Efficacy and Tolerability Evaluation of a Topical Medical Device Based on SHBF in Management of Radiodermatitis. An Observer-masked, Controlled Study.
Phase: NA
Conditions: Radiodermatitis, Dermatitis, Radiation-Induced
Sponsor: Relife Italia S.r.l.

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Page 1 of 59 
 
 
Clinical Investigation Report 
 
Investigational device:   
DERMORELIZEMATM CREAM 
 
Sponsor:  
 
 
 
Relife Italia S.r.l. 
 
Via dei Sette Santi 1/3 - 50131 Florence, ITALY 
 
Sponsor’s representative:  
Martina Manni, MD – Study Medical Expert 
 
CIP identification:        
 
Version no. 02 - 10th Feb 2022 
 
Coordinating investigator:  
Dr. Mariangela Francomano 
Dermatology Unit, Modena University Hospital 
 
 
 
 
 
Via Enrico Dal Pozzo, 71 
 
 
 
 
 
41134 Modena, 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:  
 
 
30th June, 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. 
 
 
EFFICACY AND TOLERABILITY EVALUATION OF A TOPICAL 
MEDICAL DEVICE BASED ON SHBF IN MANAGEMENT OF 
RADIODERMATITIS. AN OBSERVER-MASKED, CONTROLLED 
STUDY 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Page 2 of 59 
 
Table of contents 
1. 
Summary ........................................................................................................................ 4 
2. 
Introduction .................................................................................................................. 14 
2.1 
Rationale ............................................................................................................... 14 
3. 
Investigational device and methods .............................................................................. 16 
3.1 
Investigational device description .......................................................................... 16 
3.1.1 
Description of the investigational device ........................................................ 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) ............................................................................. 18 
3.2.1 
Clinical investigation objectives ...................................................................... 18 
Treatment Adherence ................................................................................................... 20 
Patient’s Subjective Assessments (by VAS) ................................................................. 20 
3.2.2 
Clinical investigation design ........................................................................... 21 
3.2.3 
Ethical considerations .................................................................................... 22 
3.2.4 
Data quality assurance ................................................................................... 23 
3.2.5 
Subject population for the clinical investigation .............................................. 23 
3.2.1 
Treatment and treatment allocation schedule ................................................. 24 
3.2.2 
Concomitant medications/treatments ............................................................. 26 
3.2.3 
Duration of follow-up, study visits description ................................................. 27 
3.2.4 
Statistical design, analysis and justifications .................................................. 29 
4. 
Results ......................................................................................................................... 34 
4.1 
Clinical investigation initiation date ........................................................................ 34 
4.2 
Clinical investigation completion/suspension date ................................................. 35 
4.3 
Disposal of subjects and investigational devices ................................................... 35 
4.4 
Subject demographics ........................................................................................... 36 
4.5 
CIP compliance ..................................................................................................... 37 
4.6 
Analysis ................................................................................................................. 37 
4.6.1 
Primary endpoint performance analysis ......................................................... 37 
4.6.2 
Secondary endpoints performance analysis ................................................... 38 
Time to onset and time to peak of RISR symptoms ......................................................... 38 
4.6.3 
Safety analysis ............................................................................................... 47 
5. 
Discussion and overall conclusions .............................................................................. 47 
6. 
Abbreviated terms and definitions ................................................................................ 51 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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7. 
Ethics ........................................................................................................................... 53 
8. 
Investigators and administrative structure of clinical investigation ................................ 54 
9. 
Signature page ............................................................................................................. 55 
10. Annexes to the report ................................................................................................... 56 
 
 
 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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1. 
Summary 
 
Title of clinical investigation 
EFFICACY AND TOLERABILITY EVALUATION OF A TOPICAL MEDICAL DEVICE BASED 
ON SHBF IN MANAGEMENT OF RADIODERMATITIS. AN OBSERVER-MASKED, 
CONTROLLED STUDY 
 
Introduction 
Approximately 50 percent of all cancer patients can benefit from radiation therapy (RT) in the 
management of their disease. However, RT is not free from toxicity. Acute and chronic 
radiation-induced skin reactions (RISR) represent an inevitable consequence for up to 95% of 
people receiving RT. 
The development of RISR usually occurs within few weeks after the initiation of the RT and 
persists up one month. RISR are usually characterized by swelling, redness, pigmentation, 
followed dry and then mostly desquamation, epilation, fibrosis, and ulceration of the skin and 
subjective symptoms including pain, warmth, burning, itching, psychological distress, leading 
even to discontinuation of the RT.  
Currently there are no unanimously recognised guidelines for the management of RISRs and 
so far there is no treatment considered gold standard. 
Based on DermoRelizemaTM cream ingredients properties and based on pre-clinical and 
clinical evidence, it can constitute a safe and effective treatment for dermatitis and erythema.  
 
Purpose of the clinical investigation 
DermoRelizema™ cream topical formulation (cream) based on Sodium Hyaluronate Butyrate 
Formiate (SHBF). According to the current European regulation, DermoRelizemaTM cream is 
a CE marked Class IIa Medical Device commercialized by Relife Italia Srl (Menarini Group) 
and is indicated for the symptomatic treatment of dermatitis and erythema. 
In this study, DermoRelizemaTM cream was tested in the management of RISRs in patients 
with breast cancer who started the treatment with the study product about one week before 
the start of RT, to prevent, delay and reduce the radiodermatitis signs and symptoms onset 
and severity.  
This was a monocenter, randomized, comparative vs Dexeryl® cream, observer-masked, post-
market clinical follow-up investigation. 
The clinical investigation was regularly submitted to the competent Ethics Committee and 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
Page 5 of 59 
 
notified to the Italian Ministry of Health, as for requirements in post market clinical follow-up 
studies. 
 
Description of the clinical investigation population 
This study enrolled women with breast cancer at any stage who had undergone 
quadrantectomy, for whom hypofractionated adjuvant RT of the thoracic region was indicated 
and with good cutaneous trophism, in the region to be treated, according to investigator’s 
judgement. 
A minimum of 68 evaluable patients were planned (34 in each treatment group). 
Women with the following characteristics were considered eligible:  
- Giving their written consent. 
- Aged ≥18 years. 
- With breast cancer at any stage who have undergone quadrantectomy, for whom 
hypofractionated adjuvant RT of the thoracic region is indicated. 
- RTOG/ EORTC radiodermatitis grade equal to 0 (zero) and good cutaneous trophism, in 
the region to be treated, according to investigator’s judgement. 
- Cooperative with regard to compliance with study-related constraints. 
 
The following patients were excluded from the study:  
- Pregnant or lactating women (as not eligible to RT), and fertile women not following, at the 
investigators’ judgement, an adequate contraceptive method. 
- Subjects incapable of giving consent. 
- Concomitant inflammatory skin diseases in acute phase such as: atopic dermatitis, contact 
dermatitis, psoriasis, lichen planus, pityriasis rosea. 
- Collagen vascular disease, vasculitis, scleroderma, dermatomyositis, or systemic lupus 
erythematosus. 
- Unhealed surgical sites, breast infections. 
- Bilateral breast cancer or multiple neoplasia needing other independent RT treatments. 
- Prior breast reconstructions, implants, and/or expanders. 
- Known radio-sensitivity syndromes (e.g. ataxia-telangiectasia). 
- Known history of intolerance or hypersensitivity to any ingredient of the study products. 
- Previous RT in the same or different location. 
- Topical pharmacological and medical device treatments on the skin region affected by the 
RT, in the last 2 weeks. 
- Systemic or topical (including inhaled or intranasal) treatments containing corticosteroids of 
any class in the 2 days preceding the enrolment. 
- Photo-therapy (PUVA, UVB) in the 2 weeks preceding the enrolment and/or planned to be 
administered during the course of the study. 
- Participation in another clinical trial at the time of the randomization or within 28 days before 
randomization. 
- Patient’s difficulties or problems, in the judgment of the investigator, in being compliant with 
study procedures and requirements, including social or mental constrains. 
 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Clinical investigation method used 
This was a monocenter (1 clinical site involved in Italy), randomized, comparative, observer-
masked, post-market clinical follow-up study. 
All the subjects were allocated (1:1) to the following treatment groups: 
▪ 
DermoRelizemaTM cream. Fingertip units (FTU) depending on the extent of the affected 
skin to treat, two times per day. The treatment was applied since about 7 (±3) days 
prior to RT start and continued until 14 days post RT end. After that the study product 
applications could go on for further 2 weeks, according to the investigator’s decision. 
sessions.  
▪ 
Dexeryl® cream. FTUs depending on the extent of the affected skin to treat, two times 
per day. The treatment wase applied since 7 (±3) days prior to RT start and continued 
until 14 days post RT end. After that the study product applications could go on for 
further 2 weeks, according to the investigator’s decision. 
The products were not applied within four hours before the RT. 
 
Four visits were planned: initial visit to evaluate the subject eligibility and to train the subject to 
the correct study product application, then a Visit 2 at RT completion, Visit 3 at 2 weeks after 
RT completion and Visit 4 at 4 weeks after RT completion.   
 
Performance evaluations included: 
- the portion of patients with Radiation Therapy Oncology Group/European Organisation for 
Research and Treatment of Cancer (RTOG / EORTC) radiodermatitis grade ≤ 1 and >1, at V3 
(end of study treatment at V3, 2 weeks after RT conclusion, as primary endpoint) and at V2 
(end RT, as secondary endpoint) and V4 (4 weeks after RT conclusion, as secondary 
endpoint); 
- the patient’s reported daily pain, itch, burning, and tenderness severity at application site by 
VAS, time to onset and time to peak; 
- the radiodermatitis grade (investigator) by the RTOG / EORTC at V2, V3 and V4; 
- the radiation dermatitis severity by Radiation Dermatitis Severity (RDS) scoring scale 
(investigator) at V2, V3 and V4; 
- the size of the affected area at visit 2, 3 and 4, by measuring major and minor diameters; 
- the instrumental descriptive assessment of tissue vascularization and integrity and structural 
parameters change from baseline, by OCT and D-OCT, at V2, V3 and V4; 
- the patient’s evaluation on the product pleasantness for odor, consistency, spreadability, 
satisfaction by a 5-points Likert scale, at V3; 
- the patient’s adherence to treatment (assessed by patient’s diary). 
 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Safety evaluations included: 
- number, type and severity of adverse events (AEs) related to study treatment occurring 
during the study. 
- . 
 
Results of the clinical investigation  
No. 70 patients signed the informed consent forms, attended the first visit and were 
randomized to start the treatment: 35 were randomized to DermoRelizemaTM cream and 35 to 
Dexeryl®. 
In the DermoRelizemaTM cream group four patients interrupted prematurely the study (pts. ID 
01-024, 01-029, 01-050 and 01-058). 
 
In the Dexeryl® group three patients ((pts. ID 01-005, 01-025 and 01-038) withdrew before V2 
and since no data was available after V1, they were excluded from all the populations for 
analysis. Two further patients interrupted prematurely the study (pts. ID 01-030 and 01-063).  
Protocol deviations analysis defined the populations for Safety, Intention to treat (ITT) and per 
protocol (PP) analyses, as follows: 
Safety population included all patients enrolled except the 3 patients without follow-up data 
after V1: overall 67 patients, 35 in DermoRelizemaTM cream group and 32 patients in Dexeryl® 
group.  
ITT population included overall 60 patients, 31 in DermoRelizemaTM cream group and 29 
patients in Dexeryl® group.  
PP population included overall 50 patients, 27 in DermoRelizemaTM cream group and 23 
patients in Dexeryl® group.  
All patients were female and of Caucasian origin. No statically significant difference (p value = 
0.8580) was detected between groups for age (mean age 59.11 (SD=10.86) years in 
DermoRelizemaTM cream group; mean age 59.56 (SD=9.43) years in Dexeryl® group).  
The two groups were homogeneous also for vital signs and patient’s habits (drinking, smoking, 
and sport). The only differences between groups observed at baseline were in systolic blood 
pressure (p value=0.0383, mean value 125.77 (SD=14.58) in DermoRelizemaTM cream group 
and 133.59 (SD=15.70) in Dexeryl® group) and in the number of smoked cigarettes (p value= 
0.0358, mean value 4.80 (SD=2.49) in DermoRelizemaTM cream group and 13.71 (SD=7.85) 
in Dexeryl® group).  
All the patients had at least one medical history and the most frequent (apart from breast 
cancer) 
involved 
the 
cardiovascular, 
endocrine/metabolic, 
gastrointestinal 
and 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Page 8 of 59 
 
musculoskeletal systems. No noteworthy differences between treatment groups were 
detected. 
 
Primary performance endpoint 
The primary performance endpoint was the treatment success measured as the proportion of 
patients with RTOG / EORTC radiodermatitis grade ≤ 1 and > 1 at V3. In the ITT population, 
the 96.8% of patients treated with DermoRelizemaTM cream and the 96.6% of patients treated 
with Dexeryl® cream had radiodermatitis grade ≤ 1 (Table 14.2.1.1). In the PP population, 
success was observed in 100.0% of patients treated with DermoRelizemaTM cream and in 
95.7% of patients treated with Dexeryl® cream (Table 14.2.1.2). The difference between 
treatment groups was not statistically significant (ITT p value= 0.737, PP p value= 0.460). 
 
