Open Label, Uncontrolled Clinical Investigation on the Safety and Clinical Performance of Papix Acne Scar in the Prevention and Improvement of Scars and Lesions Associated With Acne
Phase: NA
Conditions: Acne, Scars
Sponsor: Relife S.r.l.

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 1 of 63 
 
 
 
OPEN LABEL, UNCONTROLLED CLINICAL INVESTIGATION ON THE SAFETY AND 
CLINICAL PERFORMANCE OF PAPIX ACNE SCAR IN THE PREVENTION AND 
IMPROVEMENT OF SCARS AND LESIONS ASSOCIATED WITH ACNE 
 
Clinical Investigation Plan (CIP) code: ReGl/19/PAS-Acn/001 
Version 2.0, 02/07/2020 
 
 
Sponsor 
Relife S.r.l. 
 
Via dei Sette Santi 3  
50131 Florence, ITALY 
Phone: +39 055 56809345  
Fax: +39 055 56809346  
 
 
Principal Investigators 
Prof.ssa Aurora Parodi - IRCCS San Martino Genova 
Prof. Corrado Ocella -  IRCCS Gaslini Genova 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by law. In any event, persons to whom 
the information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to 
you which is indicated as privileged or confidential. 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 2 of 63 
 
Sponsor’s Approval Page 
 
 
 
Study Medical Expert:  
Martina Manni  
 
Relife S.r.l. 
 
 
Signature & Date: _________________________________________________________ 
 
 
 
 
 
Head of Scientific Affairs:  
Silvia Innocenti  
 
Relife S.r.l. 
 
 
Signature & Date: _________________________________________________________ 
 
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 3 of 63 
 
Investigator’s Approval Page 
 
I understand that all information concerning the product Papix Acne Scar supplied by Relife Srl and/or 
the CRO in connection with this study protocol are confidential information. This information include: 
CIP, Case Report Form, product documents. 
 
I understand that any change in this study protocol must be approved in writing by Relife Srl the Co-
ordinating Investigator and the Ethics Committee before implementation, except where necessary to 
eliminate apparent immediate hazard to patients. 
 
I confirm that I will conduct the study according to this protocol (except when mutually agreed to in 
writing with Relife Srl or its delegate Latis Srl, the Good Clinical Practice (GCP), the UNI EN ISO 14155, 
the Declaration of Helsinki current edition and laws and regulations in the Country where the study is 
to be conducted. 
 
I confirm that I will record and report all adverse events occurring during the study, according to this 
protocol. 
I confirm that I am informed about the need of data records retention, according to current 
regulations and that no data can be destroyed without the written consent of Relife Srl. 
I confirm that I will transfer adequate ownership of my responsibilities for the clinical investigation and 
will inform the Sponsor, in case I retire from my PI role. 
I confirm that in case the Trial Center File is stolen or anyhow damaged, I will promptly inform the 
Sponsor and declare it to the Competent Authorities. 
 
 
Principal Investigator:  
………………………. 
 
 
 
Signature & Date: _________________________________________________________ 
 
 
 
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 4 of 63 
 
Investigator’s Approval Page 
 
I understand that all information concerning the product Papix Acne Scar supplied by Relife Srl and/or 
the CRO in connection with this study protocol are confidential information. This information include: 
CIP, Case Report Form, product documents. 
 
I understand that any change in this study protocol must be approved in writing by Relife Srl the Co-
ordinating Investigator and the Ethics Committee before implementation, except where necessary to 
eliminate apparent immediate hazard to patients. 
 
I confirm that I will conduct the study according to this protocol (except when mutually agreed to in 
writing with Relife Srl or its delegate Latis Srl, the Good Clinical Practice (GCP), the UNI EN ISO 14155, 
the Declaration of Helsinki current edition and laws and regulations in the Country where the study is 
to be conducted. 
 
I confirm that I will record and report all adverse events occurring during the study, according to this 
protocol. 
I confirm that I am informed about the need of data records retention, according to current 
regulations and that no data can be destroyed without the written consent of Relife Srl. 
I confirm that I will transfer adequate ownership of my responsibilities for the clinical investigation and 
will inform the Sponsor, in case I retire from my PI role. 
I confirm that in case the Trial Center File is stolen or anyhow damaged, I will promptly inform the 
Sponsor and declare it to the Competent Authorities. 
 
 
Principal Investigator:  
………………………. 
 
 
 
Signature & Date: _________________________________________________________ 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 5 of 63 
 
General information 
 
Sponsor Representative 
Contact 
Martina Manni Study Medical Expert 
Phone. +39 055 56807184 
E-mail. mmanni@relifecompany.it 
 
Silvia Innocenti Head of Scientific Affairs 
Phone. +39 055 5680536 
E-mail. sinnocenti@relifecompany.it 
 
Manuela Chelo Clinical Trial Coordinator 
Phone. +39 055 56807111 
E-mail. mchelo@relifecompany.it  
 
Cristina Cavalli Study Safety Manager  
 
 
Phone. +39 055 56807952 / +39 342 0064647 
 
 
E-mail. ccavalli@relifecompany.it  
 
Clinical CRO 
Latis Srl 
Viale Sauli 39/5 
16121 Genova 
Phone. +39 010 562234 
Fax. +39 010 540699 
E-mail. info@latiscro.it 
 
Contacts for safety reporting 
CRO Contact for Serious 
Adverse Events (SAEs) 
Laura Michellini 
Latis Srl 
Mobile. +39 347 4785898 
Phone. +39 010 562234 
Fax. +39 010 540699 
E-mail. info@latiscro.it  
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 6 of 63 
 
Table of contents 
1. 
SYNOPSIS OF THE CLINICAL INVESTIGATION PLAN .................................................................................. 8 
2. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE ................................................. 15 
3. 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION ....................................................... 15 
4. 
RISK AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION........................... 18 
5. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION .......................................................... 18 
5.1  
PRIMARY OBJECTIVE AND ENDPOINT ............................................................................................................... 18 
5.2  
SECONDARY OBJECTIVES AND ENDPOINTS ........................................................................................................ 19 
5.3  
TOLERABILITY AND SAFETY OBJECTIVES ............................................................................................................ 20 
6. 
DESIGN OF THE CLINICAL INVESTIGATION ............................................................................................ 20 
6.1 
GENERAL .................................................................................................................................................... 20 
6.2 
INVESTIGATIONAL DEVICE .............................................................................................................................. 20 
6.2.1 
PAPIX ACNE SCAR ................................................................................................................................ 20 
6.2.1.1  
Packaging and labelling .............................................................................................................................. 21 
6.2.1.2 
Study device instructions for use ............................................................................................................... 22 
6.2.1.3 
Handling and storage ................................................................................................................................. 22 
6.2.1.4 
Study product accountability and compliance ........................................................................................... 22 
6.2.2 
Concomitant Medications/Treatments ............................................................................................... 23 
6.3 
SUBJECTS .................................................................................................................................................... 23 
6.3.1 
Inclusion criteria .................................................................................................................................. 23 
6.3.2 
Exclusion criteria ................................................................................................................................. 24 
6.4 
PROCEDURES .............................................................................................................................................. 25 
6.4.1 
Study Visits and Assessments .............................................................................................................. 25 
6.4.2 
Scar Global Assessment (SGA) ............................................................................................................ 27 
6.4.3 
Acne Investigator’s Global Assessment (IGA)...................................................................................... 27 
6.4.4 
Skin Roughness and Texture Assessment ............................................................................................ 28 
6.4.5 
Subject and Investigator Global Evaluation of Performance – Appendices 2 and 3 ........................... 28 
6.4.6 
Subject Overall Acceptability – Appendix 4 ......................................................................................... 29 
6.5 
Monitoring Plan ................................................................................................................................. 29 
7. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 30 
7.1 
SAMPLE SIZE DETERMINATION ....................................................................................................................... 30 
7.2 
DEFINITION OF STUDY POPULATIONS FOR ANALYSIS .......................................................................................... 30 
7.3 
STATISTICAL ANALYSIS .................................................................................................................................. 30 
7.3.1 
Missing Data ....................................................................................................................................... 31 
7.3.2 
Multiplicity .......................................................................................................................................... 31 
7.3.3 
Covariates, Interactions and Subgroups ............................................................................................. 31 
7.3.4 
Analysis of Demographics and Baseline Variables .............................................................................. 31 
7.3.5 
Efficacy analysis .................................................................................................................................. 31 
7.3.5.1 
Primary endpoint ....................................................................................................................................... 31 
7.3.5.2 
Secondary endpoints ................................................................................................................................. 32 
7.3.6 
Safety Analysis .................................................................................................................................... 32 
7.4 
PLANNED INTERIM ANALYSIS ......................................................................................................................... 33 
8.        DATA MANAGEMENT ........................................................................................................................ 33 
9.        AMENDMENTS TO THE CIP ................................................................................................................. 34 
10. 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ......................................................................... 34 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 7 of 63 
 
11. 
DEVICE ACCOUNTABILITY ................................................................................................................ 34 
12. 
STATEMENT OF COMPLIANCE .......................................................................................................... 35 
13. 
INFORMED CONSENT PROCESS ........................................................................................................ 36 
14. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICES DEFICIENCIES ......................................... 36 
14.1 
DEFINITIONS ............................................................................................................................................... 36 
14.2 
ADVERSE EVENT INTENSITY/CAUSALITY ........................................................................................................... 38 
14.3 ADVERSE EVENT, DEVICE DEFICIENCY, ADVERSE DEVICE EFFECT, REPORTING ............................................................... 38 
15. 
VULNERABLE POPULATION ............................................................................................................. 39 
16. 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION ................................ 39 
16.1  
STUDY DISCONTINUATION ............................................................................................................................. 39 
16.2  
STUDY INTERRUPTION .................................................................................................................................. 40 
17. 
PUBLICATION POLICY ...................................................................................................................... 40 
18. 
DATA PROTECTION REQUIREMENTS ................................................................................................ 42 
19. 
BIBLIOGRAPHY ............................................................................................................................... 49 
APPENDIX 1 .................................................................................................................................................................. 52 
Appendix 2 ................................................................................................................................................................ 54 
Appendix 3 ................................................................................................................................................................ 55 
Appendix 4 ................................................................................................................................................................ 56 
Appendix 5 ................................................................................................................................................................ 57 
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 8 of 63 
 
 
1. 
SYNOPSIS OF THE CLINICAL INVESTIGATION PLAN 
CIP Title
OPEN LABEL, UNCONTROLLED CLINICAL INVESTIGATION ON THE SAFETY 
AND CLINICAL PERFORMANCE OF PAPIX ACNE SCAR IN THE PREVENTION 
AND IMPROVEMENT OF SCARS AND LESIONS ASSOCIATED WITH ACNE 
CIP Code
ReGl/19/PAS-Acn/001
Sponsor
Relife Srl
Countries and Sites
Two recruiting clinical sites will be involved in Italy:
1. Clinica Dermatologica, IRCCS AOU San Martino – IST, Genova  
2. UOC Dermatologia e Centro Angiomi, Istituto G. Gaslini, Genova  
Indication 
Prevention and improvement of lesions and scars associated with acne. 
Study Design
Multicenter, open label, uncontrolled, single arm, post-market clinical 
follow-up study. 
Objectives 
Primary objective
To evaluate and confirm the performance of PAPIX ACNE SCAR in the 
prevention and improvement of scars in subject suffering for mild to 
moderate acne, after 4 weeks of treatment.  
 
Secondary objectives 
- To evaluate the performance of PAPIX ACNE SCAR in the prevention 
and improvement of scars after 2 and 8 weeks of treatment.  
- To evaluate the performance of PAPIX ACNE SCAR in the prevention 
of lesions after 2, 4 and 8 weeks of treatment. 
- To evaluate acne severity after 2, 4 and 8 weeks of treatment, 
through the Investigator Global Assessment. 
- To evaluate the improvement of the skin roughness after 2, 4 and 8 
weeks of treatment. 
- To evaluate the change in skin texture after 2, 4 and 8 weeks of 
treatment. 
- To evaluate the subject’s adherence to treatment by the product 
accountability. 
- To evaluate the subject’s and Investigator’s global evaluation of 
satisfaction with regards to the performance of PAPIX ACNE SCAR. 
- To evaluate the subject’s overall acceptability of the treatment. 
 
