and Investigator’s global evaluation on the performance of 
RelizemaTM cream, compared to placebo. 
Performance secondary endpoints were: 

 
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- 
the percentage of responders, evaluated according to the IGA score decrease as 
above described, assessed at Visit 2 and 4, compared to baseline (Visit 1);  
- 
the change in the EASI score (0-72) for the four key signs of AD (erythema, 
induration/papulation, excoriation and lichenification) assessed at Visit 2, 3 and 4, 
compared to baseline (Visit 1); 
- 
the change in NRS scale at Visit 2, 3 and 4, compared to baseline (Visit 1); 
- 
the change in the CDLQI questionnaire answers at Visit 2, 3 and 4, compared to 
baseline (Visit 1); 
- 
the adherence to treatment, evaluated by counting the daily applications reported on 
the patient’s diary; 
- 
the use of a rescue medication, as prescribed by the Investigator; 
- 
the patient’s/caregiver’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). 
 
Local and general tolerability of RelizemaTM cream were assessed by visiting and questioning 
the patient (or parents/legal guardian) o at visits and were compared to placebo. 
Safety endpoints were: 
1. the number and type of adverse events (AEs) occurring during the study (seriousness, 
severity, and relation to study treatment). 
2. The local tolerability at the site of administration. 
 
 
3.2.1.1 Clinical investigation tools description 
 
IGA (Investigator’s Global Assessment scale for Atopic Dermatitis)  
IGA is a tool used in the clinical routine to define the dermatitis severity. The Investigator’s 
Global Assessment is based on a five-point scale: 
0 = clear 
1 = almost clear 
2 = mild 
3= moderate  
4 = severe. 
The IGA was filled in by the Investigator at each visit. 
EASI (Eczema Area and Severity Index)    
The EASI score is a tool used to measure the extent (area) and severity of eczema.  

 
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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). 
 
EASI score calculation for patients aged ≥ 8 years: 
 
 
Body region 
Erythema     
(0-3) 
Edema/ 
Papulation   
(0-3) 
Excoriation  
(0-3) 
Lichenification 
(0-3) 
Region score 
(0-6) 
Multiplier 
Score per 
body region 
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) 
 
EASI score calculation for patients aged < 8 years: 
 
 
Body region 
Erythema     
(0-3) 
Edema/ 
Papulation   
(0-3) 
Excoriation  
(0-3) 
Lichenification 
(0-3) 
Region score 
(0-6) 
Multiplier 
Score per 
body region 
Head/neck 
(          + 
+ 
+ 
) 
X 
X 0.2 
 
Trunk 
(          + 
+ 
+ 
) 
X 
X 0.3 
 
Upper extremities 
(          + 
+ 
+ 
) 
X 
X 0.2 
 
Lower extremities 
(          + 
+ 
+ 
) 
X 
X 0.3 
 
 
The final EASI score is the sum of the 4 region scores 
 
 
(0-72) 
 

 
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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 was filled in by the Investigator at each visit. 
 
CDLQI (Children Dermatology Life Quality Index)  
CDLQI is a questionnaire used to measure the impact of skin disease on the quality of life of 
an affected children/person. A specific version for children between 4 and 16 years was 
compiled while for children below 4 years of age, no questionnaire was to be compiled. 
However, some questionnaires were compiled by parents also for children below 4 years of 
age, by mistake. Data from these patients were not entered and not used for the analyses. 
The questionnaire asks for 10 questions, covering the following topics: symptoms, 
embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, 
close relationships, 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 CDQLI was compiled by the patient at each visit. Young children were supported for the 
questionnaire compilation by the parents/guardian, if necessary. 
 
Patient and Investigator Global Evaluation of Performance  
Patients’ and Investigator’s global evaluation of the performance of the study product was 
performed by means of the 7-item 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). 
NRS (Numeric Rating Scale) for Itching  
The patient/parents/guardian was/were requested to indicate at each visit the average and the 
worst itching suffered by the patient the same, in the previous 24 hours, by giving a numeric 
assessment from 0 to 10. Young children were supported for the scale compilation by the 

 
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parents/guardian, if necessary. The scale was compiled for youngest children and newborn, 
by the parents/guardian.  
 
3.2.2 
Clinical investigation design 
This was a multicenter, double blind, controlled versus placebo, pre-market clinical 
investigation. 
Patients were randomly allocated to one of the following treatment groups: 
- 
RelizemaTM cream, topically applied twice a day in all the affected areas for three cycles 
of 13 (±2) consecutive days.  
- 
Vehicle (placebo), topically applied twice a day in all the affected areas for three cycles 
of 13 (±2) consecutive days. 
Patients started the treatment on the day (Day 1) after the first visit (screening and baseline 
visit, on Day 0) and continued until the evening before the following visit. On the day of each 
visit the study product was not applied and it was re-started in the following day. The treatment 
could have been overall prolonged or shortened of maximum 2 days; in the case intermediate 
and/or final visits were anticipated or delayed.  
Each patient for whom written consent was obtained was identified during the study by a 
“Subject Code”, automatically generated and assigned by the e-CRF.   
All screened patients received the Subject Code regardless of whether they received the 
treatment or not. If a patient discontinued from the study at any time, the Subject Code was 
not be re-used. 
All patients who signed the informed consent and receive the Subject Code were entered into 
a Subject’s Register, containing the name and surname of the patients and their Subject 
Codes. The Subject’s Register was accessible for source data verification but was preserved 
only at clinical site. 
Once eligibility of a patient was established, the study treatment was assigned through 
electronic randomization process based on the eCRF. A computer-generated randomization 
scheme was provided by the CRO and uploaded into the eCRF. The randomization list was 
generated using the PROC PLAN of SAS 9.4 for Windows (SAS Institute Inc., Cary, NC, USA). 
Treatments were assigned to patients according to this randomization list. 
Patients/parents/guardian, Investigators and site staff persons performing the assessments, 
the staff of the Sponsor and of the CRO involved in the management of the study and of the 
data, remained blinded from the time of study start until database lock. The blind was 
maintained during the study using the following methods:  
- 
indistinguishable test device and placebo 
- 
random treatment assignment  

 
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- 
blinded assessments.  
Randomization data, including any documentation identifying the treatment allocation, were 
kept strictly confidential until the time of the unblinding. 
For emergency cases, the treatment assigned to each patient was documented and provided 
in sealed envelopes, stored for the respective patients at each clinical site in a locked and 
secure storage facility accessible to the Investigator at all times.  
Whenever the code was broken, the patient had to be excluded from the study, the procedures 
for withdrawals performed, and the fact that the code, including the time, had been opened 
was to be documented on the eCRF, by the Investigator. However, no code was broken during 
the clinical investigation. 
The blind was broken after all clinical assessments were completed and the database was 
locked.  
3.2.3 
Ethical considerations 
The study was conducted in compliance with the current version of the Declaration of Helsinki, 
with the clinical investigation plan, the UNI EN ISO 14155 current version, the MDR, the GDPR, 
the Italian laws in force and the principles of the Good Clinical Practice.  
The clinical investigation started at clinical sites only after obtaining the approval of the relevant 
Ethics Committees. 
 
To date a large variety of products for the treatment of AD are available.  
RelizemaTM cream is a CE mark medical device already available on the market to treat 
dermatitis’s symptoms such as itching and flushing. In this clinical investigation RelizemaTM 
cream was used in infants from 6 months of age, children and adolescents with mild to 
moderate atopic dermatitis. The clinical performance of RelizemaTM cream in the AD symptoms 
relief was further confirmed as compared to the vehicle (placebo).   
The choice to compare the study product to its vehicle was taken to keep a study design able 
to evidence the expected beneficial effects of the study product. Placebo was, however, a 
cream with hydrating properties, without main “active ingredients” of RelizemaTM cream.  
RelizemaTM cream/placebo was recommended twice daily for three cycles of 13 (±2) days 
each, with treatment suspension only on the visit days. The product’s components are known 
to be safe and well tolerated, therefore no risk seemed to be associated to RelizemaTM cream 
use nor to its placebo.   
The only precaution for users was to avoid contact of the study product with eyes and mucous 
membranes. 
Within the clinical investigation the patient/parents/guardian were provided with instructions on 
the personal hygiene to follow, in order to further improve skin care and safety.   