Secondary performance endpoints 
Proportion of patients with RTOG / EORTC radiodermatitis grade ≤ 1 and >1 at V2 and V4  
At V2, 27 patients (87.1%) had radiodermatitis grade ≤ 1 in DermoRelizemaTM cream group 
and 26 (92.9%) in Dexeryl® group. No difference between groups was detected (p value= 
0.8781).  
At V4, 30 patients (100.0%) had radiodermatitis grade ≤ 1 in DermoRelizemaTM cream group 
and 28 (100.0%) in Dexeryl® group (Table 14.2.2.15). 
 
Time to onset and time to peak of RISR symptoms 
Four symptoms were evaluated through VAS compiled every day by the patient: pain, itch, 
burning and tenderness at application site. At first visit all symptoms were = 0 (baseline value). 
Pain mean time to onset was 15.56 days (SD=15.58, with median 12.5 days) in 
DermoRelizemaTM cream group and 17.90 days (SD=14.05, median 17.0 days) in Dexeryl® 
group (Table 14.2.2.1). No difference between groups resulted (p value= 0.5482). Mean time 
to peak was 25.22 days (SD=14.11, with median 27.0 days) and 30.80 days (SD=12.37, with 
median 28.0 days) respectively in DermoRelizemaTM cream and Dexeryl® groups. No 
difference between groups resulted (p value= 0.2059).  
 
Itch mean time to onset was 14.42 days (SD=10.29, with median 16.0 days) in 
DermoRelizemaTM cream group and 15.79 days (SD=10.81, with median 18.0 days) in 
Dexeryl® group. No difference between groups resulted (p value= 0. 6539). Mean time to peak 
was of 26.88 days (SD=11.12, with median 27.0 days) and 27.25 days (SD=9.02, with median 
28.0 days) respectively in DermoRelizemaTM cream and Dexeryl® groups (Table 14.2.2.2). No 
difference between groups resulted (p value= 0. 8985). 
 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Burning mean time to onset was 15.53 days (SD=11.97, with median 21.0 days) in 
DermoRelizemaTM cream group and 12.65 days (SD=10.21, with median 11.0 days) in 
Dexeryl® group (Table 14.2.2.3). No difference between groups resulted (p value= 0. 5776). 
Mean to time to peak was of 24.37 days (SD=11.88, with median 28.0 days) and 27.39 days 
(SD=10.33, with median 29.0 days) respectively in DermoRelizemaTM cream and Dexeryl® 
groups. No difference between groups resulted (p value= 0. 4033). 
 
Tenderness mean time to onset was 8.00 days (SD=9.28, with median 3.0 days) in 
DermoRelizemaTM cream group and of 12.96 days (SD=9.58, with median 13.0 days) in 
Dexeryl® group (Table 14.2.2.4). A statistically significant difference between groups resulted 
(p value= 0.0290) in favor of Dexeryl®. Mean to time to peak, it was of 22.70 days (SD=10.40, 
with median 25.0 days) and 27.57 days (SD=11.48, with median 25.0 days) respectively in 
DermoRelizemaTM cream and Dexeryl® groups. No difference between groups resulted (p 
value= 0. 1388). 
 
Radiation dermatitis severity assessed by the Investigator using the RTOG/ EORTC scoring 
scale 
At first visit the skin was healthy in all patients. At V2, in DermoRelizemaTM cream group 9 
patients (29.0%) had no erythema, 18 (58.1%) had erythema grade 1, 4 (12.9%) had erythema 
grade 2 and none had erythema grade 3 (Table 14.2.2.5). In Dexeryl® group 2 patients (7.1%) 
had no erythema, 24 (85.7%) had erythema grade 1, one (3.6%) had erythema grade 2 and 
one (3.6%) had erythema grade 3. The difference between groups resulted statistically 
significant (p value= 0.0321) in favor of DermoRelizemaTM cream group.  
 
At V3, in DermoRelizemaTM cream group 16 patients (53.3%) had no erythema, 13 (43.3%) 
had erythema grade 1, one (3.3%) had erythema grade 3. In Dexeryl® group 9 patients (32.1%) 
had no erythema, 18 (64.3%) had erythema grade 1, one (3.6%) had erythema grade 3. The 
difference between groups was not statistically significant (p value= 0.1976). However, the 
major effect of DermoRelizemaTM cream was observed.  
 
At V4, in DermoRelizemaTM cream group 29 patients (96.7%) had no erythema and only one 
(3.3%) had erythema grade 1. In Dexeryl® group 25 patients (89.3%) had no erythema and 3 
(10.7%) had erythema grade 1. The difference between groups was not statistically significant 
(p value= 0.3445) but the improving effect of DermoRelizemaTM cream was observable.  
 
Radiation dermatitis severity assessed by the Investigator using the RDS scoring scale 
At first visit the skin was healthy in all patients. 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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During the study, patients split between the RDS grades; at the end of the study almost all 
patients returned to grade 0.0 (29 patients (96.7%) in DermoRelizemaTM cream group and 25 
patients (89.3%) in Dexeryl® group), only 1 patient in DermoRelizemaTM cream group had RDS 
grade equal to 0.5; 2 patients in Dexeryl® group had RDS grade equal to 0.5 and 1 patient had 
RDS grade equal to 1.0. No statically significant differences were detected at each time point 
(p values at V2, V3 and V4 were respectively 0.3169, 0.8029 and 0.4115, Table 14.2.2.6). 
 
Area affected by RIRS 
Maximum diameter 
At V2 the difference between treatment groups was statistically significant (p value=0.0384): 
mean diameter 5.35 cm (SD=4.14), median 6.00 cm in DermoRelizemaTM cream group and 
mean diameter 8.07 cm (SD=4.71), median 8.00 cm in Dexeryl® group (Table 14.2.2.7).  
At V3 and V4 the differences between treatment groups were not statistically significant (p 
values respectively 0.1837 and 0.2800).  
 
Minimum diameter 
At each timepoint no statistically significant difference was detected between groups (p 
values=0.1421, 0.3158 and 0.2880 at V2, V3 and V4).  
 
Skin damage measured by instrumental assessments 
Epidermal thickness 
Epidermal thickness decreased in both treatment groups between V1 and V2 (Table 14.2.2.8). 
Thedifference between treatment groups was not statistically significant (p value=0.6906) but 
the differences within groups were statistically significant, in both groups (p value=0.0486 and 
p value=0.0235, respectively in DermoRelizemaTM cream group and in Dexeryl® group).  
From V1 to V3 the difference between groups was not statistically significant (p value=0.6043), 
while it was only within Dexeryl® group (p value=0.0100). 
From V1 to V4 no difference was observed between groups (p value=0.6580) and within each 
group. 
 
Collagen density 
Collagen density decreased in both treatment groups between V1 and V2 (Table 14.2.2.9). 
The difference between treatment groups was not statistically significant (p value=0.2817), 
while it was within each group (p value=0.0382 in DermoRelizemaTM cream group and p 
value=0.0032 in Dexeryl® group).  

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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From V1 to V3 the difference between groups was not statistically significant (p value= 0.9826); 
the difference within DermoRelizemaTM cream group was statistically significant (p 
value=0.0191) while the difference within Dexeryl® group was not statistically significant.  
From V1 to V4 the difference between groups was not statistically significant (p value=0.4900); 
the difference within DermoRelizemaTM cream group was not statistically significant while the 
difference within Dexeryl® group was statistically significant (p value=0.0011). 
 
Collagen attenuation 
Collagen attenuation increased in both treatment groups between V1 and V2 (Table 
14.2.2.10). The difference between treatment groups (p value=0.4725) and within each group 
was not statistically significant. 
From V1 to V3 the difference between groups (p value=0.9013) and within groups was not 
statistically significant.  
From V1 to V4: the difference between groups (p value=0.7081) and within groups was not 
statistically significant. 
 
Vascular extent at 300-micron depth 
Vascular extent at 300-micron depth increased in both groups between V1 and V2 (Table 
14.2.2.11). The difference between treatment groups was not statistically significant (p 
value=0.6434); the difference within groups was statistically significant in both groups: p 
value=<0.0001 in DermoRelizemaTM cream group and p value=<0.0001 in Dexeryl® group.  
From V1 to V3 the difference between groups was not statistically significant (p value= 0.8825) 
while the difference within each group was statistically significant: p value=<0.0001 in 
DermoRelizemaTM cream group and p value=<0.0016 in Dexeryl® group.  
From V1 to V4 the difference between groups was not statistically significant (p value=0.1501); 
the difference within DermoRelizemaTM cream group was statistically significant (p 
value=0.0003) while the difference within Dexeryl® group was not. 
 
Vascular extent at 500-micron depth 
Vascular extent at 500-micron depth increased in both groups between V1 and V2 (Table 
14.2.2.12). The difference between treatment groups was not statistically significant (p 
value=0.7010) while the difference within DermoRelizemaTM cream group and within Dexeryl® 
group was statistically significant (p value=0.0010 and p value=0.0175, respectively).  
From V1 to V3 the difference between treatment groups (p value=0.5958) and within groups 
was not statistically significant.  
From V1 to V4 the difference between groups was statistically significant (p value=0.0222), in 
favor of Dexeryl® while the difference within each group was not statistically significant. 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Page 12 of 59 
 
 
Patient’s adherence to treatment 
Mean treatment compliance was 92.56 (SD=7.98), median 96.50 days in DermoRelizemaTM 
cream group and 94.43 (D=8.82) days, median 97.50 days in Dexeryl® group (Table 
14.2.2.13). The difference between groups was not statistically significant (p value=0.4846). 
Also, the average days of treatment resulted 55.32 (SD=7.43), in DermoRelizemaTM cream 
group and 55.03 (SD=10.26) in Dexeryl® group. The difference between groups was not 
statistically significant (p value=0.9008). 
 
Pleasantness of the product 
The patient’s opinion on pleasantness of the product was assessed at V3 by evaluating smell, 
texture, spreadability and satisfaction of the product (Table 14.2.2.14). 
Smell: the 66.7% of patients and the 57.1%, respectively, evaluated the smell of 
DermoRelizemaTM cream and Dexeryl® cream as “Pleasant” or “Very pleasant”. No statistical 
difference between groups (p value= 0.3439). 
Texture: the 100% of patients and the 92.9%, respectively, evaluated the texture of 
DermoRelizemaTM cream and Dexeryl® cream as “Pleasant” or “Very pleasant”. No statistical 
difference between groups (p value= 0.4297). 
Spreadability: the 100% of patients in both groups evaluated the spreadability of the products 
as “Pleasant” or “Very pleasant”. No statistical difference between groups (p value= 0.7866). 
Satisfaction: the 96.7% of patients and the 92.9%, respectively, evaluated the satisfaction with 
DermoRelizemaTM cream and Dexeryl® cream as “Pleasant” or “Very pleasant”. No statistical 
difference between groups (p value= 0.7582). 
 
Safety endpoints  
Overall, 14 adverse events were registered during the study: 6 patients in DermoRelizemaTM 
cream group had 6 adverse events and 6 patients in Dexeryl® cream group had 8 adverse 
events (Table 14.2.2.16). 
None of them was serious and only 1 adverse event (hypersensitivity at the application site), 
involving patient ID 01-049, was evaluated as possibly related to the study product. The event 
was of mild intensity and spontaneously resolved within the same day.  
Two AEs (not related to study treatment) lead to two patients premature study interruption in 
DermoRelizemaTM cream group. 
 
Conclusion 
DermoRelizemaTM cream is a non-pharmacologic, safe product for the control and 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Page 13 of 59 
 
improvement of the RISR. The use of emollient and hydrating products is confirmed as a valid 
treatment to prevent damages caused by RT and to reduce the risk of premature interruption 
of RT.  
  
Clinical investigation initiation date: 02-Nov-2020 (first subject in). 
 
Clinical investigation completion date: 16-Feb-2023 (last subject out). 
 
 
 
 
 
 
 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
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Page 14 of 59 
 
 
2. 
Introduction 
DermoRelizemaTM cream is a CE marked Class IIa Medical Device commercialized by RELIFE 
Italia Srl (Menarini Group). The product is indicated for the symptomatic treatment of dermatitis 
and erythema (Product information leaflet DermoRelizemaTM cream) and has been already 
tested in vitro, in vivo and clinically in adults, both in experimental models and in patients with 
cancer exposed to radiotherapy. It has a light texture that allows ease application on wide 
areas.   
2.1 
Rationale 
More than 14 million new cases of cancer are reported worldwide per year and with more than 
3.7 million new cases each year, cancer represents the second most important cause of 
morbidity in Europe (IARC 2010; Barton MB et al., 2014). 
Approximately 50 percent of all cancer patients can benefit from radiation therapy (RT) in the 
management of their disease. RT has the potential to improve the rates of cure of 3.5 million 
people and provide palliative relief for an additional 3.5 million people (Tyldesley S et al., 2011). 
Even if RT damages both normal cells as well as cancer cells, its use is rationally justified on 
the fact that cancer cells in general are not as efficient as normal cells in repairing the damage 
caused by radiation treatment resulting in differential cancer cell killing. The biological target 
of radiation in the cell is DNA with cell damage and death occurring as direct interaction of the 
radiation with cellular DNA and also indirect DNA damage caused by the free radicals derived 
from the ionization or excitation of the water component of the cells (Begg AC et al., 2011). 
Acute and chronic radiation-induced skin reactions (RISR) represent an inevitable 
consequence for up to 95% of people receiving RT (Porock D et al., 2002). RISRs are the 
result of interference and disruption of the physiological process of cell division and renewal 
leading to resulting in deep cell damage, local acute inflammation and overproduction of 
cytokines leading into chronic inflammation and consequent cell death (Hymes SR et al., 
2006).  
Patient-related, environmental and treatment-related factors influence the course and the 
characteristics of radiodermatitis. Patient-related, usually not or poorly modifiable, factors 
include: genetic factors, age, nutritional status, ethnicity, radio-sensitiveness, obesity and 
diabetes, skin trophism and integrity and concurrent chemotherapy. Environmental factors, 
modifiable or controllable, include mainly smoking and acute and chronic sun exposure. 
Finally, treatment-related factors include: level of energy used, duration, total dose of radiation, 
size of the treated area and somehow anatomical location (breast, head and neck and genital 
areas are more likely to cause RISRs (Porock D et al., 2002)). 

