The Performance and Safety of Petit Drill in the French Paediatric Population: a Post-market Clinical Follow-up.
Conditions: Sore-throat, Cough
Sponsor: Pierre Fabre Medicament

 
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Title 
The Performance and Safety of Petit Drill in the French Paediatric 
Population: a post-market clinical follow-up. 
CIP Version and Date 
V6.0 26 March 2024 
Revision history 
Summary of the revision history in the case of amendments 
Amendment 2 
Sponsor information section: Dr Bernard SIMIAN added as new 
investigator. 
Amendment 1 
Section 1 (Number of patients required and enrolment duration) section 
6.6, section 6.9.7 and section 7.13: number of participating pharmacies 
updated from 100 to around 125. 
Section 7.13: pre-screening period updated from “June” to “July” to 
stick to the 9 month period length and mean of number of patients per 
pharmacy modified from “2 à 3” to “2”. 
Section 14.2 and section 14.3: wording of "investigating pharmacist” 
modified as follow: “investigator”. 
 
 
 
 
 
 
 
 
 
 
This document contains confidential information belonging to Pierre Fabre Médicament.  
Except as may be otherwise agreed to in writing, you agree to keep this information confidential and 
to not copy or disclose it to others or use it for unauthorized purposes. 
 
 

 
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SPONSOR INFORMATION 
 
Sponsor  
Pierre Fabre Médicament.  
Les Cauquillous, 81500 LAVAUR, FRANCE.  
Investigator(s) 
Dr Myriam SIMIAN (Coordinating Investigator) 
Dr Carole PERRIN 
Dr Sébastien BUCQUET 
Dr Rémi ROCHELET 
Dr Esther MILOJEVITCH 
Dr Bernard SIMIAN 
The different roles, responsibilities and qualifications of investigators are 
specified in the Investigator list. 
Investigation site(s) 
CEN EXPERIMENTAL (Clinical Investigation Centre) 
18, rue Pauline Kergomard 
21000 DIJON, France 
Note: The sponsor shall maintain an updated list of principal 
investigators, investigation sites, and institutions. This list can be kept 
separately from the CIP. The definitive list shall be provided with the 
clinical investigation report. 
Other organisations 
CEN (CRO) 
18, rue Pauline Kergomard 
21000 DIJON, France 
Coordinating 
Pharmacist & scientific 
committee 
Coordinating Pharmacist 
Dr Vincent ALQUIER 
 
Scientific committee 
Dr Vincent ALQUIER 
Pr Guy DUTAU (Pediatrician pulmonologist) 
 
 
 
 

 
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TABLE OF CONTENTS  

Sponsor Information ______________________________________________________ 2 
Table of contents _________________________________________________________ 3 
List of Tables ____________________________________________________________ 7 
List of abbreviations ______________________________________________________ 8 
1 
Synopsis of the clinical investigation ___________________________________ 10 
2 
Identification and Description of the Investigational Device _________________ 17 
2.1 
Summary Description of the investigational device ______________________________ 17 
2.2 
Manufacturer of the Investigational Device ____________________________________ 17 
2.3 
Model/type of the Investigational Device ______________________________________ 17 
2.4 
Traceability _____________________________________________________________ 17 
2.5 
Intended Purpose ________________________________________________________ 18 
2.6 
Populations and Indications ________________________________________________ 18 
2.7 
Clinical, Technical and Biological Description of the Investigational Device ___________ 18 
2.8 
Training requirements ____________________________________________________ 19 
2.9 
Special Medical Procedures________________________________________________ 19 
2.10 
Instructions for Use ______________________________________________________ 19 
3 
Justification for the design of the clinical investigation ____________________ 20 
3.1 
Background and Rationale _________________________________________________ 20 
3.1.1 
Risks associated with existing cough relief treatments _________________________ 20 
3.1.2 
Glycerol as an effective and safe alternative for dry cough management __________ 21 
3.1.3 
Rationale ____________________________________________________________ 21 
3.2 
Evaluation of relevant pre-clinical assessment _________________________________ 21 
3.3 
Evaluation of relevant clinical data ___________________________________________ 22 
3.3.1 
Description of the pathology _____________________________________________ 22 
3.3.2 
Data issued from clinical published studies on similar devices ___________________ 22 
3.3.3 
Data issued from clinical investigations on the device _________________________ 22 
3.3.4 
Safety data recorded from vigilance records _________________________________ 24 
3.4 
Clinical development stage ________________________________________________ 24 
4 
Risks and benefits of the investigational device and clinical investigation _____ 25 
4.1 
Anticipated clinical benefits ________________________________________________ 25 
4.2 
Anticipated adverse device effects __________________________________________ 25 
4.3 
Risks associated with participation in the clinical investigation _____________________ 25 
4.4 
Possible interactions with concomitant medical treatments ________________________ 25 
4.5 
Actions to control or mitigate risks ___________________________________________ 25 
4.6 
Risk-to-benefit rationale ___________________________________________________ 25 

 
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5 
Objectives and hypotheses of the clinical investigation ____________________ 27 
5.1 
Objectives______________________________________________________________ 27 
5.1.1 
Primary objective ______________________________________________________ 27 
5.1.2 
Secondary objectives ___________________________________________________ 27 
5.1.3 
Exploratory objectives __________________________________________________ 27 
5.2 
Hypotheses (if applicable) _________________________________________________ 27 
5.3 
Risks and anticipated adverse device effects to be assessed ______________________ 27 
6 
Clinical Investigation Design ___________________________________________ 28 
6.1 
Type of clinical investigation _______________________________________________ 28 
6.2 
Bias minimization ________________________________________________________ 28 
6.3 
Outcomes ______________________________________________________________ 29 
6.3.1 
Primary outcome ______________________________________________________ 29 
6.3.2 
Secondary outcome(s) __________________________________________________ 29 
6.3.3 
Exploratory outcomes __________________________________________________ 30 
6.4 
Variables ______________________________________________________________ 31 
6.5 
Replacement of subjects __________________________________________________ 38 
6.6 
Investigation sites ________________________________________________________ 38 
6.7 
Clinical investigation end __________________________________________________ 38 
6.8 
Investigational device(s) and comparators ____________________________________ 38 
6.8.1 
Exposure ____________________________________________________________ 38 
6.8.2 
Justification of the choice of comparator ____________________________________ 38 
6.8.3 
Other needed medical device or medication _________________________________ 38 
6.8.4 
Number of investigational devices to be used ________________________________ 38 
6.9 
Subjects _______________________________________________________________ 38 
6.9.1 
Inclusion criteria _______________________________________________________ 39 
6.9.2 
Exclusion criteria ______________________________________________________ 39 
6.9.3 
Subject withdrawal and lost-to-follow-up ____________________________________ 39 
6.9.4 
Expected duration of the clinical investigation ________________________________ 40 
6.9.5 
Expected duration of each subject’s participation _____________________________ 40 
6.9.6 
Sample size __________________________________________________________ 40 
6.9.7 
Period and point of enrolment ____________________________________________ 40 
6.9.8 
The investigation population relative to the target population ____________________ 40 
6.9.9 
Vulnerable populations _________________________________________________ 41 
6.10 
Procedures _____________________________________________________________ 41 
6.11 
Monitoring plan __________________________________________________________ 42 
7 
Statistical considerations _____________________________________________ 43 
7.1 
Analysis population ______________________________________________________ 43 
7.2 
Statistical Design and Analytical Methods _____________________________________ 43 
7.3 
Level of significance and power _____________________________________________ 43 
7.4 
Determination of Sample Size ______________________________________________ 43 
7.5 
Pass/fail criteria _________________________________________________________ 44 

 
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7.6 
Interim analyses _________________________________________________________ 44 
7.7 
Criteria for the termination of the clinical investigation (if applicable) ________________ 44 
7.8 
Management of biases ____________________________________________________ 44 
7.9 
Deviations from the original statistical analysis plan _____________________________ 44 
7.10 
Subgroups _____________________________________________________________ 44 
7.11 
Handling of missing data and drop-outs ______________________________________ 44 
7.12 
Exploratory analyses _____________________________________________________ 44 
7.13 
Number of subjects in each pre-screening centre _______________________________ 45 
8 
Data Management ____________________________________________________ 46 
8.1 
Data recording __________________________________________________________ 46 
8.1.1 
Case Report Forms ____________________________________________________ 46 
8.1.2 
Mobile application _____________________________________________________ 46 
8.1.3 
Specification of source documents ________________________________________ 46 
8.2 
Data Management System_________________________________________________ 46 
8.2.1 
Procedures for data review, database cleaning and data queries. ________________ 46 
8.2.2 
Procedures for data entry, verification, validation _____________________________ 47 
8.2.3 
Database locking and storage ____________________________________________ 47 
8.2.4 
Confidentiality and data protection ________________________________________ 47 
8.2.5 
Procedures for data retention ____________________________________________ 47 
9 
Amendments to the clinical investigation plan ____________________________ 48 
10 
Deviations from the clinical investigation plan ____________________________ 48 
11 
Device accountability _________________________________________________ 48 
12 
Statements of compliance _____________________________________________ 49 
12.1 
General statements of compliance __________________________________________ 49 
12.2 
Ethics and Regulatory Authority approval _____________________________________ 49 
12.3 
Financing ______________________________________________________________ 50 
13 
Informed consent process _____________________________________________ 51 
14 
Management and reporting of Adverse events, adverse device effects and device 
deficiencies _____________________________________________________________ 53 
14.1 
Definitions______________________________________________________________ 53 
14.1.1 
Adverse Event (AE) - Article 2 (57) from MDR _____________________________ 53 
14.1.2 
Serious Adverse Events (SAE) - Article 2 (58) from MDR ____________________ 53 
14.1.3 
Device deficiencies (DD) - Article 2 (59) __________________________________ 53 
14.1.4 
Incident – Article 2 (64) _______________________________________________ 54 
14.1.5 
Serious incident – Article 2 (65) ________________________________________ 54 
14.2 
Assessment of AE and SAEs _______________________________________________ 54 
14.3 
Reporting of medical device cases __________________________________________ 55 
14.4 
Sponsor’s responsibilities for safety reporting purposes __________________________ 56 
15 
Vulnerable population ________________________________________________ 56 
16 
Suspension or premature termination of the clinical investigation ___________ 57 
16.1 
Definitions______________________________________________________________ 57 

 
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16.2 
Criteria for suspension or early termination ____________________________________ 57 
17 
Publication policy ____________________________________________________ 58 
18 
Annex______________________________________________________________ 59 
18.1 
ANNEX I: IFU ___________________________________________________________ 59 
18.2 
ANNEX II: DT-034-PFM-520-01 Product risk management _______________________ 59 
18.3 
ANNEX III: PCQ _________________________________________________________ 59 
18.4 
ANNEX IV: PAC-QoL _____________________________________________________ 60 
18.5 
ANNEX V: VAS _________________________________________________________ 62 
19 
Bibliography ________________________________________________________ 63 
19.1 
Guides and standards for the preparation of the CIP ____________________________ 64 
Signature page __________________________________________________________ 65 
 

 
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LIST OF TABLES 
Table 1: Composition of the Petit Drill Syrup ......................................................................................... 18 
Table 2: Variables to be collected at patient enrolment ........................................................................ 31 
Table 3: Variables to be collected during patient follow-up by the parent/legal representative ............ 34 
Table 4: Variables to be collected by the investigator in case of AE or DD occurring during patient follow-
up ........................................................................................................................................................... 36 
 
 

 
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LIST OF ABBREVIATIONS  
ADE 
AE 
Adverse Device Event 
Adverse Event 
ANSM  
Agence Nationale de sécurité du médicament et des produits 
de santé 
CI 
Confidence Interval 
CIR 
Clinical Investigation Report 
CIP 
Clinical Investigation Plan  
CPP 
Comité de Protection des Personnes  
CRO 
Clinical Research Organization 
CSS 
Cough Symptom Score 
CSQ-8 
Client Satisfaction Questionnaire 
D0 
The day before treatment initiation 
D1 
The first day of treatment initiation 
D2 
The second day of treatment initiation 
D3 
Third day of treatment 
DD 
Device Deficiencies 
EC 
eCRF 
FAS 
Ethics Committee 
Electronic Case Report Form 
Full Analysis Set 
FDA 
Food and Drug Administration 
IMDRF 
International Medical Device Regulators Forum 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HCP 
Healthcare Professional  
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors 
IFU 
Instructions for Use 
K-LCQ 
Korean version of Leicester Cough Questionnaire 
MCID 
Minimum Clinically Important Difference 
MD  
Medical Device 
MDCG 
Medical Device Coordination Group guidelines 
MDD 
Medical Device Directive 
MDR 
Medical Device Regulation 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NBOG 
Notified Body Operations Group 
NRS 
Numeric Rating scale 
OTC 
Over-the-Counter 
PAC-QoL 
Parent-proxy 
Children's 
Acute 
Cough-specific 
QoL 
Questionnaire 

 
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PCQ 
Pediatric Cough Questionnaire 
PMCF 
Post-Market Clinical Follow-up 
PRO 
QoL 
Patient Reported Outcome 
Quality of Life 
QC 
Quality Control 
SAE 
SADE 
Serious Adverse Event 
Serious Adverse Device Effect 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
URTI 
Upper Respiratory Tract Infection 
VAS 
Visual Analogue Scale 
WHO 
World Health Organisation 
 
 
 
 
 

 
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1 SYNOPSIS OF THE CLINICAL INVESTIGATION 
Clinical investigation title  
The Performance and Safety of Petit Drill in the French Paediatric 
Population: a post-market clinical follow-up study. 
Sponsor  
Pierre Fabre Médicament  
Les Cauquillous, 81500 LAVAUR, FRANCE. 
Device description (name, 
model, etc.)  
Petit Drill: Glycerol Syrup Oropharyngeal Mucosa Protection Material 
PR2506. 
Class IIa medical device (MD) following Rule 5 and Rule 21 of Appendix 
VIII of the new medical device regulation (EU) 2017/745 (MDR). The 
device belongs to the category MDN 1213 “Non-active, non-implantable 
medical devices composed of substances to be introduced into the human 
body via a body orifice or the dermal route”. 
Petit Drill is a clear and colorless syrup consisting of glycerol (0.75 mL/5 
mL or 15% v/v), with a strawberry flavor presented in a 125 mL amber 
glass bottle of type III (Eur. Pharm. 3.2.1). The syrup is for oral use and to 
be applied with a measuring pipette. The 5 mL measuring pipette is 
included for dosing the oral situation. 
The pipette is a class I device with measuring function according to 
medical device directive 93/42/EEC. The measurement function of the 
pipette has been validated by Rovipharm for 60 uses (DT-034-PFM-324).  
Intended purpose  
The intended use is the treatment of throat irritation (sore throat) 
associated with dry cough for infants starting at 6 months of age and in 
children up to 6 years of age. 
Comparator(s)description, 
if applicable  
Not applicable. 
Clinical development 
stage  
Post-Market Clinical Follow-up. 
Design of the clinical 
investigation  
National (French), single-arm prospective, observational, longitudinal 
clinical investigation. 
Rationale  
Demulcent / Soothing substance is the currently recommended option to 
alleviate throat irritation associated to cough and sore throat in children 
under 6 years. The intended benefit to the patient of Petit Drill is to calm 
throat irritation (sore throat) associated to dry cough in infants starting at 
6 months of age and in children up to 6 years of age. This intended benefit 
sustained by the properties of the formula is recognized and promoted by 
the World Health Organization, health authorities and current textbooks to 
have a positive impact on patient management for the targeted population 
(infant / child).  
Pierre Fabre Médicament wishes to generate its own clinical data of this 
product in a real-life context, in order to support the clinical evaluation. 
Performance and the safety of Petit Drill will be assessed in children 
presenting throat irritation to support the conclusion of clinical evaluation 
report.  