Safety objectives 
To evaluate the local and general tolerability of PAPIX ACNE SCAR. 
 
Study Treatment
PAPIX ACNE SCAR is a CE marked, Class IIa medical device. It contains 
silicones, humectant, emollient and film-forming protective ingredients. 
PAPIX ACNE SCAR is indicated in the symptomatic treatment of acneic 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 9 of 63 
 
skin while reducing the appearance of acne scars. It is a multi-action 
treatment, which treats acneic skin, improves acne scar appearance and 
lighten dark spots, prevents the development of new acne lesions and 
scars. 
Within this clinical investigation PAPIX ACNE SCAR will be applied for 
8weeks, twice daily, on the affected area. PAPIX ACNE SCAR will be used 
according to its Instructions For Use. 
 
Study Duration 
For each subject the investigation will be of 8 weeks (56 days ±3).
The recruitment phase will be of 2 months 
The overall project duration (from First Subject-In to Last Subject-Out) 
will be of 4 months 
Number of Patients 
40 planned.
Target Study 
Population 
Outpatients, ≥12 years, of both sexes, affected by mild to moderate 
acne. 
Selection Criteria
Inclusion Criteria:
1. Subject’s or parents or guardian (depending on the age of the 
subject) written informed consent obtained prior to any study-
related procedures; 
2. Male or female subjects aged ≥ 12 years of any race; 
3. Subjects with any Fitzpatrick skin phototype; 
4. Subjects with clinical diagnosis of mild to moderate acne vulgaris 
(IGA score 2 or 3) on the face;  
5. Presence of acne scars (all types included), of grade mild or 
moderate according to SGA; 
6. Subjects with cooperative attitude, able to comprehend the full 
nature and the purpose of the investigation, including possible 
risks and side effects, and able to comply with the requirements 
of the entire investigation (including ability to attend the 
planned visits according to the time limits), based on 
Investigator’s judgement. 
 
Exclusion Criteria: 
1. 
Pregnant women 
2. 
Severe acne at inclusion or any acne requiring systemic 
treatment; 
3. 
Presence of facial warts or fungal infections; 
4. 
Active dermatitis on the face, rosacea, active herpes simplex; 
5. 
Keloids presence in the area to be treated or keloids 
development during the treatment period; 
6. 
History of radiation or skin tumors in the/close to the area to 
be treated in the past 5 years; 
7. 
Laser ablative procedures within the last month; 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 10 of 63 
 
8. 
Chemical peels within the last 6 months;
9. 
Use of topical treatments like antibiotics, corticosteroids, 
benzoyl peroxide, azelaic acid, hydroxy acids and other 
antinflammatory drugs within 2 weeks; 
10. 
Use of topical retinoids within 4 weeks; 
11. 
Use of systemic corticosteroids or antibiotics in the previous 30 
days; 
12. 
Use 
of 
systemic 
spironolactone/drospirenone 
or 
immunomodulators in the previous 3 months; 
13. 
Use of oral retinoids or cyproterone acetate/chlormadinone 
acetate in the previous 6 months; 
14. 
Use of scrub, alpha hydroxy acid (AHA), skin irritant products in 
the 2 days before study treatment start; 
15. 
Subjects with any other clinically significant or unstable 
concurrent disease or skin condition or general condition that, 
in the Investigator’s opinion, might interfere with the study 
evaluations; 
16. 
Allergy, sensitivity or intolerance to the components of the 
investigational device formulations ingredients; 
17. 
Concomitant or previous participation in other interventional 
clinical study in the past 3 months; 
18. 
Subjects planning sun exposure or tanning booths or UV 
sources throughout the course of the study. In case of sun 
exposure this shall be limited and a protection cream (SPF 50+) 
shall be applied. 
 
Concomitant 
Treatments 
Non-permitted treatments:
- topical treatments like antibiotics, corticosteroids, benzoyl 
peroxide, azelaic acid, hydroxy acids, retinoids and other 
antinflammatory drugs; 
- chemical peels; 
- systemic antibiotics, corticosteroids, spironolactone/drospirenone 
or immunomodulators, oral retinoids or cyproterone 
acetate/chlormadinone acetate; 
- scrub, alpha hydroxy acid (AHA), skin irritant products; 
- laser ablative procedures; 
- radiotherapies; 
- sun exposure (unless limited and with protection cream SPF 50+) 
or tanning booths or UV sources. 
The subject will be recommended not to use any other cleanser for the 
face than Papix cleanser, that will be provided by the Investigator. 
 
Primary study 
endpoint 
Proportion of subjects with improved acne scars and marks at week 4 of 
treatment (Visit 3) and, at the same time, without any new facial acne 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 11 of 63 
 
scars with respect to baseline (Visit 1).
 
Secondary study 
endpoints 
Performance endpoints 
- Proportion of subjects with improved acne scars and marks at week 2 
and 8 of treatment (Visits 2 and 4) and, at the same time, without 
any new facial acne scars with respect to baseline (Visit 1).  
- Proportion of subjects at week 2, 4 and 8 of treatment, without any 
new facial acne lesions with respect to baseline (Visit 1).  
- Change from baseline (Visit 1) to each following time point in the 
acne severity, according to the Investigator Global Assessment. 
- Change from baseline (Visit 1) to each following time point in the skin 
roughness, on a 4-point scale from 0 (none; very smooth) to 3 
(severe; very rough). 
- Change from baseline (Visit 1) to each following time point in the skin 
texture on a 6-point scale from 0 (worse) to 5 (complete 
improvement). 
- The subject’s adherence to treatment by the product accountability; 
- The subject’s and Investigator’s global evaluation of satisfaction with 
regards to the performance of PAPIX ACNE SCAR, through a specific 
questionnaire. 
- To evaluate the subject’s overall acceptability of the treatment, 
through a specific questionnaire. 
 
Safety endpoints 
1. Number and type of adverse events (AEs) occurring during the 
study (seriousness, severity, and relation to study treatment) 
2. Local tolerability at the site of application. 
 
Sample size 
determination 
An exact binomial test with a nominal 5% two-sided significance level 
will have 80% power to detect the difference between the Null 
hypothesis proportion, π₀ of 0.5 (i.e., 50% of patients with treatment 
success) and the Alternative proportion, π₁, of 0.75 (i.e., 75% of patients 
with treatment success) when the sample size is 30 subjects. Assuming a 
possible 25% dropout rate, 40 subjects will be enrolled. 
 
Statistical Analysis –
Primary 
performance 
endpoint 
The primary objective of this clinical investigation is to evaluate and 
confirm the performance of PAPIX ACNE SCAR in terms of improvement 
of visible acne scars and marks from baseline, assessed using the 
qualitative Scar Global Assessment (SGA) by Goodman and Baron (2006) 
and the prevention of new acne scars, by count, in subject suffering for 
mild to moderate acne, after 4 weeks of treatment. 
The primary endpoint will be proportion of subjects with improved acne 
scars and marks with respect to baseline and, at the same time, without 
any new facial acne scars after 4 weeks of treatment (treatment 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 12 of 63 
 
success).
The primary endpoint will be described using number (N) and the 
proportion of patients (%). The proportion of treatment successes will 
be compared to a referent proportion (50%, Null hypothesis proportion) 
using the exact binomial test.  
Statistical Analysis –
Secondary 
performance 
endpoints 
The proportion of subjects with improved acne scars and marks with 
respect to baseline, assessed using the qualitative Scar Global 
Assessment (SGA) by Goodman and Baron (2006) and, at the same time, 
without any new facial acne scars after 2 and 8 weeks of treatment 
(treatment success) will be described using number (N) and the 
proportion of patients (%).  
The proportion of subjects without any new facial acne lesions after 2, 4 
and 8 weeks of treatment (treatment success) will be described using 
number (N) and the proportion of patients (%).  
Acne severity after 2, 4 and 8 weeks of treatment will be assessed 
through the IGA. Changes from baseline will be compared using 
Wilcoxon signed rank-sum test. 
The improvement of skin roughness will be assessed on a 4-point scale 
from 0 (none; very smooth) to 3 (severe; very rough). Changes from 
baseline will be compared using Wilcoxon signed rank-sum test. 
Skin texture change will be assessed on a 6-point scale from 0 (worse) to 
5 (complete improvement), after 4 and 8 weeks of treatment and it will 
be summarized through the number (N) and the proportion of patients 
(%) for each item. 
The number of applications will be self-reported by the subject and the 
product accountability will be summarized to assess adherence to 
treatment.  
Subject’s and Investigator’s global evaluation on performance of the 
study product obtained at the end of the study (Visit 4) by means of a 7-
items scale will be summarized through number (N) and proportion of 
patients (%) for each item.  
Subject’s evaluation of overall acceptability with treatment, obtained by 
means of a 5-item scale will be summarized through number (N) and the 
proportion of patients (%) for each item. 
Statistical Analysis –
Safety endpoints 
AEs and ADEs will be tabulated by System Organ Class (SOC) and 
Preferred Term (PT) after medical coding using the Medical Dictionary 
for Regulatory Activities (MedDRA). An overview of AEs and ADEs will be 
prepared showing the number of AEs and ADEs and the number of 
patients with any AEs or ADEs, serious AEs or ADEs, severity of AEs or 
ADEs and AEs or ADEs leading to withdrawal.  
Summary tables showing the number of patients with at least one AE or 
ADE and event counts by SOC and PT (Preferred Term) will be prepared. 
Local tolerability at the site of administration will be summarized. 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 13 of 63 
 
Population
The following populations are defined for this investigation:
•Safety analysis set (SAF): all patients enrolled who sign informed 
consent and receive at least one administration of the investigational 
device. 
•Full analysis set (FAS): all patients of the SAF who have performed the 
baseline assessments and have at least one post-baseline assessment of 
any performance endpoint.  
•Per-Protocol analysis set (PPAS): all patients of the FAS who meet all 
inclusion/exclusion criteria and who do not have any major protocol 
deviation. 
The analysis of safety endpoints will be performed in the Safety 
population (SAF). Analysis of performance endpoints will be performed 
on the FAS population. The analysis of primary endpoint will be repeated 
in the PPAS. 
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 14 of 63 
 
Table 1: Study Flow-Chart  
 
Visit 1 
Visit 2 
Visit 3 
Visit 4* 
Week 0 
Week 2 
Week 4 
Week 8 
Day 1 
Day 14 ± 3 
Day 28 ± 3 
Day 56 ± 3 
Screening Baseline 
Treatment start 
Follow-up  
visit 
Follow-up  
visit 
End of treatment 
End of study 
Written informed consent 
 
 
 
 
Demographic data 
 
 
 
 
Medical and surgical history 
 
 
 
 
Physical examination (only dermatologic)  
 
 
 
 
Inclusion and exclusion criteria 
 
 
 
 
Acne scars and lesions count 
 
 
 
 
Scars Global Assessment (SGA) 
 
 
 
 
Acne Investigator Global Assessment (IGA) 
 
 
 
 
Face photos  
 
 
 
 
Skin evaluation (roughness, texture) 
 
 
 
 
Study product dispensed 
 
 
 
 
Study product administration 
→ (twice daily) 
Study product returned 
 
 
 
 
Global evaluation of performance1 
 
 
 
 
Global evaluation of product acceptability2 
 
 
 
 
Treatment compliance 
 
 
 
 
Concomitant medications/treatments 
 
 
 
 
Local and general adverse events 
 
 
 
 
 
*Or Early termination Visit 
1To be evaluated by both the subject and the Investigator 
2To be evaluated by the subject  
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 15 of 63 
 
 
2. 
Identification and Description of the Investigational Device 
PAPIX ACNE SCAR is a silicone gel for acne lesions and scars. It is indicated to treat oily, blemished or 
acneic skin.  
With regular use, PAPIX ACNE SCAR helps to improve acne skin and visibly improves the appearance of 
acne scars, while moisturising the skin. Thanks to its formulation, the medical device helps: 
• improving acneic skin within 30 days; 
• improving visible acne scars & marks; 
• preventing the development of new acne lesions and scars.  
 