 
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The development of RISR usually occurs within few weeks after the initiation of the RT and 
persists up one month. RISR are usually characterised by objective early signs such as 
swelling, redness, pigmentation, followed dry and then mostly desquamation, epilation, 
fibrosis, and ulceration of the skin and subjective symptoms including pain, warmth, burning, 
itching, psychological distress, leading even to discontinuation of the RT. In some cases, 
complex surgical reconstruction of damaged skin may be required (Kole AJ, et al., 2017; 
Porock D et al., 2002, Naylor W at al, 2001, Cohn AB et al., 2001). 
Today there are no national guidelines for the management of RISRs but only very few widely 
recognised guidelines (Bernier J et al., 2008; Bensadoun RJ et al., 2013). Several topical or 
systemic treatments have been proposed to prevent or cure RISRs, including dressing 
(hydrogel with vegetal extracts), skincare practices (mainly based on washing practices and 
deodorant use), application of steroidal topical creams or gels, use of non-steroidal topical 
treatment and also systemic therapies including proteolytic enzymes (papain, trypsin and 
chymotrypsin), pentoxifylline, antioxidants, oral surfactant suspension or oral zinc (Chan RJ et 
al., 2014). In general, any of these treatments is far to be ideal, suffering, in various extent, 
from poor or doubtful efficacy or poor acceptability or safety problems. Also, a recent meta-
analysis on the use of topical corticosteroids in breast cancer has led to similar conclusions 
with no benefits on dermatitis and pain and with partial effects on desquamation (Haruna F et 
al., 2017). 
 
Preclinical and clinical studies with DermoRelizemaTM cream suggest that it is a safe and 
effective treatment for dermatitis and erythema. In particular, several evidences suggest that 
topical administration of HA, the most important ingredient of DermoRelizemaTM cream is 
helpful and safe in the treatment of RISR (Guida C., 2009; Leonardi MC et al., 2008; Primavera 
G et al., 2006; Liguori V et al., 1997) and in the treatment of patients with inflammatory 
conditions at the level of the vaginal and anal mucosa, following radio and chemo-therapies 
(Cosentino D et al., 2018).  
This clinical study was conducted to investigate the benefit of DermoRelizemaTM cream in the 
treatment of RISR in breast cancer patients. The restriction of the evaluation to breast cancer 
only was justified by the need to minimize the heterogeneity of anatomical sites and by the fact 
that breast cancer is the most common female malignancy. In addition, since the effects of the 
product were studied by using instrumentals assessments such as Dynamic Optical 
Coherence Tomography (D-OCT) in parallel with traditional clinical assessments, there was 
also the need to have skin areas sufficiently flat, like breast, to easily investigated with D-OCT. 

 
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The clinical investigation was regularly submitted to the competent Ethics Committee and 
notified to the Italian Ministry of Health, as for requirements in post market clinical follow-up 
studies. 
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 
The product under investigation was DermoRelizemaTM cream. It is a class IIa, CE marked 
medical device for indicated for the symptomatic treatment of dermatitis and erythema. The 
primary package was a 75 ml labelled tubes.  
 
Manufacturer: 
RELIFE Italia Srl, Via dei Sette Santi 3 - 50131 Firenze (FI) – Italy 
Trade Name: 
DermoRelizemaTM cream 
Formulation: 
Cream 
Route of administration: 
topical application on breached/compromised skin  
Composition: 
aqua, candelilla/jojoba/rice bran polyglyceryl-3 esters, glyceryl 
stearate, cetearyl alcohol, sodium stearolyl lactylate, octyldodecyl 
myristrate, caprylic/capric triglyceride, dimethicone, glycerin, 
C10-18 triglycerides, cetyl alcohol, magnesium aluminum silicate, 
betaine, xylitol, xanthan gum, chondrus crispus extract, glucose, 
caprylyl glycol, phenoxyethanol, ethylhexylglycerin, tocopheryl 
acetate, biotin, panthenol, sodium butyroyl/formoyl hyaluronate, 
disodium EDTA. 
 
The mode of action of DermoRelizemaTM cream mainly lays on physic and chemical properties 
of four of its ingredients that allow:  
a) to create and maintain a physical barrier effect with consequent hydrating and emollient 
effect and  
b) to promote physiologic antioxidant and anti-inflammatory actions.  
It was therefore expected that in case of erythema and skin damages due to RT, hydrating, 
emollient, antioxidant and soothing properties of DermoRelizemaTM cream might help to 
maintain a good integrity of the skin layers. 

 
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Glyceryl stearate ensure humidifying action based on a chemical-physical interaction with 
water molecules of the extracellular environment leading to increase in moisture retention and 
maintenance of hydration (Product information leaflet DermoRelizemaTM cream). 
Dimethicone is a silicone and oxygen polymer that works as an effective filming emollient due 
to its oil-free occlusion properties that helps to separate the skin from the surrounding 
environment, useful for generating favourable conditions for the maintenance or the restoration 
of the physiological cutaneous layer (Pacha O et al., 2012). 
Tocopherol acetate (vitamin E) is an antioxidant agent that delay or prevent oxidative damage 
caused by the presence of Reactive Oxygen Species (ROS), such as superoxides, hydrogen 
peroxides and hydroxyl radicals, highly unstable and reactive molecules, which contribute to 
the microbicidal action of phagocytes but, on the other hand, also damage DNA, cells, 
membranes and proteins leading to inflammation. UV radiations and X-rays are potent factors 
promoting the formation of ROS in the skin (Pilkington SJ et al., 2015). 
Sodium hyaluronate butyrate formate (SHBF) (0.1%) as key functional ingredient. HA is 
produced from fibroblasts and keratinocytes, is one of the main components of the extracellular 
matrix and is present in all layers of the epidermis and dermis. HA is crucial for the integrity 
and reparative processes of the skin and for wound healing. HA butyrate formate, a patented 
polymer, derived from HA. It has been demonstrated that, in addition to elasticising and 
moisturizing properties, SHBF has an anti-inflammatoryactivity caused by a decreased 
adhesion of polymorphonuclear cells and contrast to ROS (Relife, 2019) and that might be 
helpful in the minimization of signs and RISR symptoms (Guida C., 2009; Leonardi MC et al., 
2008; Primavera G et al., 2006; Liguori V et al., 1997). 
DermoRelizemaTM can be directly applied by the subject or a caregiver, there is no specific 
need of training or professional experience to use it. 
 
3.1.2 
Intended use of the investigational device 
DermoRelizemaTM cream is indicated for the symptomatic treatment of dermatitis and 
erythema. 
 
3.1.3 
Previous intended use or indication for use, if relevant 
The study is a PMCF study, therefore this paragraph is not applicable.  
 
3.1.4 
Changes to the investigational device during the clinical investigation 
or any change from the IB  
Being the present study a post-market clinical follow-up study, no IB was issued and no change 
to the investigational device occurred. 

 
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3.2 
Clinical investigation plan (CIP) 
3.2.1 
Clinical investigation objectives 
The primary objective of this clinical investigation was to evaluate the effects of 
DermoRelizemaTM cream, in the management of the progression of RT-induced skin reactions 
and toxicity using the grading system of the Radiation Therapy Oncology Group / European 
Organization for Research and Treatment of Cancer (RTOG/ EORTC) (Cox JD et at., 1995). 
The primary objective was measured at visit 3 (two weeks since last RT session). 
 
The secondary objectives of this clinical investigation were: 
- 
to evaluate the effects of DermoRelizemaTM cream in the management of the 
progression of RT-induced skin reactions and toxicity, using the grading system RTOG/ 
EORTC at RT conclusion (visit 2) and at study end (visit 4); 
- 
to evaluate the RISR symptoms management as reported by the patient through VAS 
(pain at site, itch at site, burning at site and tenderness at site), with their time to onset 
and time to peak (Schnur JB at al., 2011). 
- 
to evaluate the radiation dermatitis severity, assessed by the investigator using the 
RTOG/ EORTC scoring scale, at visit 2, 3 and 4; 
- 
to evaluate the radiation dermatitis severity, assessed by the investigator using the 
Radiation Dermatitis Severity (RDS) scoring scale (Ryan JL, 2013) at visit 2, 3 and 4;  
- 
to evaluate, the extension of the area affected by RISR, at visit 2, 3 and 4; 
- 
to evaluate the skin damage by instrumental assessments (erythema intensity 
measured with colorimetry, vascular parameters evaluated with D-OCT, tissue integrity 
and structural parameters evaluated with OCT), at visit 2, 3 and 4; 
- 
to evaluate the patient’s overall opinion on products' pleasantness assessment by a 5-
points Likert scale (e.g. odour, consistency, spreadability, patient’s satisfaction) at visit 
3; 
- 
to evaluate the patient’s adherence to treatment (assessed by patient’s diary); 
- 
to evaluate the occurrence of Adverse Events (including local reactions and systemic 
reactions).  
 
 
3.2.1.1 Clinical investigation tools description 
 
RTOG / EORTC Radiodermatitis Grading 
RTOG / EORTC and CTC/AE are universally the most used acute radiation dermatitis scoring 
systems (Cox JD et at., 1995; NCI, 2019) and they are about equivalent. The first is typically 

 
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used in Europe, the latter in the United States. As this study was conducted in Europe, the 
RTOG / EORTC radiation dermatitis scoring system was adopted.  
RD grading consists of 5 levels of severity, each with descriptive clarification, in a range 0 (no 
change) to 5 (death), as reported below. The assessment is referred to the skin area receiving 
radiotherapy and was performed for a given patient, preferably always by the same blind 
investigator at all study visits (from V1, before RT start, to V4). 
 
 
 
 
Radiation Dermatitis Severity (RDS)  
Radiation Dermatitis Severity (RDS) scoring scale was already used in published SR (Ryan 
JL, 2013; Ryan WJ at al., 2018) and non-published (ClinicalTrial.gov NCT02289365; 
NCT02556632) studies for the treatment of RISRs.  
RDS scoring scale consists of 9 levels of severity, each with descriptive clarification, in a range 
0.0 to 4.0 and increments of 0.5, as shown below. The RDS score incorporates changes in 
redness, pigment, texture and integrity of the skin. RDS scoring was performed for a given 
patient, preferably always by the same blind investigator at all study visits, from V1 (before RT 
start) to V4, in conjunction with the RTOG / EORTC radiodermatitis grading. 
 

 
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Optical Coherence Tomography (OCT) 
Optical coherence tomography (OCT) is a non-invasive imaging technology, which allows the 
evaluation, few millimeters deep, of the structure of the skin at high resolution and with no 
discernible effect on the tissue. 
Dynamic OCT (D-OCT) allows to investigate, in vivo and in 3D, the vascular architecture and 
the blood flow of the skin. In particular this technique offers the ability to visualize and to 
measure vessel morphology of inflammatory and neoplastic skin lesions (Schuh S et al., 2017). 
OCT and D-OCT were performed according to the standard practices in place at the site at all 
visits but screening visit, and were performed for a given patient, preferably always by the 
same blind investigator at all study visits (from V1, before RT start, to V4). 
The extension of the RISR affected area was measured through the major and minor diameters 
(cm). 
 
Patient’s Overall Opinion on Products’ Pleasantness  
Odour, consistency, spreadability, satisfaction for products use was assessed by the patient 
at the end of the treatment (V3) with a five points Likert scale (1=very pleasant, 2=pleasant, 
3=not pleasant nor unpleasant, 4=unpleasant, 5=absolutely unpleasant).  
Treatment Adherence 
The treatment adherence of the patient was assessed by reviewing the patient’s diary.  
The investigator was requested to review the diary and in case of missing information to ask 
the patient about treatment application not recorded in the diary. 
 
Patient’s Subjective Assessments (by VAS) 

 
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There is no “gold standard” measure of patient-rated radiodermatitis symptoms (pain, itch, 
burning and tenderness). However, the only scales that appear to be frequently used in the 
published papers are VAS (Schnur JB et al., 2011). 
Patient’s subjective symptoms (Pain, Itch, Burning and Tenderness at site) were assessed by 
mean of a standard 100 mm VAS printed in paper and administered directly to the patient by 
the investigator at V1 and included in the patient’s diary, to collect the information every day 
from the RT start to V4. Patient’s subjective assessments were performed at initial study visits 
and on the diary. 
The subject was requested to indicate at each visit her pain, itch, burning and tenderness by 
placing a vertical mark along a 100 mm VAS (Visual Analogue Scale). The rating was recorded 
as a distance from the left side of the scale (0 mm) to the mark made by the patient. 
Example:  
 
Rating (mm): |__|__|__| 
A VAS scale for each of the 4 symptoms was completed by the subject. 
 