 
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No tests or invasive examinations were foreseen in this study that could increase the risk for 
participants.  
3.2.4 
Data quality assurance 
During each patient’s study visit, the study Investigator or designee collected and reported 
study data in the relevant patient’s chart, documenting all significant observations. 
Electronic CRFs (eCRFs) were used to record patient’s study data. The Investigator ensured 
that the eCRFs were properly and completely filled in. The Investigator reviewed all eCRFs 
and signed and dated them for each patient, verifying that the information was complete, 
accurate and correct. 
Any data correction was entered, and registered in the audit trail system of the eCRF: date, 
time and the person making the correction were recorded. Previous data and new data, after 
correction, and the reason for correction, were recorded too by the e-system. Only the Principal 
Investigator or personnel authorized by the Principal Investigator entered corrections on the 
original eCRFs.  
The access to the eCRF was controlled by user-specific account and password combinations.  
Queries were generated through the eCRF by the CRO Data Management staff. The 
Investigator was responsible for the review and approval of all queries. 
 
The study was monitored by the CRO Latis S.r.l.. The CRA assessed the adequacy of the 
study sites and the staff involved and monitored the sites on a regular basis throughout the 
study period to ensure the proper conduct of the clinical study.  
The CRO implemented and maintained quality control and quality assurance procedures with 
written standard operating procedures to ensure that the study was conducted and data was 
generated, documented and reported in compliance with the protocol, ISO14155, GCP and 
applicable regulatory requirements.  
 
3.2.5 
Subject population for the clinical investigation 
No. 60 patients were planned to be enrolled in this clinical investigation, selected on the basis 
of the inclusion/exclusion criteria listed below. Patients were divided into 3 groups: infants from 
6 months to 2 years, children from 3 to 11 years and adolescents from 12 to 16 years inclusive. 
Each site was requested to recruit a minimum of 4 patients in each age group.  
 
Inclusion criteria 
1. 
Release of the written informed consent obtained prior to any study-related procedures, 
by both the parents/the guardian; 
2. 
Male and female infants, children, adolescent aged between 6 months and 16 years, 
inclusive; 

 
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3. 
Presence of atopic dermatitis (AD) of mild-moderate severity:  
- 
IGA score 2 (=mild)  
or  
- 
IGA score 3 (=moderate) 
4. 
Patients with a baseline score for itch at least 4 on the NRS  
5. 
Patients/parents/guardian able to comprehend the full nature and the purpose of the 
investigation, 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. 
 
Exclusion criteria 
1. 
Severe dermatitis at inclusion; 
2. 
Pregnant and breastfeeding patients; 
3. 
Concomitant other skin disorders including skin infections; 
4. 
Use of antibiotics in the past 7 days; 
5. 
History of congenital or acquired immunodepression; 
6. 
Immunologic or infectious disease (e.g. hepatitis, tuberculosis, HIV or AIDS, any 
typology of lupus, rheumatoid arthritis) which could place the patient at risk or interfere 
with study results; 
7. 
Use of any topic or systemic drug for dermatitis in the past 10 days; 
8. 
Use of any topic emollient product for dermatitis in the 2 days before study treatment 
start; 
9. 
Any systemic treatment or procedure that could influence dermatitis activity within the 
past 30 days (or 5 half-lives); 
10. Use of any corticosteroids, immunosuppressant drugs or immunotherapy within the 
past 30 days (or 5 half-lives); 
11. Use of oral antihistamines and antidepressants in the past 30 days; 
12. Patients 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; 
13. Allergy, sensitivity or intolerance to the components of the investigational device 
formulations ingredients; 
14. Concomitant or previous participation in other interventional clinical study in the past 3 
months; 
15. Patients planning sun exposure or tanning booths or UV sources throughout the course 
of the study. 

 
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3.2.6 
Treatment and treatment allocation schedule 
Patients were allocated to RelizemaTM cream or to matching placebo (vehicle) according to the 
randomization system in place. Test device and vehicle were indistinguishable by appearance, 
smell and other parameters, in order to assure the blinding. 
 
RelizemaTM cream and the vehicle were provided for the study by the Sponsor of this clinical 
investigation and shipped to the clinical sites only after the completion of all Ethics and 
Administrative procedures. 
The product was labeled as experimental treatment in accordance with applicable Good 
Manufacturing Practice (GMP, Annex 13). 
 
Each patient received a total of no. 6 tubes containing 100 ml of cream, two per visit, and 
he/she used a variable amount of cream depending on the extent of the area/s affected by 
dermatitis to be treated. The quantity of product was enough for the complete treatment as 
foreseen by the present clinical investigation plan. 
Patients were instructed to start using RelizemaTM cream / vehicle (placebo) on Day 1, that 
means the morning after the initial visit. Study product was to be applied on all the affected body 
areas twice per day, once in the morning and once in the evening before bedtime, for three 
cycles of 13 (±2 days). The study was to be suspended for 1 day only on the visit days.   
No additional creams, moisturizers, lotions or cleansers other than the product provided by the 
Investigator were permitted. The study product did not have to be applied on the visit days. 
In addition to this, throughout the treatment phase, patients were required to avoid soap and 
use only the product DermoRelizema detergente liporestitutivo, a 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).  
 
3.2.7 
Concomitant medications/treatments 
Any medications that were considered necessary for the patients’ well-being and did not 
interfere with the study product could be given at the Investigator’s discretion. 
According to exclusion criteria, the following prior and concomitant medications were 
prohibited: 

 
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- 
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 the dermatitis  
- 
sun exposure or tanning booths or UV sources. 
The patient was recommended not to use any other product for the personal hygiene than 
the one provided by the Investigator. 
Any concomitant medication/treatment was recorded in the appropriate section of the eCRF. 
 
3.2.8 
Duration of follow-up 
Before any study specific evaluation and data collection carried out, patients and parents/ 
guardian received all the information about the study by the Investigator and signed an 
informed consent form. 
All patients/ parents/ guardian were given the opportunity to ask questions and were informed 
of their right to withdraw from the investigation without prejudice. 
At first visit patients were evaluated with regards to the inclusion and exclusion criteria that 
allowed their participation into the study. 
 
Visit 1 (Day 0): screening, baseline and randomization 
The following activities were performed at Visit 1, after informed consent release:  
- 
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 
- 
NRS for itching 
- 
CDLQI questionnaire 
- 
Randomization 
- 
Study product delivery to patient/ parents/ guardian and instructions on how to use it 
- 
Recommendations for personal hygiene to follow  
- 
Diary dispensation and explanations on how to fill it in. 
 

 
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On the diary each patient/ parent/ guardian was asked to record, at the end of each day, the 
study product applications performed with the date and the time of each application.   
 
Visit 2 (Day 14 ± 2) and Visit 3 (Day 28 ± 2) – follow-up visits:  
The following activities were performed at Visit 2 and Visit 3: 
- 
Physical examination, focused on skin examination   
- 
IGA on dermatitis  
- 
EASI Score  
- 
Change in concomitant medications/treatments recording  
- 
Information on any rescue medication for AD used from previous visit 
- 
NRS for itching 
- 
CDLQI questionnaire  
- 
Diary compilation check with the patient for treatment adherence and collection 
- 
New diary delivery 
- 
Study product collection and accountability 
- 
New product delivery 
- 
Adverse events (occurred since previous visit) recording. 
 
The treatment continued from day 1 until the evening before the Visit 2 (hypothetically day 13) 
and then from day 15 until the evening before the Visit 3 (hypothetically day 27). No treatment 
was to be applied on the day of the visits.  
If Visit 2 was anticipated of one or two days (Day 12 or 13) or postponed of one or two days 
(Day 15 or 16), within the allowed window, any attempt was to done to plan the following Visit 
3 on Day 28.  
 
Visit 4 – End of treatment and end of study (Day 42 ±2):  
The following activities were done at Visit 4: 
- Physical examination, focused on skin examination   
- IGA on dermatitis  
- EASI Score  
- Change in concomitant medications/treatments recording  
- Information on any rescue medication for AD used from previous visit 
- NRS for itching 
- CDQLI questionnaire  
- Diary compilation check with the patient for treatment adherence and collection 
- Study product collection and accountability 

 
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- Patient global evaluation of performance  
- Investigator global evaluation of performance  
- Patient global acceptability evaluation on the study product 
- Adverse events (occurred since previous visit) recording. 
 
Any attempt was done to fix the Visit 4 so that the overall treatment days were in the range 40 
(as minimum) and 44 (as maximum).  
 
3.2.9 
Statistical design, analysis and justifications 
The sample size estimation, was based on the primary efficacy endpoint defined as the 
percentage of patients improved at Visit 3. Improvement to the investigational medical device 
was defined as an improvement ≥1 point on IGA score in comparison to the baseline visit. 
It was estimated that the percentage of patients improved at Visit 3 was equal to 26% in the 
placebo arm and 80% in the test medical device arm. With a 0.05 two-sided significance level, 
a sample size of 48 patients in each arm had 90% power to detect the above estimated 
difference between groups. Estimating a rate of non-evaluable patients up to 20%, the 
randomization of 60 patients allowed the replacement of non-evaluable patients for any 
reason.  
 
