Impact of Adding Healsea® Isotonic Nasal Spray to Conventional Therapies for the Care of Children With Allergic Rhinitis Presenting With Symptoms of Acute Infectious Rhinitis: an Observational Study
Conditions: Common Cold, Allergy
Sponsor: Lallemand Pharma AG

 
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Version: 2.0; 08 Sep 2021 
 
Page 1 of 61 
Study Number: LPH-2101 
 
Impact of adding Healsea® isotonic nasal spray to conventional therapies for 
the care of children with allergic rhinitis presenting with symptoms of acute 
infectious rhinitis: an observational study 
CLINICAL INVESTIGATION PLAN 
 
 
Study Number: LPH-2101 
SYMBIOFILM-TAK 
 
Version 2.0; 08 Sep 2021 
 
 
This Clinical Investigation is being sponsored by: 
 
Lallemand Pharma AG 
Via Selva 2 
6900 Massagno 
Switzerland 
Represented by Dr Frédéric DURMONT 
 
Coordinating Investigator:  
Prof. Andrzej EMERYK 
Department of Lung Diseases & Rheumatology 
University of Medicine in Lublin 
A. Gębali 6 Street, 20-095 Lublin  
Poland

 
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Page 2 of 61 
Study Number: LPH-2101 
 
HISTORY OF CLINICAL INVESTIGATION PLAN’S UPDATES 
Version 
Date 
Purpose of Update 
1.0 
27 May 2021 
Creation 
2.0 
08 Sep 2021 
Update of Sites and Investigators list 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Study Number: LPH-2101 
 
COORDINATING 
INVESTIGATOR  
 
 
Prof. Andrzej EMERYK MD, 
PhD 
Paediatrician, Pulmonologist, 
Allergist 
 
Site No.1 
Klinika Pulmonologii i Alergologii, 
Uniwersytecki 
Szpital 
Dziecięcy 
w Lublinie,  
ul. Prof. Antoniego Gębali 6, 
20-093 Lublin, Polska 
Tel: +48 601 30 50 62,  
+ 48 817 185 477 
emerykandrzej@gmail.com 
INVESTIGATORS  
 
Monika Cendrowska-Pinkosz 
MD, PhD 
Paediatrician, Allergist 
 
Site No.2 
CM ALERGOLOGIA,  
ul. Stefana Kisielewskiego 6/U2,  
20-865 Lublin, Polska 
Tel: + 48 505185187 
m.cendrowskapinkosz@gmail.com 
monika@alergologia.lublin.pl  
Ewelina Wawryk-Gawda  
MD, PhD 
Paediatrician 
 
Site No.3 
Indywidualna 
Praktyka 
Lekarska 
Ewelina Wawryk-Gawda,  
ul. Graniczna 93,  
21-003 Dys, Polska 
Tel: + 48 508 191 144 
ewelina.wawryk@wp.pl 
Arkadiusz Jędrzejewski MD 
Paediatrician 
 
Site No.4 
PRIMED Centrum Medyczne 
ul. Stanisława Węglarza 16, 
20-141 Lublin, Polska 
Tel: + 48 516 609 722 
arni128@op.pl  

 
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Study Number: LPH-2101 
Lucyna Sobiczewska-Wolak 
MD, PhD 
Paediatrician, Pulmonologist 
Allergist 
Site No.5 
"Centrum Alergologii" sp. z o.o.,  
ul. Kawaleryjska 10,  
20-552 Lublin, Polska  
Tel : +48 602 607 817 
l.sobiczewska@wp.pl 
Joanna Tylżanowska-Kisiel 
MD 
Paediatrician, Pulmonologist 
Site No.6 
Adax-Med s.c.,  
ul. Chłopickiego 7/9,  
04-314 Warszawa, Polska 
Tel:+48601 851 538 
joanna.tylzanowska@gmail.com  
Piotr Siergiejko MD, PhD 
Allergist 
Site No.7 
Specjalistyczna Praktyka Lekarska 
Piotr Siergiejko,  
ul. Ogrodowa 5/3,  
15-010 Białystok,  Polska 
Tel : +48500848205, 85 664 20 02 
piotr.siergiejko@gmail.com 
 
Małgorzata Pawlukiewicz MD  
Allergist, Pulmonologist 
Site No.8 
Małgorzata Pawlukiewicz Prywatny 
Gabinet Lekarski,  
ul. Stanisława Staszica 17A,  
35-061 Rzeszów  
Tel: +48 601 322 053  
mpawlu@onet.eu 
 
Anna Poznalska MD  
Allergist, Paediatrician 
Site No.9 
Prywatna Praktyka Lekarska Anna 
Poznalska,  
ul. Piaski 29B,  
18-402 Łomża  
Tel: +48 696 358 491  

 
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Study Number: LPH-2101 
poznalskaania@op.pl 
 
Anna Płoszczuk MD, PhD  
Allergist, Paediatrician 
Site No.10 
Prywatna Praktyka Lekarska 
Gabinet Pediatryczno-
Alergologiczny Anna Płoszczuk,  
ul. Przejazd 2A,  
15-430 Białystok  
Tel: +48 605 639 706  
anna.ploszczuk@wp.pl 
 
Bożena Kucińska MD  
Allergist, Pulmonologist 
Site No.11 
Specjalistyczny Gabinet 
Pulmonologiczno-Alergologiczny 
Bożena Kucińska,  
ul. Moczydła 28,  
95-015 Głowno  
Tel: +48 606 140 120   
bozenakucinska@wp.pl 
 
Jolanta 
Pietraszek-Mamcarz 
MD, PhD  
Allergist, Paediatrician 
Site No.12  
Pietraszek-Mamcarz Jolanta 
Alergovita Alergologia Dziecięca,  
ul. Warszawska Aleja 44,  
20-803 Lublin  
Te: +48 81 533 23 04 
jolanta@mamcarz.com 
 
Bernadetta Majorek-
Olechowska MD  
Paediatrician, Pulmonologist 
Allergist 
 
Site No.13  
PZU Zdrowie S.A. Oddział Centrum 
Medyczne Tarnów,  
ul. Polskiego Czerwonego Krzyża 26, 
33-100 Tarnów  
Tel: +48 600 024 455,  
+48 14 627 26 25  
bernadettaolechowska@gmail.com 

 
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Study Number: LPH-2101 
 
Piotr Korbal MD, PhD  
Paediatrician 
Site No.14 
IN-VIVO Sp. z o.o.,  
ul. Kaszubska 17H,  
85-048 Bydgoszcz  
Tel: +48 501 109 918  
pkorbal@cm.umk.pl 
 
Izabela Tarczoń MD, PhD  
Allergist, Paediatrician 
Site No.15  
Przylądek Zdrowia,  
ul. Henryka Kamieńskiego 47,  
30-644 Kraków 
Tel: +48 508 180 797  
lekarz@przyladekzdrowia.pl 
MONITOR 
Wojciech Weklar, PharmD, 
Senior CRA 
SENSITRIAL POLSKA Sp. z o.o. 
Aleja Jana Pawla II 27 
00-867 Warszawa 
Polska 
Tel +48 504 120 990 
wojciech.weklar@sensitrial.com 
STUDY COORDINATION 
Bernard Gout, PharmD, PhD, 
CEO 
BIOMEDICAL AND GLOBAL CLINICAL 
SOLUTION 
Parc Technologique du Canal 
26 rue Hermès 
31520 Ramonville-Saint-Agne, 
France 
Tel: +33 561 531 944 
b.gout@bgclinicals.com 
MEDICAL WRITER 
 