3.2.2 
Clinical investigation design 
This was a post marketing, interventional, randomized, single-center, prospective, observer-
masked, controlled study, for the evaluation of the clinical performance and tolerability of a 
cream-based medical device (DermoRelizemaTM cream) in the management of RISR in 
women with breast cancer. 
The study aimed to recruit women with breast cancer at any stage who had undergone 
quadrantectomy, for whom hypofractionated adjuvant RT of the thoracic region was indicated. 
To better evaluate the efficacy of treatment with DermoRelizemaTM cream and for ethical 
reasons, a comparator was chosen. The comparator suggested by the principal investigator 
was Dexeryl® cream (Pierre Fabre Dermatologie), a product with a moisturizing and emollient 
action, based on glycerol, vaseline and liquid paraffin, the only reimbursed by social security 
in France (Pierre Fabre, 2019-leaflet).  
The test group only received DermoRelizemaTM cream from V1 to V3 and the control group 
received in the same fashion, Dexeryl® cream. Based on the investigator’s opinion if at visit 3 
the patient needed further treatment, this could be prolonged up to visit 4, in both treatment 
groups. 
The study treatment allocation was through randomization. Randomization was guaranteed by 
a pre-defined site-specific, computer-generated, randomization sequence. The treatments 
No pain 
 
 
 
 
 
 
 
 
 
 
Worst possible pain 
 
 
 
 
 
 
 
 
 
 

 
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were assigned to the eligible subjects in order of their presentation at the site and according 
to a randomized sequence. The investigator was not aware of the treatment to assign to a 
specific subject until the randomization, performed through randomization envelopes. Date, 
time and the responsible for the randomization for each subject was recorded. 
The design of the study did not allow a double-blind design and therefore observer-masked 
clinical assessments were performed on tests performed at V2, V3 and V4, compared to 
baseline results. The observer-masked clinical assessment involved one or more experienced 
clinicians who were trained on the protocol and related procedures and assessments but who 
were not involved in randomization and product management for individual patients 
(assignment, withdrawal, accountability) during the study and therefore were not informed 
about the treatment assigned to them. 
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 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 site only after obtaining the approval of the relevant 
Ethics Committee. 
 
DermoRelizemaTM cream is intended for topical use only. The use of DermoRelizemaTM cream 
is free from systemic adverse reactions and substantially free from topical adverse reactions, 
with exception of possible hypersensitivity to one of the components. There are no known 
interactions with potential concomitant medical treatments given in combination to 
DermoRelizemaTM cream.  
All study procedures planned by the protocol were harmless and the participation in this study 
did not imply additional risks compared to the treatment that would be anyway necessary to 
manage the complications of the RT.  
In order to control or mitigate the risks described, the study protocol:  
a) addressed specific restrictions (mainly as inclusion and exclusion criteria)  
b) required safety and efficacy verifications at study time-points  
c) prescribed instructions to the patients for the use of the study products and in general 
to minimize the risks of RISR  
d) provided study product interruption rules and the use of rescue strategies in case of 
lack of efficacy of the treatments.  
 

 
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According to current Evidence Based Medicine (EBM), the risk-benefit ratio for the participation 
in this study was not substantially different from the risk-benefit ratio of alternative treatments. 
Finally, this study did not imply the use of placebo.  
 
3.2.4 
Data quality assurance 
During each subject’s study visit, the study Investigator or designee collected and reported 
study data in the relevant subject’s chart, documenting all significant observations. 
Paper CRFs (CRFs) were used to record subject’s study data. The Investigator ensured that 
the CRFs were properly and completely filled in. The Investigator reviewed all CRFs and 
signed and dated them for each subject, verifying that the information was complete, accurate 
and correct. All the information included into the CRF were recorded from source documents.  
Queries were generated 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 site and the staff involved and monitored the site 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. 82 subjects were planned to be enrolled in this clinical investigation, selected on the basis 
of the following inclusion/exclusion criteria. 
 
Inclusion criteria 
1. 
Women who give their written consent for participation in the study and willing to 
comply with all its procedures.  
2. 
Age ≥18 years.  
3. 
Women with breast cancer at any stage who have undergone quadrantectomy, for 
whom hypofractionated adjuvant RT of the thoracic region is indicated.  
4. 
RTOG/ EORTC radiodermatitis grade equal to 0 (zero) and good cutaneous trophism, 
in the region to be treated, according to investigator’s judgement.  
5. 
Patients who are supposed will be cooperative with regard to compliance with study-
related constraints. 
 

 
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Exclusion criteria 
Vulnerable subjects  
1. 
Pregnant or lactating women (as not eligible to RT), and fertile women not following, 
at the investigators’ judgement, an adequate contraceptive method.  
2. 
Subjects incapable of giving consent.  
 
Abnormalities, previous conditions and comorbidities  
3. 
Concomitant inflammatory skin diseases in acute phase such as: atopic dermatitis, 
contact dermatitis, psoriasis, lichen planus, pityriasis rosea.  
4. 
Collagen vascular disease, vasculitis, scleroderma, dermatomyositis, or systemic 
lupus erythematosus.  
5. 
Unhealed surgical sites, breast infections.  
6. 
Bilateral breast cancer or multiple neoplasia needing other independent RT 
treatments.  
7. 
Prior breast reconstructions, implants, and/or expanders.  
8. 
Known radio-sensitivity syndromes (e.g. ataxia-telangiectasia).  
9. 
Medical history of intolerance or hypersensitivity to cosmetic products and to any 
ingredient or excipients of the study products.  
 
Past and Concomitant medications or treatments  
10. 
Previous RT in the same or for different location.  
11. 
Topical pharmacological and medical device treatments on the skin region affected 
by the RT, in the last 2 weeks prior V1.  
12. 
Systemic or topical (including inhaled or intranasal) treatments containing 
corticosteroids of any class in the 2 days preceding the enrolment.  
13. 
Photo-therapy (PUVA, UVB) in the 2 weeks preceding the enrolment and/or planned 
to be administered during the course of the study.  
 
Miscellaneous  
14. 
Participation in another clinical trial at the time of the randomization or within 28 days 
before randomization.  
15. 
Patient’s difficulties or problems, in the judgment of the investigator, in being 
compliant with study procedures and requirements, including social or mental 
constrains.  
 
3.2.1 
Treatment and treatment allocation schedule 
Patients were randomly allocated to DermoRelizemaTM cream or Dexeryl® cream. 

 
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Randomization was assured by a pre-defined site-specific, computer-generated, randomization 
sequence. The supplies were labelled with identification numbers and assigned, according to a 
randomization sequence, to the eligible subjects in order of their presentation at the sites. 
Randomization envelopes were used to assign the treatment.  
After the randomization the duration of the overall exposure to the investigational device and its 
comparator was the same. Both products were applied twice daily and therefore the total 
exposure was in the range 35-42 (± 6) days until visit 3 or 49-56 (± 6) days if the treatment 
continued until visit 4.  
In both groups the exact total amount of cream applied could not be estimated in advance, as 
the quantity of the cream was determined by the extension of the area of the affected skin. Such 
area differed subject to subject and could change over time during the study. 
For both study groups, instructions were given so that the quantity of product to be applied was 
sufficient to cover the surface of irritated skin and a small contiguous portion (to this purpose, a 
FingerTip Units (FTU) was the amount of cream squeezed from the tube and which covered 
completely the distal phalanx of an adult's index and that allowed to treat a skin area of about 
200 cm2).  
The following instructions were given to patients: 
• 
Study group DermoRelizemaTM cream. FTUs depending on the extent of the affected 
skin to treat, two times per day for 7 (±3) days prior RT until about 14 (±3) days post RT end. 
The product could be used for further 2 weeks (from V3 to V4) in case of need, according to the 
Investigator's judgment. During RT, the product was not applied within 4 hours before the 
treatment, as indicated in IFU (to avoid a bolus effect that means an increased radiation dose 
delivered to the epidermis). 
  
• 
Control group Dexeryl® cream. FTUs depending on the extent of the affected skin to 
treat, two times per day for 7 (±3) days prior RT and until about 14 (±3) days post RT end. The 
product could be used for further 2 weeks (from V3 to V4) in case of need, according to the 
Investigator's judgment. During RT, the product was not applied within 4 hours before the 
treatment.  
 
The investigational device was used according to its Instructions for Use. 
The study device and comparator were provided for the study by the Sponsor of this clinical 
investigation and shipped to the clinical site 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). 
 

 
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Daily management of the area interested by RT:  
The following recommendations were also provided to patients in order to further prevent skin 
irritation and damage (Seité S, et al 2017)  
• Skin cleansing  
◦  use liquid soap or dermatological soap bar with a pH close to 5, without perfume, plant 
or fruit extracts 
◦  dry skin delicately but meticulously.  
• Photoprotection  
◦  protect the irradiated skin zone from sun exposure  
◦  apply a sunscreen SPF 50+ with UVA/UVB protection.  
• Clothing  
◦  wear ample, soft cotton clothing  
◦  avoid wearing synthetic clothes.  
• Additional advice  
◦  use an electric razor and do not shave too close to the skin.  
◦  avoid applying products that contain alcohol (perfume, eau de toilette, ether, talcum 
powder)  
◦  avoid applying sticky plaster  
◦  avoid rubbing or scratching. 
 
3.2.2 
Concomitant medications/treatments 
Radiotherapy 
As for clinical practice at the investigational site, patients with breast carcinomas were treated 
according to a hypofractionated regimen of 2.66 Gy per day, up to a total dose of 42.56 Gy, 
through tangential portals. Patients could undergo an additional boost up to a total dose of 10 
Gy on the surgical site. Photon beams of 6 MV were used to treat this patient population. 
 
Other concomitant medications 
Any medications that were considered necessary for the subjects’ well-being and did not 
interfere with the study product could be given at the Investigator’s discretion. 
The following medications and procedures were not allowed at screening (see also exclusion 
criteria) and during the study (their use caused the exclusion the patient from the study). 
o Topical pharmacological products or medical device treatments on the skin region 
affected by the RT, in the last 2 weeks prior V1 and during the study. 
o Systemic or topical (including inhaled or intranasal) treatments containing 
corticosteroids of any class in the 2 days preceding the enrolment and during the study. 

 
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o Photo-therapy (PUVA, UVB) in the 2 weeks preceding the enrolment and/or planned to 
be administered during the course of the study. 
 
Rescue strategies 
In the event that the subject did not benefit from the use of the assigned product, she was 
allowed to use another topical or systemic treatment as suggested by the Investigator. In this 
case, the patient was considered as drop-out (not a violator). 
 
Any concomitant medication/treatment was recorded in the appropriate section of the CRF. 
 
3.2.3 
Duration of follow-up, study visits description 
Before any study specific evaluation and data collection carried out, subjects received all the 
information about the study by the Investigator and signed an informed consent form. 
Between verbal information and written informed consent the patients were given sufficient 
time. All patients were given the opportunity to ask questions and were informed of their right 
to withdraw from the investigation without prejudice. 
Patients were evaluated with regards to the inclusion and exclusion criteria that allowed their 
participation into the study. 
 
Visit 1: screening, baseline and treatment start (Day 1)  
The following activities were performed at Visit 1, after informed consent release. Visit 1, 
(Screening, randomization and treatment start) was planned about 7 (±3) days prior to RT 
start. 
The assessments and procedures approximately followed the described sequence: 

 
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- 
Evaluation of the eligibility and assessments of the inclusion / exclusion criteria. 
- 
Collection of data on: demography, lifestyle, medical history, past and concomitant 
medications. 
- 
Physical examination, including vital signs (blood pressure and heart rate) in sitting 
position. 
- 
Dermatological assessment (RTOG/ EORTC, RDS). 
- 
OCT/ D-OCT assessments. 
- 
Patient’s VAS for local pain, local itch, local burning and tenderness, to be completed 
at site. 
- 
Randomization. 
- 
Dispensing of study products, instructions for use (including definition of the area to be 
treated and instructions on standard of care to be followed). 
- 
Dispensing of patient’s diary and instructions on how to fill it in. 
Study product application (twice a day, every day) was started on Day 1 (one or two 
applications depending on the visit conclusion time). 
 
Visit 2 (Days 21-28 since RT start) – follow-up visit:  
The following activities were performed at Visit 2 (corresponding to RT completion):  
- 
New or change of any concomitant medication from previous visit.  
- 
Dermatological assessments (RTOG/ EORTC and RDS, size of affected area).  
- 
OCT/D-OCT assessments.  
- 
Diary collection and check for: VAS for local pain, local itch, local burning and 
tenderness completion.  
- 
Diary collection and check for: treatment adherence evaluation.  
- 
New diary delivery.  
- 
Safety assessments (AE/SAE/ADE/SADE/DD).  
 
Visit 3 – End of treatment (Days 35-42 ±3 since RT start):  
The following activities were done at Visit 3: 

 
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- 
New or change of any concomitant medication from previous visit.  
- 
Dermatological assessments (RTOG/ EORTC and RDS, size of affected area).  
- 
OCT/ D-OCT assessments.  
- 
Diary collection and check for: VAS for local pain, local itch, local burning and 
tenderness completion.  
- 
Diary collection and check for: treatment adherence evaluation. 
- 
New diary delivery. 
- 
Patient’s assessment on product pleasantness. 
- 
Collecting returned and/or used product. 
- 
Safety assessments (AE/SAE/ADE/SADE/DD). 
 
On the investigator’s decision, the study treatment could be concluded at this visit or further 
two-weeks treatment could be necessary. In such case, new products was delivered to 
patients. Patients maintained their treatment as assigned by the randomization process. 
 