 
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Objectives  
Primary Objective: 
To assess the performance of the Petit Drill medical device in the 
treatment of throat irritation (sore throat) associated with dry cough in 
infants starting at 6 months of age and in children up to 6 years of age.  
Secondary Objectives:  
x SO1. To describe the clinical and sociodemographic 
characteristics of children using Petit Drill. 
The following secondary objectives will describe the performance and 
clinical benefit of Petit Drill in terms of:  
x SO2. Changes in nightly cough frequency, severity, 
bothersome for the child, and ability to sleep for child and 
parent(s) throughout the 3 day-treatment;  
x SO3. Changes in daily cough severity;  
x SO4. Evolution of Quality of life. 
The following secondary objectives will describe the use and safety of 
Petit Drill:  
x SO5. Adherence to use of Petit Drill Syrup;  
x SO6. Parents’ satisfaction with Petit Drill use;  
x SO7. Safety of the Petit Drill medical device in infants aged 
from 6 months to children up to 6 years of age. 
Exploratory Objectives:  
x SO8. To describe the dispensing modalities of Petit Drill by 
age group;  
x SO9. To describe the study objectives (except SO8) 
according to child’s range of age.  
Duration of the clinical 
investigation  
Duration of the inclusion period: 9 months.  
Maximal duration of follow-up for a patient: 4 days.  
Overall study duration: 9 months.  
Number of Patients 
required and enrolment 
duration  
Determination of Sample Size:  
A total of 196 patients would provide the necessary precision of 7% of the 
confidence intervals (CI) for primary outcome in the most statistically 
unfavorable scenario (performance outcome of 50%), given that currently 
available publications cannot allow for an accurate estimate of the 
expected primary outcome for one device. 
In a previous observational study, a drop-out rate of 27% was observed in 
a cohort of children from 1 to 3 years of age, with a longer follow-up period 
and uncertainty regarding the mode of administration of patient 
questionnaires, which may suggest a slight overestimation compared to 
the proposed clinical investigation. Based on this result, a 20% drop-out 
is anticipated.  

 
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Number of patients to enrol: 245 patients (considering a 20% dropout 
rate).  
Enrolment duration: approximately 6 to 9 months (at least from 
November 2023).  
x Considering around 125 sites throughout France will be recruited 
and a 25% participation acceptance rate (optimal scenario) upon 
proposal of the clinical investigation, a maximum accrual period of 6 to 
9 months should allow to reach the target sample size.  
Eligibility Criteria  
Inclusion Criteria:  
Children meeting the following inclusion criteria will be included:  
x IC1. Boys or girls, 6 months to 6 years of age;  
x IC2. With one of his/her parents/legal guardian purchases 
Petit Drill in a participating pharmacy in accordance with 
recommendations for use (regarding age and type of cough);  
x IC3. For infants between 6 months and 12 months of age – 
a confirmed prescription from a treating physician;  
x IC4. With an acute dry cough lasting less than 48 hours 
x IC5. With a score ≥ 3 at least for 3 of the 5 items of PCQ, 
(based on assessment of the night before inclusion);  
x IC6. For whom child-minding will allow to respect the 
recommended daily doses* of Petit Drill during the 3 day-
treatment;  
x IC7. With a parent/legal guardian having a smartphone 
allowing using the ePRO App. NursTrial®;  
x IC8. With a parent/legal guardian able to understand and to 
complete to the questionnaires in timely manner;  
x IC9. With parent(s)/legal guardian who provide their signed 
informed consent for the child’s enrolment in the study.  
* 2-4 doses on D1, then 3 to 4 doses on D2 and D3, including one of the 
daily doses taken at bedtime.  
Exclusion Criteria:  
Children meeting one of the following exclusion criteria will not be 
included:  
Presenting with one of the following conditions: 
x 
EC1. Presenting with one of the following conditions: 
o 
Chronic respiratory illness such as asthma, recurrent 
wheezing associated to viral infections and bronchitis;  
o 
Lower 
respiratory 
infections, 
such 
as 
bronchitis, 
bronchiolitis, and pneumonia;  

 
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o 
Angina, otitis, or sinusitis;  
o 
Persistent cough lasting more than 3 weeks, whatever 
the etiology;  
o 
Gastrointestinal pathology, involving vomiting, nausea, or 
diarrhoea.  
x 
EC2. With ongoing use of paracetamol and/or homeopathic 
products against cough;  
x 
EC3. 
Having 
had 
corticosteroid 
treatment, 
antibiotics, 
antihistaminic or any cough medication (such as, but not limited 
to, Phytoxil, Arkotoux) in the previous 15 days since inclusion; 
x 
EC4. With a brother/sister already included in the present clinical 
investigation*;  
x 
EC5. Enrolled in another clinical trial or being in a period of 
exclusion from a previous clinical trial.  
* If several children are eligible in the same household, only one will be 
enrolled at random.  
Study 
endpoints/outcomes 
Primary outcome:  
The primary outcome will be the percentage of children with a 3 point-
decrease (minimal clinical significance) of the Pediatric Cough 
Questionnaire (PCQ) total score from baseline after up to 3 day-treatment 
with Petit Drill.  
The PCQ refers to a past night recall of 5 questions, each scored from 0 
“Not at all” to 5 “Extremely” using a 6-point Likert scale. PCQ Total score 
consists of the sum of each score and ranges from 0 to 25.  
Baseline value will rate the night before the first day of treatment with Petit 
Drill, and will be recorded at inclusion (D1). 
Final value will rate the night following 3 day-treatment or the night 
following the day of stopping the treatment, and will be collected on the 
next morning. 
Secondary outcomes: 
x SO1. 
Baseline 
clinical 
and 
sociodemographic 
characteristics of children will be summarized using 
descriptive statistics. 
Secondary criteria related to the performance and the clinical benefit of 
Petit Drill will be described as follow:  
x SO2. Score global and score of the 5 items of PCQ (Q1: 
cough frequency, Q2: sleep disturbance of the child, Q3: 
sleep disturbance of the parent, Q4: cough severity, Q5: 
degree of bothersomeness to the child) will be described after 
1, 2 and 3 day-treatment with Petit Drill. The percentage of 
children with a 3 point-decrease of PCQ total score from 

 
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baseline at 1 and 2 day-treatment with Petit Drill will be 
described;  
x SO3. Daily cough severity will be measured using visual 
analogue scale (VAS) ranging from 0 (no cough) to 100 (worst 
cough) in response to “Yesterday, how was the cough of my 
child during the day?”, measured VAS after 1, 2 and 3 day-
treatment with Petit Drill. The evolution of the severity from 
baseline will be described; 
x SO4. Scores of the Parent-proxy Children’s Acute Cough-
Specific Questionnaire PAC-QoL (global and dimensions) will 
be collected at baseline (D1) and after 3 day-treatment with 
Petit Drill (morning D4), or on the next morning of the last day 
of treatment. The evolution of scores from baseline will be 
described. 
Secondary criteria related to the assessment of use and the safety of Petit 
Drill will be described as follow:  
x SO5. The mean (SD) number of times Petit Drill was 
administered in each 24-hour period from the first (D1) to the 
third (D3) day of treatment initiation will be described;  
x SO6. Parent’s satisfaction with Petit Drill use will be 
described using a questionnaire, and responses measured 
using Likert scales. Responses will be presented as 
percentages; 
x SO7. Safety will be assessed by the analysis of:  
x  Adverse events (frequency, severity, emergence, and 
causal relationship of adverse events) tabulated 
according to IMDRF terms (International Medical Device 
Regulators Forum, Annex E). Number and percentage of 
relevant AEs during treatment with Petit Drill, defined as 
all SAEs or AEs related to the device, and any AEs of 
special interest;  
x Number and percentage of device deficiencies.  
Exploratory outcomes:  
x SO8. The percentage of children receiving Petit Drill with or 
without physician prescription will be described by two age 
groups: from 6 months to 12 months old and from 13 months 
old to 6 years of age;  
x SO9. To assess all outcomes, except SO8, in the subgroup 
of children aged 6-24 months and subgroup of children aged 
25 months to 6 years.  
Brief description of the 
clinical investigation  
Pre-screening: 

 
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Pharmacist will briefly present the clinical investigation to the parent who 
purchases Petit Drill for his/her child from 6 months to 6 years old. A 
prescription will be mandatory for infant patients from 6 to 12 months old.  
If the parent does not want to participate but gives the pharmacist his/her 
agreement, the pharmacist will record in a pre-screened log child’s age 
and gender, and main reason of parent’s refusal. 
If the parent is interested, the pharmacist will provide the study information 
note and transfer the parent’s name and contact information to the clinical 
investigation centre (CEN Expérimental).  
Inclusion visit: 
Upon receipt of a pre-screen patient, the parent will be contacted to take 
part to the remote inclusion visit with an Investigator (General Practitioner) 
of CEN Experimental, scheduled within the day of Petit Drill delivery. 
Before proceeding with the signing of the consent, the Investigator will first 
ensure that the parent is duly informed. Consent will be electronically 
signed using a solution (DocuSign) whose functionality meets 
recommended expectations of the Guidance on computerized systems 
and electronic data in clinical trials (EMA/INS/GCP/112288/2023). In non-
single-parent households, the informed parent who signed the consent will 
remain the one who completes the study data in the ePRO App 
NursTrial®.  
If several children are eligible in the same household, an algorithm will 
randomly select one of them. Then, the Investigator will check the 
inclusion and exclusion criteria, and proceed to the patient’s enrolment.  
The Investigator will record the necessary study data in the e-CRF (socio-
demographics, baseline medical data). A Clinical Research Associate will 
help the parent download the NursTrial® App on their smartphone and 
create their personal access. Then, the parent will complete the study 
questionnaires in the App.  
Study follow-up: 
The patient's follow-up will last as long as he/she receives Petit Drill but 
will not exceed 3 days and 3 nights.  
During the follow-up, the patient’s parent will have to complete the daily 
questionnaire and record Petit Drill intake in the App. Parents will be asked 
to inform the Investigator of any adverse event as soon as possible.  
Statistical Methods  
Method:  
The statistical analysis will be conducted in accordance with the protocol, 
and the Statistical Analysis Plan (SAP) which will precisely indicate the 
calculation of the variables, the populations studied (performance and 
safety), descriptive statistics, safety, handling of missing data. The SAP 
will be written as a separate document and approved prior to data review.  

 
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The data review will aim to comprehensively review the data and record 
decisions regarding the handling of outliers, and if necessary missing 
data.  
Analysis sets:  
The full set will be made up of all enrolled patients. 
The safety population will be made up of all patients who have used Petit 
Drill at least once.  
The performance population will be made up of all patients for whom at 
least one evaluation of the primary outcome is available. 
Statistical analyses:  
All study outcomes will be analyzed using descriptive statistics. 
Continuous variables will be described by the mean, standard deviation 
(SD), median and range and quartile (Q1 and Q3). Some continuous 
variables may be converted to categorical variables, for which the 
numbers and increments may be defined in a more detailed statistical 
analysis plan (SAP). Categorical and ordinal variables will be described 
by the number and percentage of patients in each category, and the 
number and percentage of patients with missing information.  
Confidence intervals of 95% will be calculated for the primary outcome 
and the safety secondary outcomes.  
Missing data:  
In case of missing data or loss to follow-up, sensitivity analyses could be 
carried out to estimate the impact of missing data on the primary outcome. 
 
 

 
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2 IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
2.1 
Summary Description of the investigational device 
Oropharyngeal Mucosa Protection Material PR2506 is a clear and colorless syrup with a strawberry 
flavor presented in a 125 ml bottle. The syrup is for oral use and to be applied with a measuring pipette. 
The 5 ml measuring pipette is included for dosing the oral solution. 
 
Oropharyngeal Mucosa Protection Material PR2506 is a class IIa device following Rule 5 and Rule 21 
of the new MDR. The applicable EMDN code for the syrup is Q0399: ENT DEVICES – OTHERS.  
 
The pipette is a class Im device with measuring function following rule 1 of the Medical Device Directive 
(MDD) 93/42/EEC. The measurement function of the pipette has been validated by Rovipharm, for 60 
uses (DT-034-PFM-324). The pipette falls under EMDN code A99 – DEVICES FOR ADMINISTRATION, 
WITHDRAWAL AND COLLECTION – OTHER.  
 
Oropharyngeal Mucosa Protection Material PR2506 was initially CE marked by Pierre Fabre in 2013.  
 
 
2.2 
Manufacturer of the Investigational Device 
The legal manufacturer of the syrup is: 
Pierre Fabre Médicament 
Les Cauquillous 
81500 Lavaur, France 
 
The legal manufacturer of the measuring pipette is: 
Rovipharm 
ZA de Lucinges 
86 route du plan d’eau, 
01370 Val-Revermont, France. 
 
The procedure pack is assembled by:  
Pierre Fabre Médicament 
Les Cauquillous 
81500 Lavaur, France 
 
2.3 
Model/type of the Investigational Device 
Oropharyngeal Mucosa Protection Material PR2506 
 
 
2.4 
Traceability 
Not applicable, as the product is commercialized (per Annexe I, clause 7 d) 2) of the EN ISO 14155 
2020).  
 
 

 
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2.5 
Intended Purpose  
The intended use is the treatment of throat irritation (sore throat) associated with dry cough for infants 
starting at 6 months of age and in children up to 6 years of age. 
 
 
2.6 
Populations and Indications 
Treatment of throat irritation (sore throat) associated with dry cough for infants from 6 months of age 
and in children up to 6 years of age.  
 
2.7 
Clinical, Technical and Biological Description of the Investigational Device 
Description of the investigational device, including any materials, that will be in contact with tissues or 
body fluids. This shall include details of any medicinal substances, human or animal tissues or their 
derivatives, or other biologically active substances and reference to compliance with applicable national 
regulations. 
 
The primary component of this syrup is glycerol (0.75 mL/5 mL). Table 1 provides further information 
with regards to the product’s composition.  
 
Table 1: Composition of the Petit Drill Syrup 
Ingredient 
Function 
Specifications 
% (g/ 100 
ml) 
Quantity per 
bottle (g) 
Quantity 
per 
pilot 
batch (kg) 
Quantity 
per batch 
(kg) 
Glycerol 99.5%  
Emollient  
Eur.Ph 
(Monograph 
No.0496) 
18.90%  
23.625  
37.8  
378 
Maltitol liquid  
Sweetener  
Eur.Ph 
(Monograph 
No.1236)  
15.00%  
18.75 
30 
300 
Hydroxyethylcellulose  
Thickening and 
viscosity 
increasing 
agent 
Eur.Ph 
(Monograph 
No.0336) 
0.60%  
0.75 
1.2 
12 
Sodium benzoate  
Preservative  
Eur.Ph 
(Monograph 
No.0123)  
0.10%  
0.125 
0.2 
2 
Citric 
acid 
monohydrate  
Antioxidant  
Eur.Ph 
(Monograph 
No.0456) 
0.50%  
0.625 
1 
10 
Sodium citrate  
Buffering agent  Eur.Ph 
(Monograph 
No.0412)  
0.40%  
0.5 
0.8 
8 
Strawberry flavour  
Flavour 
enhancer 
In House  
0.15%  
0.188 
0.3 
3 
Purified water  
Solvent  
Eur.Ph 
(Monograph 
No.0008) + In house 
-  
qs 125Ml  
qs 200L  
qs 2000L  
Total  
-  
-  
100.00  
125 ml  
200 L  
2000L  
 
Oropharyngeal Mucosa Protection Material PR2506 forms a protective film and keeps throat moisturized 
due among others to the properties of glycerol. Under physiological conditions, a thin layer of watery 
mucus covers the throat and helps to keep it moist and lubricated. However, environmental influences, 

 
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systemic conditions or disease states may lead to pharyngeal dryness and increased viscosity, 
thickness and tackiness of secretions, which may provoke discomfort and cough [3]. 
 