Géraldine Julou Schaeffer, 
PharmD, PhD 
BIOMEDICAL AND GLOBAL CLINICAL 
SOLUTION 
Parc Technologique du Canal 
26 rue Hermès 
31520 Ramonville-Saint-Agne, 
France 
Tel: +33 561 531 944 
g.schaeffer@bgclinicals.com 
DATA MANAGEMENT / 
STATISTICS  
Benjamin Poirier,  
Biometry Coordinator 
AXIODIS 
38 Avenue Pierre-Georges 
Latécoère, 31700 Blagnac, France 
Tel: +33 610 627 606 
clemee@axiodis.com 

 
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Study Number: LPH-2101 
APPROVAL FORM 
STUDY: LPH-2101 
CLINICAL INVESTIGATION PLAN  
Version 2.0; 08 Sep 2021 
 
Sponsor’s representative: 
 
 
Frédéric DURMONT, MD 
 
 
 
 
 
 
Study’s Coordinating Investigator: 
 
 
Pr Andrzej EMERYK, MD, PhD 
 
 
 
 
 
 
Study’s monitor: 
 
 
Wojciech WĘKLAR 
 
 
 
 
 
 
Study’s Statistician: 
 
 
Benjamin POIRIER  
 
 
 
 
 
 
 
 
Date: 
Signature: 
 
Date: 
Signature: 
 
Date: 
Signature: 
 
Date: 
Signature: 
 

 
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1. Table of content 
2. 
Synopsis 
14 
3. 
Flow Chart 
20 
4. 
Identification and description of the investigational Device 
21 
4.1 
Summary description of the investigational device 
21 
4.1.1 
Summary description 
21 
4.2 
Manufacturer 
21 
4.3 
Name or number of the model to permit full identification 
22 
4.4 
Traceability 
22 
4.5 
Intended purpose of the investigational device in the clinical investigation. 
22 
4.6 
Population and indications for which the device is intended 
22 
4.7 
Device Description 
22 
4.8 
Investigation Device Training/Experience 
24 
4.9 
Reference to the IFU 
24 
5. 
Justification for the design of the clinical investigation 
24 
6. 
Risks and Benefits of the Investigational Device and Clinical Investigation 
26 
6.1 
Anticipated clinical benefit 
26 
6.2 
Anticipated adverse device effects 
26 
6.3 
Risks associated with participation in the clinical investigation 
27 
6.4 
Possible interactions with concomitant medical treatments as considered under the risk 
analysis 
27 
6.5 
Steps that will be taken to control and mitigate the risks 
27 
6.6 
Rationale for the benefit-risk ratio 
28 
7. 
Objectives and hypothesis of the clinical investigation 
28 
7.1 
Hypothesis 
28 
7.2 
Primary Objective 
28 
7.3 
Secondary Objectives 
28 
7.4 
Scientific justification and clinical relevance for effect sizes, non-inferiority margins or 
equivalence 
29 
7.5 
Risks and anticipated adverse effects that are to be assessed 
29 
8. 
Design of the clinical investigation 
29 
8.1 
General 
29 

 
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8.1.1 
Design type of clinical investigation 
29 
8.1.2 
Measures to be taken to minimize or avoid bias 
30 
8.1.3 
Primary Endpoint 
30 
8.1.4 
Secondary Endpoints 
30 
8.1.5 
Methods and timing for assessing, recording and analysing variables 
31 
8.1.6 
Equipment to be used for assessing the clinical variables and arrangements for the 
monitoring maintenance and calibration 
31 
8.1.7 
Any procedures for the replacement of subjects 
31 
8.1.8 
Investigation sites: number, location 
31 
8.1.9 
Definition of the completion of the study 
31 
8.2 
Investigational device and comparator 
31 
8.3 
Subjects 
32 
8.3.1 
Eligibility criteria 
32 
8.3.1.1 
Inclusion criteria 
32 
8.3.1.2 
Non-inclusion Criteria 
32 
8.3.2 
Criteria and procedures for subject withdrawal or lost to follow-up 
33 
8.3.2.1 
Withdrawal Criteria and procedures 
33 
8.3.2.2 
Subjects lost to follow-up 
33 
8.3.2.3 
Subject replacement 
33 
8.3.3 
Point of enrolment 
33 
8.3.4 
Total expected duration of the clinical investigation 
34 
8.3.5 
Expected duration of each subject’s participation 
34 
8.3.6 
Number of subjects required to be included in the clinical investigation 
34 
8.3.7 
Estimated time needed for the enrolment 
34 
8.3.8 
Relationship of investigation population to target population 
34 
8.3.9 
Vulnerable, pregnant and breastfeeding population 
34 
8.3.10 
Compensation 
34 
8.3.11 
Study procedures 
34 
8.3.12 
Permitted and forbidden concomitant medications 
36 
8.3.13 
Activities performed by sponsor representatives (excluding monitoring) 
37 
8.3.14 
Any known/foreseeable factors that can compromise the outcome of the clinical 
investigation and methods for addressing these factors 
37 
8.3.15 
Follow-up and medical care after completion of the study 
37 

 
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8.3.16 
Potential use of samples obtained from subjects 
37 
8.4 
Monitoring plan 
37 
8.4.1 
Initiation visit 
37 
8.4.2 
Monitoring 
38 
9. 
Statistical design and analysis 
38 
9.1 
Descriptive statistics 
38 
9.2 
Study population 
38 
9.3 
Primary endpoint 
39 
9.4 
Secondary endpoints 
39 
9.5 
Safety 
39 
10. 
Data management 
40 
10.1 
Source documents 
40 
10.2 
Methods for data entry and collection 
40 
10.3 
Data review 
40 
10.4 
Procedures for verification, validation and securing of electronic clinical data system 
41 
10.5 
Procedures to maintain and protect subject privacy 
44 
10.6 
Methods for database locking at the start of analysis and storage upon completion of the 
clinical investigation 
45 
10.7 
Procedure for data retention 
45 
11. 
Amendments to the CIP 
45 
12. 
Deviation from Clinical Investigation Plan 
45 
13. 
Device accountability 
46 
14. 
Ethical consideration 
46 
14.1 
Informed consent process 
46 
14.2 
Subject confidentiality 
46 
14.3 
Insurance policy 
47 
15. 
Vigilance 
47 
15.1 
Definitions 
48 
15.2 
Reporting in the eCRF 
49 
15.3 
Investigator’s responsibilities and processing timelines 
49 
15.4 
Sponsor responsibilities and processing timelines 
49 
16. 
Suspension, premature termination and routine close out 
50 
16.1 
Suspension or Premature Termination of the Clinical Investigation 
50 

 
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16.2 
Routine close out 
50 
17. 
Publication policy 
50 
18. 
Bibliography 
52 
19. 
List of Appendix 
54 
 
 
 
 

 
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Study Number: LPH-2101 
PRINCIPAL INVESTIGATOR STUDY APPROVAL PAGE 
STUDY: LPH-2101 
CLINICAL INVESTIGATION PLAN Version:  
Version 2.0, 08 Sep 2021 
 
By signing the hereinafter form, I hereby confirm that I agree: 
▪ 
To conduct the trial described in the Clinical Investigation Plan (LPH-2101) dated 27 May 2021 
in compliance with GCP and the ethical principles that have their origin in the Declaration of 
Helsinki, with applicable regulatory requirements and with the Clinical Investigation Plan 
agreed upon by the sponsor and given approval/favourable opinion by the Ethics Committee; 
▪ 
To document the delegation of significant study related duties and to notify the sponsor of 
changes in site personnel involved in the study; 
▪ 
To comply with procedures for data recording and reporting; 
▪ 
To permit monitoring, auditing and inspection; 
▪ 
To retain the trial-related essential documents until the sponsor informs these documents are 
no longer needed. 
 