PAPIX ACNE SCAR is a CE marked medical device class IIa, manufactured by Relife Srl, that is the 
Sponsor of this post-market clinical follow-up investigation.  
The mechanism of action of the product is based on the creation of a sheer physical barrier which 
separates the skin from surrounding environment and creates favorable conditions for the 
maintenance and/or recovery of the physiological skin barrier in case of acne lesion. It improves skin 
by keeping it hydrated and works to prevent and reduce acne scars, also thanks to the presence of 
humectant/moisturizing ingredients. 
Also, PAPIX ACNE SCAR plays an important role in the control of the optimal skin pH (4.6-5.6), which 
alteration is proposed to be one of the important factors for acne development. 
In this clinical investigation PAPIX ACNE SCAR will be used for the symptomatic treatment of acneic 
skin, in the full respect of its Instructions for Use (IFU). 
 
 
3. 
Justification for the Design of the Clinical Investigation 
Acne vulgaris is a common and widespread dermatological disorder that predominantly affects 
teenagers but can also affect preadolescents and post-teen individuals. The Global Burden of Disease 
Project estimated that acne affects 9.4% of the global population, making it the eighth most prevalent 
disease worldwide [1]. 
Facial scarring is frequent skin disorder in patients with acne, especially if acne is not treated early and 
effectively [2]. Acne scars impose a considerable burden for patients, with a negative impact on their 
social life, by generating psychological pain, low self-esteem, and reduced quality of life [3].  
In general, the prevalence of scars increases with acne severity, in the presence of large lesions and 
severe inflammation, but also patients with mild acne are at risk of scarring [2].  

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 16 of 63 
 
Patients who have already developed scarring and still have active disease are at high risk for 
additional scarring. Moreover, the incidence of scarring may be increased above the background injury 
with manipulation or “picking” by the patient; these scars may be aesthetically unappealing, and if 
hypertrophic, they may be painful as well. 
Scarring can occur as a result of damage to the skin during the healing of active acne, as scar formation 
is the normal and natural response of tissue to wound healing following an injury. The majority of 
people affected by acne scars have “atrophic scars” that are associated with a loss of collagen; a 
minority show “hypertrophic scars” and “keloids” [4], that are indeed characterized by more abundant 
collagen stretched and aligned in the same plane as the epidermis [5]. 
Early treatment of active acne remains the best way to prevent or limit acne-related scarring. It is also 
imperative to ensure active acne has been treated before approaching scar treatment so as not to 
create a cycle where active lesions continue to scar in areas already addressed [6]. The choice of 
agents used to treat acne involves the integration of multiple factors such as the severity of lesions 
present, duration of disease, past and present response to therapy, and tendency for scarring and 
post-inflammatory pigmentation. Therapy is therefore tailored to the individual patient depending on 
the nature and severity of their acne. 
Oral antibiotics (e.g. tetracycline, minocycline, doxycycline, lymecycline) are highly effective for 
inflammatory acne and are widely used in clinical practice. Oral retinoids (retinol) are usually given in 
cases of severe acne, or for patients in whom inflammatory or pustular acne does not respond to other 
approaches [7]. 
Topical therapy is the standard of care for mild to moderate acne [8]. Many types of drugs are used, 
like antibiotics and retinoids, with other agents including benzoyl peroxide, salicylic acid, azelaic acid, 
and alpha-hydroxy acids [7]. Retinoids and antimicrobials such as benzoyl peroxide and antibiotics are 
the mainstay of topical acne therapy: such treatments are active at application sites, and they can 
prevent new lesions [9]. The main side effect is local irritation. 
Gels, pledgets (medication-soaked pads), washes and solutions tend to be drying and are helpful for 
oily skin. Lotions, creams and ointments are beneficial for dry, easily irritated skin. 
 
There are no general guidelines available to optimize acne scar treatment. However, there is a variety 
of therapies that may reduce the prominence of acne scars. The selection of an approach to treatment 
is based upon multiple factors such as the type and degree of acne scarring, patient preference, side 
effects, cost, and treatment availability [10].  
Surgical methods include subcutaneous incision (subcision), dermabrasion, and laser skin resurfacing. 
Among these procedures, subcision and microneedling are the most popular with good efficacy in 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 17 of 63 
 
atrophic acne scars. Laser treatments are relatively expensive and have their own risks, such as post-
inflammatory hyperpigmentation – particularly in ethnic skin – and scarring [11].  
Nonsurgical methods include subcutaneous or dermal fillers such as autologous fat, bovine collagen, 
human collagen, hyaluronic acid derivatives and polymethylmethacrylate microspheres with collagen 
[12,13]. 
Topical approaches also include chemical peels, with glycolic acid, pyruvic acid, salicylic acid and 
trichloroacetic acid [14]. Deep peels with trichloroacetic acid alone or in combination with other peels 
or microneedling can improve atrophic scars, however, repeated treatments may be necessary 
depending on the depth of the scars [15]. The side effects of peeling are generally mild and transient 
and include erythema and dryness [16]. Retinoids, specifically, have supporting sparse reports of 
treatment to keloids, hypertrophic scars and very superficial scars. The benefit is attributed to an 
increase in elasticity with dermal collagen deposition and alignment [17,18]. 
Intralesional steroids can be used for hypertrophic scars and keloids; however, steroid injections are 
painful and cutaneous use does include side effects that might include telangiectases, bruising, 
atrophy, pain, or pigmentary change [19,20]. 
Another treatment modality used for acne scarring is silicone. There is variable support to the silicone 
itself, with results more likely attributable to occlusion or hydration; silicon is inert and does not inhibit 
microbial growth, but it can act as a bacterial barrier. 
PAPIX ACNE SCAR, the medical device tested in the present post market clinical follow-up 
investigation, is a silicone gel indicated for acne lesions and scars; this acts by creating a sheer physical 
barrier that separates the skin from surrounding environment, useful for generating favorable 
conditions for the maintenance and/or recovery of the physiological cutaneous layer in case of acne 
lesion. Thus, PAPIX ACNE SCAR improves skin by keeping it hydrated and works to prevent and reduce 
acne scars, also thanks to the presence of humectant/moisturizing ingredients.  
In the acneic patient, skin care is integral in reducing and preventing lesions and maintaining healthy 
skin, especially in those patients – such as Asian – that tend to scar the most. A review done by 
Chularojanamontri et al. analyzed key components of 52 moisturizers that claim to be suitable for acne 
skin [21]. Dimethicone and glycerin were found to be the most commonly utilized agents as they can 
reduce transepidermal water loss. Hyaluronic acid and sodium pyrrolidone carboxylic acid were used 
to counterbalance the stickiness of glycerin in the same formulations. Moisturizers specifically made 
for acneic skin were found to improve the tolerability by decreasing the dryness and stinging sensation 
associated with barrier disruption, thus improving compliance to treatment [22-25]. PAPIX ACNE SCAR 
composition includes these ingredients, known to be well tolerated and useful to treat acneic skins. 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 18 of 63 
 
The present study will be conducted in Italy with the purpose of confirming and supporting the CE 
mark of PAPIX ACNE SCAR in the post-market phase. In this post-market clinical follow-up investigation 
PAPIX ACNE SCAR will be used according to its Instructions for Use (IFU), in males and females ≥ 12 
years of age, affected by mild to moderate acne.  
 
 
4. 
Risk and Benefits of the Investigational Device and Clinical Investigation 
To date a large variety of products for the treatment of acne scars are available, many of them are not 
without side effects.  
PAPIX ACNE SCAR is a medical device that is CE marked for the symptomatic treatment of acneic skin 
while reducing the appearance of acne scars. In this clinical investigation PAPIX ACNE SCAR will be 
used in adult subjects with mild to moderate acne and with oily, blemished, acneic skin, according its 
IFU.  
PAPIX ACNE SCAR will be recommended twice daily for 8 weeks maximum.  
The product’s components are known to be safe and well tolerated. PAPIX ACNE SCAR is 
dermatologically tested, non-phototoxic, paraben, fragrance and alcohol free, nickel and heavy metals 
tested. Moreover, biocompatibility assessments conducted by the manufacturer on PAPIX ACNE SCAR 
have shown no contraindications or undesirable effects, therefore no side effects are expected 
deriving from its application, when in the respect of its IFU.   
The only precaution for users is to avoid contact of the product with eyes and mucous membranes (if 
contact does occur rinse immediately with plenty of water). 
Within the clinical investigation the subject will be also provided with a specific product, Papix 
cleanser, and instructions for face cleansing, in order to further improve skin care and safety.   
No tests or invasive examinations are foreseen in this study that can increase the risk for participants.  
In the light of the above, no additional risk arising from the participation to this clinical investigation 
can be envisioned. 
 
 
5. 
Objectives and Hypotheses of the Clinical Investigation 
5.1  
Primary Objective and Endpoint 
The primary objective of this clinical investigation is to evaluate and confirm the performance of PAPIX 
ACNE SCAR in the prevention and improvement of acne scars in subject suffering for mild to moderate 
acne, after 4 weeks of treatment.  

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 19 of 63 
 
The primary endpoint will be the proportion of subjects with improved acne scars and marks with 
respect to baseline and, at the same time, without any new facial acne scars after 4 weeks of 
treatment. The improvement of acne scars and marks will be assessed as the change in the qualitative 
Scar Global Assessment (SGA) by Goodman and Baron (2006) [26] between baseline and Week 4.  The 
number of acne scars, to identify any new scars, will be assessed through the scars count and 
comparison with baseline.    
 
5.2  
Secondary Objectives and Endpoints 
The secondary objectives of this clinical investigation are: 
− To evaluate the performance of PAPIX ACNE SCAR in the prevention and improvement of acne 
scars after 2 and 8 weeks of treatment. This endpoint will be assessed as the proportion of 
subjects with improved acne scars and marks with respect to baseline and, at the same time, 
without any new facial acne scars after 2 and 8 weeks of treatment. The improvement of acne 
scars and marks will be assessed as the change in the qualitative Scar Global Assessment (SGA) 
by Goodman and Baron (2006) [26] between baseline and Week 2 and 8.  The number of acne 
scars, to identify any new scars, will be assessed through the scars count and comparison with 
baseline.   
− To evaluate the performance of PAPIX ACNE SCAR in the prevention of acne lesions after 2, 4 
and 8 weeks of treatment. The number of acne lesions, to identify any new lesions, will be 
assessed through the lesions count and comparison with baseline.    
− To evaluate the improvement in acne severity after 2, 4 and 8 weeks of treatment, through the 
Investigator Global Assessment, ranging from 0 (clear; clear skin with no lesions) to 4 (severe; 
many inflammatory and non- inflammatory lesions). 
− To evaluate the improvement of the skin roughness on a 4-point scale from 0 (none; very 
smooth) to 3 (severe; very rough) after 2, 4 and 8 weeks of treatment. 
− To evaluate the improvement of the skin texture on a 6-point scale from 0 (worse) to 5 
(complete improvement), after 2, 4 and 8 weeks of treatment. 
− To evaluate the subject’s adherence to treatment by the product accountability and 
information asked to the subject. 
− To evaluate the subject’s and Investigator’s global evaluation of satisfaction with regards to 
the performance of PAPIX ACNE SCAR, through a specific questionnaire. 
− To evaluate the subject’s overall acceptability of the treatment, through a specific 
questionnaire. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 20 of 63 
 
 
5.3  
Tolerability and Safety Objectives 
To evaluate the local and general tolerability of PAPIX ACNE SCAR. 
Adverse events and adverse reactions will be recorded and evaluated. 
 
 
6. 
Design of the Clinical Investigation 
6.1 
General 
This is a multicenter, open label, uncontrolled, post-market clinical follow-up investigation. 
All the subjects will be allocated to the following treatment group: 
- 
PAPIX ACNE SCAR, topically applied twice a day for 8 weeks. 
The subject will start treatment on the first day of study and will go on until 8 weeks after the first 
administration. 
Each subject for whom written consent is obtained will be assigned a five-digit screening code, 
consisting of the site code (01 or 02) and a progressive number within the site: for example the first 
subject screened at site 01 will be assigned the code 01-001, the second one 01-002 etc. 
All screened subjects will receive the code irrespective of whether or not they will receive the 
treatment. If a subject discontinues from the study at any time, the code will not be re-used. 
All subjects who will sign the informed consent and receive the screening code will be entered into a 
Subject’s Register, containing the name and surname of the patients and their Screening numbers. The 
Subject’s Register will be accessible for source data verification but will be preserved only at clinical 
site. 
Once eligibility of a patient is established (see Inclusion/Exclusion Criteria) the study treatment will be 
assigned. 
The Investigator will keep record of all enrolled patients in the Subject’s Screening/Enrolment Log: the 
subject screening number, the date of consent, the treatment assigned to the patient, if applicable, or 
the reason for not actively entering the study will be recorded. 
 