Visit 4 – End of study (Days 49-56 ±3 since RT start):  
The following activities were done at Visit 4: 
- 
New or change of any concomitant medication from previous visit.  
- 
Changes from the previous visit in the physical examination.  
- 
Dermatological assessments (RTOG/ EORTC and RDS, size of affected area).  
- 
OCT/ D-OCT assessments.  
- 
Safety assessments (AE/SAE/ADE/SADE/DD).  
- 
Diary collection and check for: VAS for local pain, local itch, local burning and 
tenderness completion.  
- 
Diary collection and check for: treatment adherence evaluation (if study treatment 
continued).  
 
 
3.2.4 
Statistical design, analysis and justifications 
The sample size of 68 evaluable patients (34 per group) was based on the expectation that 
data generated from such sample of patients was adequate to determine a sufficiently accurate 
effect size. 
Assuming that about 9% of patients included in the test group (3 out of 34) and about one third 
(11 out of 34) in the control group experienced a grade of toxicity >1, this sample was assumed 
as sufficient to demonstrate a statistically significant difference between treatment arms using 
a Fisher’s exact test with a one-sided significance level of 0.05. According to the results of a 

 
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previous open-label non-controlled study the effects of DermoRelizemaTM cream in breast 
cancer, this objective appeared to be realistic. 
In order to reach 68 evaluable patients, considering a possible rate of 20% between violators 
and drop-out patients, it was estimated that it was necessary to enroll about 82 patients. For 
more details, please refer to the Statistical Analysis Plans (version 1.0 date 12-Jul-2022 and 
version 2.0 date 19-Sept-2022). 
 
General Issues  
The following populations were defined for this investigation: 
 
INTENT-TO-TREAT POPULATION (ITT) 
The Intention to Treat set (ITT) included all patients of the Safety population, regardless if they 
satisfied the entry criteria, who received the study treatment and performed a post-baseline 
assessment. Patients using prohibited medications and procedures were included in the ITT 
dataset for the endpoints that were not affected by the protocol violation, i.e. timepoints before 
the start date of the forbidden treatment/procedure. 
 
PER-PROTOCOL (PP) POPULATION 
The Per Protocol set (PP) included patients of the ITT population fulfilling the protocol 
requirements and schedule. Patients with major deviation(s) were excluded from the Per 
Protocol dataset. 
 
SAFETY POPULATION 
The Safety Set (SS) population included all patients who received at least one dose of the 
study product.   
 
The analysis of safety endpoints was performed on the Safety Set population (SS). Analysis 
of performance endpoints will be performed on the ITT population. The analysis of primary 
endpoint will be repeated on the Per-Protocol population. 
Data collected at Visit 1, before any study treatment administration, were considered as 
baseline values. 
Baseline characteristics of the two groups of patients were compared by Student’s t-test or 
Chi-square 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 

 
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subjects (%). Where appropriate, 95% confidence intervals for the target variables were 
estimated.  
The significance level of statistical tests was set at 0.05. 
An interim analysis was performed on reaching 34 evaluable patients. The purpose of the 
interim analysis was to obtain preliminary data on the efficacy and tolerability profile; all 
endpoints were evaluated. For the results, please refer to the Statistical Analysis Report 
(version 1.0 date 24-Oct-2022, included in Annex G) and Interim Statistical Analysis Summary 
Report (date 27-Oct-2022, included in Annex G). 
The statistical analysis was carried out using SAS 9.4 for Windows (SAS Institute Inc., Cary, 
NC, USA), as planned.  
 
Methods for Withdrawals and Missing Data 
As per protocol, evaluable patients for primary endpoint were 68. Patients who discontinued 
before Visit 2 were not evaluable for primary endpoint, therefore in order to reach 68 evaluable 
patients, considering a possible rate of 20% between violators and drop-out patients, it was 
estimated that it will be necessary to enroll about 82 patients. If these patients applied the 
treatment will be included in the Safety population. Missing data was not replaced. 
Patients who discontinued between Visit 2 and Visit 3 were considered evaluable for available 
efficacy endpoints. Missing data of primary endpoint was treated statistically according to Last 
Observation Carried Forward (LOCF) method for ITT, regardless the reason of discontinuation. 
Missing data of secondary endpoints was not replaced. 
 
Multicenter Studies Considerations 
Not applicable; this was a single-center study. 
 
Multiple Comparisons and Multiplicity 
Not applicable. 
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 (held on the 6th of April 2023, with a follow-up meeting on 18th 
May 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 

 
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continuous variables and number of observations and their percentages for categorical 
parameters.   
The analysis of demographic and baseline characteristics was performed on the Safety Set 
population. 
Performance Analysis   
Primary Performance Endpoints   
The primary endpoint was assessed at V3 by comparing, between groups, the proportion of 
patients with RTOG / EORTC radiodermatitis grade ≤ 1 and >1. One-sided Fisher’s exact test 
was applied. 
 
Secondary Performance Endpoints   
Secondary endpoints were: 
- Proportion of patients with RTOG / EORTC radiodermatitis grade ≤ 1 and >1 at V2 and 
V4 by comparison between groups and versus baseline; one-sided Fisher’s exact test was 
used for the comparison between groups. 
- Patient’s reported pain, itch, burning and tenderness at application site (VAS) severity, 
time to onset and time to peak; Student’s t-test (or Mann-Whitney U test in case of non-
normal distribution) was used for the comparison between groups. 
- RTOG / EORTC radiodermatitis grade (investigator) at V2, V3 and V4; Fisher's Exact test 
was used for the comparison between groups. 
- RDS score (investigator) at V2, V3 and V4; Fisher's Exact test was used for the 
comparison between groups. 
- Size of the affected area measured at V2, V3 and V4 (major and minor diameters were 
measured); Mann-Whitney U test was used for the comparison between groups. 
- OCT and D-OCT parameters (instrumental descriptive assessment of tissue 
vascularization and integrity and structural parameters) at V2, V3 and V4; the following 
parameters were evaluated as absolute values and as change from baseline (V1): 
o Epidermal thickness (in mm); Student’s t-test was used for the comparison 
between groups; 
o Collagen density (automatic calculation with dedicated software); Student’s t-
test (or Mann-Whitney U test in case of non-normal distribution) was used for 
the comparison between groups; 
o Collagen attenuation (automatic calculation with dedicated software); Student’s 
t-test (or Mann-Whitney U test in case of non-normal distribution) was used for 
the comparison between groups; 

 
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o Vascular extent at 300 micron depth (automatic calculation with dedicated 
software); Student’s t-test (or Mann-Whitney U test in case of non-normal 
distribution) was used for the comparison between groups; 
o Vascular extent at 500 micron depth (automatic calculation with dedicated 
software); Student’s t-test (or Mann-Whitney U test in case of non-normal 
distribution) was used for the comparison between groups. 
- Patient’s adherence to treatment (assessed by patient’s diary); Mann-Whitney U test was 
used for the comparison between groups. 
- Pleasantness of the product (Likert scale for odor, consistency, spreadability, satisfaction), 
at V3; Fisher's Exact test was used for the comparison between groups. 
. 
The exact total amount of cream could not be estimated in advance, as the quantity of the 
cream was determined by the extension of the area of the affected skin.  
In order to quantify the adherence to treatment, the Investigator recorded in the CRF the 
number of expected applications and the number of applications recorded by the patient in the 
diary for each period (Visit 1 – Visit 2, Visit 2 – Visit 3 and Visit 3 – Visit 4). 
Treatment compliance was estimated for the period Visit 1–Visit 3 if the patient ended the 
treatment at Visit 3; treatment compliance was estimated for the period Visit 1–Visit 4 if the 
patient needed to prolong the treatment up to Visit 4. Treatment compliance was estimated by 
arithmetic mean of compliances recorded in the CRF for each period. 
The patient was considered compliant to the treatment if the arithmetic mean of compliances 
was greater than or equal to 80%. 
 
Safety Evaluation 
Extent of Exposure 
After the randomization, the duration of the overall exposure to the investigational device and 
its comparator was the same. Both products are applied twice daily and therefore the total 
exposure was in the range 35-42 (± 6) days until visit 3 or 49-56 (± 6) days if the treatment 
continued until visit 4. 
Adverse Events 
All enrolled subjects receiving at least one treatment application were included in the safety 
analysis. The safety analysis included only related events (ADE/SADE/DD). 

 
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Related Adverse Events (AEs) and Adverse Device Events (ADEs) were coded using the 
version 25.0 of the Medical Dictionary for Regulatory Activities (MedDRA) to give a preferred 
term (PT) and a system/organ class term (SOC) for each event.  
The number of patients who experienced at least one study product-related AE or ADE, serious 
AE or ADE, severe related AE or ADE and the number of patients withdrawn due to related 
AE were summarized through number (N) and proportion of patients (%).  
For each SOC and preferred term, summaries were made with respect to the proportion of 
patients having at least one occurrence of that event during the study and the total number of 
events. The incidence of related AEs and ADEs was presented overall, by SOC and preferred 
term, and additional grouping by severity and relationship to the study treatment. 
Chi-square test was used for the comparison between groups. 
 
CHANGES TO THE ANALYSIS PLANNED  
Compared to what was described in the protocol and in the Statistical Analysis Plan, which 
provided the use of LOCF method also for patients who used prohibited therapies before visit 
3, the LOCF method was re-discussed: the RTOG/ EORTC evaluations of visit 2 was  carried 
forward only for the RTOG/EORTC evaluations missing at visit 3 in the ITT population.  
Furthermore, in the Statistical Analysis Plan it was estimated that it was necessary to enroll 
about 82 patients, considering a possible rate of 20% between violators and drop-out patients, 
to reach 68 evaluable patients; the enrollment was completed reaching 70 patients, of which 
only 60 patients were evaluable for primary endpoint. 
 
 
4. 
Results 
4.1 
Clinical investigation initiation date 
The clinical investigation involved one clinical site in Italy: 
▪ 
Struttura Complessa di Dermatologia, Azienda Ospedaliero-Universitaria di Modena, 
Modena University Hospital, Largo del Pozzo, 71 - 41134 Modena, Italy; PI Dr. 
Mariangela Francomano 
 
The local Ethics Committee (EC) favourable opinion was obtained on the 04-May-2020. 
Following the completion of authorization process, with contract signature (16-Jun-2020), the 
site was initiated on the 15-Jul-2020. 

 
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The first subject was enrolled on 02-Nov-2020 and in the same day the study start was notified 
to the National Competent Authority, the Italian Ministero della Salute, on the 4-Nov-2020.  
 
4.2 
Clinical investigation completion/suspension date 
The last subject in (LSI) was enrolled on the 15-Dec-2022 and the last subject out (LSO) visit 
was on 16-Feb-2023. 
The end of study (LSO) was communicated the National Competent Authority on 17-Feb-2023 
to and the clinical site was officially closed on 11-May-2023. 
 
4.3 
Disposal of subjects and investigational devices 
A total of 70 patients were enrolled in the study and all of them started the treatment.   
The enrolment phase of the study lasted about 25 months: the first subject signed the informed 
consent and performed the Visit 1 on 02-Nov-2020 and the last subject on 15-Dec-2022.   
At the Visit 1, after eligibility confirmation, subjects received the treatment to start on the same 
day (the time of the first application depending on the time of the visit). After that, three visits 
were performed: one follow-up visit (V2) between day 21 and 28, at RT conclusion, one follow-
up visit (V3) 2 weeks after RT conclusion (± 3 days) and one follow-up visit (V4) 4 weeks after 
RT conclusion (± 3 days). The study treatment could stop at V3 or be continued, if needed, 
until V4, based on Investigator’s judgement.  
The last patient completed the study on 16-Feb-2023. Overall, the study lasted about 27 
months.  
 
Figure 1. Patients’ disposition   
 
 
        
Source: Table 14.1.1 and Listing 16.2.1. 

 
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No. 70 patients signed the informed consent forms, attended the first visit and were 
randomized to start the treatment.  
 
Among the 70 randomized patients, 35 were randomized to DermoRelizemaTM cream and 35 
to Dexeryl®. 
In the DermoRelizemaTM cream group four patients interrupted prematurely the study: 
Pt. ID 01-024 needed to use a not allowed treatment; 
Pt. ID 01-029 needed to use a not allowed treatment; 
Pt. ID 01-050 interrupted RT due to suspect breast cancer relapse; 
Pt. ID 01-058 was lost to follow-up. 
 
In the Dexeryl® group three patients (pts. ID 01-005, 01-025 and 01-038) withdrew before V2: 
- 
Pt. ID  01-005 withdrew the consent; 
- 
Pt. ID  01-025 was lost to follow-up; 
- 
Pt. ID  01-038 withdrew the consent.  
These 3 patients were not included in the Safety population, because no data after the Visit 1 
was available.  
Two further patients interrupted prematurely the study: 
Pt. ID 01-030 needed to use a not allowed treatment; 
P. ID 01-063 needed to use a not allowed treatment. 
 
Table 14.1.1 and Listing 16.2.1 show the patients’ disposition and the discontinued patients. 
Based on this, 31 and 30 patients regularly completed the study respectively in the 
DermoRelizemaTM cream and Dexeryl® groups.  
 