Furthermore, I hereby confirm that I will have and will use the availability of adequate resources, 
personnel and facilities for the conduct of this trial. 
 
Principal Investigator’s Name:  
 
__________________________________________________ 
 
Principal Investigator’s Title: 
 
__________________________________________________ 
 
Principal Investigator’s Address:  
 
__________________________________________________ 
 
__________________________________________________ 
 
Principal Investigator’s Signature: 
 
 
 
Date of signature: 
 
__________________________________________________ 
 
 
 

 
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Study Number: LPH-2101 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AsIgE 
Allergen Specific IgE 
AR 
Allergic Rhinitis 
AUC 
Area Under the Curve 
AE 
Adverse Event 
BoV 
Bag-on-Valve  
CA 
Competent Authority 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
EC 
Ethic Committee 
GDPR 
General Data Protection Regulation 
IFU 
Instruction For Use 
IgE 
Immunoglobulin E 
MDR 
Medical Device Regulation 
PI 
Principal Investigator 
PNF 
Primary Notification Form 
RAST 
RadioAllergoSorbant Test  
SAP 
Statistical Analysis Plan 
WURSS-K 
Wisconsin Upper Respiratory Symptom Survey for kids 
 
 

 
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Study Number: LPH-2101 
2. Synopsis 
 
Sponsor: LALLEMAND PHARMA AG 
Coordinating/Principal 
Investigator  
Pr Andrzej Emeryk, University Children Hospital, Lublin, Poland 
Short Title: SYMBIOFILM-TAK 
CIP version: Version 2.0 – 08 Sep 2021 
Competent Authority:  N/A 
Rational  Healsea® Children is a seawater-based nasal spray supplemented with a natural 
Symbiofilm® extract (0.02%) isolated from marine bacteria. Symbiofilm® is an 
exopolymeric composition with emulsifying properties, in vitro antibiofilm 
activity and detachment properties against various bacterial pathogens 
involved in respiratory tract infections. Symbiofilm® has no bacteriostatic nor 
bactericidal activities. Healsea® Children is indicated in the cleaning and 
moistening of nasal mucosa during common cold and rhinitis. 
 
The common cold is an acute viral infection of the upper respiratory tract, 
involving, to variable degrees, sneezing, nasal congestion and discharge 
(rhinorrhea), sore throat, cough, low-grade fever, headache, and malaise. It can 
be caused by members of several families of viruses; the most common are the 
more than 100 serotypes of rhinoviruses. Acute viral rhinitis is generally self-
limiting. In children where the illness is not self-limiting and extends beyond 7-
10 days, many agree that a bacterial infection is likely. Bacterial over infections 
and progression to a chronic state are favoured by the formation of biofilms, 
which facilitate bacterial growth and persistence as well as reducing antibiotic 
efficacy.  
Allergic diseases may play a particular role in promoting the respiratory 
infection recurrences. The physiological immune response is impaired in 
allergic subjects and allergic inflammation favours predisposition to respiratory 
infections. Subjects with allergic disorders may have functional defect of type 
1 immune response that is relevant in fighting infections. 
Allergic rhinitis (AR) may affect up to 40% of the paediatric population. Nasal 
symptoms are caused by exposure to an allergen to which a patient is 
sensitized. Typical allergens include house dust mite, grass pollen, tree pollen, 
weed pollens, cat, dog and moulds. Allergic rhinitis can thus be seasonal or 
perennial, according to the relevant allergen.  
AR is characterized by typical nasal symptoms and IgE-mediated inflammation. 
The allergic inflammatory process releases many cytokines and other 
proinflammatory proteins. Inflammation caused by nasal allergy leads to 
obstruction, fluid accumulation and acute disease. If these diseases are 
unsuccessfully treated, a chronic state of inflammation, obstruction, and 
infection develops that can cause mucosal damage and, ultimately, chronic 
disease. 
For these reasons, the paediatric IgE-dependent allergic population that is 
more prone to common cold represents a suitable target for Healsea® Children. 
 

 
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Study Number: LPH-2101 
During this prospective observational study, one cohort of IgE-dependent 
allergic children with early symptoms of infectious rhinitis will be followed, 
children being treated with Healsea® Children on top of common cold 
conventional therapies or with conventional therapies only (excluded nasal 
irrigation).  
Conventional 
therapies 
for 
non-complicated 
infectious 
rhinitis 
are 
symptomatic but are not without side effects. For example, decongestant use 
can increase blood pressure, antihistamine intake is associated with 
drowsiness. 
Healsea® Children represents an interesting alternative that can not only 
improve acute infectious rhinitis symptomatology but could also limit the 
complication and progression to chronic state.  
This observational study aimed to confirm the benefit of Healsea® Children in 
a real life setting in children with perennial allergy.  
Objectives  Primary Objective: 
- To assess the impact of both treatment modalities (Healsea® Children on top 
of common cold conventional therapies and common cold conventional 
therapies only) to reduce acute infectious rhinitis symptoms in 6-10 years old 
allergic children during a 10-day treatment period. 
 
Secondary Objectives: 
- To assess the impact of both treatment modalities to reduce the duration of 
each infectious rhinitis symptom as rated by the Wisconsin Upper Respiratory 
Symptom Survey for kids (WURSS-K). 
- To assess the impact of both treatment modalities to reduce complications 
of the acute phase during a 20-day follow-up phase.  
- To assess the impact of both treatment modalities on the intake of 
conventional common cold medication (antibiotics, antipyretics, mucolytics, 
decongestants, antitussives, systemic and topical corticosteroids).  
- To assess the impact of both treatment modalities to reduce the person to 
person spreading among close contacts (parents, siblings). 
 
- Safety: to assess systemic and local tolerance of Healsea® Children over the 
study period. 
Endpoints: Primary Endpoint: 
The primary endpoint is the AUC of the WURSS-K during first 10 days of 
symptoms. 
The WURSS-K will be assessed once daily in the evening, considering the 
symptoms from the morning to the evening, during D1-D10. 
 
Secondary Endpoints: 
- Duration of cold symptoms (items 2 to 7) will be assessed by means of the 
WURSS-K (assessed once daily in the evening). 
During treatment period, the WURSS-K will be assessed once daily in the 
evening, taking into account the symptoms from the morning to the evening.  

 
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Study Number: LPH-2101 
After D10, the WURSS-K will be assessed once daily until the subject feels not 
sick for two consecutive days. 
For each item, the duration is defined as the number of symptomatic days 
between D1 and the first day the subject reports not having the symptom for 
two consecutive days.  
To be noticed that the duration may be censored at day 30. 
- Number of subjects who develop respiratory complication requiring antibiotic 
prescription during a 20-day follow-up period. 
- Frequency and number of days of use of concomitant treatments that may 
affect common cold symptoms (antibiotics, antipyretics, systemic or local 
mucolytics, decongestants, antitussives, systemic and topical corticosteroids). 
- Number of family members in close contact developing common cold 
symptoms after the patient all over the study period. 
 