6.2 
Investigational device  
6.2.1 PAPIX ACNE SCAR 
The product under investigation is PAPIX ACNE SCAR. 
 
Manufacturer:   
 
Relife Srl, Via dei Sette Santi 3 - 50131 Firenze (FI) - Italy 
Formattato: Italiano (Italia)

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 21 of 63 
 
Device Name:   
 
PAPIX ACNE SCAR 
Formulation:   
 
silicone gel  
Route of administration:  
topical application on breached/compromised skin (body surface) 
 
Composition:   
 
Aqua, cyclopentasiloxane, dimethicone, glycerin, butylene glycol, 
polyacrylate-13, polysilicone-11, polyisobutene, Octyldodecyl lactate, 
Niacinamide, ethylexylglycerin, hydroxypropylmethylcellulose, citric 
acid, disodium phosphate, lactic acid, sodium hydroxide, polysorbate 
20, malic acid, glycoproteins, tocopheryl aceate, xanthan gum, taurine, 
zinc gluconate, hexamidine diisethionate, decyl glucoside, hydrolyzed 
glycosamminoglycans, sodium hyaluronate, caprylyl glycol, Hexylene 
glycol, phenoxyethanol, copper gluconate, sodium PCA. 
 It does not contain fragrance, parabens and alcohol. It is heavy metals 
tested. 
 
PAPIX ACNE SCAR is a CE marked, Class IIa medical device. It contains silicones, humectant, emollient 
and film-forming protective ingredients. PAPIX ACNE SCAR is indicated in the symptomatic treatment of 
acneic skin while reducing the appearance of acne scars. It is a multi-action treatment, which it treats 
acneic skin, improves acne scar appearance and lighten dark spots, prevents the development of new 
acne lesions and scars. 
PAPIX ACNE SCAR creates a sheer physical barrier that separates the skin from surrounding 
environment, useful for generating favorable conditions for the maintenance and/or recovery of the 
physiological cutaneous layer in case of acne lesion. It improves skin by keeping it hydrated. It works to 
prevent and reduce acne scars. 
 
6.2.1.1  Packaging and labelling 
PAPIX ACNE SCAR will be provided for the study by the Sponsor of this clinical investigation. 
The study product shipment to the study site will be done only after the completion of all Ethics and 
Administrative procedures. 
The product will be labeled as experimental treatment in accordance with applicable Good 
Manufacturing Practice (GMP, Annex 13). 
The primary package is a tube containing 7 ml of gel. Subjects will receive a total of no. 6 tubes.  
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 22 of 63 
 
6.2.1.2 Study device instructions for use 
Patients will be instructed to use PAPIX ACNE SCAR applied twice a day, in the morning and in the 
evening before bedtime, and massaged gently into the skin until absorbed. PAPIX ACNE SCAR shall be 
applied only on the lesions, where possible. The treatment duration will be of 8 weeks. 
 
6.2.1.3 Handling and storage 
It is the Investigator/Institution’s responsibility to set up a system for handling the clinical investigation 
treatment, so as to ensure that:  
• 
deliveries of product supply from the Sponsor are correctly received 
• 
products are handled and stored safely and properly in a secured area 
• 
treatments are only dispensed to study subjects in accordance with the clinical investigation plan 
• 
any unused, used, partially used product is returned to the Investigator (including empty tubes). 
The study product shall be carefully stored at the study site, in a safe area and separately from other 
devices/drugs/products. It shall be stored in a dry and cool place, away from direct sunlight or heat. 
The pharmacist and/or the Investigator shall maintain records of the study products receipt by the 
study site and an updated inventory of the study product.  
Treatments will be dispensed to the subjects enrolled in this clinical investigation only by authorized 
personnel.  
After study conclusion, all unused study product shall be returned to the Sponsor or destroyed at site 
after written Sponsor approval. 
 
6.2.1.4 Study product accountability and compliance 
The Investigator is responsible for ensuring the accountability of the study product. 
Accountability records will include: 
• 
confirmation of product delivery and receipt to/at the clinical site 
• 
records concerning the product delivery to each subject and the return from each subject 
• 
the return to the Sponsor or alternative disposition of unused products. 
The Investigator should maintain records that adequately document: 
• 
that the subjects were provided with the quantities specified by the clinical investigation 
plan/amendment(s) 
• 
that all study products provided by the Sponsor were fully reconciled. 
Unused products must not be discarded or used for any purpose other than the present clinical 
investigation.  
Products that have been allocated to one subject must not be re-dispensed to a different subject.  

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 23 of 63 
 
Subjects will be reminded of the importance of strictly complying with the instructions received from 
the Investigator and to return all unused treatment or empty tubes to the Investigator.  
Compliance to the treatment will be visually checked by the Investigators when the subjects are 
bringing back to the site the used/unused products.  
 
6.2.2 Concomitant Medications/Treatments 
Any medications (other than those excluded by the clinical investigation plan) that were considered 
necessary for the patients’ well-being and do not interfere with the study product can be given at the 
Investigator’s discretion. 
According to exclusion criteria, the following prior and concomitant medications are prohibited: 
 
topical treatments like antibiotics, corticosteroids, benzoyl peroxide, azelaic acid, hydroxy 
acids, retinoids and other antinflammatory drugs 
 
chemical peels 
 
systemic antibiotics, corticosteroids, spironolactone/drospirenone or immunomodulators, oral 
retinoids or cyproterone acetate/chlormadinone acetate; 
 
scrub, alpha hydroxy acid (AHA), skin irritant products; 
 
laser ablative procedures 
 
radiotherapies 
 
sun exposure (unless limited and with the use of protection cream SPF 50+) or tanning booths 
or UV sources. 
The subject will be recommended not to use any other cleanser for the face than Papix cleanser, 
provided by the Investigator. 
Any concomitant medication/treatment shall be recorded in the appropriate section of the CRF. 
 
6.3 
Subjects 
In this clinical investigation 40 subjects will be enrolled fulfilling the following eligibility criteria. 
 
6.3.1 Inclusion criteria 
1. Subject’s or parents or guardian (depending on the age of the subject) written informed 
consent obtained prior to any study-related procedures; 
2. Male or female subjects aged ≥ 12 years of any race; 
3. Subjects with any Fitzpatrick skin phototype; 
4. Subjects with clinical diagnosis of mild to moderate acne vulgaris (IGA score 2 or 3) on the face  
5. Presence of acne scars (all types included), of grade mild or moderate according to SGA; 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 24 of 63 
 
6. Subjects with cooperative attitude, able to comprehend the full nature and the purpose of the 
investigation, including possible risks and side effects, and able to comply with the 
requirements of the entire investigation (including ability to attend the planned visits 
according to the time limits), based on Investigator’s judgement. 
 
6.3.2 Exclusion criteria 
1. Pregnant women 
2. Severe acne at inclusion or any acne requiring systemic treatment; 
3. Presence of facial warts or fungal infections; 
4. Active dermatitis on the face, rosacea, active herpes simplex; 
5. Keloids presence in the area to be treated or keloids development during the treatment 
period; 
6. History of radiation or skin tumors in the/close to the area to be treated in the past 5 years; 
7. Laser ablative procedures within the last month; 
8. Chemical peels within the last 6 months; 
9. Use of topical treatments like antibiotics, corticosteroids, benzoyl peroxide, azelaic acid, 
hydroxy acids and other anti-inflammatory drugs within 2 weeks; 
10. Use of topical retinoids within 4 weeks; 
11. Use of systemic corticosteroids or antibiotics in the previous 30 days; 
12. Use of systemic spironolactone/drospirenone or immunomodulators in the previous 3 months; 
13. Use of oral retinoids or cyproterone acetate/chlormadinone acetate in the previous 6 months; 
14. Use of scrub, alpha hydroxy acid (AHA), skin irritant products in the 2 days before study 
treatment start; 
15. Subjects with any other clinically significant or unstable concurrent disease or skin condition or 
general condition that, in the Investigator’s opinion, might interfere with the study 
evaluations; 
16. Allergy, sensitivity or intolerance to the components of the investigational device formulations 
ingredients; 
17. Concomitant or previous participation in other interventional clinical study in the past 3 
months; 
18. Subjects planning sun exposure or tanning booths or UV sources throughout the course of the 
study. In case of sun exposure this shall be limited and a protection cream (SPF 50+) shall be 
applied. 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 25 of 63 
 
6.4 
Procedures 
6.4.1 Study Visits and Assessments 
Visit 1 screening – baseline- treatment start (day 1):  
Subjects will be evaluated with regard to the inclusion and exclusion criteria that will allow their 
participation into the study. 
Before any study specific evaluation is carried out, subjects will receive all the information about the 
study by the Investigators and will sign an informed consent form. In the case of minors, the informed 
consent form shall be signed by the parents or the guardian.  
 
The following activities will be performed:  
 
Collection of information about demography  
 
Medical and surgical history  
 
Acne medical history (duration, previous treatments)  
 
Physical examination (only dermatologic)   
 
Face cutaneous examination:  
o type of skin (dry/normal/oily) 
o site of acne lesions (on the face) and count 
o acne scars count  
o acne scars global assessment by the SGA 
o acne global assessment by IGA 
o roughness and skin texture evaluations 
 
Photographs of the face 
 
Previous (in the 6 months before) and concomitant medications/treatments 
recording  
 
Inclusion/exclusion criteria assessment 
 
Study product delivery to subject and instructions on how to use it 
 
Recommendations for face cleaning to follow.  
 
Recommendations for face cleaning to follow: throughout the study subjects will be required to avoid 
soap and use only the product Papix cleanser for their face. The product will be provided by the 
Sponsor of the study. No other cleanser other than the product provided by the Investigator will be 
permitted. 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 26 of 63 
 
PAPIX ACNE SCAR application: apply twice a day for 8 weeks, 2 FTU (finger tip units) in the morning 
and in 2 FTU the evening before bedtime, on the face, and massaged gently into the skin until 
absorbed.  
   
Visits 2 and 3 – follow-up (Day 14 ± 3 and 28 ± 3, respectively):  
The following activities will be done at visit 2 and 3: 
 
Face cutaneous examination:  
o acne scars and lesions count  
o acne scars global assessment by the SGA 
o acne global assessment by IGA 
o roughness and skin texture evaluations 
 
Photographs of the face 
 
Changes in concomitant medications/treatments recording  
 
Study product collection and new delivery to subject (only at visit 3)  
 
Treatment adherence check with the subject 
 
Recommendations for face cleaning to follow  
 
Adverse events (occurred since previous visit) recording. 
 
Visit 4 – End of treatment and end of study (Day 56 ±3):  
The following activities will be done at visit 4: 
 
Brief physical examination (dermatologic physical examination)  
 
Face cutaneous examination:  
o acne scars and lesions count  
o acne scars global assessment by the SGA 
o acne global assessment by IGA 
o roughness and skin texture evaluations 
 
Photographs of the face 
 
Changes in concomitant medications/treatments recording  
 
Study product collection  
 
Treatment adherence check with the subject 
 
Adverse events (occurred since previous visit) recording 
 
Subject global evaluation of performance  
 
Investigator global evaluation of performance  

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 27 of 63 
 
 
Subject global acceptability evaluation on the study product. 
 
6.4.2 Scar Global Assessment (SGA)  
The qualitative scarring grading system proposed by Goodman and Baron [26] is simple and universally 
applicable. According to this classification, four different grades can be used to identify an acne scar, 
as shown in the table below.  
 