The medical device presented here achieves its intended purpose by means of its main component 
glycerol which is a well-known demulcent agent. The efficacy of glycerol is related to its physical and 
chemical properties, as glycerol does not have any known pharmacological actions [4]. Indeed, 
hygroscopicity, or the ability to absorb moisture from the atmosphere/environment and hold it, is among 
the most valuable attributes of glycerol. Glycerol will absorb more than half of its weight of moisture 
when left exposed to the air. In addition, glycerol is characterized by a low volatility or low vapor pressure 
and high viscosity [4, 5]. These characteristics provide outstanding permanent humectancy, flexibility 
and plasticity. 
 
Due to its properties (i.e., emollient/demulcent qualities and high viscosity), glycerol has the ability to 
form a soothing film covering the irritated mucous membrane of the throat and pharynx in patients 
suffering from cough. This coating film serves to lubricate and moisten the delicate pharyngeal mucosal 
tissues and to reduce the friction between moving surfaces of the pharynx and tongue, thus alleviating 
irritation while offering some protection from irritants such as smoke or dust particles. Glycerol may also 
influence the structure of the protein surface of the pharynx by decreasing the volume of proteins, and 
this may contribute to smoothing the surface and a lubricant effect. Overall, soothing of the throat helps 
reducing dry cough through a reduction of the afferent impulses from inflamed/irritated pharyngeal 
mucosa without centrally masking the cough reflex [4, 6-9]. 
 
In particular, a 2001 World Health Organization (WHO) report [9] states that demulcents may be useful 
to reduce cough associated with a dry throat in coating the throat and soothing irritated mucus 
membranes in children. It confirms the claimed mode of action by coating or lubrification of the posterior 
pharynx.  
 
2.8 
Training requirements 
No special training is required to administer the product. The instructions for use (IFU) for this device 
explain how parents can give the treatment to their children using the pipette. 
 
2.9 
Special Medical Procedures 
No special medical procedures are involved in the use of this device. Adult users should be able to 
administer the product to their children after reading the IFU. Petit Drill syrup, however, must be kept 
out of reach of children, especially the pipette.  
 
2.10 Instructions for Use 
The IFU for the device is provided in ANNEX I: IFU 
Briefly, the device is recommended to be used up to 4 times in 24 hours, as needed. At each 
administration, a single dose of 5 mL is to be given to infants and children between 6 months and 6 
years of age. 
 

 
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3 JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION 
3.1 
Background and Rationale 
Coughing is one of the body's natural, necessary reflexes to clear the respiratory tract. It is triggered by 
the irritation of sensory nerves caused by the mechanical stimulation of the pharynx and tongue surfaces 
sliding over each other during swallowing and speech [4]. There are different kinds of cough: 
"productive" cough, associated with expectorations (mucus secretions), or dry cough, called "non-
productive," without expectoration. 
 
Dry cough is accompanied by a stinging sensation in the throat which generally intensifies at night, lying 
down, deteriorating the quality of life (QoL). Approximately one in ten of the population suffers from 
chronic cough, half of it interfering with daily activities [10]. Cough in children is different from that in 
adults in terms of duration, presentation, etiology and management. Common causes of acute cough in 
children are viral upper respiratory tract infections (URTI) and acute bronchitis, possibly associated to a 
pulmonary consolidation (medical diagnosis by thoracis auscultation (pulmonary rales such as crackles). 
In school children, URTIs with cough typically occurs 7-10 times per year [1]. 
 
An ideal cough treatment for children should relieve symptoms without any serious adverse effect and 
should not mask concomitant infection. Current cough management alternatives for the target 
population (from 6 months to 6 years of age) include medicinal products, medical devices or herbal 
preparations, available over the counter (OTC) or under prescription, which are based on various modes 
of action [9]. These include: 
 
x 
Cough relieving products: 
o 
Centrally acting cough suppressants: codeine & other 
opiate derivatives, 
dextromethorphan, antihistamines, corticosteroids and steroids; 
o 
Soothing remedies: demulcents, including glycerol preparations; 
o 
Clearing products: expectorants, mucolytics, oral hydration and mist therapy. 
x 
Natural remedies, such as lemon, honey, eucalyptus, etc. 
3.1.1 
Risks associated with existing cough relief treatments 
In 2007, the Nonprescription Drug Advisory Committee to the Food and Drug Administration (FDA) and 
Paediatric Committee voted for immediate action against the use of cough and cold medicines in 
children under the age of six because of their side-effects [1]. 
 
FDA does not recommend the use of these products in children below two years of age and withdrew 
some OTC cough products or restricted their use in children, especially those under the age of two years 
due to serious and life-threatening adverse effects [4, 11, 12]. Health Canada does not recommend their 
use in children below the age of six.  
 
The risks and benefits of OTC cough remedies for children were reassessed by the Medicines and 
Healthcare products Regulatory Agency (MHRA) in 2009 [13], following which it was concluded that 
antitussives (dextromethorphan and pholcodine), expectorants (guaifenesin and ipecacuanha), nasal 
decongestants (ephedrine, oxymetazoline, phenylephrine, pseudoephedrine, and xylometazoline) and 
antihistamines (brompheniramine, chlorphenamine, diphenhydramine, doxylamine, promethazine, and 
triprolidine) should be prohibited in children under 6 years of age. These products may be administered 
in children between 6-12 years, subject to basic principles of best care and available in pharmacies 
where advice can be given.  
 

 
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3.1.2 
Glycerol as an effective and safe alternative for dry cough management 
The WHO [9] and MHRA [13] recommend the use of soothing products in children under the age 
of 6 years as an alternative to medicinal products with a negative benefit/risk ratio. Soothing syrups 
that contain demulcents like glycerol, have been reported to be frequently used and safe and it has been 
concluded that their use should be encouraged in children. The effect of the demulcents is attributed to 
the “coating” or lubrication of the posterior pharynx.  
 
Glycerol does not have any known pharmacological actions, and its efficacy is related to its physical and 
chemical properties:  
x Glycerol coats and lubricates the pharyngeal surface (demulcent and lubricant properties), thus 
helping in reducing the friction between moving surfaces while swallowing and speaking. 
x Inflamed mucosal surfaces in the pharynx may also be soothed by the moisturizing properties of 
glycerol. 
x Glycerol may also decrease the volume of proteins on the pharyngeal mucosa, which may 
contribute to the lubricant effect [4]. 
x The sweet taste in cough syrups has been suggested to influence the production of endogenous 
opioids and therefore modulate cough at the level of the nucleus tractus solitarius [4]. 
The safety profile of glycerol is well known and has been documented since the beginning of its use in 
therapy, as an excipient in medicinal products or as an ingredient in the agro-alimentary industry. No 
significant toxicity has been reported following prolonged use of glycerol in humans. Glycerol is rapidly 
incorporated in standard metabolic pathways where it is completely bio-transformed by the body to 
endogenous compounds. 
 
3.1.3 
Rationale 
Petit Drill is a clear and colorless syrup, consisting of glycerol (0.75mL/5mL or 15% v/v) presented in an 
amber glass bottle of type III (Eur. Pharm.3.2.1.), intended to be filled with 125 mL solution, with 
polypropylene child resistant closure. A 5 mL measuring pipette is included with Petit Drill, for dosing 
the oral solution.  
 
Petit Drill was initially CE marked in 2013 under the Medical Devices Directive 93/42/EEC as Class I 
medical device. Due to new classification rules under the Regulation (UE) 2017/745 (MDR), it has been 
upgraded to Class IIa.  
 
The clinical evaluation of this device has been categorized as a “Well Established Technology” 
according to MDCG 2020-6 (April 2020). Nevertheless, Pierre Fabre Médicament wishes to generate its 
own clinical data of this product in a real-life context, in order to support the clinical evaluation. 
 
3.2 
Evaluation of relevant pre-clinical assessment 
 
The toxicological profiles of all ingredients were evaluated on the basis of the quantitative formulation 
of Petit Drill cough syrup. All of the ingredients in the Petit Drill cough syrup are well characterized in 
analytical, microbiological and toxico-pharmacological contexts. A biological evaluation of Petit Drill 
cough syrup has been conducted in conformity among others to the requirements of EN ISO 10993-1, 
EN ISO 10993-5, EN ISO 10993-9 and EN ISO 10993-10.  
 
Results from the literature review performed on each component to evaluate the different biological 
endpoints identified in the risk management process according to EN ISO 10993-1, indicate that Petit 

 
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Drill cough syrup is not expected to induce cytotoxicity, sensitization or irritation. The local tolerance of 
the medical device was confirmed in biocompatibility studies (Biological Evaluation Report DT-034-
PFM-630). 
 
3.3 
Evaluation of relevant clinical data 
3.3.1 
Description of the pathology 
Coughing is one the body’s natural, necessary reflexes to clear the respiratory tract. There are different 
kinds of cough: chesty cough, called “productive”, associated with expectorations (mucus secretions), 
or dry cough, called “non-productive”, without expectoration. Dry cough is accompanied by a stinging 
sensation in the throat which generally intensifies at night, deteriorating the patient’s quality of life. 
 
3.3.2 
Data issued from clinical published studies on similar devices 
No clinical trials on demulcent glycerol-based syrups are available in the pediatric population affected 
by acute cough. A single sponsored limited randomized, placebo-controlled trial investigating glycerol 
in adult patients suffering from dry cough is cited in the systematic review conducted by the Italian 
Society of Pediatric Allergy and Immunology for Acute cough in children and adolescents published in 
2021 [14]. This trial was sponsored by Naturveda Laboratory [4]. The experimental device is described 
as a hypertonic, highly osmotic, filmogen glycerol-based spray. The main inclusion criteria were: patients 
male and female in the 18-65 years age group presenting all clinical signs and symptoms of severe dry 
cough, sore throat with pain, and inflammation. The authors report that the group receiving the 
experimental filmogen glycerol-based spray showed a significant decrease in the mean scores of dry 
cough severity and frequency, throat pain, irritation, swelling, and redness when compared to saline 
placebo spray. No further details are given for the experimental formula. It is unknown if this 
experimental spray has obtained "market clearance".  
 
Although, no clinical data are available in the pediatric population, cough syrups containing glycerol are 
promoted as the first-choice of cough treatment in infants and children up to 6 years old by health 
organizations (such as the WHO [9] and MHRA [13]) and professional guidelines.  
 
Evidence-based reviews, systematic reviews and guidelines demonstrate the physiological effect of 
glycerol demulcent, thus establishing the ability of the demulcent to soothe the throat and to reduce 
symptoms of coughing.  
 
3.3.3 
Data issued from clinical investigations on the device 
Pierre Fabre participated in the MAGICIA study [15] (MAnagement of couGh for Infants and Children 
during Infections of Airways). This study aimed at assessing the impact of acute cough on patients’ and 
parents’ sleep and children’s activities in four European countries (Greece, Poland, Belgium and 
Portugal). MAGICIA study [15] was not designed explicitly for the evaluation of Petit Drill (known as 
Balsokids in Belgium). The benefits of Petit Drill could not be evaluated in the MAGICIA study because 
of the concomitant use of other medications in included patients.  
 
The MAGICIA had a follow-up period of one week. The main objective of the study was to assess the 
impact of acute dry or mixed cough on the patient’s and parents’ sleep and activities. Secondary 
objectives included: evaluation the social impact of acute cough, description of symptoms associated 
with acute cough, of the therapeutic management of acute cough by pediatricians and general 
practitioners in each country, of cough evolution on one-week follow-up, of parents’ observance and 

 
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satisfaction with treatment and therapeutic management, and of the profile of patients suffering from 
acute cough. 
 
Children aged six months to six years visiting their general practitioner or pediatrician for common upper 
respiratory infections associated with acute dry or mixed cough, for up to three days before physician 
examination, were included. Exclusion criteria included receipt of antibiotics or corticosteroids during 
the past two weeks, diagnosis of chronic disease and need for hospitalization. These criteria aimed at 
including only patients with acute banal cough secondary to common viral infections without 
complications.  
 
Ethical approval of this study was obtained from the relevant local ethics committees in Belgium, 
Portugal and Greece. Ethics approval was not required in Poland. Parental written informed consents 
were obtained, and all data were stored in an anonymous form.  
 
The study included 1239 children (mean age: 3.1±1.7 years) aged six months to six years. Medicinal 
products were often prescribed (83.6–99.6% of the patients), mainly demulcent syrup (except in 
Portugal) and antipyretics, while active antitussives with pharmacological agents were less often 
prescribed. In Portugal, a high proportion of patients (46.5%) received antibiotics compared to the three 
other countries. Petit Drill (or Balsokids) was reported as having been taken by patients in 218 children 
(49.6%) in Greece, 257 (55.3%) in Poland, 73 (47.7%) in Belgium and in none in Portugal; that is, a total 
of 548 patients of 3.1 (±1.7) years, (44.2% of the cohort of 1239).  
 
As most of the children (n=474) received other medications as well, it was not possible to evaluate the 
efficacy of glycerol syrup. However, 115 patients were prescribed only saline rinses and glycerol syrup 
as a treatment for cough, and 74 took only glycerol syrup between D0 and D7. The profile of the patients 
receiving glycerol syrup alone seems to be children with fewer symptoms such as fever, runny nose, 
nasal congestion, body aches, sore throat or ear pain, diarrhea, vomiting or reduced 
appetite. Compliance was high; 82.1% in Greece, 96.8% in Poland, 91.6% in Belgium and 89.3% in 
Portugal. When Petit Drill was prescribed, compliance was 83% in Belgium, 91% in Poland and 95% in 
Greece; this brand was not prescribed in Portugal.  
 
Overall, at D0, cough frequency was reported as occasional in 26.9% of patients; frequent in 60.1%, 
and almost permanent in 12.9%. This decreased over time, being occasional at D7 in 89.8% of patients, 
frequent in 9.4% and almost permanent in 0.9%. At D0, cough intensity was mild in 23.7% of patients, 
moderate for 54.3% and severe for 22.0%, while these frequencies were 87.6%, 10.6% and 1.8%, 
respectively at D7.  
 
Parents’ satisfaction was assessed using the Client Satisfaction Questionnaire which includes eight 
questions (CSQ-8) related to initial information and advice, therapeutic management, with score ranging 
from 8 (very dissatisfied) to 32 (very satisfied) or on a visual analogue scale (0–10). At D7, the CSQ-8 
scores evaluating parents’ satisfaction ranged from 17 to 32 (maximum value of the score). The mean 
score in the three countries using the CSQ-8 was 27.8/32. Specifically, the mean CSQ-8 score was 29.5 
in Greece, 28.3 in Poland and 21.7 in Belgium. In Portugal, satisfaction was assessed with a visual 
analogue scale and the mean score was 9.2 out of 10. The mean CSQ-8 score assessing parents’ 
satisfaction for the population of children who received only glycerol syrup was 29.6 (out of 32), which 
was slightly higher than the country-wise mean satisfaction scores obtained in children who also 
received other treatments (21.7–29.5).  
 