General Issues  
The following populations were defined for this investigation: 
• Safety analysis set (SAF): included all patients enrolled who signed informed consent 
and received at least one administration of the investigational device.  
• Full analysis set (FAS): included 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): included all patients of the FAS who also met all 
inclusion/exclusion criteria and who do not have any major protocol deviation (i.e. 
wrong inclusion, use of forbidden concomitant medications, etc.). Patients showing a 
compliance below 80% or over 120% were not considered evaluable to the purpose of 
clinical performance per-protocol analyses.   
The analysis of safety endpoints was performed in the Safety population (SAF). Analysis of 
performance endpoints was performed on the FAS population. The analysis of primary endpoint 
was repeated in the PPAS. 

 
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Data and measures collected at Visit 1, before any study treatment application, were 
considered as baseline values. Baseline characteristics of the two groups of patients were 
compared by Student’s t-test or Fisher’s Exact test, as appropriate. 
Descriptive statistical analysis of all relevant variables was performed. Continuous variables 
were summarized by the number of subjects (N), mean, standard deviation, median, minimum, 
maximum. Categorical variables were summarized by the number (N) and the proportion of 
subjects (%). Where appropriate, 95% confidence intervals for the target variables were 
estimated.  
No interim analysis was foreseen nor done. 
No changes to the planned analysis of the study data were introduced, however the within - 
group analyses for performance endpoints have been addedd, according to the specifications 
provided in the relevant SAR v 2.0 of 26/10/2023.The within analyses were done by Wilcoxon 
signed-rank test. 
Descriptive statistics of all relevant variables were performed. Continuous variables were 
summarized by the number of patients (N), mean, standard deviation, median, minimum, 
maximum. Categorical variables were summarized by the number (N) and the proportion of 
patients (%).  
The significance level of statistical tests was set at 0.05 for all endpoints. 
The normality of distribution of the considered variables was evaluated with Shapiro-Wilks test. 
In case of normally distributed continuous variables, comparison of the values before-after 
treatment was evaluated with Student’s t-test for paired data and differences were compared 
between treatment groups with Student's t-test.  When appreciable deviation from normality 
was detected, the non-parametric Wilcoxon signed-rank test and Mann-Whitney U test were 
used, respectively. In case of categorical variables, differences were compared between 
treatment groups with Chi-Square test or Fisher's Exact test, as appropriate.   
The statistical analysis was performed using SAS 9.4 for Windows (SAS Institute Inc., Cary, 
NC, USA). 
 
Methods for Withdrawals and Missing Data 
Missing data was not replaced in any statistical analysis. 
 
Multicenter Studies Considerations 
No covariates or interaction analysis was planned nor performed. 
 

 
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Multiple Comparisons and Multiplicity 
Pairs of treatment groups were compared to assess if any statistically significant difference 
was detectable. No adjustment was needed. 
 
Protocol Deviations 
Protocol deviations were detected during monitoring activities and during data management 
activities. They were fully reviewed and discussed with the Sponsor before the database lock 
during Data Review Meeting (on the 18th of September 2023). 
 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics were analysed by descriptive statistics including 
number of observations, mean, standard deviation, median, minimum and maximum for 
continuous variables and number of observations and their percentages for categorical 
parameters.  Fisher’s Exact Test was used to compare the distribution of the gender and the 
age category between groups. Age of the two groups of patients was compared using 
Student’s t-test. Other baseline characteristics of the two groups of patients were compared 
using Fisher’s Exact Test. 
 
Performance Analysis   
Primary Endpoint   
The primary endpoint was assessed at Visit 3 by comparing, between groups, the proportion 
of responders (patients with IGA ≥ 1 decrease). Fisher's Exact Test was applied. The 
percentage of responders was also compared to a referent percentage (50%, taken as the 
best response possible using vehicle only) using the exact binomial test. Additionally, the 
distribution of patients within each IGA category was described using descriptive statistics and 
Mann-Whitney U Test was used to assess a significant change in IGA from baseline to Visit 3. 
 
Secondary Endpoints   
1) The proportion of responders (decrease in IGA ≥ 1) in the two groups, assessed at Visit 
2, compared to baseline (Visit 1). Fisher's Exact Test was applied. The percentage of 
responders was also compared to a referent percentage (50%, taken as the best response 
possible using vehicle only) using the exact binomial test. Additionally, the distribution of 
patients within each IGA category was described using descriptive statistics and Mann-
Whitney U Test was used to assess a significant change in IGA from baseline to Visit 2. 
2) The proportion of responders (decrease In IGA ≥ 1) assessed at Visit 4, compared to 
baseline (Visit 1). Comparison between groups was analyzed using Fisher's Exact Test. 
The percentage of responders was also compared to a referent percentage (50%, taken 

 
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as the best response possible using vehicle only) using the exact binomial test. 
Additionally, the distribution of patients within each IGA category was described using 
descriptive statistics and Mann-Whitney U Test was used to assess a significant change 
in IGA from baseline to Visit 4. 
3) The change from baseline (Visit 1) to each time point (Visit 2, Visit 3 and Visit 4) in EASI 
score. EASI score was described using descriptive statistics and Mann-Whitney U Test 
was used to assess a significant change from baseline to each time point. Mann-Whitney 
U test was used for the comparison between groups instead of Student’s t-test, because 
the variable was not normally distributed. 
4) The change from baseline (Visit 1) to each time point (Visit 2, Visit 3 and Visit 4) in NRS 
(Numerical Rating Scale) scale. NRS rating (Mean itching rating and Worst itching rating) 
was described using descriptive statistics and Student’s t-test (or Mann-Whitney U Test in 
case of non-normal distribution) was used to assess a significant change from baseline to 
each time point. 
5) The change from baseline (Visit 1) to each time point (Visit 2, Visit 3 and Visit 4) in CDLQI 
score. CDLQI score was described using descriptive statistics and Student’s t-test (or 
Mann-Whitney U Test in case of non-normal distribution) was used to assess a significant 
change from baseline to each time point. 
6) Patient’s adherence to treatment. Treatment compliance was described using descriptive 
statistics and Student’s t-test was used for the comparison between groups. Also, the 
treatment days were described using descriptive statistics and the same test was used for 
the comparison between groups. 
7) Proportion of patients using rescue medication during investigation. The distribution of 
patients was described using descriptive statistics and Chi-square test/Fisher’s exact test 
was used for the comparison between groups. 
8) Subject’s and Investigator’s global evaluation on performance of the study product at the 
end of the study (Visit 4) by means of a 7-items scale. The distribution of patients within 
each performance category was described using descriptive statistics and Fisher's Exact 
Test was used to compare treatment groups. 
 
With regard to treatment compliance, it was assessed by counting the number of applications 
performed, recorded in the patient’s diaries. The number of expected applications was 
estimated based on the treatment duration x 2 times, excluding the day of each visit at the 
clinical site. 
The following formula was used: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑎𝑝𝑝𝑙𝑖𝑐𝑎𝑡𝑖𝑜𝑛𝑠 𝑝𝑒𝑟𝑓𝑜𝑟𝑚𝑒𝑑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑎𝑝𝑝𝑙𝑖𝑐𝑎𝑡𝑖𝑜𝑛𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑∗100 

 
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Treatment compliance was estimated by arithmetic mean of compliances for each period. The 
patient was considered compliant to the treatment if the arithmetic mean of compliances was 
between 80% and 120%. 
Safety Analysis 
Extent of Exposure 
The extent of exposure was 1,5 month (42 days ±2). 
 
Adverse Events 
The safety analysis included all adverse events occurred during the study.  
The number of patients 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 patients withdrawn due to AE 
was summarized through number (N) and proportion of patients (%). 
Adverse events were coded using the version 26.0 of the Medical Dictionary for Regulatory 
Activities (MedDRA) to give a preferred term (PT) and a system organ class (SOC) for each 
event and summarized by treatment group.  
Local tolerability at the site of administration was carefully considered. 
 