Qualitative scarring grading system SGA.
Grades of 
Post Acne 
Scarring 
Level of 
disease 
Clinical features 
1 
Macular 
These scars can be erythematous, hyper- or hypopigmented flat marks. They do not 
represent a problem of contour like other scar grades but of color. 
2 
Mild 
Mild atrophy or hypertrophy scars that may not be obvious at social distances of 50 cm or 
greater and may be covered adequately by makeup or the normal shadow of shaved beard 
hair in men or normal body hair if extrafacial. 
3 
Moderate 
Moderate atrophic or hypertrophic scarring that is obvious at social distances of 50 cm or 
greater and is not covered easily by makeup or the normal shadow of shaved beard hair in 
men or body hair if extrafacial, but is still able to be flattened by manual stretching of the 
skin (if atrophic). 
4 
Severe 
Severe atrophic or hypertrophic scarring that is evident at social distances greater than 
50 cm and is not covered easily by makeup or the normal shadow of shaved beard hair in 
men or body hair if extrafacial and is not able to be flattened by manual stretching of the 
skin. 
 
6.4.3 Acne Investigator’s Global Assessment (IGA)  
IGA is a tool used in the clinical routine to define acne vulgaris severity. The Investigator’s Global 
Assessment is based on a 5-point scale: 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 28 of 63 
 
 
6.4.4 Skin Roughness and Texture Assessment 
Skin roughness will be scored through a 4-point scale: 
0 = none; very smooth  
1 = mild, slightly rough 
2 = moderate, rough 
3 = severe; very rough 
 
Skin texture change from baseline will be scored through a 6-point scale: 
0 = worse  
1 = slightly worse 
2= no change 
3= slightly improved 
4 = improved 
5 = complete improvement. 
 
6.4.5 Subject and Investigator Global Evaluation of Performance – Appendices 2 and 3 
Subjects’ and Investigator’s global evaluation of the performance of PAPIX ACNE SCAR will be 
performed by means of the 7-item scale, where 1 = very much improved, 2 = improved, 3 = minimally 
improved, 4 = no change, 5 = minimally worse, 6 = worse, 7 = very much worse at the end of the study 
(Visit 4). 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 29 of 63 
 
6.4.6 Subject Overall Acceptability – Appendix 4 
Subjects’ evaluation of overall acceptability with the study treatment, which takes into account the 
pleasant or unpleasant feeling with the product and the ease of use, will be performed by means of a 
5-item scale, where 1 = very much satisfied, 2 = satisfied, 3 = neither satisfied nor dissatisfied, 4 = 
dissatisfied, 5= very much dissatisfied.  
Global acceptability evaluation by the subject will be assessed at the end of the treatment (Visit 4).  
 
6.5 
Monitoring Plan 
The study will be monitored on a regular basis by the CRO’s adequately qualified and trained clinical 
Monitors throughout the study period to ensure the proper conduct of the clinical Investigation.  
The purposes of study monitoring are to verify that the rights and well-being of study subjects are 
protected, that the reported study data are accurate, complete and verifiable against the source 
documents, and that the study is conducted in accordance with the current clinical investigation plan, 
Good Clinical Practice guideline (UNI EN ISO 14155) and applicable regulatory requirements. 
During the monitoring visits, Monitors will verify the following, including but not limited to: subject 
informed consent, subject’s eligibility, safety data and reporting, quality of source documents and CRF 
data against subject’s medical records. If inconsistencies are found, the corresponding corrections to 
the CRF data will have to be made by the Investigator or designated person. Monitors will also check 
subject compliance, accrual, study product handling, including dispensing procedures and 
accountability logs, delegation of responsibilities within the Investigator’s team, relevant 
communications with family doctors, if any, ancillary equipment and facilities, etc. The Investigator 
and other site staff involved in the study must allocate enough time to the Monitor at these visits. 
Upon request by the Sponsor, on-site study audits may be conducted in order to ensure the study is in 
compliance with GCP, applicable regulatory requirements, and the clinical investigation plan. The 
auditing activities may also be conducted after study completion. 
The Investigator agrees to allow Sponsor/auditors/CRO monitors to have direct access to his/her study 
records for review, being understood that they are bound by professional secrecy, and as such will not 
disclose any personal identity or personal medical information. 
Regulatory Authorities may wish to conduct on-site inspections (during the study or after its 
completion). If a Regulatory Authority notifies the Investigator of an inspection or visits the site 
unannounced for purposes of conducting an inspection, the Investigator must inform the Sponsor and 
CRO immediately. The Investigator will make all efforts to facilitate the conduct of the audits and 
inspections giving access to all necessary facilities, data and documents. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 30 of 63 
 
Any result or information arising from the inspection will be immediately communicated by the 
Investigator to the Sponsor. The Investigator will take all appropriate measures required by the 
Sponsor to implement corrective actions for all problems found during audits or inspections. 
 
 
7. 
Statistical Considerations 
This section summarizes the statistical principles and methods planned to analyze the data for this 
clinical investigation. 
 
7.1 
Sample Size Determination 
An exact binomial test with a nominal 5% two-sided significance level will have 80% power to detect 
the difference between the Null hypothesis proportion, π₀ of 0.5 (i.e., 50% of patients with treatment 
success) and the Alternative proportion, π₁, of 0.75 (i.e., 75% of patients with treatment success) when 
the sample size is 30 subjects. Assuming a possible 25% dropout rate, 40 subjects will be enrolled.  
 
7.2 
Definition of Study Populations for Analysis 
The following populations are defined for this investigation: 
• 
Safety analysis set (SAF): all patients enrolled who sign informed consent and receive at least 
one administration of the investigational device. 
• 
Full analysis set (FAS): all patients of the SAF who have performed the baseline assessments 
and have at least one post-baseline assessment of any performance endpoint (primary or secondary).  
• 
Per-Protocol analysis set (PPAS): all patients of the FAS who also meet all inclusion/exclusion 
criteria and who do not have any major protocol deviation (i.e. wrong inclusion, use of forbidden 
concomitant medications, etc.). 
The analysis of safety endpoints will be performed in the Safety population (SAF). Analysis of 
performance endpoints will be performed on the FAS population. The analysis of primary endpoint will 
be repeated in the PPAS. 
 
7.3 
Statistical Analysis 
Descriptive statistical analysis of all relevant variables will be performed. Continuous variables will be 
summarized by the number of patients (N), mean, standard deviation, median, minimum, maximum. 
Categorical variables will be summarized by the number (N) and the proportion of patients (%). Where 
appropriate, 95% confidence intervals for the target variables will be estimated. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 31 of 63 
 
The significance level of statistical tests will be set at 0.05. Parametric tests (e.g., paired t-test) will be 
used to analyze continuous variables; when continuous variables are not normally distributed, the 
corresponding non-parametric tests (e.g. Wilcoxon signed-sum rank test) will also be performed. 
Details of statistical analysis are provided in the following paragraphs. 
The statistical analysis will be performed using SAS 9.4 for Windows (SAS Institute Inc., Cary, NC, USA). 
 
7.3.1 Missing Data 
Missing data will not be replaced in any statistical analysis. 
 
7.3.2 Multiplicity 
This is a single-arm clinical investigation and no adjustment for multiplicity will be used.  
 
7.3.3 Covariates, Interactions and Subgroups 
This is a single-arm clinical investigation. No covariates or interaction analysis will be performed. 
Subgroup analyses could be performed to better describe the performance and safety of the study 
device. 
 
7.3.4 Analysis of Demographics and Baseline Variables 
Demographic (gender, age) and baseline characteristics will be summarized using mean, median, 
standard deviation, minimum and maximum for continuous variables and frequencies and percentages 
for categorical variables.   
 
7.3.5 Efficacy analysis 
7.3.5.1 Primary endpoint 
The primary objective of this clinical investigation is to evaluate and confirm the performance of PAPIX 
ACNE SCAR in the prevention and improvement of acne scars, in terms of improvement of visible acne 
scars and marks from baseline and prevention of new acne scars, in subject suffering for mild to 
moderate acne, after 4 weeks of treatment. 
The primary endpoint will be the proportion of subjects with acne scars and marks improved with 
respect to baseline and, at the same time, without any new facial acne scars after 4 weeks of 
treatment (treatment success). The improvement of acne scars and marks will be assessed as the 
change of at least one grade in the qualitative Scar Global Assessment (SGA) by Goodman and Baron 
[26] between baseline and Week 4. The number of new lesions will be assessed by count and 
comparison with baseline. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 32 of 63 
 
 
The primary endpoint will be described using number (N) and the proportion of patients (%). The 
proportion of treatment successes will be compared to a referent proportion (50%, Null hypothesis 
proportion) using the exact binomial test.  
 
7.3.5.2 Secondary endpoints 
The prevention and improvement of acne scars after 2 and 8 weeks of treatment will be assessed as 
the difference from baseline and analysed using paired t-test. The number of new scars will be 
assessed by count and comparison with baseline. The improvement of acne scars and marks will be 
assessed as the change of at least one grade in the qualitative Scar Global Assessment (SGA) by 
Goodman and Baron [26] between baseline and Week 2 and 8.   
The number of new lesions will be assessed by count after 2 and 8 weeks and comparison with 
baseline. 
Acne severity after 2, 4 and 8 weeks of treatment will be assessed through the IGA. Changes from 
baseline will be compared using Wilcoxon signed rank-sum test. 
The improvement of skin roughness will be assessed on a 4-point scale from 0 (none; very smooth) to 
3 (severe; very rough). Changes from baseline will be compared using Wilcoxon signed rank-sum test. 
Skin texture change will be assessed on a 6-point scale from 0 (worse) to 5 (complete improvement), 
after 2, 4 and 8 weeks of treatment and it will be summarized through the number (N) and the 
proportion of patients (%) for each item. 
The number of applications will be self-reported by the subject and the product accountability will be 
summarized to assess adherence to treatment.  
Subject’s and Investigator’s global evaluation on performance of the study product obtained at the 
end of the study (Visit 4) by means of a 7-items scale will be summarized through number (N) and 
proportion of patients (%) for each item.  
Subject’s evaluation of overall acceptability with treatment, obtained by means of a 5-item scale will 
be summarized through number (N) and the proportion of patients (%) for each item. 
 
7.3.6 Safety Analysis 
All enrolled subjects receiving at least one treatment application will be included in the safety analysis. 
Adverse events (AEs) and Adverse Device Events (ADEs) will be coded using the last updated version of 
the Medical Dictionary for Regulatory Activities (MedDRA) dictionary to give a preferred term (PT) and 
a system/organ class term (SOC) for each event. The number of subjects who experienced at least one 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 33 of 63 
 
AE or ADE, study product-related AE or ADE, serious AE or ADE, severe AE or ADE and the number of 
subjects withdrawn due to AE will be summarized. 
For each SOC and preferred term, summaries will be made with respect to the proportion of subjects 
having at least one occurrence of that event during the study and the total number of events. The 
incidence of AEs and ADEs will be presented overall, by SOC and preferred term, and additional 
grouping by severity and relationship to the study treatment.  
Local tolerability at the site of administration (e.g. skin increased itching or redness or irritation) will be 
reported and summarized. 
 
7.4     Planned Interim Analysis 
No interim analysis is planned. 
 
8.        Data Management 
During each study visit, the study Investigator (or designee) will collect and report study data in the 
relevant patient’s chart, documenting all significant observations. 
Any contact with the patient via telephone or other means that provides significant clinical 
information shall be documented in the source data. 
Paper Case Report Forms (CRFs) will be used for recording patient’s study data. It is the responsibility 
of the Investigator to ensure that the Case Report Forms are properly and completely filled in. The 
CRFs must be completed for all subjects who have been included in the clinical investigation. The 
Investigator will review all CRFs and sign and date them for each subject, verifying that the information 
is complete, true and correct. 
Subjects will be provided with paper questionnaires. Such documents will be filled by the subjects 
during the study visits, to record data concerning their QoL with respect to acne scars condition.  
It is responsibility of the Investigators to instruct the study participants on how to fill in questionnaires 
in a clear way and preferably in black ball-point pen. The questionnaires will be anonymous, each 
subject is identified through the subject code. Questionnaires will be considered source data. 
All CRF entries are to be done in black ballpoint ink. Changes and/or additions to data entered on 
original CRFs must be made in the following manner: the original entry will be lined out with a single 
line through the error (neither erasures nor correction fluid may be used) so as to leave it legible. The 
correction will be entered, initialed, and dated by the person making the correction. The Investigator 
or personnel authorized by the Investigator may enter corrections on the original CRFs. 
All fields on the CRF must be completed as applicable. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 34 of 63 
 
After the CRFs are approved and signed by the Investigator, the monitor will collect and forward them 
to the CRO in charge of data management where they will be processed. Data Clarification Forms 
generated by Data Management after data entry will be sent to the clinical site for resolution. The 
Investigator is responsible for the review and approval of all query resolutions. 
The data collected by CRFs will be entered in a dedicated database. The access to the database will be 
controlled by user-specific account and password combinations and audit trailed.  
 