 
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No complaints or vigilance cases related to the intake of glycerol syrup have been reported in any of the 
four countries. Additionally, this study confirms the absence of undesirable side effects due to possible 
interactions of demulcent syrups with drugs.  
 
3.3.4 
Safety data recorded from vigilance records 
 
The tested product is already CE marked and has been on the market in several European countries 
since 2013. Up to 31-Aug-20232023, 47 cases were received for the tested product. Only 11 cases were 
associated with adverse reactions and all were assessed as non-serious. 
 
The recorded safety data did not highlight any safety concern and showed good tolerability of the 
product. 
 
3.4 
Clinical development stage  
This is a post-market clinical investigation, which aims to confirm clinical safety and performance data 
on the Petit Drill® Syrup.  
 
 

 
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4 RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL 
INVESTIGATION 
4.1 
Anticipated clinical benefits 
The anticipated clinical benefits are not different to those claimed in the IFU of the device. 
Petit Drill® Syrup soothes the irritation associated with dry cough by coating and moisturizing the throat. 
Due to its composition, Petit Drill® Syrup forms a protective film and moisturizes the throat, which makes 
it possible to calm the irritation and sore throat associated with dry cough.  
 
4.2 
Anticipated adverse device effects 
Risks associated with the investigational device and its related clinical procedure shall be estimated in 
accordance with EN ISO 14971 prior to design and conduct of a clinical investigation (see Annex H of 
EN ISO 14155-2020). The risk assessment shall include or refer to an objective review of published and 
available unpublished medical and scientific data. 
A summary of the benefit-risk analysis shall be disclosed in the relevant clinical investigation documents.  
The CIP shall include all anticipated adverse device effects and a rationale for the related benefit-risk 
ratio (see Annex A of EN ISO 14155-2020).  
The risk assessment is provided in the Petit Drill Product Risk Management document DT-034-PFM-
520-01, which is provided in ANNEX II: DT-034-PFM-520-01 Product risk management. 
 
4.3 
Risks associated with participation in the clinical investigation 
The participants in this clinical investigation will not be exposed to any additional risks than those 
disclosed in the above sections, as this device is intended to be used as described in the IFU and in 
real-life practice.  
 
4.4 
Possible interactions with concomitant medical treatments 
None known to date. 
 
4.5 
Actions to control or mitigate risks 
These actions have been detailed in the Petit Drill Product Risk Management document DT-034-PFM-
520-01, which is provided in ANNEX II: DT-034-PFM-520-01 Product risk management. 
Most identified risks could be mitigated by following the instructions for usage and safe storage of the 
device, that have been elaborated in the IFU (ANNEX I: IFU). 
 
4.6 
Risk-to-benefit rationale 
There will be no additional benefits or risks to the patient participating in the investigation, as it is a real-
life observational study in which the device will be used per the IFU. 
 
The results of this investigation would be essential for obtaining clinical data on device performance and 
safety, which will be utilized to support the clinical evaluation of the device as it is upgraded from a Class 
I to a Class IIa device, per the MDR, as explained in section 3.1.3.  
 

 
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No potential threats to this observational study have been identified, and no interactions with 
concomitant interventions are anticipated, other than those addressed in sections 4.2 and 4.3.  
 
 

 
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5 OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
The objective of this investigation is to obtain real-life clinical safety and performance data to support 
the current clinical evaluation of the Petit Drill device.  

5.1 
Objectives 
5.1.1 
Primary objective 
To assess the performance of the Petit Drill medical device in the treatment of throat irritation (sore 
throat) associated with dry cough in infants starting at 6 months of age and in children up to 6 years of 
age. 
 
5.1.2 
Secondary objectives 
x SO1. To describe the clinical and sociodemographic characteristics of children using Petit 
Drill. 
The following secondary objectives will describe the performance and clinical benefit of Petit Drill in 
terms of:  
x SO2. Changes in nightly cough frequency, severity, bothersome for the child, and ability 
to sleep for child and parent(s) throughout the 3 day-treatment;  
x SO3. Changes in daily cough severity;  
x SO4. Evolution of Quality of life. 
The following secondary objectives will describe the use and safety of Petit Drill:  
x SO5. Adherence to use of Petit Drill Syrup;  
x SO6. Parents’ satisfaction with Petit Drill use;  
x SO7. Safety of the Petit Drill medical device in infants aged from 6 months to children up 
to 6 years of age. 
5.1.3 
Exploratory objectives 
x SO8. To describe the dispensing modalities of Petit Drill by age group; 
x SO9. To describe the study objectives (except SO8) according to child’s range of age.  
5.2 
Hypotheses (if applicable) 
Since this is an observational study, there are no formal hypotheses to test. 
 
5.3 
Risks and anticipated adverse device effects to be assessed 
No additional risks or anticipated device effects were observed since the first CE mark application, apart 
from the ones already known or identified. Clinical safety data for Petit Drill will be obtained for the first 
time as part of a clinical investigation. 
 

 
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6 CLINICAL INVESTIGATION DESIGN 
6.1 
Type of clinical investigation 
This will be an observational, prospective, single-arm descriptive clinical investigation, monocentric with 
national (French) patient pre-screening, which will not mandate or recommend any additional 
interventions or in-person visits. Since Petit Drill is an OTC treatment, patient contact, eligibility pre-
screening will occur via pharmacies selling this device. Enrolment of the patients will be conducted 
remotely by the investigators (General Practitioners) of the Clinical Investigation Centre CEN 
Experimental located in DIJON (France). 
All decisions regarding the treatment of included patients could be made by the investigators, dispensing 
pharmacist, and prescribing physician where applicable. All patients will be treated according to the local 
clinical practice and their parent/legal guardian will be instructed to fill questionnaires via a mobile 
application at specific timepoints.  
 
The investigation and data collection are patient centered. The secure mobile application for PRO 
NursTrial® will be used to allow parents/ legal guardians to record the following data: 
x 
Any AEs that may occur during the 3-day/3-night follow-up period; 
x 
The number of times Petit Drill was administered to the patient on a daily basis; 
x 
Patient-reported outcomes (PRO) – questionnaires to be filled by the patient to provide their 
assessment of the performance and useability of the device and their quality of life. 
  
6.2 
Bias minimization 
1) Site and patient selection bias: Parent/legal representative of patients who refuse to participate 
may limit the representativeness of the study results. A screening log (see section 6.4) will be 
maintained, which will capture selected details from patients who were excluded or who parent/legal 
representative refused to participate, in order to counter this limitation. Another aspect is that this 
device can be purchased online, whereas recruitment will only be carried out via pharmacies. 
Therefore, patients who use Petit Drill syrup through online purchases will not be covered by this 
study. 
 
2) Attrition bias: patients lost to follow-up are the main source of attrition bias in cohort studies. This 
can threaten sample representativeness if too many patients are lost to follow-up or if they differ 
from patients continuing follow-up (such as in their baseline characteristics or in their outcomes). To 
minimize any risks and potential impact, efforts will be undertaken to collect the data from the lost-
to-follow up patient’s most recent data recording, and investigators will be encouraged to contact 
the patient for a discontinuation assessment. Baseline characteristics of patients lost-to-follow up 
and those who completed the investigation may also be described to assess representativeness. 
Nevertheless, the follow-up period for this investigation is very short (3 days), the mobile application 
will send alerts resulting in parent/legal representative recall. Taken together, these measures are 
expected to minimize attrition bias.  
 
3) Recall bias: is an inherent limitation of recollections from events or experiences from the past. This 
may apply to data collected for certain time periods in the past, such as the onset of improvement 
following treatment administration from the previous night. Since the periods of recall for this 
investigation will be very short, the impact of this bias will be minimized. Additionally, parents will be 
briefed on important timepoints from which data is to be retained so they are aware of the most 

 
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important information that needs to be retained for recording. As just mentioned above, missing data 
will result in alerts and recall of parent/legal representative. 
 
4) Measurement error and missing data: This investigation relies on the patients’ parents recording 
data for most study outcomes. Since they are not trained professionals and not used to responding 
to medical questionnaires, human error is to be anticipated in the estimation of numerical data, in 
the interpretation of questionnaires and in the recording of information. Measures will be put in place 
during eCRF and the mobile application NursTrial® to minimize these errors. The following quality 
checks are anticipated: 
- 
Limiting the use of free fields for data entry – limiting responses to multiple choice questions, or 
list selection; 
- 
Prompts and reminders in case of missing data. 
In case of missing data or loss to follow-up, sensitivity analyses could be carried out to estimate the 
impact of missing data on the primary outcome. 
 
6.3 
Outcomes 
6.3.1 
Primary outcome 
The primary outcome will be the percentage of children with a 3 point-decrease (minimal clinical 
significance) of the Pediatric Cough Questionnaire (PCQ) total score from baseline after up to 3 day-
treatment with Petit Drill.  
The PCQ refers to a past night recall of 5 questions, each scored from 0 “Not at all” to 5 “Extremely” 
using a 6-point Likert scale. PCQ Total score consists of the sum of each score and ranges from 0 to 
25.  
Baseline value will rate the night before the first day of treatment with Petit Drill, and will be recorded at 
inclusion (D1).  
Final value will rate the night following 3 day-treatment or the night following the day of stopping the 
treatment, and will be collected on the next morning. 
6.3.2 
Secondary outcome(s) 
x SO1. Baseline clinical and sociodemographic characteristics of children will be 
summarized using descriptive statistics;  
Secondary criteria related to the performance and the clinical benefit of Petit Drill will be described as 
follow:  
x SO2. Score global and score of the 5 items of PCQ (Q1: cough frequency, Q2: sleep 
disturbance of the child, Q3: sleep disturbance of the parent, Q4: cough severity, Q5: degree 
of bothersomeness to the child) will be described after 1, 2 and 3 day-treatment with Petit 
Drill. The percentage of children with a 3 point-decrease of PCQ total score from baseline 
at 1 and 2 day-treatment with Petit Drill will be described;  
x SO3. Daily cough severity will be measured using visual analogue scale (VAS) ranging 
from 0 (no cough) to 100 (worst cough) in response to “Yesterday, how was the cough of 

 
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my child during the day?”, measured VAS after 1, 2 and 3 day-treatment with Petit Drill. the 
evolution of scores from baseline will be described; 
x SO4. Scores of the Parent-proxy Children’s Acute Cough-Specific Questionnaire PAC-
QoL (global and dimensions) will be collected at baseline (D1) and after 3 day-treatment 
with Petit Drill (morning D4), or on the next morning of the last day of treatment. The 
evolution of scores from baseline will be described. 
Secondary criteria related to the assessment of use and the safety of Petit Drill will be described as 
follow:  
x SO5. The mean (SD) number of times Petit Drill was administered in each 24-hour period 
from the first (D1) to the third (D3) day of treatment initiation will be described;  
x SO6. Parent’s satisfaction with Petit Drill use will be described using a questionnaire, and 
responses measured using Likert scales. Responses will be presented as percentages;  
x SO7. Safety will be assessed by the analysis of:  
x  Adverse events (frequency, severity, emergence, and causal relationship of adverse 
events) tabulated according to IMDRF terms (International Medical Device Regulators 
Forum, Annex E). Number and percentage of relevant AEs during treatment with Petit 
Drill, defined as all SAEs or AEs related to the device, and any AEs of special interest;  
x Number and percentage of device deficiencies.  
6.3.3 
Exploratory outcomes 
x SO8. The percentage of children receiving Petit Drill with or without physician prescription 
will be described by two age groups: from 6 months to 12 months old and from 13 months 
old to 6 years of age;  
x SO9. To assess all outcomes, except SO8, in the subgroup of children aged 6-24 months 
and subgroup of children aged 25 months to 6 years.  
PRO questionnaires in order to assess the user’s perspective of the device’s performance are given 
below. The variables for each questionnaire are detailed in section 6.4. 
 
The Pediatric Cough Questionnaire (PCQ) (Annex III) 
The PCQ is a reliable and validated questionnaire by Hartnick et al. [17]. The five questions, which could 
be answered by the child's parent or proxy, cover cough frequency (Q1), sleep disturbance of the child 
(Q2), sleep disturbance of the parent (Q3), cough severity (Q4), and the degree of bothersomeness to 
the child (Q5). Each of the five items was scored on a 6-point Likert scale, from 0 to 5, and possible over 
scores range from 0 to 25. The higher the scores, the higher the severity. A 3-point difference in PCQ 
score is clinically significant. 
 
Parent-proxy Children’s Acute Cought-Specific Questionnaire (PAC-QoL) (Annex IV) 
The PAC-QoL instrument is an acute cough-specific QoL in young children, that measures the burden, 
of acute cough in children. Original PAC-QoL16 has been validated by Anderson-James et al. [18], then 
re-validated by Anderson-James et al. [19] concomitantly with the shorter form of 6 items (PAC-QoL6), 
that has been found as robust and as reliable than the 16 item-form. 
PAC-QoL6 consisted of 6 items utilizing a 7-point Likert-type rating scale (1 = all the time or very, very 
worried and concerned to 7 = none of the time or not worried and concerned). Items referred to a 24-
hour recall. Higher PAC-QoL scores reflect better QoL with lower scores reflecting greater frequency 

 
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and worries or concerns. The minimal clinical significance for the overall PAC-QoL6 questionnaire is 
therefore estimated to be 0.71–1.11 [19]. 
 
 
Daily cough severity using an electronic VAS (Annex V) 
Subjective assessment of cough severity using 0-100 VAS for rating cough severity (0: no cough to 100: 
worst cough) has been validated by Lee et al. [20]. In this clinical investigation, subjective assessment 
of cough severity will be performed using e-VAS thanks to NursTrial® App. Even length of the scale 
could vary depending on the screen of the patient’ smartphone, electronic and paper VAS presented 
comparable results, as 100 mm length is not a requirement [21]. 
 
6.4 
Variables 
Variables to be collected in pre-screening log by the pharmacist: 
x Patient age in years and months; 
x Reason for non-inclusion to the investigation (if applicable). For example: antibiotics, previous cough 
treatment; 
x Reason for refusal to participate in the investigation (if applicable). 
 
Variables to be collected in screening log by the investigator: 
x Patient age in years and months; 
x Reason for non-inclusion to the investigation (if applicable); 
x Approximate date of dry cough start; 
x PCQ-score (based on the recall of the night prior inclusion) – only patients with a score of 3 or above 
at least for 3 of the 5 items of PCQ are to be included (see section 6.9.1). 
 
Table 2: Variables to be collected at patient enrolment  
Sociodemographic data and dispensing 
modalities 
Age in years and months 
(To be recorded by the investigator in the 
eCRF) 
Rank among siblings 
 
Weight and height 
 
Sex and geographic region 
 
Did the patient receive a doctor’s prescription for Petit 
Drill? (Yes/No) 
Baseline medical data 
Pre-existing medical conditions 
(To be recorded by the investigator in the 
eCRF) 
Investigator’s assessment of patient’s condition 
Acute dry cough Yes/No  
 
Approximate date of dry cough start 
 
Prior treatments for ongoing cough 
 
Ongoing, non-interfering medications 
 
Associated symptoms at baseline 
 
Fever (Yes/No) 
 
Runny nose (Yes/No) 
 
Congestion (Yes/No) 
 
Sore throat (Yes/No) 
 
Ear Pain (Yes/No) 
 
Sensation of pain or more frequent crying than usual 
(Yes/No) 
 
Digestive symptoms (vomiting or diarrhoea) (Yes/No 
 
Reduced appetite (Yes/No) 
PCQ (to be recorded by the parent/legal representative in the NursTrial® app with the help of 
the investigator) 

 
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Q1. How frequent was your child's cough 
last night? 
0- Not at all 
1- Occasionally 
2- A little 
3- Somewhat 
4- Very much 
5- Extremely 
Q2. How much did last night's cough affect 
your child's ability to sleep? 
 