- Safety: Assessment of adverse event/incidents/ undesirable expected side 
effects throughout the study. 
Indication: Treatment of acute rhinitis in children 6-10 years old 
Investigation Design: Prospective, open label, observational study 
 
Visit 1 (V1) – (Day 1): Screening/Inclusion  
Information and provision of the information sheet to legal guardians and 
participants, consent and assent signatures, demographic data and medical 
history, ongoing medication, physical and clinical examination, inclusion/non-
inclusion criteria, record of patient choice regarding Healsea® Children use.  
 
D1-D10 (at home):  
Daily completion of the electronic diary (WURSS-K, adverse events/incident/ 
undesirable 
expected 
side 
effects 
and 
concomitant 
medications, 
contamination of relatives if applicable, Healsea® Children daily administration 
if applicable). 
 
D5±2 (at home): Telephone call 1 
Investigator/nurse call to review patient status and study progress, adverse 
event/incident/undesirable expected side effects and concomitant treatments. 
 
Visit 2 (V2) – (Day 10±2): End of treatment 
End of Healsea® Children nasal spray treatment if applicable, assessment of 
symptoms, diary review, reporting of adverse events/incident/undesirable 
expected side effects. 
 
D11-D30±5 (at home):  
Daily completion of the diary (Adverse event, concomitant medications, 
contamination of relatives if applicable, WURSS-K if applicable, until the subject 
feels not sick for two consecutive days).  
 
D20±2 (at home): Telephone call 2 
Investigator/nurse call to review patient status and study progress, adverse 
events and concomitant treatments.  

 
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Visit 3 (V3) – (Day 30±2): End of study 
Physical and clinical examination, diary review, reporting of adverse events and 
concomitant treatments. 
Number of Subjects: 15 centers will be involved in this study. We plan to follow a cohort of 200 
subjects . The recruitment will be competitive in both group, exposed to 
Healsea® Children or not exposed to Healsea® Children. However, when 100 
patients will be recruited in one group, the recruitment will be stopped in this 
group but will continue in the other group until 100 patients to be enrolled. 
Target Population: Children with allergic rhinitis and symptoms of acute infectious rhinitis 
Inclusion/Exclusion 
criteria: 
Inclusion Criteria: 
Subjects will be enrolled if they meet all of the following criteria: 
1. Male/Female subjects ≥6 and ≤10-year-old  
2. AsIgE ≥ class 2 (RAST) or positive prick test for at least one perennial 
allergen 
3. Acute infectious rhinitis/rhinosinusitis for ≤48h before trial entry 
4. Patient presenting with fever ≥ 37.5 °C at screening 
5. Symptoms of headache, muscle ache, chilliness, sore throat, blocked 
nose, runny nose, cough, sneezing with a total score ≤9 (according to 
a physician-rated symptom score; scale: 0 → 3 [0: no symptom to 3: 
severe intensity]) 
6. At least one of these symptoms: sore throat, runny nose or blocked 
nose (i.e., with a score ≥1) 
7. Written consent obtained from parent/legal guardians 
8.  Written assent obtained from patient 
Non-inclusion Criteria: 
Subjects will not be enrolled if one of the following criteria is present:  
1. Known hypersensitivity/allergy to any component of the test device 
2. Medical history that is considered by the investigator as a reason for 
non-inclusion,  
3. Severe nasal septum deviation or other condition that could cause 
nasal obstruction such as the presence of nasal polyps 
4. History of nasal or sinus surgery that in the opinion of the investigator 
may influence symptom scores 
5. Antibiotic intake within 2 weeks before screening 
6. Systemic corticosteroids within 4 weeks before screening 
7. Antihistamines intake for allergy when treatment was started from less 
than 4 weeks 
8. Bacterial lysate intake within 6 months before screening 
9. Chronic decongestant use 

 
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10. Recent (within the previous 2 days) intake of a common cold medicine 
that in the opinion of the investigator may influence symptom score at 
screening (NSAID, nasal decongestants, cough medicines) 
 
Number of sites: 15 sites in Poland 
Treatments: -Healsea® Children nasal spray, one puff (1-2 sec) in each nostril twice a day for 
10 days on top of conventional therapies as needed 
or 
-Conventional therapies only, nasal irrigation excluded 
Comparator Device: Non applicable 
Duration of 
investigation: 
Duration of inclusion period: 3 months 
Duration of patient’s participation: 30 days 
Total study duration: 4 months 
Study Start Date: September 2021 
Statistical Analysis: The cohort is described: continuous variables will be summarized using the 
mean, standard deviation, median, minimum, maximum and quartiles, 
categorical variables will be summarized using frequency counts and 
percentages.  
Two groups (called treatment groups for a sake of simplicity) will be extracted 
from the cohort according to the treatment chosen by the patient and a 
description of each group will be performed. 
 
Details of the statistical analyses, methods and data conventions will be 
described in the SAP. 
 
All statistical tests will be 2-sided and performed using a 0.05 significance level. 
 
The selection of variables in multivariate analyses will be performed using a 0.2 
significance level and a stepwise method. Whole the multivariate analyses 
specified below involve the treatment and, in order to adjust for confounding, 
all the potential confounding factors as explanatory variables. 
 
The impact of the treatment chosen on the primary endpoint will be analysed 
by means of a multivariate regression model with the AUC of the WURSS-K 
during first 10 days of symptoms as dependent variable. 
 
The impact of the treatment chosen on the cold symptoms’ duration will be 
analysed by means of a Cox model.  
The impact of the treatment chosen on the risk to develop respiratory 
complication requiring antibiotic prescription during a 20-day follow-up period 
will be analyzed by a multivariate logistic model.  
The impact of the treatment chosen on the intake of conventional common 
cold medication (antibiotics, antipyretics, mucolytics, decongestants, 
antitussives, systemic and topical corticosteroids) will be analyzed by 
multivariate Poisson regressions for the numbers of days and a multivariate 
logistic regression for the frequency.  

 
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The impact of the treatment chosen on the number of family members in close 
contact developing common cold symptoms after the patient all over the study 
period will be analyzed by means of a multivariate Poisson regression.  
 
- Safety: All adverse events and incidents will be listed, but only treatment-
emergent adverse events/incidents (non-serious + serious)/ undesirable 
expected side effects will be summarized. 
Two groups (called treatment groups) will be extracted from the cohort 
according to the treatment chosen by the patient. 
Adverse events and incidents will be summarized by the number and 
percentage of patients (by treatment group), classified by System Organ Class 
and Preferred Term as defined by MedDRA dictionary. 
For a given treatment group, a given adverse event will be counted treatment 
emergent only once per patient during the treatment period. 
Frequency and percentage of patients with at least one reported adverse 
event/ incident/ expected side effect will be tabulated by System Organ Class 
and by treatment group. 

 
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3. Flow Chart 
 
ACUTE PHASE 
FOLLOW-UP 
Visit name 
Screening/Inclusion 
At home 
Telephone 
call 
End of 
treatment 
At home 
Telephone 
call 
End of 
study 
Visit Number 
V1 
 
TC1 
V2 
 
TC2 
V3 
Days/Weeks 
D1 
D1 – D10 
D5±2 
D10±2 
D11 – D30±5 
D20±2 
D30 ± 5 
Screening and General Assessments  
Information and consent process 
X 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
Demography and Medical history 
X 
 
 
 
 
 
 
Physical and clinical examination 
X 
 
 
X 
 
 
X 
Ongoing medication 
X 
 
 
 
 
 
 
Patient’s choice for using Healsea® Children 
self-administration or not 
X 
 
 
 
 
 
 
Treatment  
Acute phase (Healsea® Children or no saline 
irrigation as add on therapy) 
 
X 
 
 
 
 
 
Assessments 
Subject e-diary (WURSS-K) 
 
X 
 
 
X* 
 
 
Adverse Events/incidents/undesirable 
expected side effects and concomitant 
medication reporting 
X 
X 
X 
X 
X 
X 
X 
* After D10, the WURSS-K will be assessed once daily until the subject feels not sick for two consecutive days if applicable. 