 
4. 
Results 
4.1 
Clinical investigation initiation date 
The clinical investigation involved three clinical sites in Italy: 
- 
Site 01 - Dermatology Unit, Santa Maria della Misericordia Hospital, P.le Menghini, 3 - 
06129 Perugia. PI Prof. Luca Stingeni 
- 
Site 02 – Dermatology Unit, Presidio Ospedaliero Gaspare Rodolico, AOU Policlinico 
“G. Rodolico-San Marco”, Via S. Sofia, 78 - 95123 Catania. PI Prof. Giuseppe Micali 
- 
Site 03 - Dermatology Unit, A.O.U "Federico II" di Napoli, Via Sergio Pansini, 5 - 80131 
Napoli. PI Prof. Massimiliano Scalvenzi 
The first Ethics Committee (EC) favourable opinion was obtained on the 27-Oct-2021 for site 
01, the second one on the 10-Dec-2021 for site 03 and the third one on the 20-Dec-2021 for 
site 02. The National Competent Authority, the Italian Ministry of Health authorized the study 
conduction on the 27-Jan-2022. Following the completion of authorization process, with sites’ 
contracts signature, sites were initiated: the site 01 was initiated on the 13-Sept-2022, site 02 
on the 11-Oct-2022 and site 03 on 05-Sept-2022. 
The first patient (FPI) was enrolled on 27-Oct-2022 and on 03-Nov-2022 the study start was 
notified to the Ministry of Health.  

 
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4.2 
Clinical investigation completion/suspension date 
The last patient in (LPI) was enrolled on the 27-Apr-2023 and the last patient out (LPO) visit 
was on 09-Jun-2023. The enrolment period was initially planned of 3 months (end October 
2022 – end January 2023) and subsequently it was prolonged of 3 further months (up to end 
of April 2023). Due to planned enrolment period expiration and due to the summertime 
incoming (season when AD spontaneously improves) the Sponsor decided not to further 
extend such deadline.  The clinical investigation was regularly closed at the expiration of the 
timing foreseen for enrolment, also considering that the number of evaluable patients had been 
reached. 
The last clinical site (site 01) was officially closed on 19-Sep-2023. 
The clinical investigation conclusion (LPO as for protocol definition) was regularly notified to 
the National Competent Authority.  
 
4.3 
Disposal of subjects and investigational devices 
A total of 50 patients were randomized in the study and 47 of them completed the study (24 
RelizemaTM cream group and 23 Placebo group).   
The enrolment phase of the study lasted 6 months: the first patient signed the informed consent 
and performed the Visit 1 on 27-Oct-2022 and the last patient on 27-Apr-2023.   
At the Visit 1, after eligibility confirmation, patients received the treatment to be started on the 
following day. After that, three visits were performed: one follow-up visit after 2 weeks (± 2 
days) of treatment, one follow-up visit after 4 weeks (± 2 days) of treatment and a conclusive 
visit (end of treatment/end of study) after 6 weeks (± 2 days) of treatment.  
Overall, the study lasted about 7,5 months.  
 
Figure 1. Patients disposition   
           
 
 
 
 
Source: Table 1.1 and Listing 1.  

 
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All 50 patients were randomized: 25 patients were treated with RelizemaTM cream and 25 
patients were treated with Placebo.  
Three patients withdrew from the study between V1 and V4: 
▪ 
Patient ID 03-009, randomized to RelizemaTM cream group was lost to follow-up after 
Visit 1 (no data was available after V1); 
▪ 
Patient ID 02-004 randomized to Placebo group interrupted the study after Visit 2 
because of a Serious Adverse Event;  
▪ 
Patient ID 02-006, randomized to Placebo group withdrew the consent after Visit 2. 
Table 1.1 and Listing 1 show the Subjects’ disposition and the list of discontinued subjects. 
Based on that, 47 subjects, out of 50, regularly completed the study (24 in RelizemaTM cream 
group and 23 in Placebo group).  
 
4.4 
Subject demographics 
Out of 50 patients enrolled, 19 patients were female and 31 were male: in RelizemaTM cream 
group 10 patients (40.0%) were female and 15 patients (60.0%) were male; in Placebo group 
9 patients (36.0%) were female and 16 patients (64.0%) were male. No statistically significant 
difference was detected for gender between groups. 
No statistically significant difference was detected for age between groups: mean age (SD) 
6.72 (4.97) years, median 6.33 years in RelizemaTM cream group and mean age (SD) 6.62 
(4.45) years, median 6.42 years in Placebo group. 
Patients were also distributed into three age categories: from 6 months to 2 years, from 3 to 
11 years and from 12 to 16 years as shown in Table 1 below. Again, the age categories were 
homogeneous between groups. 
 
Table 1. Patients distribution per age category 
 
6 months – 2 years 
3 years – 11 years 
12 years – 16 years 
RelizemaTM cream group 
n=8 (32.0%) 
n=10 (40.0%) 
n=7 (28.0%) 
Placebo group 
n=5 (20.0%) 
n=16 (64.0%) 
n=4 (16.0%) 
Total 
n=13 (26.0%) 
n=26 (52.0%) 
n=11 (22.0%) 
 
Source: Table 1.3 and Listing 4.1  
 
The body areas most affected by atopic dermatitis were “Face, Legs, Arms, Trunk”: 15 patients 
(60.0%) in RelizemaTM cream group and 16 patients (64.0%) in Placebo group. The remaining 
19 patients were evenly distributed among the other body area. No statistically significant 
difference was detected between groups. Finally, the analysis of atopic dermatitis year of onset 

 
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showed no statistically significant difference between the two groups: patients were evenly 
distributed among the years, from 2008 to 2023. 
Demographic data are reported in Table 1.3 and baseline AD characteristics in Table 1.4. 
Details are respectively in Listing 4.1 and 4.4 
The medical history and the surgical history of the patients are reported in Table 1.5 and Table 
1.6, respectively (details are in Listings 4.2 and 4.3). Only 2 patients (8.0%) in Placebo group 
had at least one significant medical condition (food allergy and milk allergy) and only 1 patient 
(4.0%) in Placebo group underwent surgery (orchidopexy) in the past. No noteworthy 
differences between treatment groups were detected. 
 
4.5 
CIP compliance 
A total of 60 protocol deviations occurred during the study, 31 in RelizemaTM cream group and 
29 in Placebo group. Overall, 20 patients (40.0%) had at least one protocol deviation: 11 
patients (44.0%) in RelizemaTM cream group and 9 patients (36.0%) in Placebo group. 
All deviations were evaluated as minor (Table 1.2) therefore no protocol deviation caused the 
exclusion of any subject from the study populations for analyses. 
Details about protocol deviations by patient are reported in the Listing 2. 
The majority of protocol deviations were related to treatment compliance (90.3% and 93.1% 
respectively in RelizemaTM cream and Placebo groups) and a minority were related to delay in 
scheduled visits (6.5% and 6.9% respectively in RelizemaTM cream and Placebo groups).  
 
 
4.6 
Analysis 
Overall, 50 patients were screened and randomized to treatment: 25 to RelizemaTM cream and 
25 to Placebo.  
Primary and secondary performance endpoints were analyzed on the Full Analysis Set (FAS) 
population: 49 patients in total, 24 in RelizemaTM cream group (patient ID 03-009 was excluded 
because no data was available after initial visit) and 25 in Placebo group. 
Additionally, the primary endpoint was analyzed on the Per-Protocol Analysis set (PPAS) made 
of 46 patients: 

 
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- 
patient ID 03-009 randomized to RelizemaTM cream was excluded from PPAS because 
no data was available after initial visit;  
- 
patients ID 02-004, 02-006 randomized to Placebo were excluded because they drop 
out from the study after second visit;  
- 
patient ID 01-020 randomized to Placebo was excluded because of poor treatment 
compliance (<80%).  
Safety endpoints were analyzed on the Safety Analysis Set (SAF) population (i.e 50 patients).   
The distribution of populations used for the statistical analysis is reported in the Listing 3 and 
summarized in the Figure 2 below. 
 
Figure 2. Patients disposition for analysis 
 
 
4.6.1 
Primary endpoint performance analysis 
The primary endpoint was the proportion of responders (decrease in IGA ≥ 1) assessed at Visit 
3, compared to baseline (Visit 1). 
According to the clinical investigation plan, at Visit 1 the patients were distributed into two 
categories of IGA: “Mild” and “Moderate”, based on the severity of dermatitis.  
In FAS population (Table 2.1.1), at baseline 19 patients (79.2%) in RelizemaTM cream group 
and 17 patients (68.0%) in Placebo group had mild dermatitis, while 5 patients (20.8%) in 
RelizemaTM cream group and 8 patients (32.0%) in Placebo group had moderate dermatitis. 
No statistically significant difference in baseline AD severity between groups was detected. 
At Visit 3 patients were split between the IGA categories:  

 
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- 
15 patients (62.5%) in RelizemaTM cream group and 8 patients (33.3%) in Placebo group 
had “Almost clear” IGA,  
- 
8 patients (33.3%) in RelizemaTM cream group and 12 patients (50.0%) in Placebo group 
had “Mild” IGA;  
- 
1 patient (4.2%) in RelizemaTM cream group and 3 patients (12.5%) in Placebo group 
had “Moderate” IGA;  
Only 1 patient in Placebo group had “Clear” IGA. 
In both groups an improvement was evident, more noticeable with RelizemaTM cream 
treatment, but no statistically significant difference between groups was detected (p value= 
0.1855). 
 