0- Not at all 
1- Occasionally 
2- A little 
3- Somewhat 
4- Very much 
5- Extremely 
Q3. How much did last night's cough affect 
your ability to sleep? 
 
0- Not at all 
1- Occasionally 
2- A little 
3- Somewhat 
4- Very much 
5- Extremely 
Q4. How severe was your child's cough last 
night? 
 
0- Not at all 
1- Occasionally 
2- A little 
3- Somewhat 
4- Very much 
5- Extremely 
Q5. How bothersome was last night's cough 
to your child? 
 
0- Not at all 
1- Occasionally 
2- A little 
3- Somewhat 
4- Very much 
5- Extremely 
PAC-QoL (to be recorded by the parent/legal representative in the NursTrial® app with the 
help of the investigator) 
1-Were you worried/concerned about your 
child’s cough becoming worse? 
 
1- very, very worried and concerned 
2- very, worried and concerned 
3- fairly, worried and concerned 
4- somewhat worried and concerned 
5- a little worried and concerned 
6- hardly worried and concerned 
7- not worried and concerned 
2-Did you feel tired or exhausted because 
of your child’s cough? 
 
1- all the time  
2- most of the time 
3- quite often 
4- some of the time 
5- once in a while 
6- hardly any of the time 
7- none of the time 
3-Were you worried/concerned about the 
effects of your child’s cough on him/her? 
 
1- very, very worried and concerned 
2- very worried and concerned 
3- fairly, worried and concerned 
4- somewhat worried and concerned 
5- a little worried and concerned 
6- hardly worried and concerned 
7- not worried and concerned 
4-Were you worried/concerned about the 
cause of your child’s cough? 
1- very, very worried and concerned 
2- very worried and concerned 

 
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3- fairly, worried and concerned 
4- somewhat worried and concerned 
5- a little worried and concerned 
6- hardly worried and concerned 
7- not worried and concerned 
5-Were you worried/concerned about your 
child not sleeping well because of the 
cough? 
 
1-very, very worried and concerned 
2- very worried and concerned 
3- fairly, worried and concerned 
4- somewhat worried and concerned 
5- a little worried and concerned 
6- hardly worried and concerned 
7- not worried and concerned 
6- Did your family need to change plans 
because of your child’s cough? 
 
1-all the time  
2- most of the time 
3- quite often 
4- some of the time 
5- once in a while 
6- hardly any of the time 
7- none of the time  
Daily cough severity (to be recorded by the parent/legal representative in the NursTrial® app 
with the help of the investigator) 
“Yesterday, how was the cough of my child 
during the day?” 
 
eVAS 
0 _____________________________________100 
No cough                                               Worse cough 
 
 
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Table 3: Variables to be collected during patient follow-up by the parent/legal representative 
 
Outcome 
Suggested schedule 
Variables 
For primary outcome and secondary 
performance 
outcome 
1: 
PCQ 
global and scores of the 5 items Q1, 
Q2, Q3, Q4 and Q5 
 
D2 – first thing in the morning after 1st 
night of treatment 
D3 – first thing in the morning after 2nd 
night of treatment 
D4 – first thing in the morning after 3rd 
night of treatment 
0 – Not at all 
1 – Occasionally 
2 – A little 
3 – Somewhat 
4 – Very much 
5 – Extremely 
For 
secondary 
performance 
outcome 2: Daily cough severity 
D2 – first thing in the morning after 1st 
night of treatment 
D3 – first thing in the morning after 2nd 
night of treatment 
D4 – first thing in the morning after 3rd 
night of treatment 
0-100 eVAS value 
 
For 
secondary 
clinical 
benefit 
outcome: PAC-QoL 
D4 – first thing in the morning after 3rd 
night of treatment 
1- all the time or very, very worried and concerned 
2- most of the time or very, worried and concerned 
3- quite often or fairly, worried and concerned 
4- some of the time or somewhat worried and concerned 
5- once in a while or a little worried and concerned 
6- hardly any of the time or hardly worried and concerned 
7- none of the time or not worried and concerned 
For secondary safety outcome: 
number and percentage of AEs, 
including device deficiencies (DD) 
(to be completed by the investigator 
during 
an 
interview 
with 
the 
parent/legal representative) 
Once a day, at a time of choice and at 
investigation end. 
All AEs during the 3-day period will be asked to be reported by the patient, 
whether they think it is related to the investigational device or not.  
 
Once a day the following questions will be asked. 
 
x 
Today did your child experience any sort of illness or negative 
effects (whether related to the Syrup or not)? Yes/ No  
 
If yes, please contact the investigator. 
 

 
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Outcome 
Suggested schedule 
Variables 
Adherence 
At least once a day or at each intake 
How many times in the previous 24 hours did your child use Petit Drill? 
(Insert a single digit number) 
 
For each dose, please give the approximate time: HH:MM 
 
If Petit Drill is stopped before the recommended treatment duration of 3 days, 
please specify the reason: 
Cough improvement / Cough worsening / Other /Other specify 
Parent Satisfaction with Petit Drill 
Syrup Use 
At study end (after 3 days of use) 
x How would you rate the quality of therapeutic management your child 
received? (Excellent/ Good/ Fair/ Poor) 
x To what extent did this treatment meet your child’s needs? (Almost all of 
my child’s needs were met/ Most of my child’s needs were met/ Only few of 
my child’s needs were met/ None of my child’s needs were met) 
x Would you recommend this treatment to another parent? (No, definitely not/ 
Not really/ Yes, generally/ Yes, definitely) 
x How satisfied are you with information received from the IFU to use this 
treatment? (Quite dissatisfied/ Indifferent or mildly dissatisfied/ Mostly 
satisfied/ Very satisfied) 
x In a general sense, was it easy to use this treatment? (No, definitely not/ 
Not really/ Yes, generally/ Yes, definitely) 
x Did your child seem to like the taste of the syrup? (No, definitely not/ Not 
really/ Yes, generally/ Yes, definitely) 
 
 
 
 

 
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Table 4: Variables to be collected by the investigator in case of AE or DD occurring during patient follow-up 
Outcome 
Suggested schedule 
Variables 
For secondary safety outcome: 
number and percentage of AEs, 
including device deficiencies (DD) 
(to be completed by the investigator 
during 
an 
interview 
with 
the 
parent/legal representative) 
Anytime during patient’s 
follow-up 
Select all that apply 
x Any new illness or symptom (diagnosed or undiagnosed) 
x Any worsening of an existing illness or symptoms (diagnosed or undiagnosed) 
x Any medical interventions (such as vaccination, surgery etc.) 
x Any usual or unusual health-related event (such as loss of appetite, teething pain, 
reflux etc.) 
 
For each event, please provide the following details: 
x Describe event in own words 
x Date of event start: DD/MM/YYYY 
x Action taken in response to event (select all that apply): medications given/ 
hospitalization/ visit to a healthcare professional (HCP)/ no action taken 
x Assessment of seriousness:  
x 
Did the event lead to death? Yes/ No 
x 
Did the event lead to a life-threatening illness or injury? Yes/ No 
x 
Did the event lead to permanent impairment of a body part or body function? Yes/ No 
x 
Did the event lead to hospitalization or prolongation/ Yes/ No 
x 
Did the event require a medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body part or body function? Yes/ No 
x 
Did the event lead to development of a chronic disease? Yes/No 
 
x 
Outcome at the end of the 3-day follow-up (select only ONE): Ongoing/ Completely 
Resolved/ Resolved with after-effects/ Not sure 
 
x 
Please select all that apply regarding the use of Petit Drill 
x 
The external packaging was damaged upon reception 
x 
The bottle cap was not sealed, or damaged upon reception 
x 
The bottle was damaged upon reception/during use 
x 
The pipette was damaged upon reception 
x 
The pipette was damaged during use 
x 
I used more or less than the prescribed dose because it was confusing to use the 
pipette 

 
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x 
I used more or less than the prescribed dose because the IFU was not clear 
x 
The syrup fell into eyes or ears during use 
x 
My child was taking another medication while using the syrup  
 
If yes, please mention the medication 
x 
My child may be allergic to the syrup 
x 
Someone else, other than my child used the syrup (including accidental use) 
x 
Child accidently accesses the bottle 
x 
I did not use the designated pipette 
x 
Syrup reached air tube 
x 
Pipette reached air tube 
 
 

 
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6.5 
Replacement of subjects 
Not applicable. 
 
6.6 
Investigation sites 
Patient pre-screening will occur via pharmacies. Around one hundred and twenty-five pharmacies 
throughout France will be required to participate in this investigation to reach the required patient number 
(see section 6.9.6). 
 
6.7 
Clinical investigation end 
A patient accrual period of 6 to 9 months is estimated to achieve the targeted sample size of 245 patients 
(see section 6.9.6). Given that the patient follow-up period is only 3 days, the length of the investigation 
will also be around 6 to 9 months.  
 
6.8 
Investigational device(s) and comparators 
The investigational device is Petit Drill® Syrup by Pierre Fabre Médicament.  
No comparators are to be used in this single-arm observational study. 
 
6.8.1 
Exposure 
Not applicable. 
 
6.8.2 
Justification of the choice of comparator 
Not applicable. 
 
6.8.3 
Other needed medical device or medication 
Pipette to dispense the syrup is provided with the investigational device, as described in section 2.1. 
 
6.8.4 
Number of investigational devices to be used 
Only one investigational device will be assessed in this clinical investigation: the Petit Drill® Syrup. The 
device is to be used per the IFU. 
 
6.9 
Subjects 
If the parent/legal representative does not want to participate but gives the pharmacist his/her agreement 
for pseudonymous data collection of his/her response, the pharmacist will record in a pre-screened log 
the following data in the study website: 
- Patient age in years and months; 
- Reason for refusal to participate in the investigation (if applicable); 
- Reason for non-inclusion to the investigation (if applicable, i.e., patient not meeting a main 
entry criteria). 
 
 

 
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6.9.1 
Inclusion criteria 
Children meeting the following inclusion criteria will be included: 
x IC1. Boys or girls, 6 months to 6 years of age;  
x IC2. With one of his/her parents/legal guardian purchases Petit Drill in a participating 
pharmacy in accordance with recommendations for use (regarding age and type of cough);  
x IC3. For infants between 6 months and 12 months of age – a confirmed prescription from 
a treating physician;  
x IC4. With an acute cough lasting less than 48 hours 
x IC5. With a score ≥ 3 at least for 3 of the 5 items of PCQ, (based on assessment of the 
night before inclusion);  
x IC6. For whom child-minding will allow to respect the recommended daily doses* of Petit 
Drill during the 3 day-treatment;  
x IC7. With a parent/legal guardian having a smartphone allowing using the ePRO App. 
NursTrial®;  
x IC8. With a parent/legal guardian able to understand and to complete to the questionnaires 
in timely manner;  
x IC9. With parent(s)/legal guardian who provide their signed informed consent for the child’s 
enrolment in the study.  
* 2-4 doses on D1, then 3 to 4 doses on D2 and D3, including one of the daily doses taken at bedtime.  
6.9.2 
Exclusion criteria 
Children meeting one of the following exclusion criteria will not be included:  
x 
EC1. Presenting with one of the following conditions:  
o 
Chronic respiratory illness such as asthma, recurrent wheezing associated to viral 
infections and bronchitis;  
o 
Lower respiratory infections, such as bronchitis, bronchiolitis, and pneumonia;  
o 
Angina, otitis, or sinusitis;  
o 
Persistent cough lasting more than 3 weeks, whatever the etiology;  
o 
Gastrointestinal pathology, involving vomiting, nausea, or diarrhoea.  
x 
EC2. With ongoing use of paracetamol, and/or homeopathic products against cough;  
x 
EC3. Having had corticosteroid treatment, antibiotics, antihistaminic or any cough medication 
(such as, but not limited to, Phytoxil, Arkotoux) in the previous 15 days since inclusion; 
x 
EC4. With a brother/sister already included in the present clinical investigation*;  
x 
EC5. Enrolled in another clinical trial or being in a period of exclusion from a previous clinical 
trial.  
* If several children are eligible in the same household, only one will be enrolled at random.  
6.9.3 
Subject withdrawal and lost-to-follow-up 
The risk of loss-to follow-up in this investigation is minimal due to the very short follow-up duration of 3 
days, which is the recommended treatment duration per the Petit Drill® Syrup IFU. 
 

 
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Nevertheless, a subject will not be prevented from withdrawing their parent/legal representative consent 
at any time between enrolment and the 3 days of participation, whereby the subject will be withdrawn 
from the investigation and no further data will be collected. In each case, reasons for withdrawing their 
consent will be obtained.  
 
6.9.4 
Expected duration of the clinical investigation 
This will be equal to the length of the planned accrual period of 6-9 months, as the follow-up duration 
for each patient is only 3 days long. 
 
6.9.5 
Expected duration of each subject’s participation 
Subjects will be followed-up for 3 days since the initiation of the Petit Drill® syrup intervention.  
 
6.9.6 
Sample size 
A sample size of 245 patients is proposed for this clinical investigation, considering a dropout rate of 
20% (see section 7.4). The rationale for this sample size is discussed in section 7.4 below.  
 
6.9.7 
Period and point of enrolment  
Patients will be recruited from participating pharmacies throughout metropolitan France. The maximum 
recruitment period will be at least from November 2023, over a period of 6 to 9 months.  
 
Based on sales numbers, a monthly sales rate of 4 units per pharmacy was estimated for Petit Drill® 
Syrup in France. Considering around 125 sites will be recruited, and a 25% participation acceptance 
rate (optimal scenario) upon proposal of the clinical investigation, a patient accrual period of 3 months 
during the winter season should permit reaching the targeted sample size.  
However, since this is a real-life study and that the participation acceptance rate may have been 
overestimated, enrollment period is extended by 6 to 9 months. 

6.9.8 
The investigation population relative to the target population 
The Petit Drill® Syrup is intended to be used for the treatment of throat irritation (sore throat) associated 
with dry cough in infants from 6 months of age and in children up to 6 years of age.  
Minimum exclusion criteria have been defined for the selection of patients, so that the most 
representative sample can be included in the study. Nevertheless, for the purpose of proving the 
performance of the device certain selection criteria had to be implemented, which will mean that certain 
characteristics of the investigation population will be slightly different to the target population. These 
selection criteria include: 
x Inclusion of patients only with score ≥ 3 at least for 3 of the 5 items of PCQ, (based on the 
recall of the night prior inclusion), which means milder forms of cough will not be investigated; 
x Exclusion of patients taking concomitant treatments, up to 15 days before Petit Drill start, that 
may interfere with or mask Petit Drill® device’s performance, such as paracetamol, anti-
histamines, steroids, antibiotics or cough medication; 
x Exclusion of patients with chronic respiratory conditions (such as asthma or bronchitis) and 
persistent cough lasting more than 3 weeks; 
x Patients with lower respiratory infections, such as bronchitis, bronchiolitis and pneumonia; 
x Angina, otitis, or sinusitis; 
x Gastrointestinal pathology, involving vomiting, nausea, or diarrhoea. 

 
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Nevertheless, the differences between the investigation and target population are not so large that it 
would impact the overall transposability of clinical performance and safety data to the general target 
population.  