 
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4. Identification and description of the investigational Device 
4.1 Summary description of the investigational device 
4.1.1 Summary description 
Healsea® Children is a CE marked nasal spray composed with an isotonic seawater solution (0.9% NaCl) 
and Symbiofilm® (0.02%). Symbiofilm® is a Lallemand proprietary marine postbiotic composition 
including an exopolysaccharide mainly composed of N-acetyl hexosamines, acidic and neutral 
monosaccharides. 
The sponsor certifies that the Healsea® Children Medical Device: 
● does not contain any human blood derivative, 
● does not contain any medicinal product,  
● is not manufactured using tissues of animal origin.  
 
Healsea® Children is a nasal spray indicated in children above 6 years to clean and moisten the nose 
during colds and rhinitis. Healsea® Children is administered with the help of an adult for colds and 
rhinitis, one puff (1-2 sec) twice a day in each nostril for 10 days.  
The technical performances are summarized below:  
Ingredient 
Function(s) 
Isotonic Seawater solution 0.9% 
- 
Improve nasal mucosa function  
- 
Clean the nasal cavity and eliminate allergens 
and infectious agents 
Symbiofilm 
- 
Enhancing the cleansing efficacy 
- 
Reducing biofilm formation  
 
Intended clinical performances in the intended destination are: 
− Cleans and moistens the nose during colds and rhinitis.  
− Cleans the nasal cavity and eliminates allergens and infectious agents.  
 
4.2 Manufacturer 
Healsea® Children is a Class IIa Medical Device manufactured by Lallemand Pharma. CE marking has 
been obtained on 30th of March 2021. The subcontractor for the manufacturing is AURENA, 
Fjarrvikvagen 22, ES-653 50 Karlstad, Sweden. 
 

 
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4.3 Name or number of the model to permit full identification 
The test device is named Healsea® Children. It is a nasal spray (100ml presentation), isotonic seawater 
(0.9%) supplemented with Symbiofilm® (0.02%) identified by the code article: 7640149724004. 
 
4.4 Traceability 
Traceability of the Device will be achieved through the lot number (YYMMXXX, YY for year, MM for 
Month and XXX internal number of the manufacturer), the manufacturing date (YYYY/MM/DD) and 
the expiry date (YYYY/MM/DD).  
 
4.5 Intended purpose of the investigational device in the clinical 
investigation. 
This is an observational study. Healsea® Children will be used in the paediatric IgE-dependent allergic 
population that is more prone to common cold and represents a suitable target for Healsea® Children. 
Healsea® Children will be used within its intended purpose i.e., in children above 6 years to clean and 
moisten the nose during colds and rhinitis.  
 
4.6 Population and indications for which the device is intended 
Healsea® Children is a nasal spray indicated in children above 6 years to clean and moisten the nose 
during colds and rhinitis. Healsea® Children is administered with the help of an adult for colds and 
rhinitis, one puff (1-2 sec) twice a day in each nostril for 10 days.  
 
4.7 Device Description 
Healsea® Rescue is a nasal spray (available in 100mL) using the Bag-on-Valve (BoV) technology.  
The BoV technology consists of an aerosol valve with a welded bag. The product is placed inside the 
bag while the propellant is filled in the space between bag and can. The product is dispensed by the 
propellant simply squeezing the bag when the spray button is pressed, the product is squeezed out of 
the bag by the compressed air/nitrogen, which creates the dispensing as a spray. Therefore, the 
product keeps its integrity, remaining separated from the propellant at all times. Compared to 
traditional aerosol spray technology, BoV has several benefits, for manufacturers, consumers and the 
environment. Packaging description of Healsea Children is reported in Figure 1.

 
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*The Spray Pin: Packaging element ensuring the delivery of the product in the patient’s nose. 
 
*The Actuator: Pacifica Spray actuator with a flow rate of 8ml/10s pressed enables the 
propellant to squeeze the bag to dispense the product through the Spray Pin. 
*The Valve assembly: Packaging element ensuring the link between the Bag and the Actuator. 
 
 
 
 The Can: Standard aerosol aluminum can contain the bag and the propellant. 
 
 The Product: Isotonic seawater solution (0.9%) supplemented with Symbiofilm® 0.02%.  
 
*The Bag: FDA-approved laminated bag containing the product. 
 
The Propellant: Because of the separation between product and propellant, BoV technology is 
used with compressed nitrogen filled between the can and the bag. 
 
*Packaging element in contact with the product 
Figure  SEQ Figure \* ARABIC 1- Packaging description of Healsea® Children 

 
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As summarized below, Healsea® Children is intended to be used on nasal mucosa. The duration of use 
is 10 days.  
Table 1 : Device Category / Intended Use  
Type of contact 
Device in contact with a surface 
Type of tissues 
Mucous membranes  
Total duration treatment 
It can be used for 10 days 
 
4.8 Investigation Device Training/Experience 
There is no need for specific training in using Healsea® Children.  
A usability engineering process test according to the standard EN ISO 62366-1: 2015 was conducted 
with Healsea® Children with 10 people representative of the parents/legal guardians of the target 
population to ensure that the leaflet and the label were well understood, and that the medical device 
was used correctly to ensure its safe understanding and use. 
The analysis of the results demonstrates that: 
- 
The information provided by the user interface is readable and understandable by 
participants: the information tested was easy to understand, without interpretation.  
- 
The observations made during the simulations of use of the device have confirmed that all 
safety-related handling steps are properly followed, in accordance with the instructions given 
in the instruction for use. 
 
Briefly, the children (with the help of an adult if necessary) to place the nozzle into the nostril while 
keeping head straight. Once the nozzle is placed, to press on the nozzle for 1-2 seconds in each nostril. 
To let flow the excess of solution, and wipe. To clean the nozzle with tissue, soapy water rinse and dry 
after use.  
 