The change of IGA between Visit 1 and Visit 3 was compared between groups using Mann-
Whitney U Test: mean (SD)= -0.79 (0.59), median= -1.00 in RelizemaTM cream group and 
mean (SD)= -0.63 (0.71), median= -1.00 in Placebo group. Within each group the change of 
IGA from Visit 1 to Visit 3 was statistically significant (p value<0.0001* in RelizemaTM cream 
treatment and p value=0.0009* in Placebo group) and no statistically significant difference 
between groups was observed (p value= 0.4021). 
 
The proportion of responders (decrease in IGA >= 1) was described using the number (N) and 
the percentage of patients (%). The number of responders was 17 (70.8%) in RelizemaTM 
cream group and 15 (60.0%) in Placebo group; consequently 7 patients (29.2%) in RelizemaTM 
cream group and 10 patients (40.0%) in Placebo group were not responder. The proportion of 
responders was statistically significant only within RelizemaTM cream group (p value=0.0412*; 
p-value from an Exact binomial test with null hypothesis proportion = 50% vs alternative 
proportion ≠ 50%) while it was not within Placebo group (p value =0.3173). The difference 
between treatment groups was not statistically significant (p value= 0.5512).  
Figure 2.1.1 shows the IGA distribution at Visit 1 and 3 by groups for the FAS population. 
 

 
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The same analysis was performed on the PPAS population and similar conclusions were 
drawn.  
 
In PPAS population (Table 2.1.2), at baseline 19 patients (79.2%) in RelizemaTM cream group 
and 14 patients (63.6%) in Placebo group had mild dermatitis, while 5 patients (20.8%) in 
RelizemaTM cream group and 8 patients (36.4%) in Placebo group had moderate dermatitis. 
No statistically significant difference in baseline AD severity between groups was detected. 
At Visit 3 patients were split between the IGA categories:  
- 
15 patients (62.5%) in RelizemaTM cream group and 7 patients (31.8%) in Placebo group 
had “Almost clear” IGA,  
- 
8 patients (33.3%) in RelizemaTM cream group and 11 patients (50.0%) in Placebo group 
had “Mild” IGA;  
- 
1 patient (4.2%) in RelizemaTM cream group and 3 patients (13.6%) in Placebo group 
had “Moderate” IGA;  
Only 1 patient in Placebo group had “Clear” IGA. 
As well as for FAS analysis, in both groups an improvement was evident, more noticeable in 
RelizemaTM cream group, but no statistically significant difference between groups was 
detected (p value= 0.1346). 

 
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The change of IGA between Visit 1 and Visit 3 was compared between groups using Mann-
Whitney U Test: mean (SD)= -0.79 (0.59), median= -1.00 in RelizemaTM cream group and 
mean (SD)= -0.64 (0.73), median= -1.00 in Placebo group. The within-groups analysis showed 
a statistically significant change of IGA from Visit 1 to Visit 3 in both groups (p value<0.0001* 
within RelizemaTM cream treatment and p value=0.0016* in Placebo group) and no statistically 
significant difference between groups was observable (p value= 0.4564). 
 
The number of responders was 17 (70.8%) in RelizemaTM cream group and 13 (59.1%) in 
Placebo group; consequently 7 patients (29.2%) in RelizemaTM cream group and 9 patients 
(40.9%) in Placebo group were not responder. The proportion of responders was statistically 
significant only within RelizemaTM cream group (p value=0.0412*; p-value from an Exact 
binomial test with null hypothesis proportion = 50% vs alternative proportion ≠ 50%) while it 
was not within Placebo group (p value =0.3938). The difference between treatment groups 
was not statistically significant (p value= 0.5379). 
Likewise, figure 2.1.2 shows the IGA distribution at Visit 1 and 3 by groups for the PPAS 
population. 
 
 
 

 
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4.6.2 
Secondary endpoints performance analysis 
Secondary endpoints analysis was conducted on the FAS population only. 
 
Proportion of responders (decrease in IGA ≥ 1) assessed at Visit 2, compared to 
baseline (Visit 1) 
At Visit 2 patients were split between the IGA categories: 7 (29.2%) patients treated with 
RelizemaTM cream and 5 (20.0%) patients treated with Placebo had “Almost clear” IGA, 17 
(70.8%) patients treated with RelizemaTM cream and 17 (68.0%) patients treated with Placebo 
had “Mild” IGA and the remaining 3 patients (12.0%) treated with Placebo had “Moderate” IGA. 
No statistically significant difference between groups was detected (p value=0.2739). 
 
The change of IGA between Visit 1 and Visit 2 was compared between groups using Mann-
Whitney U Test: mean change (SD)= -0.50 (0.51), median= -0.50 in RelizemaTM cream group 
and mean change (SD)= -0.40 (0.65), median= 0.00 in Placebo group. The within-groups 
analysis showed a statistically significant change of IGA from Visit 1 to Visit 2 in both groups 
(p value=0.0005* within RelizemaTM cream group and p value=0.0107* within Placebo group). 
No statistically significant difference was detected (p value= 0.5020) between the two groups. 
 
The proportion of responder (decrease in IGA >= 1) was described using the number (N) and 
the percentage of patients (%). The number of responders was 12 (50.0%) in RelizemaTM 
cream group and 10 (40.0%) in Placebo group; consequently 12 patients (50.0%) in 
RelizemaTM cream group and 15 patients (60.0%) in Placebo group were not responder. The 
proportion of responders was not statistically significant within each treatment group, at Visit 
2. The difference between treatment groups was not statistically significant (p value= 0.5709). 
Table 2.2.1 and the below Figure 2.2.1 show the IGA distribution at Visit 1 and 2 by groups. 
 

 
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Proportion of responders (decrease in IGA ≥ 1) assessed at Visit 4, compared to 
baseline (Visit 1) 
As shown in Table 2.2.2, at Visit 4 patients were split between the IGA categories: 4 (16.7%) 
patients treated with RelizemaTM cream and 3 (12.5%) patients treated with Placebo had 
“Clear” IGA, 13 (54.2%) patients treated with RelizemaTM cream and 9 (37.5%) patients treated 
with Placebo had “Almost clear” IGA, 6 (25.0%) patients treated with RelizemaTM cream and 8 
(33.3%) patients treated with Placebo had “Mild” IGA and the remaining 5 patients (1 in 
RelizemaTM cream group and 4 in Placebo group) had “Moderate” IGA. No statistically 
significant difference between groups was observed (p value=0.4198). 
 
The change of IGA between Visit 1 and Visit 4 was compared between groups using Mann-
Whitney U Test: mean change (SD)= -1.04 (0.75), median= -1.00 in RelizemaTM cream group 
and mean change (SD)= -0.79 (0.83), median= -1.00 in Placebo group. The within-groups 
analysis showed a statistically significant change of IGA from Visit 1 to Visit 4 in both groups 
(p value<0.0001* in RelizemaTM cream group and p value=0.0002* in Placebo group) and no 
statistically significant difference between groups was observable (p value=0.2632). 
 
The proportion of responder (decrease in IGA >= 1) was described using the number (N) and 
the percentage of patients (%). The number of responders was 18 (75.0%) in RelizemaTM 
cream group and 14 (56.0%) in Placebo group; consequently 6 patients (25.0%) in RelizemaTM 

 
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cream group and 11 patients (44.0%) in Placebo group were not responder. The proportion of 
responders was statistically significant only within RelizemaTM cream group (p value=0.0143*; 
p-value from an Exact binomial test with null hypothesis proportion = 50% vs alternative 
proportion ≠ 50%) while it was not within Placebo group (p value =0.5485). The difference 
between treatment groups was not statistically significant (p value=0.2321). 
Figure 2.2.2 shows the IGA distribution at Visit 1 and 4 by groups. 
 