4.4 
Subject demographics 
All patients of the Safety population (n=67, 35 patients in DermoRelizemaTM cream group and 
32 patients in Dexeryl® group) were female and of Caucasian origin. As shown in Table 14.1.3, 
no statically significant difference (p value = 0.8580) was detected between groups for age 
(mean age 59.11 (SD=10.86) years in DermoRelizemaTM cream group; mean age 59.56 
(SD=9.43) years in Dexeryl® group). Details are in Listing 16.2.4.1. 
Vital signs and patient’s habits (drinking, smoking, and sport) are reported in Table 14.1.4 and 
detailed in Listing 16.2.4.5. No statistically significant difference was evidenced between the 

 
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two groups except than for the baseline systolic blood pressure (p value=0.0383, mean value 
125.77 (SD=14.58) in DermoRelizemaTM cream group and 133.59 (SD=15.70) in Dexeryl® 
group) and for the number of smoked cigarettes (p value= 0.0358, mean value 4.80 (SD=2.49) 
in DermoRelizemaTM cream group and 13.71 (SD=7.85) in Dexeryl® group).  
The medical history, the surgical history and the physical examination of the patients are 
reported in Table 14.1.5, Table 14.1.6 and Table 14.1.7, respectively. Details are in Listings 
16.2.4.2-16.2.4.4 All the patients had at least one medical history and the most frequent (apart 
from breast cancer) involved the cardiovascular, endocrine/metabolic, gastrointestinal and 
musculoskeletal systems. No noteworthy differences between treatment groups were 
detected. 
 
4.5 
CIP compliance 
Overall, 114 protocol deviations (Table 14.1.2 and Listing 16.2.2) were registered during the 
study, no. 64 in the DermoRelizemaTM cream group and 50 in the Dexeryl® group.  
The majority of deviations regarded the treatment compliance, the incorrect or missing diary 
filling, the delay in the visits and mistakes in informed consent and privacy consent completion 
and signature.  
In both treatment groups occurred some major deviations: no. 15 and no.14 respectively in 
DermoRelizemaTM cream and in Dexeryl® groups.  
 
Protocol deviations were duly examined during the two Data Review Meetings and, once 
evaluated the impact of the deviation on the data collected, it was decided to include 8 patients 
major protocol deviations in the PP analysis (Pts. ID 01-007, 01-020, 01-032, 01-047, 01-058, 
01-068 in the DermoRelizemaTM cream group and 01-004, 01-041 in Dexeryl® group). On 
patient (ID 01-067 from Dexeryl® group) was instead excluded form PP analysis even if her 
protocol deviation was classified as minor, because the deviation met the discontinuation 
criteria drafted in the study protocol.  
 
 
4.6 
Analysis 
4.6.1 
Primary endpoint performance analysis 
Primary endpoint data was analyzed in the ITT population (overall 60 patients, 31 in 
DermoRelizemaTM cream and 29 in Dexeryl® group) and the analysis was then repeated in the 
PP population (overall 50 patients, 27 in DermoRelizemaTM cream and 23 in Dexeryl® group). 

 
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The primary endpoint was assessed at V3 by comparing, between groups, the proportion of 
patients with RTOG / EORTC radiodermatitis grade ≤ 1 and >1. One-sided Fisher’s exact test 
was applied. 
In ITT population, 30 patients (96.8%) had radiodermatitis grade ≤ 1 in DermoRelizemaTM 
cream group and 28 (96.6%) in Dexeryl® group. Only 1 patient in each group had grade >1. 
No difference between groups was detected (p value= 0.737). See table 14.2.1.1. 
In PP population, 27 patients (100.0%) had radiodermatitis grade ≤ 1 in DermoRelizemaTM 
cream group and 22 (95.7%) in Dexeryl® group. Only 1 patient in Dexeryl® group had grade 
>1. No difference between groups was detected (p value= 0.460). See table 14.2.1.2. 
Details about RTOG / EORTC radiodermatitis grade by patient are reported in Listing 16.2.6.1. 
 
4.6.2 
Secondary endpoints performance analysis 
Secondary endpoints analysis was conducted on the ITT population only. 
 
Proportion of patients with RTOG / EORTC radiodermatitis grade ≤ 1 and >1 at V2 and 
V4  
One-sided Fisher’s exact test was used for the comparison between groups (Table 14.2.2.15). 
At V2, 27 patients (87.1%) had radiodermatitis grade ≤ 1 in DermoRelizemaTM cream group 
and 26 (92.9%) in Dexeryl® group. Four patients (12.9%) in DermoRelizemaTM cream group 
had grade >1 and two (7.1%) in Dexeryl® group. No difference between groups was detected 
(p value= 0.8781).  
At V4, 30 patients (100.0%) had radiodermatitis grade ≤ 1 in DermoRelizemaTM cream group 
and 28 (100.0%) in Dexeryl® group. 
 
Details about RTOG / EORTC radiodermatitis grade by patient are reported in Listing 16.2.6.1. 
 
Time to onset and time to peak of RISR symptoms 
Time to onset and time to peak of RISR symptoms was reported daily on the diary by the 
patient through VAS. Four symptoms were evaluated: pain, itch, burning and tenderness at 
site. Student’s t-test/ Mann-Whitney U test were used for the comparison between groups. 
Student’s t-test was used when the variable was normally distributed; Mann-Whitney U test 
was used when the variable was not normally distributed. 

 
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The symptom pain (Table 14.2.2.1) had a mean time to onset of 15.56 days (SD=15.58, with 
median 12.5 days) in DermoRelizemaTM cream group and of 17.90 days (SD=14.05, median 
17.0 days) in Dexeryl® group. No difference between groups resulted (p value= 0.5482). 
With regard to mean time to peak, it was of 25.22 days (SD=14.11, with median 27.0 days) 
and of 30.80 days (SD=12.37, with median 28.0 days) respectively in DermoRelizemaTM cream 
and Dexeryl® groups. No difference between groups resulted (p value= 0.2059). 
 
The symptom itch (Table 14.2.2.2) had a mean time to onset of 14.42 days (SD=10.29, with 
median 16.0 days) in DermoRelizemaTM cream group and of 15.79 days (SD=10.81, with 
median 18.0 days) in Dexeryl® group. No difference between groups resulted (p value= 0. 
6539). 
With regard to mean time to peak, it was of 26.88 days (SD=11.12, with median 27.0 days) 
and of 27.25 days (SD=9.02, with median 28.0 days) respectively in DermoRelizemaTM cream 
and Dexeryl® groups. No difference between groups resulted (p value= 0. 8985). 
 
The symptom burning (Table 14.2.2.3) had a mean time to onset of 15.53 days (SD=11.97, 
with median 21.0 days) in DermoRelizemaTM cream group and of 12.65 days (SD=10.21, with 
median 11.0 days) in Dexeryl® group. No difference between groups resulted (p value= 0. 
5776). 
With regard to mean time to peak, it was of 24.37 days (SD=11.88, with median 28.0 days) 
and of 27.39 days (SD=10.33, with median 29.0 days) respectively in DermoRelizemaTM cream 
and Dexeryl® groups. No difference between groups resulted (p value= 0. 4033). 
 
The symptom tenderness (Table 14.2.2.4) had a mean time to onset of 8.00 days (SD=9.28, 
with median 3.0 days) in DermoRelizemaTM cream group and of 12.96 days (SD=9.58, with 
median 13.0 days) in Dexeryl® group. A statistically significant difference between groups 
resulted (p value= 0.0290) in favor of Dexeryl®. 
With regard to mean time to peak, it was of 22.70 days (SD=10.40, with median 25.0 days) 
and of 27.57 days (SD=11.48, with median 25.0 days) respectively in DermoRelizemaTM cream 
and Dexeryl® groups. No difference between groups resulted (p value= 0. 1388). 
 
Details about VAS by patient are reported in Listing 16.2.6.2 
 
Radiation dermatitis severity assessed by the Investigator using the RTOG/ EORTC 
scoring scale 
The evaluation of the radiation dermatitis severity, assessed by the Investigator according to 
the RTOG/ EORTC scoring scale, at V2, V3 and V4 was analysed by Fisher's Exact Test, for 

 
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the comparison between groups instead of Chi-square test, because Fisher's Exact Test is 
particularly suitable for small samples (Table 14.2.2.5).  
 
At V1, all patients had RTOG/ EORTC radiodermatitis grade equal to 0, as this was required 
by the clinical investigation plan: 31 patients (100%) in DermoRelizemaTM cream group and 29 
(100%) in Dexeryl® group. 
 
At V2, in DermoRelizemaTM cream group 9 patients (29.0%) had no erythema, 18 (58.1%) had 
erythema grade 1, 4 (12.9%) had erythema grade 2 and none had erythema grade 3.  
In Dexeryl® group 2 patients (7.1%) had no erythema, 24 (85.7%) had erythema grade 1, one 
(3.6%) had erythema grade 2 and one (3.6%) had erythema grade 3. 
The difference between groups resulted statistically significant (p value= 0.0321) in favor of   
DermoRelizemaTM cream group.  
 
At V3, in DermoRelizemaTM cream group 16 patients (53.3%) had no erythema, 13 (43.3%) 
had erythema grade 1, one (3.3%) had erythema grade 3.  
In Dexeryl® group 9 patients (32.1%) had no erythema, 18 (64.3%) had erythema grade 1, one 
(3.6%) had erythema grade 3. 
The difference between groups was not statistically significant (p value= 0.1976). However, 
the major effect of DermoRelizemaTM cream was observed.  
 
At V4, in DermoRelizemaTM cream group 29 patients (96.7%) had no erythema and only one 
(3.3%) had erythema grade 1.  
In Dexeryl® group 25 patients (89.3%) had no erythema and 3 (10.7%) had erythema grade 1. 
Also in this case, the difference between groups was not statistically significant (p value= 
0.3445) but the improving effect of DermoRelizemaTM cream was observable.  
 
Figure 14.2.2.5 displays the RTOG/ EORTC at each time point (including baseline, before RT 
start) in the two treatment groups. 

 
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Details about RTOG / EORTC radiodermatitis grade by patient are reported in Listing 16.2.6.1. 
 
Radiation dermatitis severity assessed by the Investigator using the Radiation 
Dermatitis Severity (RDS) scoring scale 
Fisher's Exact Test was used for the comparison between groups instead of Chi-square test, 
because Fisher's Exact Test is particularly suitable for small samples. 
 
At V1, all patients had RDS score equal to 0.0: 31 (100%) in DermoRelizemaTM cream group 
and 29 (100%) in Dexeryl® group. 
 
During the study, patients split between the RDS grades; at the end of the study almost all 
patients returned to grade 0.0 (29 patients (96.7%) in DermoRelizemaTM cream group and 25 
patients (89.3%) in Dexeryl® group), only 1 patient in DermoRelizemaTM cream group had RDS 
grade equal to 0.5; 2 patients in Dexeryl® group had RDS grade equal to 0.5 and 1 patient had 
RDS grade equal to 1.0.  
No statically significant differences were detected at each time point (p values at V2, V3 and 
V4 were respectively 0.3169, 0.8029 and 0.4115) (Table 14.2.2.6). 
Figure 14.2.2.6 shows the RDS score distribution at visits. 

 
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Details about RDS scoring scale are reported by patient in Listing 16.2.6.1. 
 
Area affected by RIRS 
The size of the area affected by dermatitis was evaluated using maximum and minimum 
diameters (cm) at each time point. The maximum and the minimum diameters were compared 
between treatment groups using Mann-Whitney U Test. 
 
Maximum diameter 
At V2 the difference between treatment groups was statistically significant (p value=0.0384) in 
favor of DermoRelizemaTM cream: mean diameter 5.35 cm (SD=4.14), median 6.00 cm in 
DermoRelizemaTM cream group and mean diameter 8.07 cm (SD=4.71), median 8.00 cm in 
Dexeryl® group.  
At V3 and V4 the differences between treatment groups were not statistically significant (p 
values respectively 0.1837 and 0.2800).  
At V3: mean diameter 4.13 cm (SD=4.61), median 3.50 cm in DermoRelizemaTM cream group 
and mean diameter 5.71 cm (SD=5.02), median 5.00 cm in Dexeryl® group.  
At V4: mean diameter 0.17 cm (SD=0.91), median 0.00 cm in DermoRelizemaTM cream group 
and mean diameter 0.61 cm (SD=1.97), median 0.00 cm in Dexeryl® group) (Table 14.2.2.7). 
 
Minimum diameter 

 
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At V2 the difference between treatment groups was not statistically significant (p 
value=0.1421). In DermoRelizemaTM cream group mean diameter was 3.65 cm (SD=3.27), 
median 4.00 cm and in Dexeryl® group mean diameter was 5.93 cm (SD=4.25), median 4.50 
cm).  
The same conclusions can be drawn at V3 and V4 (p values respectively 0.3158 and 0.2880). 
At V3 mean diameter was 2.77 cm (SD=3.22), median 2.00 cm in DermoRelizemaTM cream 
group and mean diameter was 3.86 cm (SD=3.91), median 2.50 cm in Dexeryl® group. 
At V4 mean diameter was 0.10 cm (SD=0.55), median 0.00 cm in DermoRelizemaTM cream 
group and mean diameter 0.32 cm (SD=1.19), median 0.00 cm in Dexeryl® group (Table 
14.2.2.7). 
 