4.9 Reference to the IFU 
The IFU of Healsea® Children is provided in Appendix A.  
 
5. Justification for the design of the clinical investigation 
Although clinical evidence from well-designed trials is scarce [1], European guidelines for acute 
rhinitis/rhinosinusitis recommend daily nasal saline irrigation for reduction of the severity of 
symptoms and for speeding recovery [2]. The exact mechanisms by which nasal irrigation works are 

 
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not known. However, most of the experts agree that it is primarily a mechanical intervention leading 
to direct cleaning of the nasal mucosa [3] [4]. The mucus lining the nasal cavity may be softened and 
dislodged. The increase of mucociliary clearance is associated with a decrease of pathogens burden. 
Moreover, inflammatory mediators such as cytokines, prostaglandins and leukotrienes can be 
removed, favoring the resolution of URTIs. Nevertheless, the efficacy of such saline irrigation remains 
moderate [1].  
Symbiofilm® is an exopolysaccharide composition with emulsifying properties and in vitro antibiofilm 
activity. Antibiofilm properties have been demonstrated with a microtiter plate assay [5]. In both 
models, a significant inhibition of Staphylococcus aureus and Haemophilus influenzae biofilms was 
observed. Detachment properties from human nasal epithelial cells of Staphylococcus aureus and 
Pseudomonas aeruginosa has also been demonstrated in vitro, suggesting an inhibition of biofilm 
formation at early stage in this model. The antibiofilm activity of Symbiofilm® is likely to rely on its 
emulsifying properties. In all models, the absence of bacteriostatic or bactericidal activities against all 
strains tested has been confirmed.  
The technical performances of Symbiofilm® may enhance the interest of saline nasal irrigation for the 
treatment of acute infectious rhinitis and common cold. 
The common cold is the most frequent upper respiratory tract infection (URTI), which is the most 
commonly treated acute problem in primary pediatric care [6]. Despite the usually benign nature of 
the illness, the common cold is an enormous economic burden on society in terms of visits to doctors, 
treatments, and absences from work, school, or day care [6][7].The common cold is an acute viral 
infection of the upper respiratory tract, involving, to variable degrees, sneezing, nasal congestion and 
discharge (rhinorrhea), sore throat, cough, low-grade fever, headache, and malaise [2]. It can be 
caused by members of several families of viruses. However, rhinoviruses have been consistently found 
to be the most common cause in all age groups, irrespective of the viral detection techniques 
used. Yearly, rhinoviruses account for about 30-50% of all respiratory illnesses, but during the autumn 
peak season these viruses can cause up to 80% of all upper respiratory infections. Coronaviruses and 
Influenza viruses account for about 10-15% and for 5-15% of acute infectious rhinitis respectively. 
Other viruses such as Respiratory Syncytial Virus, Adenoviruses and Parainfluenza viruses are less 
involved [7]. Acute viral rhinitis is generally self-limiting. In children where the illness is not self-limiting 
and extends beyond 7-10 days, many agree that a bacterial infection is likely [2]. Acute bacterial 
rhinosinusitis is diagnosed in a child based on several criteria: persistent upper respiratory tract 
symptoms more than 10 days (cough or nasal discharge or both); or recurrence of symptoms after 
initial improvement: fever, worsening cough, or worsening or new purulent rhinorrhea; or severe 
onset of symptoms like fever or purulent nasal discharge lasting more than three consecutive days 
associated with facial tenderness or headache. Bacterial over infections and progression to a chronic 
condition are favored by the formation of biofilms, which facilitate bacterial growth and persistence 
as well as reducing antibiotic efficacy [8][9].  
Allergic diseases may play a particular role in promoting the respiratory infection recurrences. The 
physiological immune response is impaired in allergic subjects and allergic inflammation favours 
predisposition to respiratory infections [10]. Subjects with allergic disorders may have functional 
defect of type 1 immune response that is relevant in fighting infections [11][12]. Allergic rhinitis (AR) 

 
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may affect up to 40% of the paediatric population. Nasal symptoms are caused by exposure to an 
allergen to which a patient is sensitized. Typical allergens include house dust mite, grass pollen, tree 
pollen, weed pollens, cat, dog and moulds. Allergic rhinitis can thus be seasonal or perennial, according 
to the relevant allergen. AR is characterized by typical nasal symptoms and IgE-mediated inflammation. 
The allergic inflammatory process releases many cytokines and other proinflammatory proteins. 
Inflammation caused by nasal allergy leads to obstruction, fluid accumulation and acute disease. If 
these diseases are unsuccessfully treated, a chronic status of inflammation, obstruction, and infection 
develops that can cause mucosal damage and, ultimately, chronic disease [14]. 
For these reasons, the paediatric IgE-dependent allergic population that is more prone to common 
cold represents a suitable target for Healsea® Children [15][16]. During this prospective observational 
study, one cohort of IgE-dependent allergic children with early symptoms of infectious rhinitis will be 
followed, children being treated with Healsea® Children on top of common cold conventional therapies 
or with conventional therapies only (excluded nasal irrigation). Conventional therapies for non-
complicated infectious rhinitis are symptomatic but are not without side effects [17][6]. For example, 
decongestant use can increase blood pressure, antihistamine intake is associated with drowsiness that 
can not only improve acute infectious rhinitis symptomatology but could also limit the complication 
and progression to chronic state.  
This observational study aimed to confirm the benefit of Healsea® Children in a real life setting in 
children with perennial allergy.  
 
6. Risks and Benefits of the Investigational Device and Clinical Investigation 
6.1 Anticipated clinical benefit 
Both groups will receive effective treatments.  
Due to the presence of Symbiofilm®, the group receiving Healsea® Children is anticipated to recover 
more quickly from acute rhinitis than the group of children receiving only conventional therapies for 
the common cold. 
 
6.2 Anticipated adverse device effects 
The only anticipated adverse device effect is the feeling of nasal itching and irritation while initiating 
the treatment with the medical device Healsea® Children. In case of such adverse reaction, the 
parents/legal guardians/patients will be instructed to contact the investigator if the patient wishes to 
stop the nasal spray use.  
 

 
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6.3 Risks associated with participation in the clinical investigation 
No design element, subject to safety-related questioning is identified. The instructions for use include 
mentions to control risks. Patients with known hypersensitivity/allergy to any component of the test 
device will not be enrolled in the study. The clinical procedures comprise daily completion of an 
electronic diary comprising a validated questionnaire (WURSS-K) [18] only.  
 
6.4 Possible interactions with concomitant medical treatments as 
considered under the risk analysis 
No interaction is expected. Nevertheless, patient will be instructed to respect a 60-minute minimum 
interval after administration of the investigational medical device before administration of another 
local medication e.g., decongestant or mucolytics (if permitted).  
 
6.5 Steps that will be taken to control and mitigate the risks 
In the line with NF EN ISO 14971:2019 standard (Medical Devices – Application of risk management to 
medical devices), a risk analysis has been conducted to estimate the risks associated with each step of 
the device lifecycle. Most of the risk has been mitigated through product design and manufacturing. 
The residual risk to patients who are administered this intervention is low. A list of potential risks 
associated with the device, procedures undertaken to minimise them, and methods used for their 
management is described in the device Risk Management Process File. 
Considering:  
- 
the risk analysis (ISO 14 971 activities) that demonstrates:  
o There is no longer High level risk,  
o That, the 41 Medium risk level residuals risks have an acceptable benefit-risk balance, 
o And all of the others residual risks (85) are at Low risk. 
- 
the fact that the device Healsea® Children can be considered as safe and effective according 
to the Clinical Evaluation Report.  
 
the overall residual risk is acceptable, and the benefit/risk ratio is considered satisfactory.  
The verification of the implementation of risk control measures during life cycle phases of Healsea® 
Children is mainly performed by LALLEMAND PHARMA AG using the operating procedures currently 
used. 
No specific risk for subject in participating in the study is identified, provided that the eligibility criteria 
are fulfilled. Thus, the establishment of risk acceptability thresholds is not deemed necessary although 
it is a requirement from the ISO 14155:2020. Nevertheless, the safety and well-being of subjects will 
be monitored throughout the study. Should a potential unanticipated risk be detected, the clinical 
investigation will be suspended, the risk assessment will be updated to adapt the risk control measures 
and the benefit-risk analysis.  