 
9.        Amendments to the CIP 
Changes to the clinical investigation plan may only be made by means of a written amendment, which 
has to be approved and signed by the authorized representatives of the Sponsor, and by the 
Investigator. 
Exhaustive justifications that motivate the amendment to the clinical investigation plan should clearly 
be addressed in the document.  
All substantial Clinical Investigation Plan amendments must be submitted for approval to IEC and 
notified to the Regulatory Authority. In case of non-substantial amendment the IEC and the Regulatory 
Authority (when applicable) will be only notified of the amendment without the request to review and 
approve it. 
The Investigator, the Sponsor and IEC, separately or together, should decide whether the subject’s 
informed consent form needs to be changed. 
 
 
10. 
Deviations from Clinical Investigation Plan 
The Investigator is to conduct the study in accordance with the relevant, current clinical investigation 
plan and will only deviate when necessary to protect the safety, rights and welfare of the subjects. In 
the event that an isolated, unforeseen instance occurs resulting in a clinical investigation plan 
deviation, the Investigator is to document this deviation and notify the CRO or the Sponsor as soon as 
possible. In no instance should this increase the subject’s risk or affect the validity of the study. 
 
 
11. 
Device Accountability 
The Investigator is responsible of ensuring accountability of the study product, including reconciliation 
of study product and maintenance of records. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 35 of 63 
 
Upon receipt of the study product, the Investigator (or designee) will check the contents and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the Sponsor 
and returning it to the Sponsor. A copy will be retained in the Investigator File. 
The dispensing of the study product will be carefully recorded on the appropriate accountability forms 
provided by the Sponsor and an accurate accounting will be available for verification by the Study 
Monitor at each monitoring visit. 
Study product accountability records will include: 
• Confirmation of study product receipt at the clinical site. 
• The inventory at the site of study product provided by the Sponsor. 
• The tubes delivery to each subject. 
• The tubes return from each subject. 
• The return to the Sponsor or alternative disposition of unused study product. 
The Investigator should maintain records that adequately document: 
• That the subjects were provided with the quantities specified by the Clinical Investigation 
Plan/amendment(s), and 
• That all study products provided by the Sponsor were fully reconciled. 
Unused study product must not be discarded or used for any purpose other than the present study. 
Study product that has been dispensed to a subject must not be re-dispensed to a different subject. 
The Study Monitor will periodically collect the study product accountability forms and will check all 
returns (both unused and used containers) before arranging for their return to the Sponsor or 
authorizing their destruction by the clinical site. 
 
 
12. 
Statement of Compliance 
The study will be conducted in compliance with the current version of the Declaration of Helsinki 
(Appendix 5), with the clinical investigation plan, the ISO 14155:2012, the Italian laws in force and the 
principles of the Good Clinical Practice.  
The clinical investigation will start at clinical site only after obtaining the approval of the relevant Ethics 
Committee. 
  
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 36 of 63 
 
13. 
Informed Consent Process 
The Investigator is responsible for and will obtain informed consent from each subject or from parents 
or guardian, according to the subject’s age, in accordance with the UNI EN ISO 14155, and the current 
version of the Declaration of Helsinki.  
All subjects invited to participate in the study are entitled to make their voluntary decision based on all 
current available information provided to them by the Investigator/designee. In addition, they will be 
given a document in native language written in clear concise lay language for review and 
consideration. Minors will receive an information sheet specifically adapted for their young age. The 
document will previously have been approved by the relevant independent Ethics Committee (IEC) and 
may further be updated as new important information becomes available that may affect subject’s 
willingness to participate or continue in the study. 
The subject must be made aware that he/she may refuse to join the study or may withdraw his/her 
consent at any time without prejudicing further medical care and that he/she is covered by the 
Sponsor's indemnity insurance in the event of a study related injury. Subjects must also know that 
their personal medical records may be reviewed in confidence by the Sponsor's staff or 
representatives and by Regulatory Authority and IEC and that personal information will be collected 
and retained in a confidential database. Consent will always be given in writing after the subject has 
had adequate time to review the information and ask questions, if need be. Consent for minors will be 
requested to both parents or the guardian, where applicable. 
 
14. 
Adverse Events, Adverse Device Effects and Devices Deficiencies 
14.1 Definitions 
Adverse Event (AE) 
Any undesirable experience occurring to a subject, whether or not it is considered causally related to 
the investigational medical device. An AE may be a clinical finding, a clinical laboratory abnormality or 
a symptomatic complaint which is considered by the Investigator to be outside the normal variation 
for that parameter. 
 
Adverse Device Effect (ADE) 
Any untoward and unintended response to a medical device. This includes any event resulting from 
insufficiencies or inadequacies in the instructions for use or the deployment of the device and any 
event that is a result of a user error. 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 37 of 63 
 
Device Deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, safety or performance 
(included malfunctions, use errors and inadequate labelling). 
 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) could be any event that suggests a significant hazard, contraindication, 
side effect, or precaution. The seriousness of an AE relates to its clinical significance and its potential 
impact on health.  
An AE will be considered as serious when: 
Lead to death 
Lead to serious deterioration in the health of the subject, that either results in: 
a. a life-threatening illness or injury, or 
b. a permanent impairment of a body structure or a body function, or 
c. in-patient or prolonged hospitalization, or 
d. medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function 
Lead to foetal distress, foetal death or a congenital abnormality or birth defect. 
 
Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event or that might have led to any of these consequences if suitable action had not been taken or 
intervention had not been made or if circumstances had been less opportune. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect that by its nature, incidence, severity or outcome has not been identified 
in the risk analysis report. 
 
Incident 
Any malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any lack of labelling or instructions for use which, directly or indirectly, may cause or have 
caused death or serious deterioration in the health of the patient or of a user or of other persons. 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 38 of 63 
 
14.2 Adverse Event Intensity/Causality 
The Investigator, based on his direct observation or on subjects' report, will record the event according 
to the current version of CTCAE: 
Description 
Definition 
Grade 1 (Mild):
asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 (Moderate): 
 
minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental daily life activities. 
Grade 3 (Severe):
 
medically 
significant 
but 
not 
immediately 
life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self -care daily life activities. 
Grade 4 (Life-threatening 
consequences):  
urgent intervention indicated.
Grade 5:
death related to AE
 
 
The relationship of any AE to the product will be classified by the Investigator as follows: 
Description
Definition
Certain
The AE is clearly related to the study product 
Probable
The AE is likely related to the study product
Possible
The AE may be related to the study product
Doubtful
The AE is unlikely related to the study product
None 
The AE is clearly not related to the study product 
Unknown
Causality is not assessable, for one reason or another, e.g. because of 
insufficient evidence, conflicting data or poor documentation 
 
 
14.3 Adverse Event, Device Deficiency, Adverse Device Effect, reporting 
The Investigator will record any AEs, Device Deficiency and ADEs occurring during the study. He/She 
will also co-operate with the Sponsor in connection with the reporting of any SAE/SADE, Serious 
Incident to the Competent Authority and to the Independent EC, if applicable.  
All AEs regardless of severity occurring between recruitment and completion of the study by a subject 
must be recorded on the AE form provided with the CRF. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 39 of 63 
 
If there is a significant worsening of a medical condition that was present before starting the study, 
this should be considered as a new AE and a complete evaluation recorded. 
Signs and symptoms considered as lack of efficacy and occurring during the study will not be recorded 
on the AEs Section of the CRF except on the condition that, in the Investigator’s opinion, these signs 
and symptoms are caused by any reason different from lack of efficacy of the study product or meet 
the definition of serious AE. 
 
In the event of a SADE/SAE, Serious Incident the Investigator has to: 
▪ 
Complete the relevant CRF pages and a reporting form with the all available initial information, 
▪ 
Immediately inform the Sponsor or the CRO by telephone,  
▪ 
Fax the completed report form to the contact person at the Sponsor or the CRO as soon as 
possible. 
SAE/SADE, Serious Incidents reporting contacts are on page 4 of this Clinical Investigation Plan. 
The Investigator is responsible for ensuring the follow-up of any subject who experiences an 
SAE/SADE/ Serious Incident during the study. The investigator must re-examine the subject at regular 
intervals until the symptoms have completely disappeared or stabilized. 
The Sponsor or its delegate will be responsible for reporting the SAE/SADE/Serious Incident to the 
appropriate Authorities and EC, according to the local regulations. 
 
 
15. 
Vulnerable Population 
Minors will be recruited for participating in this study. They will receive specifically considered 
protection in accordance with international and national regulations, GCP guidelines and the 
provisions of the Declaration of Helsinki. 
 
16. 
Suspension or Premature Termination of the Clinical Investigation 
Unless premature interruption occurs, the end of the study will be the last closure visit at the clinical 
sites. 
 
16.1  Study Discontinuation 
Subjects may be discontinued at any time from the study for any of the following reasons: 
 
An AE occurs that, in the opinion of the Investigator, makes it unsafe for the subject to continue 
in the study 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 40 of 63 
 
 
Lack of compliance of the subject to the study treatment or assessments 
 
The subject needs to use a medication/treatment not allowed  
 
The subject is lost to follow-up 
 
The subject dies 
 
The subject withdraws consent 
 
The Investigator, for any reason, terminates the entire study, or terminates the study for that 
subject or the attending physician requests that the subject be withdrawn for any medical 
reason 
 
The Sponsor or the Regulatory Authority or the Ethics Committee, for any reason, terminates 
the entire study or terminates the study for this site or this particular subject. 
If a subject is discontinued from the study, the Investigator will, as far as possible, complete the end of 
study visit (Visit 4) CRF pages. The Investigator should try to ascertain the reason(s) for withdrawal, 
while fully respecting the subject’s rights. 
 
16.2  Study Interruption 
The Sponsor may consider study closure at the clinical site if the following occurs: 
 serious and/or persistent non-compliance with the Clinical Investigation Plan 
 inadequate collaboration of site personnel with CRO/Sponsor 
 administrative reasons 
 non-compliance with GCP, SOPs or regulatory requirements 
 lack of confidentiality and/or non-compliance with the contract spread with the Sponsor. 
 