6.9.9 
Vulnerable populations  
Petit Drill® Syrup is intended to be used in a vulnerable population, i.e., paediatric patients from 6 months 
to 6 years of age.  
Since this is a real-life investigation, patients will not be required to undergo any additional procedures 
or interventions, apart from those defined in the Petit Drill® Syrup IFU. Furthermore, the parent(s) or 
legal guardians of children will be informed in detail about the investigation, and the benefits and risks 
to their ward of participating in it, prior to obtaining their written consent.  
 
6.10 Procedures 
Pre-screening  
Pharmacist will briefly present the clinical investigation to the parent/legal representative who purchases 
Petit Drill for his/her child/relative from 6 months to 6 years old. The pharmacist will also orally verify the 
eligibility criteria (Cf. sections 6.9.1 and 6.9.2). 
If the parent does not want to participate but gives the pharmacist his/her agreement, the pharmacist 
will record in a pre-screened log child’s age and gender, and main reason of parent’s refusal.  
If the parent is interested, the pharmacist will provide the study information note and transfer the parent’s 
name and contact information to the clinical investigation centre (CEN Expérimental) via a dedicated 
page of the study website. 
Inclusion visit  
Upon receipt of a pre-screen patient on the study website, the parent/legal representative will be 
contacted to take part to the remote inclusion visit with an Investigator (General Practitioner) of CEN 
Experimental, scheduled within the day of Petit Drill delivery. 
Before proceeding with the signing of the consent, the investigator will first ensure that the parent/legal 
representative is duly informed. Consent will be electronically signed using a solution (DocuSign) whose 
functionality meets recommended expectations of the Guidance on computerized systems and 
electronic data in clinical trials (EMA/INS/GCP/112288/2023). The informed consent process is detailed 
in section 13. 
In non-single-parent households, the informed parent who signed the consent will remain the one who 
completes the study data in the ePRO App NursTrial®.  
If several children are eligible in the same household, an algorithm will randomly select one of them. 
Then, the Investigator will check the inclusion and exclusion criteria, and proceed to the patient’s 
enrolment.  

 
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The Investigator will record the necessary study data in the e-CRF (socio-demographics, baseline 
medical data). A Clinical Research Associate will help the parent download the NursTrial® App on their 
smartphone and create their personal access. Then, the parent will complete the study questionnaires 
in the App.  
Study follow-up  
The patient's follow-up will last as long as he/she receives Petit Drill but will not exceed 3 days and 3 
nights. Indeed, to stay close to real-word condition of use of Petit Drill, the treatment duration is 
recommended as per IFU but not imposed in the present clinical investigation. However, the parent must 
specify reason for stopping the treatment in the App. 
During the follow-up, the patient’s parent will have to complete the daily questionnaire and record Petit 
Drill intake in the App. Parents will be asked to inform the investigator of any adverse event as soon as 
possible.  
 
6.11 Monitoring plan  
Since this study has a patient-driven mode of data collection via a mobile application, no monitoring 
procedures are applicable in this case. Monitoring may not even be necessary at the patient enrolment 
stage in CEN Experimental, as the investigator will fill in the eCRFs without access to any source 
documents.  
 
Nevertheless, alternative quality control measures can be implemented in the eCRFs and mobile 
application, such as field checks, predefined data entry rules to prevent incorrect or missing data entry. 
Simple instructions and prompts for each form or field can guide the parents and the investigators in 
filling the forms as accurately as possible.  
 
Signature of the informed consent will be automatically monitored via the electronic process. 
  
 

 
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7 STATISTICAL CONSIDERATIONS 
7.1 
Analysis population 
The analysis population will be those patients who have been included in this clinical investigation after 
fulfilling all selection criteria, and whose parent(s) or legal guardian did not withdraw their consent at 
any time (Full Analysis Set - FAS). 
 
The analysis population is estimated to be at around 245 patients. Patient characteristics data 
(sociodemographic and medical) at baseline will be obtained from the analysis population (FAS). 
The safety population will be made up of all patients who have used Petit Drill at least once.  
The performance population will be made up of all patients for whom at least one evaluation of the 
primary outcome is available. 
7.2 
Statistical Design and Analytical Methods 
The statistical analysis will be conducted in accordance with the protocol, and the Statistical Analysis 
Plan (SAP) which will precisely indicate the calculation of the variables, the populations studied (all, 
performance and safety), descriptive statistics, safety, handling of missing data. The SAP will be written 
as a separate document and approved prior to data review.  
 
Statistical analyses will be performed using SAS® software (version 9.4, SAS Institute, North Carolina 
USA). 
 
Since this is a purely descriptive investigation with no hypothesis, analyses of all outcomes will be 
performed using descriptive statistics, and no statistical tests are planned. Summary statistics will be 
produced for all study variables. 
 
Continuous variables will be described by the mean, standard deviation (SD), median and range and 
quartile (Q1 and Q3). Some continuous variables may be converted to categorical variables, for which 
the numbers and increments may be defined in a more detailed statistical analysis plan (SAP). 
Categorical and ordinal variables will be described by the number and percentage of patients in each 
category, and the number and percentage of patients with missing information.  
 
Confidence intervals of 95% will be calculated for the primary outcome and the safety secondary 
outcomes. 
 
7.3 
Level of significance and power  
Not applicable as this is a descriptive investigation. 
 
7.4 
Determination of Sample Size  
The sample size was estimated based on the worst-case scenario of the primary outcome (percentage 
of patients with a cough symptom score of 1 or 0 at the third night of treatment with Petit Drill® Syrup).  
 
A total of 196 patients would provide the necessary precision of 7% of the confidence intervals (CI) for 
primary outcome in the most statistically unfavorable scenario (performance outcome of 50%), given 

 
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that currently available publications cannot allow for an accurate estimate of the expected primary 
outcome for one device. 
In a previous observational study [1], a drop-out rate of 27% was observed in a cohort of children from 
1 to 3 years of age, with a longer follow-up period and uncertainty regarding the mode of administration 
of patient questionnaires, which may suggest a slight overestimation in the context of this clinical 
investigation.  
 
Due to feasibility concerns and a shorter follow-up period of 3 days, the proposed sample size is 245 
patients, based on a 20% dropout rate. 
 
7.5 
Pass/fail criteria 
Not applicable. 
 
7.6 
Interim analyses 
No interim analyses are planned.  
 
7.7 
Criteria for the termination of the clinical investigation (if applicable) 
Not applicable. Nevertheless, patients will not be prevented from withdrawing their consent to participate 
at any point of their participation in the investigation, and all data collection will be stopped immediately.  
 
7.8 
Management of biases 
No statistical management of biases is planned, except for "missing data":  
In case of missing data or loss to follow-up, sensitivity analyses could be carried out to estimate the 
impact of missing data on the primary outcome.  
 
7.9 
Deviations from the original statistical analysis plan 
Any deviation(s) from the statistical plan during the analysis will be discussed in the final clinical 
investigation report (CIR). 
Procedures for dealing with deviations from the original analysis plan will also be elaborated in the SAP. 
 
7.10 Subgroups 
Patients aged 6 months to 24 months old. 
Patients aged 25 months old to 6 years old. 
 
7.11 Handling of missing data and drop-outs  
No imputation of missing data is planned. 
In case of a considerable proportion of missing data for key outcomes (such as the primary performance 
outcome), sensitivity analyses will be performed. Characteristics of patients with missing and non-
missing data for key variables will also be described. 
 
7.12 Exploratory analyses 
None anticipated. 

 
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7.13 Number of subjects in each pre-screening centre 
Around 125 pharmacies have been proposed for patient pre-screening over a period of 6 to 9 months 
(at least Nov 2023 to July 2024). Given that 245 patients are planned to be recruited, this gives a mean 
of 2 patients per pharmacy.  
 

 
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8 DATA MANAGEMENT 
A data management plan will be prepared and validated before data collection can begin. It will describe 
all functions, processes, and specifications for data collection, cleaning, and validation. This will ensure 
that the data are as clean and accurate as possible when presented for analysis. In addition, data 
collection and validation procedures will be detailed in appropriate operational documents.  
 
8.1 
Data recording 
8.1.1 
Case Report Forms  
An eCRF will be maintained for each enrolled participant after they pass the screening stage. eCRFs 
will be filled by the Investigator of CEN Expérimental at the time of patient inclusion, where they will 
record patient sociodemographic and baseline medical data. Each patient will be pseudo-anonymized 
and will only be identifiable via an automatically generated unique patient ID number. Only the 
investigation team of CEN Expérimental or suitably trained designee will be authorized for data entry 
into the eCRF. 
 
All eCRFs will be approved with an electronic signature to acknowledge/approve the data entered.  
 
8.1.2 
Mobile application 
Patients’ parents will record daily Petit Drill intake, respond to PROs and notify the occurrence of AEs 
via a mobile application over a period of 3 days from the time of inclusion. Instructions and prompts will 
be programmed into the mobile application to help the patients’ parents with filling the form.  
 
8.1.3 
Specification of source documents  
Since Petit Drill® Syrup is an OTC medication that can be purchased from the pharmacy without a 
prescription, the patient will not be managed in a medicalized setting. Therefore, no source documents 
will be available or required. Baseline data will be recorded by Investigator of CEN Expérimental via 
interviews with the patients’ parents and legal guardians.  
 
8.2 
Data Management System  
 
8.2.1 
Procedures for data review, database cleaning and data queries. 
Data collection in this study is patient-driven and via a mobile application. As a result, there will be limited 
potential for rectifying data entry errors at a later stage as all patient-reported data will be locked after 
study end. Therefore, quality control measures will be programmed in the mobile application, such as 
field checks and predefined data entry rules to prevent incorrect or missing data entry. 
Simple instructions and prompts for each form or field will guide the parents in filling the forms as 
accurately as possible.  
 
eCRFs will be managed by the investigators at CEN and similar verification features will be implemented 
in the eCRF to prevent incorrect data entry by the user. Based on the automatically generated queries, 
the data manager of CEN will be able to review and answer the found discrepancies directly in the 
system. All changes of data entered in the eCRF can be followed by an audit trail. A final quality control 
will be performed before the database is closed. 
 

 
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8.2.2 
Procedures for data entry, verification, validation  
Verification, validation and securing procedures of electronic clinical data systems will be implemented 
and documented by the provider of data capture systems to ensure authenticity, accuracy, reliability, 
and consistent intended performance of the data system from design until decommissioning of the 
system. 
 
8.2.3 
Database locking and storage 
Statistical processing will only take place once the database has been locked, i.e., after the totality of 
the data has been validated and a final quality control has been performed according to the Data 
Validation Plan, documented by CEN. Once the data have been validated, the database will be 
transferred to the statistical department mandated by the sponsor for analysis. 
 
8.2.4 
Confidentiality and data protection 
All personal and medical data will be pseudo-anonymized (data recorded in the pre-screen log will not 
contain identifying information, and collected after oral agreement of the parent). Pierre Fabre is the sole 
Sponsor of the study. The sponsor of the study and data controller are responsible for the processing 
of personal data following the provisions of Regulation (EU) 2016/679 of the European Parliament and 
of the Council of 27 April 2016 on the protection of natural persons concerning the processing of 
personal data and the free movement of such data (GDPR – General Data Protection Regulation) and 
national provision (“Reference Methodology" MR-001), the data collected being for research purposes 
in the field of health, the legal basis of the processing being the legitimate interest of the data controller.  
 
Confidentiality of subject records will be maintained at all times. All study reports will contain aggregate 
data only and will not identify individual subjects. At no time during the study the sponsor nor the 
employees of the CRO (Clinical Research Organization) CEN not involved in the investigation tasks 
(i.e., datamanager, statisticians, project manager, medical writer) will receive subjects identifying 
information. In order to maintain subject confidentiality, each subject will be assigned a unique subject 
identifier upon study enrolment. This subject identifier will be used in place of the subject name for the 
purpose of data analysis and reporting. All parties will ensure protection of subject personal data and 
will not include subject names or other identifiers (i.e., initials, full date of birth, address etc.) on any 
study forms, reports, publications or in any other disclosures, except where required by law. 
 
8.2.5 
Procedures for data retention  
The Investigator must agree to preserve the following documents: the identification log of all participating 
subjects, a screening log, electronic copy of the eCRF, including the electronically signed and dated 
informed consents, the audit trail and detailed records to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees.  
 
These documents will be kept for all participants for a period of time specified by local regulations or 
specified in the Clinical Investigation Site Agreement between the investigator at CEN and the sponsor. 
No data should be destroyed without agreement with the sponsor. 
 
The sponsor will maintain all documentation pertaining to this clinical investigation for the lifetime of the 
product. The sponsor and investigators shall take measures to prevent accidental or premature 
destruction of these documents and they may rely on a third party for document retention. In this case 
the final location and transfer procedures have to be documented.  

 
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9 AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN 
Any amendment to this Clinical Investigation Plan (CIP) must be approved by the sponsor and the 
coordinating investigator (if applicable)/or scientific committee (if applicable). When applicable, the 
amendment, including supporting justifications will be submitted for approval to appropriate Ethic 
Committee (EC) and regulatory authorities before being implemented by investigators. Furthermore, 
investigators will sign any amendment to indicate their agreement. It will be the responsibility of the 
Investigator to update study subject to new amendments that might affect willingness to continue in the 
study. This must be recorded in participating subject’s medical file. CIP amendment approval and 
approval of any associated changes to the ICF must be obtained prior to implementation of the CIP 
amendment except when necessary to eliminate an apparently immediate hazard to participating 
subjects or when the change involves purely administrative or logistical aspects of the study. 
 
 
10 DEVIATIONS FROM THE CLINICAL INVESTIGATION PLAN 
Since this is a post-marketing clinical follow-up observational study, based in a real-life setting, no major 
deviations from the CIP are expected. 
 
 
11 DEVICE ACCOUNTABILITY 
Not applicable, as the product is commercialized (per Annexe I, clause 7 d) 1) of the EN ISO 14155 
2020). 
 
The investigator must ensure that the patients’ parents or legal guardians understand the objectives of 
this investigation and the ICF before signing it and that they understand that the device can only be used 
in the patient who has been enrolled in the investigation. 
 
In the event of a device deficiency or an adverse device effect, all details will be recorded by the 
parent/legal guardian in the mobile application, after which a notification will be sent to the Investigator 
and the data service provider (CEN). Contact will be established with the user as soon as possible by 
the Investigator, who will confirm the event details.  
 
 
 
 

 
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12 STATEMENTS OF COMPLIANCE 
12.1 General statements of compliance 
The current versions of the Guidelines of the World Medical Association’s Declaration of Helsinki, EN 
ISO 14155 standard as well as demands of the national and European medical product laws and data 
protection laws (such as the GDPR) will be implemented and followed.  
Compliance with these standards will ensure that the rights, safety and well-being of study subjects are 
protected and that data from the clinical investigation are of the highest quality standards. 
 
All clinical work conducted under this protocol will be subject to GCP (Good Clinical Practice). The 
Investigator must agree to the inspection of investigation-related documents and records by health 
authorities, auditors and/or the sponsor or its designee upon request.  
 