Skin damage measured by instrumental assessments 
Epidermal thickness 
Epidermal thickness decreased in both treatment groups between V1 and V2. 
The mean change from V1 to V2 was -0.01 mm (SD=0.02), median 0.00 mm in 
DermoRelizemaTM cream group and -0.01 mm (0.01), median: 0.00 in Dexeryl® group. 
The difference between treatment groups was not statistically significant (p value=0.6906) but 
the differences within groups were statistically significant, in both groups (p value=0.0486 and 
p value=0.0235, respectively in DermoRelizemaTM cream group and in Dexeryl® group).  
The analysis of epidermal thickness between V1 and V3 provided similar results: mean change 
-0.01 mm (SD0.02), median -0.00 mm in DermoRelizemaTM cream group and mean change -
0.01 mm (SD=0.01), median: -0.00 mm in Dexeryl® group).  
Also in this case, the difference between groups was not statistically significant (p 
value=0.6043), while it was only within Dexeryl® group (p value=0.0100). 
The change from V1 to V4 was not different between groups (p value=0.6580) and within each 
group (p value=0.1586 and p value= 0.0679 respectively in DermoRelizemaTM cream and in 
Dexeryl® groups). 
From V1 to V4 mean change was -0.01 mm (SD=0.02), median 0.00 mm in DermoRelizemaTM 
cream group and -0.00 mm (SD=0.02), median -0.01 mm in Dexeryl® group (Table 14.2.2.8). 
Collagen density 
Collagen density decreased in both treatment groups between V1 and V2. 
Mean change was -3.44 molecule/μm2 (SD=8.83), median -4.33 molecule/μm2 in 
DermoRelizemaTM cream group and -6.10 molecule/μm2 (SD=9.97), median -4.42 
molecule/μm2 in Dexeryl® group. The difference between treatment groups was not statistically 
significant (p value=0.2817), while it was within each group (p value=0.0382 in 
DermoRelizemaTM cream group and p value=0.0032 in Dexeryl® group).  

 
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The analysis of collagen density between V1 and V3 was as follows: mean change -3.56 
molecule/μm2 (SD=7.86), median -3.78 molecule/μm2 in DermoRelizemaTM cream group and 
mean -3.51 molecule/μm2 (SD=9.56), median -3.54 molecule/μm2 in Dexeryl® group. Again, 
the difference between groups was not statistically significant (p value= 0.9826); the difference 
within DermoRelizemaTM cream group was statistically significant (p value=0.0191) while the 
difference within Dexeryl® group was not statistically significant.  
The change of collagen density between V1 and V4 was as follows: mean change -3.91 
molecule/μm2 (SD=10.79), median -2.44 molecule/μm2 in DermoRelizemaTM cream group 
and -5.67 molecule/μm2 (SD=8.20), median -7.00 molecule/μm2 in Dexeryl® group. The 
difference between groups was not statistically significant (p value=0.4900); the difference 
within DermoRelizemaTM cream group was not statistically significant while the difference 
within Dexeryl® group was statistically significant (p value=0.0011) (Table 14.2.2.9). 
 
Collagen attenuation 
Collagen attenuation increased in both treatment groups between V1 and V2: mean change 
0.000041 mm-1 (SD=0.001091), median -0.000187 mm-1 in DermoRelizemaTM cream group 
and 0.000219 mm-1 (SD=0.000746), median 0.000299 mm-1 in Dexeryl® group. The 
difference between treatment groups was not statistically significant (p value=0.4725); the 
difference within DermoRelizemaTM cream and within Dexeryl® group was not statistically 
significant, as well. 
Collagen attenuation increased in both treatment groups between V1 and V3: mean change 
0.000296 mm-1 (SD=0.000938), median 0.000186 mm-1 in DermoRelizemaTM cream group 
and 0.000269 mm-1 (SD=0.000741), median 0.000320 mm-1 in Dexeryl® group and again the 
difference between groups (p value=0.9013) and within groups was not statistically significant.  
The same conclusions can be drawn for the change of collagen attenuation between V1 and 
V4: mean change 0.000229 mm-1 (SD=0.001027), median 0.000357 mm-1 in 
DermoRelizemaTM cream group and 0.000324 mm-1 (SD=0.000872), median 0.000322 mm-
1 in Dexeryl® group. Also in this case the difference between groups (p value=0.7081) and 
within groups was not statistically significant (Table 14.2.2.10). 
 
Vascular extent at 300-micron depth 
Vascular extent at 300-micron depth increased in both groups between V1 and V2: mean 
change was 7657.65 red pixels (SD=7423.32), median 4764.00 red pixels in 
DermoRelizemaTM cream group and 10177.50 red pixels (SD=12023.13), median 6497.00 red 
pixels in Dexeryl® group. The difference between treatment groups was not statistically 
significant (p value=0.6434); the difference within groups was statistically significant in both 

 
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groups: p value=<0.0001 in DermoRelizemaTM cream group and p value=<0.0016 in Dexeryl® 
group.  
Between V1 and V3 the analysis provided similar results and again the difference between 
groups was not statistically significant (p value= 0.8825): mean change 3113.97 red pixels 
(SD=4077.80), median 2082.50 red pixels in DermoRelizemaTM cream group and 3802.11 red 
pixels (SD=6857.72), median 2418.50 red pixels in Dexeryl® group. The difference within each 
group was statistically significant: p value=<0.0001 in DermoRelizemaTM cream group and p 
value=<0.0001 in Dexeryl® group.  
Between V1 and V4 the change was as follows: 2349.40 red pixels (SD=3646.62), median 
1340.50 red pixels in DermoRelizemaTM cream group and 460.36 red pixels (SD=4175.40), 
median 794.50 red pixels in Dexeryl® group. The difference between groups was not 
statistically significant (p value=0.1501); the difference within DermoRelizemaTM cream group 
was statistically significant (p value=0.0003) while the difference within Dexeryl® group was not 
statistically significant (Table 14.2.2.11). 
 
Vascular extent at 500-micron depth 
Vascular extent at 500-micron depth increased in both groups between V1 and V2: mean 
change was 14180.65 red pixels (SD=21738.75), median 7035.00 red pixels in 
DermoRelizemaTM cream group and 11844.64 red pixels (SD=24755.39), median 8972.50 red 
pixels in Dexeryl® group. The difference between treatment groups was not statistically 
significant (p value=0.7010) while the difference within DermoRelizemaTM cream group and 
within Dexeryl® group was statistically significant (p value=0.0010 and p value=0.0175, 
respectively).  
Between V1 and V3 vascular extent at 500-micron depth increased in DermoRelizemaTM 
cream group and in Dexeryl® group: mean change 2365.23 red pixels (SD=14762.87), median 
4226.50 red pixels in DermoRelizemaTM cream group and 4995.04 red pixels (SD=22270.35), 
median 2328.50 red pixels in Dexeryl® group; the difference between treatment groups and 
within groups was not statistically significant (p value=0.5958).  
Vascular extent at 500-micron depth increased in DermoRelizemaTM cream group and 
decreased in Dexeryl® group between V1 and V4 mean 4881.43 red pixels (SD=18051.29), 
median 3598.00 red pixels in DermoRelizemaTM cream group and -5863.25 red pixels 
(SD=15602.13), median -2812.50 red pixels in Dexeryl® group. The difference between groups 
was statistically significant (p value=0.0222), in favor of Dexeryl® while the difference within 
each group was not statistically significant (Table 14.2.2.12). 
 
Patient’s adherence to treatment 

 
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Treatment compliance was summarized by the number of patients (N), mean, standard 
deviation, median, minimum, maximum. As shown in Table 14.2.2.13 treatment compliance 
was generally very high in both treatment groups: mean compliance was 92.56 (SD=7.98), 
median 96.50 days in DermoRelizemaTM cream group and 94.43 (D=8.82) days, median 97.50 
days in Dexeryl® group. The difference between groups was not statistically significant (p 
value=0.4846). 
Also, treatment days were summarized: in DermoRelizemaTM cream group the average days 
resulted 55.32 (SD=7.43), with a minimum of 42.00 days and a maximum of 71.00 days, while 
in Dexeryl® group was 55.03 (SD=10.26), with a minimum of 33.00 days and a maximum of 
78.00 days. The difference between groups was not statistically significant (p value=0.9008). 
 
Pleasantness of the product 
The patient’s opinion o pleasantness of the product was assessed at V3 by evaluating smell, 
texture, spreadability and satisfaction of the product. Each characteristic was obtained by 
means of a 5-item Likert scale; for each item the number (N) and the proportion of patients (%) 
were reported (Table 14.2.2.14). 
Smell 
10 patients (33.3%) treated with DermoRelizemaTM cream and 12 patients (42.9%) treated with 
Dexeryl® cream evaluated “Not pleasant nor unpleasant” the smell of the product. The 
remaining 20 patients (66.7%) treated with DermoRelizemaTM cream and 16 patients (57.1%) 
treated with Dexeryl® cream evaluated “Pleasant” or “Very pleasant” the smell of the product. 
The difference between groups was not statistically significant (p value=0.3439) (Table 
14.2.2.14). 
Texture 
No patients treated with DermoRelizemaTM cream evaluated “Not pleasant nor unpleasant” the 
texture of the product while 2 patients (7.1%) treated with Dexeryl® cream evaluated “Not 
pleasant nor unpleasant” the texture of the product. All 30 patients treated with 
DermoRelizemaTM cream and the remaining 26 patients (92.9%) treated with Dexeryl® cream 
evaluated “Pleasant” or “Very pleasant” the texture of the product. The difference between 
groups was not statistically significant (p value=0.4297) (Table 14.2.2.14). 
Spreadability 
All patients (30 in DermoRelizemaTM cream group and 28 in Dexeryl® group) evaluated 
“Pleasant” or “Very pleasant” the spreadability of the product. The difference between groups 
was not statistically significant (p value=0.7866) (Table 14.2.2.14). 
Satisfaction 

 
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One patient (3.3%) in DermoRelizemaTM cream group and 2 patients (7.1%) in Dexeryl® group 
evaluated “Not pleasant nor unpleasant” the satisfaction of the product. The remaining 29 
patients (96.7%) treated with DermoRelizemaTM cream and 26 patients (92.9%) treated with 
Dexeryl® cream evaluated “Pleasant” or “Very pleasant” the satisfaction of the product. The 
difference between groups was not statistically significant (p value=0.7582) (Table 14.2.2.14). 
 
4.6.3 
Safety analysis 
Safety analysis was conducted on the Safety population (i.e., 67 patients). The safety analysis 
included only related events (ADE/SADE/DD). 
Overall, 14 adverse events were registered during the study: 6 adverse events involving 6 
patients treated with DermoRelizemaTM cream (pts. ID 01-007, 01-016, 01-029, 01-032, 01-
049 and 01-050) and 8 adverse events involving 6 patients treated with Dexeryl® cream (pts. 
ID 01-010, 01-015, 01-017, 01-018, 01-041 and 01-055). 
None of them was serious and only 1 adverse event (Hypersensitivity), involving patient ID 01-
049, was possibly related to the study product, of mild intensity and spontaneously resolved 
within the same day (Table 14.3.1 and Listing 16.2.7).  
Two AEs (not related to study treatment) lead to premature study interruption: 
- 
Pt. ID 01-029 (DermoRelizemaTM cream group) needed to start a not allowed treatment 
for dermatitis reacutization; 
- 
Pt. ID 01-050 (DermoRelizemaTM cream group) had a suspected cancer relapse, 
subsequently evaluated as false positive. 
 
5. 
Discussion and overall conclusions 
Approximately 50 percent of all cancer patients can benefit from radiation therapy (RT) in the 
management of their disease. However, RT is not free from toxicity. Acute and chronic 
radiation-induced skin reactions (RISR) represent an inevitable consequence for up to 95% of 
people receiving RT. 
The development of RISR usually occurs within few weeks after the initiation of the RT and 
persists up one month. RISR are usually characterized by objective early signs such as 
swelling, redness, pigmentation, followed dry and then mostly desquamation, epilation, 
fibrosis, and ulceration of the skin and subjective symptoms including pain, warmth, burning, 
itching, psychological distress, leading even to discontinuation of the RT.  
Currently there are no unanimously recognised guidelines for the management of RISRs and 
consequently many centres develop their own prophylactic or therapeutic protocols. So far 
there is no treatment considered gold standard. 

 
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Based on DermoRelizemaTM cream ingredients properties and based on pre-clinical and 
clinical evidence, it can constitute a safe and effective treatment for dermatitis and erythema.  
In this study, DermoRelizemaTM cream was investigated in the management of RISRs in 
patients with breast cancer who started the treatment with the study product about one week 
before the start of RT, to prevent, delay and reduce the radiodermatitis onset and severity. To 
better evaluate the efficacy of DermoRelizemaTM cream and for ethical reasons, Dexeryl® 
cream was used as comparator, being a product widely used in Europe and indicated for the 
management of various types of dermatoses including atopic dermatitis, ichthyosis, xerosis 
and in case of erythema induced by radiotherapy. Furthermore, in order to collect objective 
and reliable data, the study was conducted with an observer-masked method: clinical 
assessments were performed by an experienced physician unaware of the treatment used by 
the patient.  
Finally, patients started the study treatment 1 week before RT start, to prepare the skin to 
receive RT. For this reason, baseline values/assessments were those of a healthy skin (no 
signs nor symptoms of dermatitis). 
 