 
17. 
Publication Policy 
All information obtained as a result of the study will be regarded as confidential. 
The results of the clinical study will be documented in an integrated clinical study report according to 
ISO 14155. 
The Sponsor and the Investigators agree that no publications presenting or discussing data and/or 
results from this clinical study sponsored by Relife Srl will take place until the participating centers 
have completed the study, the data have been interpreted, and the final report has been issued. 
As a rule, the Sponsor is free to use the data collected in the sponsored study for world-wide scientific 
product documentation, and for publication. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 41 of 63 
 
In general, the Sponsor has no objections if the Investigator publishes the results of the study. 
However, the Investigator is requested to provide the Sponsor with a copy of the manuscript for 
review before submitting it to the publisher with a cover letter informing the Sponsor about the 
intention to publish the study results. When permission for presentation or for publication is granted, 
Investigators, prior to submission of a manuscript or abstract to the publisher, shall forward a copy of 
said manuscript or abstract to the Sponsor who shall have 45 days to request any reasonable 
amendment thereto, which shall be taken into due account and consideration by the Investigator. 
The Sponsor is entitled to include as authors of the publication all Sponsor’s personnel who 
contributed substantially to the theoretical or experimental work and also to take part in the decision 
that establishes the order in which the authors’ names will be given. Costs for publication must be 
regulated by written agreement between the parties.  
If publication of the results of the study, either in part or in full, is prepared by the Sponsor, the 
Investigators will be provided with a copy of the manuscript before the submission to the publisher 
and asked to give approval of the document. The Investigators will be asked in writing if they accept to 
be included as authors of the publication. Answers should be sent in writing to the Sponsor within a 
reasonable time limit (30 days). If no answer is received, it is assumed that the Investigators agrees to 
the Sponsor’s proposal. 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 42 of 63 
 
18. 
Data protection requirements 
All clinical trial information shall be recorded, processed, handled, and stored in such a way that it can 
be accurately reported, interpreted and verified; at the same time, the confidentiality of records and 
of the personal data of the patients shall remain protected in accordance with the applicable law on 
personal data protection (such as the EU General Data Protection Regulation 679/2016). 
Acknowledgment 
The Site, the Principal Investigator, the CRO as well as their appointed staff and service providers 
acknowledge that:  
(a) 
the performance of the study will imply processing of sensitive personal data; 
(b) 
personal data processing is regulated by the applicable EU General Data Protection Regulation 
679/2016 the ISO 14155and local laws as well as by the Sponsor’s national legislation.  In particular, it 
is hereby acknowledged that being the Sponsor a company incorporated under  Italian law, it has to 
mandatorily comply with  Italian legal provisions on data protection: therefore The Site, the Principal 
Investigator, the CRO shall cooperate with the Sponsor to allow the fulfillment of such obligations; 
(c) 
strict compliance with the applicable data protection laws and this section of the protocol is 
deemed by the Sponsor as an essential condition of collaboration with the The Site, the Principal 
Investigator, the CRO. 
Data Controllers and Data Processors  
The Sponsor, the Site, the Principal Investigator and the CRO acknowledge that according to the 
applicable privacy laws, Sponsor and Site will act as independent data controllers while CRO and the 
Principal investigator will act as data processors respectively of the Sponsor and of Site. Before the 
beginning of the study, the Site will instruct in writing Principal Investigator as its data processor. 
However, if specific local laws or regulations mandate a different definition of the privacy roles, the 
Sponsor,  the Site, the Principal investigator and  the CRO  will implement the relevant legal 
instruments (e.g. if pursuant to the local laws  the Site is a data processor of the Sponsor, a Data 
Processing Agreement will be finalised; if  pursuant to the local laws Sponsor and Site are join 
controllers, a Joint Controllership Agreement will be finalised). 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 43 of 63 
 
Duties of the Parties involved in the performance of the study 
Collection and use of patients’ personal data (i.e. subjects' data), will be carried out in full respect of 
the provisions of the information notices submitted to patients, as well as the privacy rights, the 
fundamental freedoms and the dignity of data subjects. All the parties involved in this study  
undertake to adopt adequate measures to warrant that data will always be processed securely and in 
compliance with privacy laws. 
The Site, the Principal Investigator, the Sponsor and the CRO  as well as their appointed staff and 
service providers, each in its respective remit and within the limits of their specific role in the study, 
shall implement the following safety measures (physical, logical, organizational, technical, electronic, 
I.T. etc) to ensure adequate protection of the personal data of the patients involved in the study. In 
particular: 
(i) 
DATA SAFETY. The Site and/or the Principal Investigator  shall adopt all the necessary measures 
to prevent or minimise the risks of theft, fire, flooding, partial or total loss, accidental disclosure or 
illegal/unauthorised access to patient’s data or Sponsor’s proprietary confidential information; to this 
extent, before the beginning of the study, the Site and/or the Principal Investigator shall ensure that 
the actual measures they have implemented are fit-for-purpose and law-compliant, and in particular: 
- in order to minimise the risk of unauthorized access and theft, the hardware on which patients’ 
personal data are stored shall be placed in a restricted-access area, accessible only to those 
individuals who need to retrieve the patients’ personal data included in the database for 
professional purposes; the same safeguards shall be put in place for non-electronic databases; 
- any electronic database containing the patients’ personal data shall be password-protected by 
means of a strong password. Systems shall be set so that passwords must be updated at least every 
three months  and feature at least 8 characters, with upper-case and lower-case recognition, 
containing at least three "special" characters, such as upper case letters [A-Z], lower case letters [a-
z], numbers [0-9], symbols [!, #, $, etc.] or other special characters [Á, ë, ö etc.]. Passwords shall not 
include elements which may easily be associated with the assignee or information regarding 
him/her , such as name and year of birth (e.g. “johnbrown80”) or easily predictable strings of 
characters (e.g. “qwerty”, “12345”, “admin”, “user”, etc.);  

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 44 of 63 
 
- adequate cryptographic protection measures shall be put in place for data “at rest” and “in transit” 
(these include, for example, file system or database cryptography, or any other equivalent IT 
measure which renders data unintelligible to those who are not authorised to access them);  
- high level security measures shall be implemented also on the files or databases which contain the 
“key” to match the patients’ personal data (i.e. name, surname, etc.) with their respective “Patient 
IDs” (as defined at point (iv) below); 
- Backup processes and other measures that ensure rapid restoration of business critical systems 
shall be implemented; 
- Updated Antivirus and firewall programs shall be installed on the IT devices. 
The Site shall, regularly test and update the measures listed above.  
The Site shall, upon request from the Sponsor and/or the CRO, provide detailed written information 
about the measures listed above.  
The CRO shall ensure that the selected sites for the study have implemented the above listed 
measures.  
(ii) TRANSMISSION OF DATA. All the parties that transfer data through internet and/or to the 
centralised database(s) used to process study’s data or to generate statistical analyses shall implement 
secure protocols based on cryptographic standards which make data unintelligible to unauthorized 
individuals. 
(iii) 
SECURITY OF THE CENTRALISED DATA BASE. The centralised database held by the Sponsor shall 
have the following safeguards in place:  
- 
appropriate authentication methods, which differentiate between different users according to 
their respective roles so as to ensure that access to a specific set of subjects' data is permitted 
exclusively to those for whom access to such data is essential in the context of their work for the 
study; 
- 
appropriate measures to ensure that the authentication credentials are periodically updated 
(i.e.  password change); 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 45 of 63 
 
(iv) 
PSEUDONYMIZATION. All personal data that may allow identification of the patients involved 
in the study shall be adequately dissociated from the other data pertaining to the study (“pseudo-
anonymisation” process). The Principal investigator  shall adequately dissociate the identification data 
of patients from the data pertaining to the study by linking results to a an alphanumerical code 
“Patient ID”, whose format shall not make it possible to identify the patient directly or indirectly, so as 
to ensure that only anonymous data are transmitted to the Sponsor and the CRO. Site/Principal 
Investigator shall securely store a separate list (e.g: identification log) with the identification code, 
together with all signed informed consents, in accordance with the security measures as defined 
above. (v) 
TRAINING. The parties shall ensure that any personnel involved in the study have 
received proper training on data protection issues. 
All actions related to the implementation of the afore mentioned measures shall be provided by the 
Sponsor, the CRO to the competent authorities (including data protection authorities) and Ethics 
Committees if and when requested. If such authorities or the Sponsor consider the implementation of 
the afore mentioned measures insufficient to guarantee an adequate level of protection of the 
patients’ personal data, The Site, the Principal investigator and the CRO undertake to adopt all the 
necessary activities to overcome such remarks to assure the full compliance with the data protection 
laws.  
Archiving of the clinical trial master file and patients’ personal data 
Unless other EU laws require archiving for a longer period, the Sponsor the Centre and the Principal 
Investigator shall archive the content of the clinical trial master file, including the relevant patients’ 
personal data, for at least 10 years after the end of the clinical trial. However, medical records shall be 
archived in accordance with the national laws of the country where the study is performed. The 
patient code pairing list (i.e. the list that where the Patient ID is linked to the patients’ identification 
data such as name and surname), shall be archived care of the Principal Investigator. 
  The content of the clinical trial master file shall be archived in a way that ensures that it is readily 
available and accessible, upon request, to the competent authorities. 
Any transfer of ownership of the content of the clinical trial master file shall be documented. The new 
owner shall undertake the responsibilities set out in this protocol. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 46 of 63 
 
The sponsor appoints the clinical trial coordinator and Study medical expert for archives within the 
Sponsors’ organisation as responsible persons for archives. Access to archives shall be restricted to 
those individuals. 
The media used to archive the content of the clinical trial master file shall be such that the content 
remains complete and legible throughout the period referred to in the first paragraph. Any 
modification to the content of the clinical trial master file shall be traceable. 
 
Data Breach  
Data Breach is an incident regarding personal data security and leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, stored 
or otherwise processed. In particular: destruction of personal data is where the data no longer exists, 
or no longer exists in a form that is of any use to the Site, Sponsor, CRO, Principal Investigator.; data 
loss is when the data may still exist, but the Site, sponsor, CRO, Principal Investigator etc  has lost 
control or access to it, or no longer has it in its possession; damage is where personal data has been 
altered, corrupted, or is no longer complete; data unavailability is where, following a data 
incident  (such as a network outage, a natural or man-made disaster, etc.), personal data become 
temporarily inaccessible to the Site, sponsor, CRO, Principal Investigator etc. 
Anomalous Event is an event that is not part of the standard operational scope of an infrastructure, 
network or service and which affects, or is likely to affect, personal data; this may include theft or loss 
of IT devices and other physical events (e.g. an unauthorised access to a locked storage room 
containing paper files with personal data), and/or electronic/IT anomalies (e.g. cyber-attacks, default 
or hacking of cloud services), which may in any way entail loss, unavailability, alteration, theft, copy or 
dissemination of personal data.   
Whoever becomes aware in any way of an Anomalous Event and/or of a Data Breach (see definitions 
above) affecting the patients’ personal data and/or personal data collected in the context of the study, 
shall, as appropriate, immediately (and in any case no later than 24 hours from the knowledge of an 
Anomalous Event and/or of a Data Breach) inform the SME, the Sponsor’s Data Protection Officer, who 
may be contacted at dpo@menarini.com, the Sites at dpo@hsanmartino.it and dpo@gaslini.org and 
the CRO at dpo@latis.it and shall provide the following information: 
Codice campo modificato
Codice campo modificato
Codice campo modificato
Codice campo modificato

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 47 of 63 
 
(i) Anomalous  Event  / Data Breach  Type  (e.g. data loss, unauthorized access, loss of company device, 
etc.);  
(ii) Person or source that first reported the Anomalous Event/ Data Breach; 
(iii) Date and Time when the person who first reported the Anomalous Event / Data Breach became 
aware of it; 
(iv) Anomalous Event / Data Breach Date and Time  (actual or presumed); 
(v) Place (specify if actual or alleged) where the Anomalous Event / Data Breach  occurred; 
(vi) Anomalous Event  / Data Breach Description;  
(vii) Indicate the source of the Anomalous Event / Data Breach (e.g. I.P. source) - (if relevant); 
(viii) Indicate the affected infrastructure / system / application / cloud/ software / hardware / database 
and their location; 
(ix) List or describe the processing/storage systems affected by the Anomalous Event/Data Breach (if 
relevant); 
(x) Number of data subjects involved (if known); 
(xi) Amount of allegedly breached data  
(xii) Other relevant information 
Once all the above information have been provided, the Sponsor and the Site should have a 
reasonable degree of certainty that a security incident has occurred that has led to personal data being 
compromised.  
Then, as appropriate, Sponsor and Site, each one in its respective remit, shall manage the Data Breach 
in accordance with the applicable data protection regulations. 
For Data Breach affecting personal data of patients enrolled within the European Union, Sponsor and 
Site autonomously or jointly depending on the circumstances and their privacy responsibilities as 
defined by the Regulation 679/2016- shall:  
1. Collect the necessary evidence and information; 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 48 of 63 
 
2. Categorise the breach; 
3. Determine the risk probability and level to the rights and freedom of the concerned patients; 
4. Identify and put in place appropriate remedies to minimise the impact of the Data Breach 
5. Determine the notification and communication duties vis à vis the competent supervisory authority 
and/or the concerned patients. 
 