 
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6.6 Rationale for the benefit-risk ratio 
Although infectious rhinitis is in most cases self-limiting, it impacts the children’s quality of life during 
generally about 7-10 days. Furthermore, bacterial over infections with worsening of symptoms can 
occur requiring antibiotic prescription. Progression to a chronic state, i.e., chronic rhinosinusitis is also 
observed.  
Conventional therapies for infectious rhinitis are symptomatic and not without side effect. For 
example, decongestant use can increase blood pressure, antihistamine intake is associated with 
drowsiness. 
Healsea® Children represents an interesting alternative because the nasal spray could alleviate acute 
infectious rhinitis symptoms but also limit the complication and progression to chronic state. 
Furthermore, apart from feeling of nasal itching and irritation while initiating the treatment, no 
adverse effect is anticipated.  
 
7. Objectives and hypothesis of the clinical investigation 
7.1 Hypothesis 
Our hypothesis is that Healsea® Children nasal spray on top of conventional therapies for common 
cold can improve the symptomatology of acute infectious rhinitis in allergic children (6-10 years) with 
more efficacy than conventional therapies only without safety concerns.  
 
7.2 Primary Objective 
To assess the impact of both treatment modalities (Healsea® Children on top of common cold 
conventional therapies and common cold conventional therapies only) to reduce acute infectious 
rhinitis symptoms in 6-10 years old allergic children during a 10-day treatment period.  
 
7.3 Secondary Objectives 
- To assess the impact of both treatment modalities to reduce the duration of each infectious rhinitis 
symptom as rated by the Wisconsin Upper Respiratory Symptom Survey for kids (WURSS-K) [18]. 
- To assess the impact of both treatment modalities to reduce complications of the acute phase during 
a 20-day follow-up phase.  
- To assess the impact of both treatment modalities on the intake of conventional common cold 
medication (antibiotics, antipyretics, mucolytics, decongestants, antitussives, systemic and topical 
corticosteroids).  

 
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- To assess the impact of both treatment modalities to reduce the person-to-person cold spreading 
among close contacts (parents, siblings).  
- Safety: to assess systemic and local tolerance of Healsea® Children over the study period. 
 
7.4 Scientific justification and clinical relevance for effect sizes, non-
inferiority margins or equivalence 
This is a prospective, open label, observational study. An arbitrary cohort of 200 children has been 
chosen. A cohort of 100-exposed and 100-not exposed patients is anticipated to allow to demonstrate 
the interest of using Healsea® Children in the allergic paediatric population. Indeed, 100 patients by 
arms are enough to detect a Cohen’s effect size of 0.4 with a power of 80% and a type I error of 5%. 
Cohen’s effect size is defined as the standardized difference between AUC in groups. Following Cohen’s 
methodology, 0.4 is an intermediate size between a small effect (0.2) and a medium effect (0.5) and is 
coherent with the expected result. 
The recruitment will be competitive in both group, exposed to Healsea Children or not exposed to 
Healsea® Children. However, when 100 patients will be recruited in one group, the recruitment will be 
stopped in this group but will continue in the other group until 100 patients to be enrolled. 
No assumption of expected outcomes across treatment group is performed. 
 
7.5 Risks and anticipated adverse effects that are to be assessed 
No specific risk for subject in participating in the study is identified, provided that the eligibility criteria 
are fulfilled. Nevertheless, the safety and well-being of subjects will be monitored throughout the 
study.   
 
8. Design of the clinical investigation 
8.1 General 
8.1.1 Design type of clinical investigation 
This is a prospective, open label, observational, national (Poland), multicentre study.  
During this prospective observational study, one cohort of IgE-dependent allergic children with early 
symptoms of infectious rhinitis will be followed, children being treated with Healsea® Children on top 
of common cold conventional therapies or with conventional therapies only (nasal irrigation excepted). 
This observational study aimed to confirm the benefit of Healsea® Children in a real life setting in 
children with perennial allergy. 

 
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8.1.2 Measures to be taken to minimize or avoid bias 
Not applicable.  
8.1.3 Primary Endpoint 
The primary endpoint is the area under the curve (AUC) of the Wisconsin Upper Respiratory Symptom 
Survey for Kids (WURSS-K) during first 10 days of symptoms. AUC will be calculated applying the 
trapezoidal rule, with the y-axis, defined by daily WURSS-K scores, and the x-axis, defined as duration 
of illness, starting with the first symptoms and ending at day 10. 
WURSS-K is a 3-dimensional structure questionnaire specifically designed for children 4 to 10 years of 
age [18] (appendix B). This survey has been demonstrated to be responsible, reliable, and valid for 
assessing illness specific symptoms and impact on quality of life during an acute infectious rhinitis in 
paediatric population. 
It includes 6 items assessing symptoms (symptoms score: runny nose, stuffy nose, sneezing, sore 
throat, cough, feeling tired), 7 items assessing functional impairments (quality of life score: think, 
sleep, breathe, talk, walk/climb stairs/exercise, go to school, play with friends), 1 item assessing global 
severity. All these items are scored using visual representation of happy and sad faces to assist Likert 
scale ratings from 0 (absent or no impairment) through 1 (a little bad), 2 (bad) and 3 (very bad). The 
sum of the 14 items on a 4-point ordinal scale results in a global total score ranging from 0 (low 
symptoms and low functional impairment) to 42 (high symptoms and high functional impairment). One 
item assessing global change as compared to the day before is rated from 0 (a lot better) to 4 (a lot 
worse) is not included in the overall score. 
Using an electronic diary, the patient will score the WURSS-K daily in the evening, taking in account 
the symptoms from the morning to the evening, during D1-D10. After D10, the WURSS-K will be 
assessed once daily until the subject feels not sick for two consecutive days. 
8.1.4 Secondary Endpoints 
- Duration of cold symptoms (items 2 to 7) will be assessed by means of the WURSS-K (assessed once 
daily in the evening).  
During treatment period, the WURSS-K will be assessed once daily in the evening, taking in account 
the symptoms from the morning to the evening.  
After D10, the WURSS-K will be assessed once daily until the subject feels not sick for two consecutive 
days. 
For each item, the duration is defined as the number of symptomatic days between D1 and the first 
day the subject reports not having the symptom for two consecutive days.  
To be noticed that the duration may be censored at day 30. 
- Number of subjects who develop respiratory complication requiring antibiotic prescription during 
a 20-day follow-up period. Healsea® Children is expected to reduce acute rhinitis complications. 
- Frequency and number of days of use of concomitant treatments that may affect common cold 
symptoms (antibiotics, antipyretics, mucolytics, decongestants, antitussives, systemic and topical 

 
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corticosteroids). By reducing duration of common cold symptoms, Healsea® Children will very likely 
reduce the use of common rescue medication. 
- Number of family members in close contact developing common cold symptoms after the patient 
all over the study period. The daily use of Healsea® Children started at the onset of common cold 
symptoms is expected to reduce relative’s contamination. 
- Safety: Assessment of adverse events/incidents/undesirable expected side effects throughout the 
study.  
8.1.5 Methods and timing for assessing, recording and analysing variables 
The primary endpoint will be assessed and record into an electronic diary once daily in the evening, 
considering the symptoms from the morning to the evening, during D1-D10. After D10, the WURSS-K 
will be assessed once daily until the subject feels not sick for two consecutive days. To be noted that 
the duration may be censored at day 30. Should the children require some or lot of help to fill in the 
questionnaire, this will be recorded in the diary as part of the WURSS-K questionnaire.  
A specific field will be designed in the electronic diary for adverse event/incidents/expected side 
effects and concomitant treatments recording, contamination of relative(s) and for report of Healsea® 
Children intake if applicable.  
8.1.6 Equipment to be used for assessing the clinical variables and 
arrangements for the monitoring maintenance and calibration 
Not applicable.  
8.1.7 Any procedures for the replacement of subjects 
Not applicable.  
8.1.8 Investigation sites: number, location 
The clinical investigation will be undertaken in 15 sites in Poland. All investigators are paediatricians 
and /or allergist and/or pulmonologists. The investigation does not require specific environment as it 
is an observational study. 
8.1.9 Definition of the completion of the study 
This is defined as the date of last patient last visit (LPLV).  
 