 
 
Change from baseline (Visit 1) to each time point (Visit 2, Visit 3 and Visit 4) in EASI 
(Eczema Area and Severity Index) score  
As shown in Table 2.2.3, EASI score decreased in both treatment groups between Visit 1 and 
Visit 2: mean change (SD)= -3.13 (4.70), median= -1.15 in RelizemaTM cream group and mean 
change (SD)= -3.32 (5.54), median= -1.20 in Placebo group. The change within each treatment 
group was statistically significant (p value< 0.0001* in both groups) and the difference between 
treatment groups was not statistically significant (p value=0.8101).  
The analysis of EASI score between Visit 1 and Visit 3 provided similar results: mean change 
(SD)= -4.30 (5.51), median= -2.50 in RelizemaTM cream group and mean change (SD)= -4.64 
(6.04), median= -2.05 in Placebo group and again the change within each treatment group 

 
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was statistically significant (p value<0.0001* in both groups) and the difference between 
groups was not statistically significant (p value=0.9343).  
Similar conclusions can be drawn for the change of EASI score between Visit 1 and Visit 4: 
mean change (SD)= -5.45 (6.62), median =-2.95 in RelizemaTM cream group and mean change 
(SD)= -4.31 (6.26), median= -2.80 in Placebo group. Again, the change within each treatment 
group was statistically significant (p value< 0.0001* in RelizemaTM cream group and p 
value=0.0003* in Placebo group) and no difference was observed between groups (p 
value=0.7259). 
 
Change from baseline (Visit 1) to each time point (Visit 2, Visit 3 and Visit 4) in NRS  
(Numerical Rating Scale) 
The itching was evaluated using the Numeric Rating Scale; at each visit the patient indicated 
the average and the worst itching suffered. The analysis was performed on both indices: mean 
itching rating and worst itching rating (Table 2.2.4). 
 
Mean itching rating  
Mean itching rating decreased in both treatment groups between Visit 1 and Visit 2: mean 
change (SD)= -0.96 (1.16), median= -1.00 in RelizemaTM cream group and mean change 
(SD)= -0.50 (1.25), median= 0.00 in Placebo group. The change was statistically significant 
only within RelizemaTM cream group (p value=0.0007*; in Placebo group p value was 0.0546) 
and the difference between the two treatment groups was not statistically significant (p 
value=0.2404).  
The analysis of the mean itching rating between Visit 1 and Visit 3 provided similar results: 
mean change (SD)= -1.58 (1.21), median= -2.00 in RelizemaTM cream group and mean change 
(SD)= -1.26 (1.66), median= -1.00 in Placebo group. The change was statistically significant 
within each treatment group (p value<0.0001* in RelizemaTM cream group and p value=0.0034* 
in Placebo group) and again the difference between groups was not statistically significant (p 
value=0.4579).  
Similar conclusions were drawn for the change of itching rating between Visit 1 and Visit 4: 
mean change (SD)= -2.42 (1.67), median= -2.50 in RelizemaTM cream group and mean change 
(SD)= -1.83 (1.86), median= -2.00 in Placebo group. The change was statistically significant 
within each treatment group (p value<0.0001* in RelizemaTM cream group and p value=0.0001* 
in Placebo group) and the difference between groups was not statistically significant (p 
value=0.2580). 
 
Worst itching rating  

 
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Worst itching rating decreased in both treatment groups between Visit 1 and Visit 2: mean 
change (SD)= -1.21 (1.41), median= -1.00 in RelizemaTM cream group and mean change 
(SD)= -0.63 (1.17), median= 0.00 in Placebo group. The change was statistically significant 
within each treatment group (p value=0.0002* in RelizemaTM cream group and p value= 
0.0239* in Placebo group) and the difference between treatment groups was not statistically 
significant (p value=0.1746).  
The analysis of the worst itching rating between Visit 1 and Visit 3 provided similar results: 
mean change (SD)= -1.96 (1.49), median= -2.00 in RelizemaTM cream group and mean change 
(SD)= -1.65 (1.40), median= -2.00 in Placebo group. The change was statistically significant 
within each treatment group (p value<0.0001* in both groups) and again the difference 
between groups resulted not statistically significant (p value=0.5032).  
Similar conclusions can be drawn for the change of worst itching rating between Visit 1 and 
Visit 4: mean change (SD)= -2.63 (2.34), median =-2.50 in RelizemaTM cream group and mean 
change (SD)= -2.00 (1.62), median= -2.00 in Placebo group. The change was statistically 
significant within each treatment group (p value<0.0001* in both groups) and also at Visit 4 the 
difference between groups was not statistically significant (p value=0.3563). 
 
Change from baseline (Visit 1) to each time point (Visit 2, Visit 3 and Visit 4) in CDLQI 
(Children Dermatology Life Quality Index) score 
The analysis of quality of life results is reported in Table 2.2.5. 
CDLQI score decreased in both treatment groups between Visit 1 and Visit 2: mean change 
(SD)= -2.29 (2.52), median= -1.50 in RelizemaTM cream group and mean change (SD)= -1.28 
(2.22), median= 0.00 in Placebo group. The change was statistically significant within each 
treatment group (p value=0.0078* in RelizemaTM cream group and p value= 0.0273* in Placebo 
group) and the difference between treatment groups was not statistically significant (p 
value=0.2612).  
The analysis of CDLQI score between Visit 1 and Visit 3 provided similar results: mean change 
(SD)= -3.86 (4.33), median= -1.50 in RelizemaTM cream group and mean change (SD)= -2.56 
(2.94), median= -1.50 in Placebo group. The change was statistically significant within each 
treatment group (p value=0.0010* in RelizemaTM cream group and p value= 0.0002* in Placebo 
group) and again the difference between groups was not statistically significant (p 
value=0.5360).  
Similar conclusions were drawn for the change of CDLQI score between Visit 1 and Visit 4: 
mean change (SD)= -5.29 (4.73), median= -3.00 in RelizemaTM cream group and mean change 
(SD)= -3.53 (4.00), median= -2.00 in Placebo group. The change was statistically significant 

 
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within each treatment group (p value=0.0005* in RelizemaTM cream group and Placebo group) 
and no statistically significant difference was observed between groups (p value=0.2138). 
 
Patient’s adherence to treatment 
Treatment compliance was summarized by the number of patients (N), mean, standard 
deviation, median, minimum, maximum. As shown in Table 2.2.6 treatment compliance was 
generally very high in both treatment groups: mean (SD)= 97.46 (5.13)%, median 100.00% in 
RelizemaTM cream group and mean (SD)= 96.96 (7.32)%, median= 100.00% in Placebo group. 
The difference between groups was not statistically significant (p value=0.9183). 
Also, treatment days were summarized: in RelizemaTM cream group the average days of 
treatment was 39.50 (SD=1.25), with a minimum of 37.00 days and a maximum of 43.00 days, 
while in Placebo group the average days of treatment is 38.28 (SD=5.99), with a minimum of 
13.00 days (mainly due to patient 02-004 who withdrew after Visit 2 due to a SAE), and a 
maximum of 43.00 days. The difference between groups was not statistically significant (p 
value=0.6505). 
With a high level of certainty, it can be concluded that treatment days approximate the duration 
of exposure to treatment, as both groups have high compliance. 
 
Proportion of patients using rescue medication during investigation 
As shown in Table 2.2.7 no patients in both groups used rescue medication during the 
investigation.  
 
Subject’s and Investigator’s Global Evaluation on performance of the study product at 
the End of the Study (Visit 4)  
At the End of Study the clinical performance of the study product was evaluated by means of 
a 7-items scales by the investigator and by the subject (Table 2.2.8). 
 
Investigator's Global Evaluation of Performance 
Patients were split between almost all the items on the scale. The investigator evaluated the 
patients’ condition after treatment “Very much improved” / “Improved” / “Minimally improved” 
for 19 (79.1%) patients treated with RelizemaTM cream and for 17 (70.8%) patients treated with 
Placebo. No change in dermatitis was observed by the investigator in 3 (12.5%) patients 
treated with RelizemaTM cream and in 5 (20.8%) patients treated with Placebo. For the 
remaining 2 patients in RelizemaTM cream group and 2 patients in Placebo group the 
investigator evaluated their condition “Minimally worsened” / “Worsened” after treatment. No 
statistically significant difference between groups was observed (p value=0.6476). 
 