In accordance with national provisions, the start of the investigation is notified immediately (i.e. as soon 
as the sponsor or his representative in charge of the clinical investigation becomes aware of it) to the 
CPP and ANSM (Agence Nationale de sécurité du medicament et des produits de santé) by email until 
EUDAMED is made available. The effective date of the start of the clinical investigation corresponds to 
the date of signature of the consent form of the first person who agrees to the clinical investigation in 
France. 
A notification of the end of the study will be sent within 15 days following the end of the clinical 
investigation, or its temporary interruption or its early termination to the authorities. 
The summary and the clinical report will be transmitted according to the local regulation within 1 year 
after the end of the clinical investigation or within 3 months following the temporary interruption or early 
termination. 
The sponsor has been informed that the competent authority (ANSM) may contact the CPP which is 
reviewing or which has reviewed the authorization and opinion application file for this clinical 
investigation. 
This clinical investigation conducted under Article 82 of Regulation (EU) 2017/745 which is not subject 
to an insurance obligation. 
The data recorded during this research is subject to computerized processing at CEN, responsible for 
the implementation of data processing in compliance with Regulation (EU) 2016/679 of the European 
Parliament and of the Council relating thereto. to the protection of individuals with regard to the 
processing of personal data and the free movement of such data and law n°78-17 of 6 January 1978 
relating to data processing, files and freedoms, as amended by law 2018-493 of June 20, 2018. 
This research is part of the "Reference Methodology" (MR-001) pursuant to the provisions of Article 54 
paragraph 5 of the amended law of January 6, 1978 relating to information, files and freedoms. This 
change was approved by decision of January 5, 2006, updated on July 21, 2016. CEN has signed a 
commitment to comply with this “Reference Methodology”. 
The secure data collection application on smartphone NursTrial® has specific security and 
anonymization measures. 
Pending the European database EUDAMED, this clinical investigation is registered under number ID-
RCB: 2023-A01929-36. 
 
12.2 Ethics and Regulatory Authority approval 
Prior to study initiation, the CIP, sample ICF and the data collection tools will be submitted to the National 
Ethics Committee (Comité de Protection des Personnes – CPP – in France) for review and approval 
and the national competent authority (ANSM) for approval of the submitted file. 
 

 
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The clinical investigation will not begin until all necessary approvals/favourable opinions are obtained 
from the CPP and the regulatory authorities. Should the CPP and authorities impose any additional 
requirements, they will be duly implemented.  
The sponsor and/or designee will keep on file records of approval of all documents pertaining to this 
study.  
 
12.3 Financing  
The costs associated with the clinical investigation and investigator/site compensation will be 
documented in a separate agreement that will be signed by the sponsor, the investigator and/or the 
management of the study site.  
 
 
 

 
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13 INFORMED CONSENT PROCESS 
The parent(s) or legal guardian of each patient will be provided with oral (overall presentation of the 
study by the pharmacist) and written information in lay and native language which describes: 
- 
The objective, nature, advantages, consequences, risks and disadvantages of the clinical 
investigation, the constraints, the foreseeable risks and the expected benefits of the clinical 
investigation; 
- 
The rights and guarantees of the patient concerning his protection, in particular his right to refuse 
to participate in the clinical investigation and his right to withdraw from it at any time without 
incurring prejudice and without having to justify himself, and specifies the rights of the patient in 
the context of a clinical trial on the medical device; 
- 
The conditions under which the clinical investigation must take place, including the planned 
duration of the participation of the person concerned, including the follow-up measures if the 
participation is terminated; 
- 
Information relating to the identification of the clinical investigation, and the availability of results. 
 
Each subject will be given a paper copy of the information note and of the inform consent content by the 
pharmacist at pre-screening step, and will encourage to carefully read this information note prior the 
remote visit with the Investigator. 
In this clinical investigation conducted in young children, to comply with the French Public Health Code 
regarding the assent of the children able to understand their participation to the study, a dedicated 
information note will be given to the parent/legal representative. The investigator will read the letter to 
the child if applicable.  
 
It is the responsibility of the Investigator to explain the details of the investigation to the subject’s 
parent(s)/legal guardian. The Investigator or the delegated doctor/health professional answers all of the 
questions of the patient's parent/legal representative and ensures that he/she has understood the 
information and explanations provided. The patient's parent/legal representative is given the necessary 
duration to provide their decision to participate in the clinical investigation. 
 
If the patient's parent/legal representative agrees to participate, the Investigator and the patient's 
parent/legal representative proceed to the electronic signature of the informed consent (ICF). 
Before any procedures related to the research, the investigator must obtain the free, informed 
and written consent of the patient’s parent/legal representative. 
 
Consent will be electronically signed using a solution (DocuSign) whose functionality meets 
recommended expectations of the Guidance on computerized systems and electronic data in clinical 
trials (EMA/INS/GCP/112288/2023). Briefly, the system will include functionality to: 
- 
authenticate the signatory; 
- 
ensure non-repudiation; 
- 
ensure an unbreakable link between the electronic record and its signature; 
- 
provide a timestamp. 
In this clinical investigation, a double level of authentication will be used (personal email and phone 
number). Then, the patient’s parent/legal representative will receive an email with a link to access to the 
electronic ICF and proceed to signature after confirmation of having read the ICF. 
Once signed by the patient’s parent/legal representative and the Investigator), both received an 
electronic ICF specifying date and time for signature. The Investigator will document the signature in the 
e-CRF, and stored the e-ICF in the dedicated study file. 
 

 
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In the event that an amended ICF is implemented, it must be reviewed and signed by the subject’s party 
and the investigator in the same way as the original consent.  
 
The subject will not be included in the investigation under any circumstance if his/her parent(s) or legal 
guardian did not provide their informed consent.  
 
 

 
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14 MANAGEMENT AND REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE 
EFFECTS AND DEVICE DEFICIENCIES 
14.1 Definitions 
A qualified and suitably trained medical professional will assess all declared adverse events (AE) and 
adverse device effects (ADE), that would be reported by the patient/parents during the 3 days of using 
Petit Drill.  
All definitions are issued from REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND 
OF THE COUNCIL of 5 April 2017 on medical devices, and corresponding Medical Device Coordination 
Group (MDCG) guidelines. 
 
14.1.1 Adverse Event (AE) - Article 2 (57) from MDR 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs including 
an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical 
investigation, whether or not related to the investigational device. 
 
Note 1: This includes events related to the study product (including test product and/or associated 
products) and/or related to the procedures involved (any procedure in the clinical investigation plan). 
Note 2: For users or other persons this is restricted to events related to the investigational medical 
device. 
Note 3: An Adverse Device Effect (ADE) is an AE related to the use of the investigational medical device. 
 
14.1.2 Serious Adverse Events (SAE) - Article 2 (58) from MDR 
Any adverse event that led to any of the following: 
(a) death, 
(b) serious deterioration in the health of the subject that resulted in any of the following: 
(i) life-threatening illness or injury, 
(ii) permanent impairment of a body structure or a body function, 
(iii) hospitalisation or prolongation of patient hospitalisation, 
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
(v) chronic disease. 
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect. 
 
Note 1: A planned hospitalisation for pre-existing condition, or a procedure required by the protocol, 
without a serious deterioration in health, is not considered to be a serious adverse event. 
Note 2: This also includes device deficiencies that might have led to a SAE if a) suitable action had not 
been taken or b) intervention had not been made or c) if circumstances had been less fortunate. 
 
A Serious Adverse Device Effect (SADE) is an AE related to the use of an investigational medical device 
and leading to the situations described above for SAEs. 
 
14.1.3 Device deficiencies (DD) - Article 2 (59) 
Any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational 
device, including malfunction, use errors or inadequacy in information supplied by the manufacturer. 
 

 
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14.1.4 Incident – Article 2 (64) 
Any malfunction or deterioration in the characteristics or performance of a device made available on the 
market, including use-error due to ergonomic features, as well as any inadequacy in the information 
supplied by the manufacturer and any undesirable side-effect. 
 
14.1.5 Serious incident – Article 2 (65) 
Any incident that directly or indirectly led, might have led or might lead to any of the following: 
(a) the death of a patient, user or other person, 
(b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of 
health, 
(c) a serious public health threat i.e. an event which could result in imminent risk of death, serious 
deterioration in a person's state of health, or serious illness, that may require prompt remedial action, 
and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the 
given place and time (Article 2 (66)). 
 
14.2 Assessment of AE and SAEs 
Each AE must be assessed for seriousness, causality, severity by the investigator or another suitably 
qualified physician in the research team who is trained in recording and reporting AEs. 
The expectedness assessment will be performed by the sponsor.  
The investigator and sponsor will make an assessment of seriousness (as defined above). 
The investigator and sponsor will also make an assessment of the causal relationship with the study 
product, and/or associated products, and/or study procedures according to the following definitions: 
1. Not related: where an event is not considered to be related to the study product and/or associated 
products and/or study procedures. 
2. Possibly related: the relationship with the use of the investigational device or comparator, or the 
relationship with procedures, is weak but cannot be ruled out completely. Alternative causes are 
also possible (e.g., an underlying or concurrent illness/ clinical condition or/and an effect of another 
device, drug or treatment). Cases where relatedness cannot be assessed, or no information has 
been obtained should also be classified as possible. 
3. Probably related: the relationship with the use of the investigational device or comparator, or the 
relationship with procedures, seems relevant and/or the event cannot be reasonably explained by 
another cause. 
4. Causal relationship: the adverse event is associated with the investigational device, comparator 
or with procedures beyond reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or of similar devices 
and procedures; 
- the event has a temporal relationship with investigational device use/application or procedures; 
- the event involves a body-site or organ that: 
o  the investigational device or procedures are applied to; 
o  the investigational device or procedures have an effect on. 
- the adverse event follows a known response pattern to the medical device (if the response pattern 
is previously known); 
- the discontinuation of medical device application (or reduction of the level of activation/exposure) 
and reintroduction of its use (or increase of the level of activation/exposure), impact on the adverse 
event (when clinically feasible); 
- other possible causes (e.g., an underlying or concurrent illness/ clinical condition or/and an effect 
of another device, drug or treatment) have been adequately ruled out; 
- harm to the subject is due to error in use; 

 
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- the event depends on a false result given by the investigational device used for diagnosis when 
applicable. 
 
The investigator will make an assessment of severity for each AE and this should be recorded on the 
eCRF according to the following categories:  
- Mild: an event that is easily tolerated by the research participant, causing minimal discomfort and not 
interfering with every day activities; 
- Moderate: an event that is sufficiently discomforting to interfere with normal everyday activities. 
- Severe: an event that prevents normal everyday activities. 
 
The term ‘severe’ used to describe the intensity of an event should not be confused with the term 
‘serious’, which is a regulatory definition based on trial participant/event outcome action criteria. For 
example, a headache may be severe but not serious, while a minor stroke may be serious but is not 
severe. 
 
14.3 Reporting of medical device cases 
All AEs and DD that would occur during the 3-day follow-up period will be asked to be reported by the 
parents/guardians via the mobile application daily, whether they think it is related to the investigational 
device or not. The questionnaire to be used by the parents/guardians is provided in Table 3 above.  
The questionnaire will be formulated such that the parents/guardians will be able to describe the AE to 
allow the determination of seriousness and causality by the investigator.  
Following a declaration, an automatic notification will be sent to the investigator who will then be required 
to follow-up on the event. 
 
The following would be defined as elements that could be a potential AE during the 3-day follow-up: 
x 
Any new illness or symptom (diagnosed or undiagnosed); 
x 
Any worsening of an existing illness or symptoms (diagnosed or undiagnosed); 
x 
Any usual or unusual health-related event (such as loss of appetite, teething pain, reflux etc.). 
 
Investigator’s responsibility: 
 
All these foreseeable events can be mitigated by carefully reading the IFU and by storing the device out 
of the reach of children and in suitable conditions as detailed in the IFU. 
 
All AE, SAE and DD observed during the study must be reported in the eCRF by the investigator. Each 
AE must be assessed for seriousness, severity and causality by the investigator. 
 
For AE or SAE including DD whether or not considered as related to the device or to the procedure the 
investigator will complete immediately and within 3 calendar days the form (FORM_CVI_6585) “Solicited 
adverse event collection form” and collect the results of the carried-out examinations and the reports of 
hospitalisation if applicable. 
In case the investigator is aware of any new information, it should be reported to the sponsor. 
 
Contractor’s responsibility: 
The contractor conducting the study will be required to provide the following information that has been 
brought to his attention about the investigational device within 1 business day after its acknowledgment 
in the eCRF: 
- Any AE or SAE including DD which arises from the use of Petit Drill; 
- Any SAE considered as related to the procedure of the study. 

 
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 The safety information will be communicated to Pierre Fabre Vigilance department no later than 24 
hours upon its reception by the contractor, through the form (FORM_CVI_6585) “Solicited adverse event 
collection form”, which will be sent by email: HQ.pharmacovigilance@pierre-fabre.com.  
  
After completion of the study, newly occurring AEs potentially related to a Pierre Fabre product should 
be reported as spontaneous reports to the Pierre Fabre local vigilance department; a corresponding 
reporting form can be requested via the above contact data. 
 
14.4 Sponsor’s responsibilities for safety reporting purposes 
Sponsor or delegate will submit expedited reports to both Competent Authorities and Ethics Committees 
per MDR (EU) 2017/745, vigilance provisions (Articles 87-90) post-market clinical follow-up (PMCF) 
requirements (Article 80(5)) and the acts adopted pursuant to Article 91 of the Regulation as well as 
Article 80(6) where a causal relationship to the preceding investigational procedure and SAE has been 
established. 
Article 87 – Manufacturer will notify the competent authority of the Member State in which the incident 
occurred according to the following timelines in the case of: 
 
Serious public health threat: immediately (without any unjustified delay), but not later 
than 2 calendar days after sponsor was informed of the threat; 
 
Death or any unanticipated serious deterioration in a person's state of health: 
immediately but not later than 10 calendar days after sponsor became aware of the 
event; 
 
Any other reportable incident: immediately but not later than 15 calendar days after 
sponsor became aware of the event; 
 
Field safety corrective actions: in advance of the action being undertaken, except in 
cases of urgency. 
Note: Field safety corrective action’ means corrective action taken by a manufacturer for technical or 
medical reasons to prevent or reduce the risk of a serious incident in relation to a device made available 
on the market. 
  
In line with the regulations within Regulation (EU) 2017/745 (MDR Article 80) and according to the 
guidance provided by MDCG-2020-10-1, the sponsor will inform all of the competent authorities of the 
countries in which the clinical investigation is being conducted via the summary reporting tab: 
 
immediately, but no later than 2 calendar days, of all SAE related to the study procedure leading 
to a Subject’s death, or to a life-threatening situation, serious injury or serious deterioration in 
Subject's health; 
 
immediately, but not later than 7 calendar days following the date of awareness by the sponsor 
of all SAE related to the study procedure leading to any other reportable events or new 
information in relation with an already reported event. 
  
Sponsor or delegate will submit to all investigators information that may affect the safety of persons 
undergoing research. 
 
15 VULNERABLE POPULATION  
The investigational device, Petit Drill® Syrup is only intended to be used in a population that are 
designated as a vulnerable population: pediatric patients between 6 months and 6 years of age, who 
are unable to freely give their consent. All procedures pertaining to their handling and treatment have 
already been detailed in the above sections. There is no additional information to provide in this section. 

 
CLINICAL INVESTIGATION PLAN (CIP) 
 
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16 SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION 
16.1 Definitions 
Suspension: a temporary postponement of activities relating to enrollment.  
Termination: a full stop of a site’s study activity. 
 
16.2 Criteria for suspension or early termination 
Suspension or termination of a site may include but is not limited to:  
EC approval expiration; 
Consistent non-compliance to the CIP; 
Lack of enrollment;  
Non-compliance to regulations and the terms of the agreement with Pierre Fabre Médicament; 
EC suspension of the product.  
 