Information notice on personal data protection and pseudo-anonymisation 
Prior to patients’ enrolment in the study, the Principal Investigator and the Site  (including their 
personnel) shall provide each patient with adequate, law-compliant “information notices and consent 
forms to process personal data” as included in the ICF (or, as the case may be, through a separate, 
specific form) provided by the Sponsor or delegated CRO and shall collect his/her written consent to 
the processing of personal data according to the actual performance conditions in which the study  is 
carried out. The Principal Investigator is responsible to archive the signed ICF in accordance with the 
security measures described above. 
Among other things, the ICF (or the separate form) shall inform patients about:  
(i) the applicable data protection legislation 
(ii) what kind of data shall be collected during the study by listing them in detail or by category; 
(iii) the purpose of data processing  
(iv) whether granting the consent(s) to process personal data is a necessary or an optional condition to 
take part in the study;  
 (v) the pseudonymisation procedure and scope; 
(vi) who can access patients’ data and under what circumstances  
(vii) the period of data retention/storage as defined in 10 years; 
 (viii) patients’ data protection rights as defined by the EU General Data Protection Regulation 
679/2016. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 49 of 63 
 
(ix) Data Controllers / Data Processors and the relevant contact details 
(x) Sponsor’s Data Protection Officer contacts (DPO)  
 
Transfer of patients’ data outside the European union 
The study performance does not entail transferring patients’ personal data (coded data) outside the 
EU. 
 
Exercise of patients’ data privacy rights 
Each study patient has the right to contact the Sponsor, the Site, the Principal investigator, the CRO to 
exercise the rights afforded to the patient by the law, including the afforded ones under articles 15 to 
22 of Regulation (EU) 2016/679, namely: knowing whether or not any data referring to his/her is being 
processed in the context of the study; access his/her data; verify the data’s content, origin, exactness, 
location (including, where applicable, the non EU countries where the data might be); obtain a copy of 
the data including their transmission to another entity indicated by the patient; ask that the data are 
supplemented, updated, amended; in the circumstances set forth by the law, ask that the processing 
of data is restricted, that data are anonymised or frozen; oppose to the processing of his/her data for 
legitimate reasons.  Each patient has the right to lodge a complaint with his/her local supervisory 
authority and/or to notify to the Data Protection Officer any use of his/her personal data the patient 
regards as inappropriate. 
Each study patient is free to withdraw at any time from the study. In such case, each study patient may 
ask the Sponsor, the Site, the Principal investigator, the CRO to destroy/delete his/her personal data, 
thus preventing any further processing or analysis of his/her data. However, data and results of tests 
that may have been used to determine the results of the study shall not be deleted, to avoid altering 
or impairing altogether the results of the study.  
The request shall be fulfilled within the term set forth by the applicable privacy laws (normally 30 
days).  The Sponsor, the Site, the Principal investigator, the CRO shall implement adequate 
organisational measures to reply to patients within the above mentioned deadline. 
 
 
19. 
Bibliography 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 50 of 63 
 
1. Tan KJL, Bhate K. A global perspextive on the epidemiology of acne. Br J Dermatol. 2015 Jul;172 
Suppl 1:3-12. 
 
2. Dréno B, Bissonnette R, Gagné-Henley A, Barankin B, Lynde C, Kerrouche N, Tan J. Prevention and 
Reduction of Atrophic Acne Scars with Adapalene 0.3%/Benzoyl Peroxide 2.5% Gel in Subjects 
with Moderate or Severe Facial Acne: Results of a 6-Month Randomized, Vehicle-Controlled Trial 
Using Intra-Individual Comparison. Am J Clin Dermatol. 2018 Apr;19(2):275-286. 
 
3. Fife D. Practical evaluation and management of atrophic acne scars: tips for the general 
dermatologist. J Clin Aesthet Dermatol. 2011 Aug; 4(8):50-7. 
 
4. Fabbrocini G, Annunziata MC, D’arco V, De Vita V, Lodi G, Mauriello MC, Padtore F, Monfrecola G. 
Acne scars: pathogenesis, classification and treatment. Dermatol Res Pract. 2010; 2010: 893080. 
 
5. Tuan TL, Nichter LS. The molecular basis of keloid and hypertrophic scar formation. Mol Med 
Today 1998; 4:19-24. 
 
6. Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet. 2012 Jan 28; 379(9813):361-72. 
 
7. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am 
Acad Dermatol, Vol. 49, Number 3. 
 
8. Strauss JS, Pochi PE. Handbuch der Haut – unt Geschlechtskrankheiten; Normale und 
Pathologische Anatomie der Haut I. In: Gans O, Steigleder GK, editor. Berlin: Springer-Verlag; 
1999. p.184. 
 
9. James WD. Clinical practice. Acne. N Engl J Med. 2005 Apr 7; 352(14):1463-72. 
 
10. Saedi N, Uebelhoer N. Management of acne scars. Available at:  
 
11. Sobanko JF, Alster TS. Management of acne scarring, part I: a comparative review of laser surgical 
approaches. Am J Clin Dermatol. 2012 Oct 1; 13(5):319-30. 
 
12. Jacob C, Jeffrey D, Kaminer MS. Acne scarring. A classification system and review of treatment 
options. Journal of the American Academy of Dermatology, Vol. 45(1), pp 109-117, July 2001. 
 
13. Forbat E, Ali FR, Al-Niami F. The role of fillers in the management of acne scars. Clin Exp Dermatol. 
2017 Apr 10. 
 
14. Ghersetich I, Brazzini B, Lotti T. Chemical peeling. In: Lotti TM, Katsambas AD, editors. European 
Handbook of Dermatological Treatments. 2nd edition. Berlin, Germany: Springer; 2003. 
 
15. Hession MT, Graber EM. Atrophic acne scarring: a review of treatment options. J Clin Aesthet 
Dermatol. 2015 Jan; 8(1):50-8. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 51 of 63 
 
 
16. Grimes PE. The safety and efficacy of salicylic acid chemical peels in darker racial-ethnic groups. 
Dermatol Surg. 1999 Jan; 25(1):18-22. 
 
17. Harris DW, Buckley CC, Ostler LS, Rustin MHA. Topical retinoic acid in the treatment of fine acne 
scarring. Br J Dermatol 1991; 125:81-3. 
 
18. Berardesca E, Gabba P, Farinelli N, Borroni G, Rabbiosi G. In vivo tretinoin-induced changes in skin 
mechanical properties. Br J Dermatol 1990; 122:525-9. 
 
19. Rivera AE. Acne scarring: a review and current treatment modalities. J Am Acad Dermatol. 
 
October 2008. 
 
20. Signorini M, Clementoni MT. Clinical evaluation of a new self-drying silicone gel in the treatment of 
scars: a preliminary report. Aesth Plast Surg 31:183-187, 2007. 
 
21. Chularojanamontri L, Tuchinda P, Kulthanan K, Pongparit K. Moisturizers for acne. J Clin Aesthet 
Dermatol. 2014 May; 7(5): 36–44. 
 
22. Draelos ZD, Ertel KD, Berge CA. Facilitating facial retinization through barrier improvement. Cutis. 
2006 Oct; 78(4):275-81. 
 
23. Munehiro A, Murakami Y, Shirahige Y, Nakai K, Moriue T, Matsunaka H, Yoneda K, Kubota Y. 
Combination effects of cosmetic moisturisers in the topical treatment of acne vulgaris. J 
Dermatolog Treat. 2012 Jun; 23(3):172-6. 
 
24. Hayashi N, Kawashima M. Study of the usefulness of moisturizers on adherence of acne patients 
treated with adapalene. J Dermatol. 2014 Jul; 41(7):592-7. 
 
25. Matsunaga K, Leow YH, Chan R, Kerrouche N, Paliargues F. Adjunctive usage of a non comedogenic 
moisturizer with adapalene gel 0.1% improves local tolerance: a randomized, investigator-blinded, 
split-face study in healthy Asian subjects. J Dermatolog Treat. 2013 Aug; 24(4):278-82. 
 
26. Goodman GJ, Baron JA. Post acne scarring: A qualitative global scarring grading system.Dermatol 
Surg.2006; 32:1458–66. 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 52 of 63 
 
APPENDIX 1  
 
List of Abbreviations   
 
 
ADE 
Adverse Device Effect 
AE
Adverse Event
CIP
Clinical Investigation Plan
CRF
Case Report Form
CRO
Contract Research Organization 
CTCAE
Common Terminology Criteria for Adverse Events
DLQI
Dermatology Life Quality Index questionnaire
FAS
Full Analysis Set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
ICH 
International Conference on Harmonization
IFU
Instructions For Use
IGA
Investigator Global Assessment
IEC
Indipendent Ethics Committee
MedDRA
Medical Dictionary for Regulatory Activities
PPAS
Per-Protocol Analysis Set
PT
Preferred Term
ml
Milliliters
SADE
Serious Adverse Device Effect
SAF
Safety Analysis Set
SAE
Serious Adverse Event
SGA
Scar Global Assessment

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 53 of 63 
 
SOC
System Organ Class
SOP
Standard Operating Procedure
USADE
Unanticipated Serious Adverse Device Effect
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 54 of 63 
 
Appendix 2  
 
Questionnaire for the patient’s evaluation of the performance 
 
Subject n°: |___|___|-|___|___|___| 
 
Date of completion of the questionnaire: |___|___| |___|___| |___|___|___|___| 
      
 
                                                            day                month                   year 
 
 
How do you rate the appearance of your facial skin overall, in relation to scars and signs 
caused by acne, compared to before treatment with the PAPIX ACNE SCAR product? 
 
 Very improved  
 Improved 
 Only slightly improved 
 No changes compared to before 
 Sightly worse worsened 
 Worsened 
 Much worse 
  
 
 
 
 
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 55 of 63 
 
Appendix 3 
 
Questionnaire for the evaluation by the Investigator of the 
performance 
 
Subject n°: |___|___|-|___|___|___| 
 
Date of completion of the questionnaire: |___|___| |___|___| |___|___|___|___| 
      
 
                                                            day                month                   year 
 
 
How do you rate the overall skin of your patient’s face, in relation to scars and marks caused 
by acne, compared to before treatment with the product PAPIX ACNE SCAR? 
 
 Very improved  
 Improved 
 Only slightly improved 
 No changes compared to before 
 Sightly worse worsened 
 Worsened 
 Much worse 
  
 
 
 
 
 
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 56 of 63 
 
Appendix 4 
 
Questionnaire for assessing acceptability by the patient 
 
 
Subject n°: |___|___|-|___|___|___| 
 
Date of completion of the questionnaire: |___|___| |___|___| |___|___|___|___| 
      
 
                                                            day                month                   year 
 
Regarding the pleasant sensation of the PAPIX ACNE SCAR product on the skin, we ask you to 
express your level of satisfaction: 
 
 Very satisfied  
 Satisfied 
 Neither satisfied nor dissatisfied 
 Not satisfies 
 Definitely not satisfied 
 
 
 
 
 
 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 57 of 63 
 
Appendix 5 
 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving human 
subjects. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 58 of 63 
 
6.         The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. The responsibility for the protection of research subjects must always rest with the 
physician or other health care professionals and never with the research subjects, even though they 
have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other 
health care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve risks and burdens. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 59 of 63 
 
           Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
           Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.            
 
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable 
group. In addition, this group should stand to benefit from the knowledge, practices or interventions 
that result from the research. 
 
Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 60 of 63 
 
incentives for subjects and information regarding provisions for treating and/or compensating subjects 
who are harmed as a consequence of participation in the research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and approval 
to the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations of 
the country or countries in which the research is to be performed as well as applicable international 
norms and standards but these must not be allowed to reduce or eliminate any of the protections for 
research subjects set forth in this Declaration.  
           The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After 
the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.  
 
Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent  
25.       Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any possible 
conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, post-study provisions and any other relevant 
aspects of the study. The potential subject must be informed of the right to refuse to participate in the 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 61 of 63 
 
study or to withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the methods used 
to deliver the information. 
           After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed.       
           All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be 
performed with persons capable of providing informed consent, and the research entails only minimal 
risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is able 
to give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorised representative. The potential subject’s dissent should 
be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances the 
physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 62 of 63 
 
31.       The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from 
the study must never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
           Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive any 
intervention less effective than the best proven one, placebo, or no intervention will not be subject to 
additional risks of serious or irreversible harm as a result of not receiving the best proven 
intervention.  
           Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent 
process. 
 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 

CIP ReGl/19/PAS-Acn/001 
Version 2.0 date 02/07/2020 
 
CONFIDENTIAL  
 
Page 63 of 63 
 
ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise 
made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be 
declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorised representative, may use an unproven intervention if in 
the physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. 
This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available.