 
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Subject's Global Evaluation of Performance 
Likewise, the clinical performance of the study product was evaluated by the patient 
(parents/guardian) and similar conclusions can be drawn. Overall, 21 (87.5%) patients of 
RelizemaTM cream group and 16 (66.6%) patients of Placebo group evaluated their disease 
“Very much improved” / “Improved” / “Minimally improved” after the treatment received. Two 
patients (8.3%) treated with RelizemaTM cream and 6 (25.0%) of patients treated with Placebo 
observed no change on the dermatitis severity; finally, 1 patient (4.2%) of RelizemaTM cream 
group and 2 (8.4%) patients of Placebo group evaluated their dermatitis as “Minimally 
worsened” / “Worsened” after the treatment. Again, no statistically significant difference 
between groups was detected (p value=0.5172). 
Figures 2.2.8.1 and 2.2.8.2 shows the Investigator’s and Subject’s Global Evaluation on 
performance of the study product at the End of the Study by groups. 
 
 
 
 
 

 
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4.6.3 
Safety analysis 
Safety analysis was conducted on the Safety population (i.e. 50 subjects).  
Only 2 adverse events occurred to 2 patients during the study. None of the adverse events 
occurred was evaluated as related to the study treatment, by the Investigator. 
One event was serious, not related to study treatment and leading to study premature 
discontinuation: patient ID 02-004, randomized to placebo, had a bacterial gastroenteritis 
requiring hospitalization. The event was resolved but the patient withdrew from the study. 
The second event was of mild intensity and not related to study treatment:  patient ID 01-002, 
randomized to RelizemaTM cream group, had a limb injury. The patient continued the study and 
at the time of study conclusion the event was not yet resolved, but stable.   
Safety analysis is reported in Tables 3.1 and 3.2 and safety details are in Listing 7. 
According to clinical investigation plan, adverse events were coded using the MedDRA 
dictionary; Table 3.2 shows the two adverse events summarized by body system and preferred 
terms. 
 
5. 
Discussion and overall conclusions 
Atopic dermatitis (AD) is a long-term (chronic) cutaneous inflammatory disease, very common 
condition in babies and children. Depending on the severity of the disease, symptoms can 

 
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include erythema, dry, scaly skin, itching, redness and swelling, thickened skin, pale skin on 
the face, small-raised bumps that may become crusty and leak fluid if scratched, rough bumps 
on the face, upper arms, and thighs, darkened skin, lichenification etc. Importantly, the disease 
can cause significant sleep disruption and impact the quality of life of patients and families. 
Since there is no curative etiological therapy for AD, the aim of all therapeutic interventions is 
the is the control and relief of symptoms and prevention of flare-ups.  
Currently available pharmacologic treatments for dermatitis management include the topical 
corticosteroids or immunosuppressants, which have a significant efficacy but are also 
associated with high incidence of transient skin reactions and, for this reason, are generally 
not recommended for the young children. 
There is strong evidence that the use of topical moisturizers, emollients and protective agents 
can reduce the need for pharmacologic intervention to treat AD symptoms and are particularly 
recommended in young patients. RelizemaTM cream is a dermatological cream for topical use 
indicated for the treatment of itching, and flushing associated with dermatitis, including atopic 
and contact dermatitis and/or erythema. Thanks to its derma-protective action it helps 
maintaining and restoring the physiological skin barrier.  
This pre-market clinical investigation was aimed to evaluate the clinical benefit of RelizemaTM 
cream in infants, children and adolescents suffering for AD symptoms. To assess in objective 
way the effects of RelizemaTM cream in the relief of AD symptoms, it was compared to placebo 
(vehicle) in a double-blind designed study. 
 
The proportion of responder (decrease in IGA >= 1) at Visit 3 (i.e. after 28 days of treatment) 
was the primary performance endpoint. The 70.8% of patients in RelizemaTM cream group was 
responders while only the 60.0% in Placebo group was. The analysis repeated on PPAS 
showed the same result, with the 70.8% of patients in in RelizemaTM cream group and the 
59.1% in Placebo group responders. The difference between treatment groups was not statistically 
significant (Table 2.1.1 and 2.1.2) but the within group analysis showed that RelizemaTM cream 
has a pronounced and statistically significant clinical performance (proportion of responders p 
value=0.0412*). 
Also, the proportion of responders analysed at Visit 2 and Visit 4 (i.e. after 2 and 6 weeks of 
treatment) showed the 50.0% of responders in RelizemaTM cream group and the 40.0% in 
Placebo group at Visit 2 (Table 2.2.1) and the 75.0% in RelizemaTM cream group and 56.0% 
in Placebo group at Visit 4 (Table 2.2.2). No statistically significant difference between groups 
was observable but the within groups analysis evidenced the marked and statistically 
significant clinical performance of RelizemaTM cream, at Visit 4 (proportion of responders: p 
value=0.0143*). 
 

 
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EASI score decreased in both treatment groups in similar and statistically significant way: 
mean changes from baseline to, respectively 14, 28 and 42 days of treatment were of -3.13 
(SD=4.70), -4.30 (SD=5.51) and -5.45 (SD=6.62) in RelizemaTM cream group and -3.32 
(SD=5.54), -4.64 (6.04) and -4.31 (6.26), in Placebo group (Table 2.2.3). No statistically 
significant difference was observable between the two groups at each time point. 
Mean itching rating decreased in both treatment groups from baseline to, respectively 14, 28 
and 42 days of treatment: mean changes were -0.96 (SD=1.16), -1.58 (SD=1.21) and -2.42 
(SD=1.67) in RelizemaTM cream group and -0.50 (SD=1.25), -1.26 (SD=1.66) and -1.83 
(SD=1.86), in Placebo group (Table 2.2.4). The RelizemaTM cream performance was 
statistically significant at each time point while the one of Placebo was only at Visit 3 and 4. In 
any case, no statistically relevant difference was observed between the two groups at each 
time point of the study. 
 
As well, mean worst itching rating decreased in both treatment groups from baseline to, 
respectively 14, 28 and 42 days of treatment, always with statistical significance within each 
treatment group: mean changes were -1.21 (SD=1.41), -1.96 (SD=1.49) and -2.63 (SD=2.34) 
in RelizemaTM cream group and -0.63 (SD=1.17), 1.65 (SD=1.40) and -2.00 (SD=1.62) in 
Placebo group (Table 2.2.4). No statistically significant difference was observable between the 
two groups at each time point. 
 
CDLQI score decreased (meaning an improvement in the QoL) in both treatment from baseline 
to, respectively 14, 28 and 42 days of treatment, always with statistical significance within each 
treatment group: mean changes were -2.29 (SD=2.52), -3.86 (SD=4.33) and -5.29 (SD=4.73) 
in RelizemaTM cream group and -1.28 (SD=2.22), -2.56 (SD=2.94) and -3.53 (SD=4.00) in 
Placebo group (Table 2.2.5). No statistically significant difference was observable between the 
two groups at each time point. 
 
Finally, the Investigators evaluated that at the end of treatment (6 weeks) there was an 
improvement respect to initial condition in the 79.1% of patients treated with RelizemaTM cream 
and in the 70.8% of patients treated with Placebo (Table 2.2.8). 
The patients (parents/guardian) opinion was more likely to find it RelizemaTM cream 
satisfactory (87.5%) than Placebo (66.6%).  
Finally, that treatment compliance was very high in almost all patients and none of them used 
alternative treatments for the management of AD during the study. 
 
From the safety point of view, no adverse events related to the study treatment were reported: 
only two AEs occurred to two patients during the study: one event was of mild severity (limb 
injury) while the other was a Serious Adverse Event (a bacterial gastroenteritis leading to 
hospitalization and to study discontinuation). 

 
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In conclusion, in all performance items analysed the two treatments showed no statistically 
significant difference, however, looking to all the performance endpoints, the improvement of 
the AD condition and symptoms resulted always more relevant within the RelizemaTM cream 
group than within the Placebo group. 
In this regard, it is necessary to underline that the Placebo used in this study was a vehicle 
with hydrating properties, both for ethical reasons as it was not acceptable to use a totally inert 
product in young patients suffering for AD symptoms, and because of technical/manufacturing 
reasons (a cream inevitably contains substances that give emollient and hydrating properties). 
In light of this it is understandable and justified that no relevant statistically significant difference 
between treatments emerges from data analysis. The relevant result of this clinical 
investigation is that both from statistical and clinical point of view the RelizemaTM cream has 
shown to be effective and safe in the relief of AD symptoms in young patients, from 6 months 
of age. 
 