Consideration of suspension may include but is not limited to: 
If Pierre Fabre Médicament decides to terminate or suspend the investigation: Pierre Fabre 
Médicament will promptly inform the site of the termination/suspension along with the reason 
and inform regulatory authorities, where required:  
o 
In the case of termination or suspension for reasons other than a temporary EC 
approval lapse, the site will promptly inform the Ethics Committee, if applicable; 
o 
In case of site termination, the site must inform the subjects  
 
If the site terminates or suspends participation without prior agreement of Pierre Fabre 
Médicament: 
The site must promptly inform Pierre Fabre Médicament and provide a detailed written 
explanation of the termination or suspension, who must then inform the EC, if applicable. 
 
If the EC terminates or suspends its approval: 
The site must promptly inform the sponsor and provide a detailed written, explanation of the 
termination or suspension within 5 business days; 
Subject enrolment must stop until the EC suspension is lifted; 
Subjects already enrolled should continue to be followed in accordance with the EC’s policy or 
its determination that an overriding safety concern or ethical issue is involved; 
The site must inform his/her institution (where required per local requirements).  
 
 

 
CLINICAL INVESTIGATION PLAN (CIP) 
 
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17 PUBLICATION POLICY 
The sponsor reserves the right to publish and present the results of this investigation at scientific 
meetings or to submit these data to national and international regulatory authorities.  
 
The sponsor recognizes the right and interest of all participating investigators to scientifically publish the 
results obtained from this investigation for non-commercial purposes, even if the effects ascribed to the 
investigational device fail to materialize. Prior to any publication or presentation of results, the 
participating investigators will submit a draft of the intended publication or presentation to the sponsor 
for review and approval. For this purpose, the sponsor will be provided with a final draft in good time to 
allow review and comment, prior to submission (as a manuscript or abstract) or presentation. The 
sponsor’s proposals for modifications will be taken into consideration by the participating investigators 
if such proposals do not interfere with the scientific nature and content of the publication.  
 
Any publication shall suitably address contributions of co-authors. Contributors will be eligible for 
authorship only if they fulfil the International Committee of Medical Journal Editors (ICMJE) criteria for 
authorship [16]. 
 
The sponsor may request that the publication or presentation be postponed for no more than 2 months 
to exercise patent, copyright, or related rights. Sponsor and investigators should intend to compile a 
comprehensive publication of the investigation’s results from all participating centers. If such a joint 
publication is not achieved within 2 years after the end of the study, all participating investigators shall 
have the right to publish the individual results from their site.  
 
Publications from single investigational sites must make clear reference to the overall clinical 
investigation or CIP. The obligation to submit manuscripts for review and comment shall apply; 
accordingly, submissions must be made both to the sponsor and the coordinating investigator.  
The identity of the sponsor and the nature of his/her contribution to the investigation is to be disclosed 
in any publication or presentation relating to it.  
 
 
 
 
 
 
 
 

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18 ANNEX
18.1 ANNEX I: IFU
335141_Notice_Petit 
Drill_FR_signed.pdf
18.2 ANNEX II: DT-034-PFM-520-01 Product risk management
DT-034-PFM-520-01 
Annex_Product risk m
18.3 ANNEX III: PCQ

 
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18.4 ANNEX IV: PAC-QoL 
 
 
 
 

 
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18.5 ANNEX V: VAS
Yesterday, how was the cough of my child during the day?”

 
CLINICAL INVESTIGATION PLAN (CIP) 
 
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19 BIBLIOGRAPHY 
1. 
Allaert, F.A., et al., Observational study on the dispensing of cough syrups to children with acute 
cough by community pharmacists in France. Minerva Pediatr, 2018. 70(2): p. 117-126. 
2. 
Koo, H.K., et al., Development and validation of the COugh Assessment Test (COAT). 
Respirology, 2019. 24(6): p. 551-557. 
3. 
Roy, N., et al., An evaluation of the effects of three laryngeal lubricants on phonation threshold 
pressure (PTP). J Voice, 2003. 17(3): p. 331-42. 
4. 
Eccles, R. and P. Mallefet, Soothing Properties of Glycerol in Cough Syrups for Acute Cough 
Due to Common Cold. Pharmacy (Basel), 2017. 5(1). 
5. 
Deichmann, W., Glycerol:—Behavior in the Animal Organism—(A Review of the Literature). 
American Industrial Hygiene Association Quarterly, 1940. 1(4): p. 60-67. 
6. 
Eccles, R., The powerful placebo in cough studies? Pulm Pharmacol Ther, 2002. 15(3): p. 303-
8. 
7. 
Gray, B.A.A.B.R.E.G., Minor Illness or Major Disease. 5th ed. 2012, London: Pharmaceutical 
Press and Royal Pharmaceutical Society of Great Britain. 
8. 
Parihar, M., et al., A review: cough and treatments. 2011. 1(1): p. 9-18. 
9. 
World Health, O., Cough and cold remedies for the treatment of acute respiratory infections in 
young children. 2001, World Health Organization: Geneva. 
10. 
Morice, A.H., Developing antitussives the clinician's pipeline-what do we need? J Thorac Dis, 
2014. 6(Suppl 7): p. S735-8. 
11. 
FDA. Should You Give Kids Medicine for Coughs and Colds? 2021  [cited 2022 12/09/2022]; 
Available 
from: 
https://www.fda.gov/consumers/consumer-updates/should-you-give-kids-
medicine-coughs-and-colds. 
12. 
Kigen, G., et al., A Review of the Ingredients Contained in Over the Counter (OTC) Cough Syrup 
Formulations in Kenya. Are They Harmful to Infants? PLoS One, 2015. 10(11): p. e0142092. 
13. 
MHRA. Q&A for children’s cough and cold medicines. 2009  [cited 2022 12/09/2022]; Available 
from: 
http://www.mhra.gov.uk/home/groups/commspo/documents/websiteresources/con038905.pdf. 
14. 
Marseglia, G.L., et al., Acute cough in children and adolescents: A systematic review and a 
practical algorithm by the Italian Society of Pediatric Allergy and Immunology. Allergol 
Immunopathol (Madr), 2021. 49(2): p. 155-169. 
15. 
Jackowska, T., et al., PIH26 - European Study on Acute Cough in Children: Results of Poland. 
Value in Health, 2017. 20(9): p. A524. 
16. 
ICMJE. Defining the Role of Authors and Contributors. 2021  [cited 2021 02-December-2021]; 
Available 
from: 
http://www.icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html. 
17. 
 Hartnick CJ, Zurakowski D, Haver K. Validation of a pediatric cough questionnaire. Ear Nose 
Throat J. 2009;88(11):1213-1217. 
18. 
 Anderson-James S, Newcombe PA, Marchant JM, et al. An acute cough-specific quality-of-life 
questionnaire for children: Development and validation. 
J Allergy Clin Immunol. 
2015;135(5):1179-1185.e1-4. doi:10.1016/j.jaci.2014.08.036 
19. 
 Anderson-James S, Newcombe PA, Marchant JM, Turner CT, Chang AB. Children’s Acute 
Cough-Specific Quality of Life: Revalidation and Development of a Short Form. Lung. 
2021;199(5):527-534. doi:10.1007/s00408-021-00482-2 
20.  
 Lee KK, Matos S, Evans DH, White P, Pavord ID, Birring SS. A longitudinal assessment of acute 
cough. Am J Respir Crit Care Med. 2013;187(9):991-997. doi:10.1164/rccm.201209-1686OC 
21.  
Byrom B, Elash CA, Eremenco S, et al. Measurement Comparability of Electronic and Paper 
Administration of Visual Analogue Scales: A Review of Published Studies. Ther Innov Regul Sci. 
2022;56(3):394-404. doi:10.1007/s43441-022-00376-2 

 
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19.1 Guides and standards for the preparation of the CIP 
 
1. The Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 
on medical devices amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and 
Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC 
2. The EN ISO 14155-2020 standard for Clinical investigation of medical devices for human 
subjects - Good Clinical Practice 
3. MDCG 2020-10/1 Rev 1 Guide on Safety reporting in clinical investigations of medical devices 
under the Regulation (EU) 2017/745  
4. MDCG 2020-6 Guide on Regulation (EU) 2017/745: Clinical evidence needed for medical 
devices previously CE marked under Directives 93/42/EEC or 90/385/EEC 
5. Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on 
the protection of natural persons with regard to the processing of personal data and on the free 
movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation) 
6. Law n°78-17 of 6 January 1978 relating to data processing, files and freedoms, as amended by 
law 2018-493 of June 20, 2018 
 
 
 
 

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SIGNATURE PAGE
The signatures of the sponsor and coordinating investigator(s), or any other relevant third party (such 
as a CRO representative) indicating their agreement with the contents of the report, should be provided. 
If no coordinating investigator is appointed, then the signature of the principal investigators should be 
obtained. The signature pages may be separate from the clinical investigation report itself.
The undersigned declare that they agree with the contents of this Clinical Investigation Plan.
Signatures 
Name and Responsibility*
Date
Signature
Pierre Fabre Representative 1
Eric GARRIGUE
Pierre Fabre 
Global Medical Director
Pierre Fabre Representative 2
Farida BEGHDAD
Pierre Fabre 
RWE Project Leader
Scientific Committee Representative 1
Docteur Vincent ALQUIER
Coordinating Pharmacist
Scientific Committee Representative 2
Professeur Guy DUTAU
CRO Representative
Georges MAYEUX
CEN DIRECTOR
Coordinating Investigator 1
Myriam SIMIAN
CEN EXPERIMENTAL
I agree to conduct the study in accordance with the current Clinical Investigation Plan. 
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form in your study files. Please return a copy of this signed original form as 
instructed by Pierre Fabre Médicament.
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Amandine FRY
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DIJON, FR  21000
amandine.fry@groupecen.com
Adresse IP: 212.234.11.105 
Suivi du dossier
État: Original
             25/06/2024 12:34:02
Titulaire: Amandine FRY
             amandine.fry@groupecen.com
Emplacement: DocuSign
Événements de signataire
Signature
Horodatage
Abir TADMOURI
abir.tadmouri.sellier@pierre-fabre.com
RWE & Data Director
Pierre Fabre
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Envoyée: 25/06/2024 12:44:30
Renvoyé: 25/06/2024 15:58:30
Consultée: 27/06/2024 15:15:53 
Signée: 27/06/2024 15:16:36
Divulgation relative aux Signatures et aux Dossiers électroniques: 
      Accepté: 27/06/2024 15:15:53
      ID: a66d327b-e73a-4971-a324-bab6be0d91e1
Didier Junquero
didier.junquero@pierre-fabre.com
Corporate Medical Advisor, Pharmaceutical Care
Pierre Fabre Médicament
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Envoyée: 25/06/2024 12:44:29
Consultée: 26/06/2024 23:14:52 
Signée: 26/06/2024 23:16:05
Divulgation relative aux Signatures et aux Dossiers électroniques: 
      Accepté: 26/06/2024 23:14:52
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Événements de signataire
Signature
Horodatage
Georges Mayeux
georges.mayeux@groupecen.com
Gérant
CEN
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Envoyée: 25/06/2024 12:44:31
Consultée: 25/06/2024 14:28:06 
Signée: 25/06/2024 14:28:30
Divulgation relative aux Signatures et aux Dossiers électroniques: 
      Non offerte par DocuSign
Guy Dutau
guy.dutau@wanadoo.fr
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Envoyée: 25/06/2024 12:44:31
Consultée: 25/06/2024 13:43:38 
Signée: 25/06/2024 13:44:39
Divulgation relative aux Signatures et aux Dossiers électroniques: 
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      ID: 5ff1b761-d8b8-4e07-bf2d-bdc099981e9f
Myriam SIMIAN
simian.myriam@gmail.com
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Envoyée: 25/06/2024 12:44:31
Consultée: 27/06/2024 14:07:58 
Signée: 27/06/2024 14:08:34
Divulgation relative aux Signatures et aux Dossiers électroniques: 
      Accepté: 27/05/2024 18:39:33
      ID: 62cf4c10-655a-4f77-ad4f-644f51b4d399

Événements de signataire
Signature
Horodatage
Vincent ALQUIER
vincentalquier2905@gmail.com
Pharmacien titulaire
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Envoyée: 25/06/2024 12:44:30
Consultée: 25/06/2024 21:04:06 
Signée: 27/06/2024 10:28:07
Divulgation relative aux Signatures et aux Dossiers électroniques: 
      Accepté: 25/06/2024 21:04:06
      ID: 23ba094c-464b-4c50-86f5-c605a8632c69
Événements de signataire en personne Signature
Horodatage
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État
Horodatage
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État
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Événements de livraison intermédiaire État
Horodatage
Événements de livraison certifiée
État
Horodatage
Événements de copie carbone
État
Horodatage
Constance BATTIN
constance.battin.ext@pierre-fabre.com
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Copié
Envoyée: 25/06/2024 12:44:32
Consultée: 27/06/2024 16:39:59 
Divulgation relative aux Signatures et aux Dossiers électroniques: 
      Non offerte par DocuSign
Pauline GOUBET
pauline.goubet@groupecen.com
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Copié
Envoyée: 25/06/2024 12:44:33
Consultée: 28/06/2024 09:32:07 
Divulgation relative aux Signatures et aux Dossiers électroniques: 
      Accepté: 06/11/2023 12:26:44
      ID: 138fe9c3-2735-4869-b4b7-be9bbde814ca
Événements de témoins
Signature
Horodatage
Événements notariaux
Signature
Horodatage
$H.,:4>?6,>41/0=H@H80708>=/0
6J08@069::0
État
Horodatages
Enveloppe envoyée
Haché/crypté
25/06/2024 12:44:33
Enveloppe mise à jour
Sécurité vérifiée
25/06/2024 15:58:29
Enveloppe mise à jour
Sécurité vérifiée
25/06/2024 15:58:29
Enveloppe mise à jour
Sécurité vérifiée
25/06/2024 15:58:29
Livraison certifiée
Sécurité vérifiée
25/06/2024 21:04:06

$H.,:4>?6,>41/0=H@H80708>=/0
6J08@069::0
État
Horodatages
Signature complétée
Sécurité vérifiée
27/06/2024 10:28:07
Complétée
Sécurité vérifiée
27/06/2024 15:16:36
Événements de paiement
État
Horodatages
Divulgation relative aux Signatures et aux Dossiers électroniques

ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time, CEN (we, us or Company) may be required by law to provide to you certain 
written notices or disclosures. Described below are the terms and conditions for providing to you 
such notices and disclosures electronically through the DocuSign system. Please read the 
information below carefully and thoroughly, and if you can access this information electronically 
to your satisfaction and agree to this Electronic Record and Signature Disclosure (ERSD), please 
confirm your agreement by selecting the check-box next to ‘I agree to use electronic records and 
signatures’ before clicking ‘CONTINUE’ within the DocuSign system. 
 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
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Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact CEN:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: arnaud.terrillon@groupecen.com 
 
To advise CEN of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at arnaud.terrillon@groupecen.com 
and in the body of such request you must state: your previous email address, your new email 
address.  We do not require any other information from you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from CEN  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to arnaud.terrillon@groupecen.com and in 
the body of such request you must state your email address, full name, mailing address, and 
telephone number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with CEN  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 

i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to arnaud.terrillon@groupecen.com and in the body of such request you must 
state your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent..  The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
x 
You can access and read this Electronic Record and Signature Disclosure; and 
x 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
x 
Until or unless you notify CEN as described above, you consent to receive exclusively 
through electronic means all notices, disclosures, authorizations, acknowledgements, and 
other documents that are required to be provided or made available to you by CEN during 
the course of your relationship with CEN.