The primary performance endpoint was the treatment success measured as the proportion of 
patients with RTOG / EORTC radiodermatitis grade ≤ 1 at V3 (i.e. 2 weeks after RT 
conclusion). In the ITT population, the 96.8% of patients treated with DermoRelizemaTM cream 
and the 96.6% of patients treated with Dexeryl® cream had radiodermatitis grade ≤ 1. When 
the analysis was repeated in PP population, success was observed in 100% of patients treated 
with DermoRelizemaTM cream and in 95.7% of patients treated with Dexeryl® cream. The 
difference between treatment groups was not statistically significant (Table 14.2.2.1 and Table 
14.2.2.2), however DermoRelizemaTM cream showed to be as performant as Dexeryl® or even 
slightly more. Also, at V2 (i.e. at RT conclusion) and V4 (i.e. 4 weeks after RT conclusion) both 
products showed a high success rate. In particular, at V2 the rate of success was 87.1% and 
92.9% respectively in DermoRelizemaTM cream and Dexeryl® groups, while at V4 the 100% of 
patients had radiodermatitis grade ≤ 1 in both treatment groups. 
During the study, patients experienced erythema measured through the RTOG/ EORTC grade 
(scoring from no erythema to grades 1 to 3); at V2 DermoRelizemaTM cream showed a very 
good performance in the erythema management, with a difference statistically significant 
respect to Dexeryl® (p value= 0.0321). At V2 in fact the 29.0% of patients under 
DermoRelizemaTM cream had no erythema and the 58.1% had grade 1, while only the 7.1% of 
patients under Dexeryl® had no erythema and the 85.7% had grade 1. No erythema grade 3 
was observed in DermoRelizemaTM cream group while 1 patient reached grade 3 in Dexeryl® 

 
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group. No statically significant differences were detected at other time points. At V4 almost all 
patients returned to the initial condition of “No Erythema” (Table 14.2.2.5). 
Radiation dermatitis severity was assessed by the Investigator using the Radiation RDS 
scoring scale. During the study, patients split between the RDS grades; at the end of the study 
almost all patients returned to grade 0.0. Even if no statically significant differences were 
detected at each time point between the two treatment groups, a trend in favor of 
DermoRelizemaTM cream was observable: at V2 the 25.8% of patients had grade 0.0 vs 7.1% 
in Dexeryl®, the 22.6% vs 32.1% had grade 0.5, the 35.5% vs. 43.3% had grade 1.0 (diffuse 
erythema). Grade 2 was observed in 3.2% vs 7.1% of the patients and grade 3 was only 
detected in Dexeryl® group (3.6%).  Same trend was observed at V3, with 36.7% of patients 
with grade 0.0 in DermoRelizemaTM cream group and the 28.6% in Dexeryl® group, the 43.3% 
with grade 0.5 vs the 50%. Finally, no grade 3 was observed in DermoRelizemaTM cream 
group, while it was in Dexeryl® group (3.6%) (Table 14.2.2.6). 
 
RISR symptoms were reported by patients every day by compiling VAS scales on the diary. 
Time to onset and time to peak were evaluated for 4 symptoms: pain, itch, burning and 
tenderness at RT site. Both DermoRelizemaTM cream and Dexeryl® showed similar time to 
onset and time to peak for pain (Table 14.2.2.1), itch (Table 14.2.2.2) and burning (Table 
14.2.2.3), with a trend in favor of Dexeryl® cream. Only in the tenderness time to onset resulted 
a statistically significant difference between groups, in favor of Dexeryl® (p value= 0.0290). No 
difference in the time to peak for this symptom (Table 14.2.2.4). 
 
With regards to OCT and D-OCT parameters measured during the study, a statistically 
significant result (p value=0.0384) was observed on the dimension of the area affected by 
RIRS: at V2 the mean maximum diameter of the area was 5.35 cm in DermoRelizemaTM cream 
group and 8.07 cm in Dexeryl® group. At V3 and V4 the differences between treatment groups 
were not statistically significant.  
Skin damage was instrumentally measured through the change from baseline in epidermal 
thickness, collagen density, collagen attenuation, vascular extent at 300 and 500 micron depth. 
In general, no differences were identified between the two groups, except than in Vascular 
extent at 500-micron depth between V1 and V4, where Dexeryl® resulted reduce the vascular 
extent more than to decrease more than DermoRelizemaTM cream (p value=0.0222). 
Both treatments groups had a very good compliance and patients’ evaluation on the 
peasantness of the two creams was generally very good with a slight preference for 
DermoRelizemaTM cream. 

 
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From the safety point of view, 14 adverse events were registered during the study but only one 
was related to DermoRelizemaTM cream: one case of mild and transient hypersensitivity at 
application site (Table 14.3.1 and Listing 16.2.7). No serious adverse events occurred.  
 
Based on this evidence, it can be concluded that DermoRelizemaTM cream is a non-
pharmacologic, safe product for the control and improvement of the RISR, as the comparator. 
The use of emollient and hydrating products is confirmed as a valid treatment to prevent 
damages caused by RT and to reduce the risk of premature interruption of RT.  
 
 

 
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6. 
Abbreviated terms and definitions 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical Classification System 
AOU 
Azienda Ospedaliero Universitaria 
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 
DM 
Data manager 
D-OTC 
Dynamic Optical Coherence Tomography 
DRM 
Data Review Meeting 
EC 
Ethics Committee 
EORTC 
European Organization for Research and Treatment of Cancer 
FAS 
Full Analysis Set 
FTU 
Fingertip Unit 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 679/2016 
GMP 
Good Manufacturing Practice 
ICH  
International Conference on Harmonization 
IFU 
Instructions For Use 
LLT 
Low Level Term 
LOCF 
Last Observation Carried Forward 
LSI 
Last Subject In 
LSO 
Last Subject Out 
MDD 
Medical Device Directive 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDR 
Medical Device Regulation 
ml 
Milliliters 
mm 
Millimeters  
OTC 
Over the Counter 

 
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PI 
Principal Investigator 
PMCFS 
Post Market Clinical Follow-up Study 
PP 
Per-Protocol  
PT 
Preferred Term 
QoL 
Quality of Life 
RDS 
Radiation Dermatitis Severity 
RISR 
Radiation-Induced Skin Reaction 
RT 
Radiotherapy 
RTOG 
Radiation Therapy Oncology Group 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SHBF 
Sodium Hyaluronate Butyrate Formate 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
TEWL 
Trans-Epidermal Water Loss 
USADE 
Unanticipated Serious Adverse Device Effect 
VAS 
Visual Analogue Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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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 everyone.  
One clinical site was involved and the competent EC approval was requested and obtained. 
The EC of the coordinating site (Comitato Etico Azienda Ospedaliero-Universitaria di Modena), 
evaluated this clinical investigation in the meeting of the 04-May-2020 and expressed a 
favourable opinion.  
The Italian CA (Ministry of Health) was notified about the study start on the 02-Nov-2020, after 
the first subject was enrolled on the same day. 
During the study two substantial amendments were issued: 
1. 
Amendment 1 date 02-Jan-2021 for the PI change at clinical site 
2. 
Amendment 2 date 10-Feb-2022 to specify the interim analysis process, to update 
timelines of the project and make some changes in the Sponsor’s and CRO 
personnel and some corrections in the protocol. 
The end of study (LSO) was communicated the National Competent Authority on 17-Feb-2023 
to and the clinical site was officially closed on 11-May-2023. 
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 Investigator 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 
Struttura Complessa di Dermatologia 
Azienda Ospedaliero-Universitaria di 
Modena 
Largo del Pozzo, 71 - 41134 Modena, 
Italy 
Principal Investigator 
Mariangela Francomano  
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 and Project 
Manager  
Phone: +39 010 562234 
Mobile: +39 347 4785898 
e-mail: michellini@latiscro.it  
 
Leila Romio Project Manager 
Phone: +39 010 562234 
e-mail: romio@latiscro.it  
 
 
Camilla Palermiti Head of Statistics & Data 
Management 
Phone: +39 010 562234 
e-mail: palermiti@latiscro.it  
 
 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
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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  
Statistical Analysis Report version 1.0 date 24 Oct 2022 
Interim Statistical Analysis Summary Report date 27 Oct 2022 
Statistical Analysis Report version 2.0 date 14 Jun 2023 
14. List of Tables 
14.1 Demographic data 
Table 14.1.1 Patients’ disposition (Safety population) 
Table 14.1.2 Protocol deviations (Safety population) 
Table 14.1.3 Demographic characteristics (Safety population) 
Table 14.1.4 Baseline characteristics (Safety population) 
Table 14.1.5 Medical history (Safety population) 
Table 14.1.6 Surgical history (Safety population) 
Table 14.1.7 Physical examination (Safety population) 
 
14.2 Performance data 
14.2.1 
Primary endpoints 
Table 14.2.1.1  
 Proportion 
of 
patients 
with 
RTOG 
/ 
EORTC 
radiodermatitis grade ≤ 1 and >1 at Visit 3 (ITT 
population) 
 
Table 14.2.1.2  
 Proportion 
of 
patients 
with 
RTOG 
/ 
EORTC 
radiodermatitis grade ≤ 1 and >1 at Visit 3 (PP population) 
14.2.2    Secondary endpoints 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
Page 57 of 59 
 
Table 14.2.2.1  
Time to onset and time to peak – Patient’s reported pain 
at application site (VAS) severity (ITT population) 
 
Table 14.2.2.2  
Time to onset and time to peak – Patient’s reported itch 
at application site (VAS) severity (ITT population) 
Table 14.2.2.3  
Time to onset and time to peak – Patient’s reported 
burning at application site (VAS) severity (ITT population) 
Table 14.2.2.4  
Time to onset and time to peak – Patient’s reported 
tenderness at application site (VAS) severity (ITT 
population) 
Table 14.2.2.5  
 RTOG/EORTC radiodermatitis grade (investigator) at 
each time point (Visit 1, 2, 3 and 4) (ITT population) 
Table 14.2.2.6  
RDS score (investigator) at each time point (Visit 1, 2, 3 
and 4) (ITT population) 
Table 14.2.2.7  
Size of the area (cm) affected by dermatitis (major and 
minor diameters) at each time point (Visit 2, 3 and 4) (ITT 
population) 
Table 14.2.2.8  
Change from baseline (Visit 1) to each time point (Visit 2, 
3 and 4) in the Epidermal thickness (mm) (ITT population) 
Table 14.2.2.9  
Change from baseline (Visit 1) to each time point (Visit 2, 
3 and 4) in the Collagen density (molecule/μm2 (mean)) 
(ITT population) 
Table 14.2.2.10  
Change from baseline (Visit 1) to each time point (Visit 2, 
3 and 4) in the Collagen attenuation (mm-1 (mean)) (ITT 
population) 
Table 14.2.2.11  
Change from baseline (Visit 1) to each time point (Visit 2, 
3 and 4) in the Vascular extent at 300-micron depth (red 
pixels (mean)) (ITT population) 
Table 14.2.2.12  
Change from baseline (Visit 1) to each time point (Visit 2, 
3 and 4) in the Vascular extent at 500-micron depth (red 
pixels (mean)) (ITT population) 
Table 14.2.2.13   
Patient’s adherence to treatment (ITT population) 
Table 14.2.2.14  
Pleasantness of the product (Likert scale for smell, 
texture, spreadability, satisfaction) at Visit 3 (ITT 
population) 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
Page 58 of 59 
 
Table 14.2.2.15  
Proportion 
of 
patients 
with 
RTOG 
/ 
EORTC 
radiodermatitis grade ≤ 1 and >1 at Visit 2 and Visit 4 (ITT 
population) 
Table 14.2.2.16  
 Occurrence of Adverse Event at the end of study (ITT 
population) 
 
14.3 
Safety data 
Table 14.3.1  
 
Analysis of adverse events observed (Safety population) 
Table 14.3.2  
 Display of related adverse events observed (Safety 
population) 
 
Figures included in the text  
Figure 14.2.2.5  
RTOG/EORTC at each timepoint (ITT Population) 
Figure 14.2.2.6  
RDS at each timepoint (ITT Population) 
 
16.2 List of Subject Data Listings 
Listing 16.2.1  
 
Discontinued Patients 
Listing 16.2.2  
 
Protocol Deviations 
Listing 16.2.3  
 
Patients Excluded from the Efficacy Analysis 
Listing 16.2.4.1  
 Demographic Data and Other Baseline Characteristics – 
Demography 
Listing 16.2.4.2  
 Demographic Data and Other Baseline Characteristics – 
Medical History 
Listing 16.2.4.3  
 Demographic Data and Other Baseline Characteristics – 
Surgical History 
Listing 16.2.4.4  
 Demographic Data and Other Baseline Characteristics – 
Breast Cancer Surgery 
Listing 16.2.4.5  
 Demographic Data and Other Baseline Characteristics – 
Lifestyle 
Listing 16.2.5  
 
Compliance 
Listing 16.2.6.1  
 Individual 
Efficacy 
Response 
Data 
– 
Dermatitis 
Characteristics 
Listing 16.2.6.2   
Individual Efficacy Response Data – VAS 

 
Clinical Investigation Report  
 
Study Code: RELI/19/Der-Rdt/001 
Report data: 30th June, 2023                                        Investigational Device: DermoRelizemaTM cream 
                                                                                        
 
CONFIDENTIAL 
 
Page 59 of 59 
 
Listing 16.2.6.3  
 Individual 
Efficacy 
Response 
Data 
– 
Product 
Pleasantness Evaluated By The Patient 
Listing 16.2.6.4   
Individual Efficacy Response Data – OCT and D-OCT 
Listing 16.2.7  
 
Adverse Events 
Listing 16.2.8  
 
Concomitant Medications 
Listing 16.2.9  
 
Vital Signs 
Listing 16.2.10   
Physical Examination 
Listing 16.2.11   
Radiotherapy 
 
H. AUDIT CERTIFICATE, IF APPLICABLE 
I. 
REFERENCES 
J. SUPPLEMENTARY TABLES