 
 

 
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6. 
Abbreviated terms and definitions 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AO 
Azienda Ospedaliera 
CDLQI 
Children Dermatology Life Quality Index questionnaire 
CE 
Conformité Européenne (European Conformity) 
CI 
Interval of Confidence 
CIP 
Clinical Investigation Plan 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization  
CTCAE 
Common Terminology Criteria for Adverse Events 
DRM 
Data Review Meeting 
EASI 
Eczema Area and Severity Index 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FPI 
First Patient In 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 679/2016 
GMP 
Good Manufacturing Practice 
ICH  
International Conference on Harmonization 
IFU 
Instructions For Use 
IGA 
Investigator Global Assessment 
LPI 
Last Patient In 
LPO 
Last patient Out 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDR 
Medical Device Regulation 
ml 
Milliliters 
mm 
Millimeters  
NRS 
Numeric Rating Scale 
PI 
Principal Investigator 
PT 
Preferred Term 

 
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QoL 
Quality of Life 
SADE 
Serious Adverse Device Effect 
SAF 
Safety Analysis Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
 
 
 

 
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7. 
Ethics 
The study was conducted in full compliance with the principles of the "Declaration of Helsinki". 
Before undertaking any study-related procedures with patients, the purpose and nature of the 
study as well as possible adverse effects were explained to them in understandable terms and 
written informed consent was obtained from parents/guardian. Specific information sheets 
were developed for different age groups: 6-11 years and 11-17 years. One information sheet 
and informed consent form for adults was developed in order to obtain the consent to study 
participation and data collection and management from parents or guardian. 
Three clinical sites were involved and for each of them the competent EC approval was 
requested and obtained. The EC of the coordinating site (Comitato Etico Regionale Umbria), 
evaluated this clinical investigation in the meeting of the 27-Oct-2021 and expressed a 
favorable opinion. The two other ECs expressed their favourable opinion on the 10 and 20-
Dec-2021 (respectively for site 03 Napoli and site 02 Catania). 
The clinical investigation was submitted to the Italian CA (Ministry of Health) on 24-Nov-21 
(after coordinating site EC approval) and the validation process completion was notified to the 
CRO on 27-Jan-2022. The CA was notified about the study start on the 03-Nov-2022, after the 
first subject was enrolled and about study conclusion on the 13-Sep-2023. 
During the study one substantial amendment for the change of the PI at clinical site no.3 
(Napoli) and some non-substantial amendments were issued.  
The study essential documents were archived according to the CRO SOPs (in line with ISO 
14155 guideline) and will be kept by the investigational sites and the Sponsor according to 
MDR 2017/45 requirements. It will be responsibility of the Principal Investigators to assure that 
the study essential documents are duly filed in the Trial Centre File and that the Trial Centre 
File is correctly stored and preserved after the study closure. 
 
 
 

 
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8. 
Investigators and administrative structure of clinical 
investigation 
Study Site 01 – Coordinating Site 
Unità Operativa di Dermatologia 
Ospedale Santa Maria della Misericordia 
P.le Menghini, 3 - 06129 Perugia 
Principal Investigator 
Luca Stingeni 
 
Study Site 02 
Unità Operativa Complessa di 
Dermatologia  
Azienda Ospedaliero Universitaria  
Policlinico “G. Rodolico-San Marco”  
Via S. Sofia, 78 - 95123 Catania 
Principal Investigator 
Giuseppe Micali 
Study Site 03 
Unità Operativa di Dermatologia  
Azienda Ospedaliero Universitaria  
"Federico II" di Napoli,  
Via Sergio Pansini, 5 - 80131 Napoli 
Principal Investigator 
Massimiliano Scalvenzi 
Sponsor  
 
Relife S.r.l. 
 
Via dei Sette Santi 3  
50131 Florence, ITALY 
Phone: +39 055 56809345  
Fax: +39 055 56809346 
Sponsor Representative Contacts 
 
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@menarini.it  
Contract Research Organization  
 
Latis S.r.l.  
Viale Sauli, 39/5  
16121 Genova – ITALY 
Phone: +39 010 562234 
Fax: +39 010 540699 
e-mail: info@latiscro.it 
CRO Representative Contacts 
 
Laura Michellini Scientific Director  
Phone: +39 010 562234 
Mobile: +39 347 4785898 
e-mail: michellini@latiscro.it    
 
Paola Soldati Project Manager 
Phone: +39 010 562234 
e-mail: soldati@latiscro.it  
 
 
Camilla Palermiti Head of Statistics & Data 
Management 

 
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Phone: +39 010 562234 
e-mail: palermiti@latiscro.it  
 
 
 
 

 
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10. Annexes to the report 
A. CLINICAL INVESTIGATION PROTOCOL (including amendments, if any) 
B. INSTRUCTIONS FOR USE 
C. LIST OF PRINCIPAL INVESTIGATORS AND THEIR AFFILIATED 
INVESTIGATION SITE, INCLUDING COPY OF THEIR CVs 
D. LIST OF NAMES AND ADDRESSES OF ANY THIRD PARTIES 
E. LIST OF MONITORS 
F. LIST OF ECs 
G. TABULATION OF ALL RELEVANT DATASETS  
List of Tables 
 
Demographic data 
Table 1.1  
Patients’ disposition (Safety population) 
Table 1.2  
Protocol deviations (Safety population) 
Table 1.3  
Demographic characteristics (Safety population) 
Table 1.4  
Disease details at baseline (Safety population) 
Table 1.5  
Medical history (Safety population) 
Table 1.6  
Surgical history (Safety population) 
 
Performance data 
Primary endpoints 
Table 2.1.1  
Proportion of responders (decrease in IGA ≥ 1) assessed at Visit 
3, compared to baseline (Visit 1) (FAS population) 
Table 2.1.2  
Proportion of responders (decrease in IGA ≥ 1) assessed at Visit 
3, compared to baseline (Visit 1) (PPAS Population) 
Secondary endpoints 
Table 2.2.1  
Proportion of responders (decrease in IGA ≥ 1) assessed at Visit 
2, compared to baseline (Visit 1) (FAS Population) 
Table 2.2.2  
Proportion of responders (decrease in IGA ≥ 1) assessed at Visit 
4, compared to baseline (Visit 1) (FAS Population) 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
Page 59 of 60 
 
Table 2.2.3  
Change from baseline (Visit 1) to each time point (Visit 2, Visit 3 
and Visit 4) in EASI (Eczema Area and Severity Index) score 
(FAS Population 
Table 2.2.4  
Change from baseline (Visit 1) to each time point (Visit 2, Visit 3 
and Visit 4) in NRS (Numerical Rating Scale) (FAS Population) 
Table 2.2.5 
 Change from baseline (Visit 1) to each time point (Visit 2, Visit 3 
and Visit 4) in CDLQI (Children Dermatology Life Quality Index) 
score (FAS Population) 
Table 2.2.6  
Patient’s adherence to treatment (FAS Population) 
Table 2.2.7  
Proportion of patients using rescue medication during 
investigation (FAS population) 
Table 2.2.8  
Subject’s and Investigator’s global evaluation on performance of 
the study product at the end of the study (Visit 4) by means of a 
7-items scale (FAS Population) 
 
Safety data 
Table 3.1  
Analysis of adverse events observed (Safety population) 
Table 3.2  
Display of adverse events observed (Safety population) 
 
List of Subject Data Listings 
Listing 1   
Discontinued Patients 
Listing 2   
Protocol Deviations 
Listing 3   
Analysis Populations 
Listing 4.1  
Demographic Data and Other Baseline Characteristics – 
Demography 
Listing 4.2  
Demographic Data and Other Baseline Characteristics – Medical 
History 
Listing 4.3 
Demographic Data and Other Baseline Characteristics – Surgical 
History 
Listing 4.4  
Demographic Data and Other Baseline Characteristics – Disease 
Details 
Listing 5   
Treatment Compliance 
Listing 6.1  
Individual Efficacy Response Data – Investigator’s Global 
Assessment (IGA) 

 
Clinical Investigation Report  
 
Study Code: ReGl/21/Rcr-Dpe/001 
Report date: 20-Nov-2023                                                       Investigational Device: RelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
Page 60 of 60 
 
Listing 6.2  
Individual Efficacy Response Data – EASI (Eczema Area and 
Severity Index) score 
Listing 6.3  
Individual Efficacy Response Data – NRS (Numerical Rating 
Scale) for itching 
Listing 6.4  
Individual Efficacy Response Data – CDLQI (Children 
Dermatology Life Quality Index) score 
Listing 6.5  
Individual Efficacy Response Data – Subject’s and Investigator’s 
global evaluation of performance 
Listing 7   
Adverse Events 
Listing 8   
Concomitant Medications 
Listing 9   
Physical Examination 
 
H. AUDIT CERTIFICATE, IF APPLICABLE 
I. 
REFERENCES 
J. SUPPLEMENTARY TABLES