8.2 Investigational device and comparator 
The investigational device which is Healsea® Children. This is a CE marked Medical Device. 
Patients/parents will be allowed to use or not the investigational nasal spray. If they choose nasal 
symptoms to be treated with Healsea® Children, they will start the nasal spray treatment following 

 
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their inclusion visit (Visit 1). Healsea® Children will be used on the top of conventional therapies for 
common cold and administered with the help of an adult, spraying one puff (1-2 sec) twice a day in 
each nostril for 10 days.  
No comparator is used in this study. Patient/parents who prefer not to use Healsea® Children will use 
conventional therapies for common cold only. However, use of nasal irrigation will not be authorized 
for these patients.  
 
8.3 Subjects 
The target population is allergic children with early symptoms of acute infectious rhinitis.  
8.3.1 Eligibility criteria 
8.3.1.1 
Inclusion criteria  
Subjects will be enrolled if they meet all of the following criteria: 
1. Male/Female subjects ≥6 and ≤10- year old  
2. AsIgE ≥ class 2 (RAST) or positive prick test for at least one perennial allergen 
3. Acute infectious rhinitis/rhinosinusitis for ≤48h before trial entry 
4. Patient presenting with fever ≥ 37.5 °C at screening 
5. Symptoms of headache, muscle ache, chilliness, sore throat, blocked nose, runny nose, 
cough, sneezing with a total score ≤9 (according to a physician-rated symptom score; scale: 
0 → 3 [0: no symptom to 3: severe intensity]) 
6. At least one of these symptoms: sore throat, runny nose or blocked nose (i.e., with a score 
≥1) 
7. Written consent obtained from parent/legal guardians 
8. Written assent obtained from patient 
 
8.3.1.2 
Non-inclusion Criteria 
Subjects will not be enrolled if one of the following criteria is present:  
1. Known hypersensitivity/allergy to any component of the test device 
2. Medical history that is considered by the investigator as a reason for non-inclusion  
3. Severe nasal septum deviation or other condition that could cause nasal obstruction such as 
the presence of nasal polyps 
4. History of nasal or sinus surgery that in the opinion of the investigator may influence symptom 
scores 
5. Antibiotic intake within 2 weeks before screening 
6. Systemic corticosteroids within 4 weeks before screening 
7. Antihistamines intake for allergy when treatment was started from less than 4 weeks 
8. Bacterial lysate intake within 6 months before screening 
9. Chronic decongestant use 

 
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10. Recent (within the previous 2 days) intake of a common cold medicine that in the opinion of 
the investigator may influence symptom score at screening (NSAID, nasal decongestants, 
cough medicines) 
8.3.2 Criteria and procedures for subject withdrawal or lost to follow-up 
8.3.2.1 
Withdrawal Criteria and procedures 
The reasons for a subject’s premature withdrawal from the study may be the following: 
● A parent can withdraw his/her consent and/or a subject can withdraw his/her assent from the 
study for any reason at any time, but he/she must inform the investigator. In all cases, 
whenever possible, the investigator should attempt to contact the patient as soon as possible 
for a final assessment in order to: 
o Obtain the reason(s) for withdrawal and report it/them in the Case Report Form,  
o Evaluate the patient’s clinical condition, 
o If necessary, take appropriate therapeutic measures: management of an adverse 
effect or concomitant disease, prescription of another treatment. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
● If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best interest 
of the participant.  
● If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. In the context of COVID-19 pandemic, 
the diagnosis of COVID-19 during the study will justify the withdrawal of the patient from the 
study.  
A premature end of study visit will be scheduled. Available data will be retained for the safety/efficacy 
analysis.  
8.3.2.2 
Subjects lost to follow-up 
If a patient cannot be contacted to collect follow-up information even beyond the 10 days from visit 3, 
he/she will be considered “lost to follow-up”. But before declaring that a patient is "lost to follow-up", 
the Principal Investigator (or his/her team) must do his/her best effort to contact patients and 
attempts should be made via all available routes. A certified letter should be sent to the permanent 
address on file. 
The methods used to attempt to contact the patient should be noted in the patient medical file. 
8.3.2.3 
Subject replacement  
It is not anticipated to replace withdrawal patients.  
8.3.3 Point of enrolment 
The subjects will be recruited by the sites among outpatients coming in consultation because of early 
symptoms of common cold.  

 
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To facilitate the enrolment, parents/legal guardians of allergic children coming for routine consultation 
will be informed of this clinical trial. In case of the onset of acute infectious rhinitis/rhinosinusitis 
symptoms, they will be invited to contact the site and to come for a consultation if they are interested. 
Before performing any study procedure, the investigator will give all the information pertaining to the 
study and the patient’s legal guardians will sign the consent form if they accept their child study 
participation. Children will also receive an information specific to their age and will be invited to sign 
an assent presented by the investigator. 
8.3.4 Total expected duration of the clinical investigation 
The total study duration is planned to be 4 months.  
8.3.5 Expected duration of each subject’s participation 
The duration of each patient’s participation is 30 days.  
8.3.6 Number of subjects required to be included in the clinical investigation 
A cohort of 200 children is expected to participate in the study.  
 
8.3.7 Estimated time needed for the enrolment 
It is expected to enrol a cohort of 200 patients within 3 months. 
8.3.8 Relationship of investigation population to target population 
Healsea® Children will be used within its intended use. This observational study aimed to confirm the 
benefit of Healsea® Children in a real life setting in children with perennial allergy and early symptoms 
of infectious rhinitis.  
8.3.9 Vulnerable, pregnant and breastfeeding population 
Patient under tutorship or legal guardianship are not eligible. 
Pregnant and breastfeeding women: not applicable because it is a paediatric observational study.  
8.3.10 Compensation  
No compensation is planned because this is an observational study. Travel expenses will be reimbursed 
in full on presentation of receipts attesting to such expenses for visits 2 and 3, considering that visit 1 
is a routine care consultation.  
8.3.11 Study procedures 
The study will comprise 3 visits and 2 telephone calls. 

 
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Visit 1 (V1) – (Day 1): Screening/Inclusion  
The investigator will give oral information relative to the study to parents/legal guardians and the 
participant. If both parents/legal guardians agree that their child participate in the study, they will 
receive the information sheet and will be also asked to give a written consent. In case one parent will 
not be available for the visit; he/she will be asked to confirm in writing that he/she agrees with the 
participation of the child in the study. Children will also receive an information specific to their age and 
will be invited to sign an assent by the investigator. 
Each screened subject will be assigned a subject identifier number during screening. The subject 
identifier number will contain the site number and the subject number and will be assigned in 
numerical order at the screening visit based on chronological order of screening dates (e.g., 01-010 for 
the 10th subject screened at the Site #01). 
The investigator or his/her delegated designee will: 
Ɣ Record demographic data and medical history and ongoing medication,  
Ɣ Perform a physical and clinical examination,  
Ɣ Record the score of the common cold symptoms (headache, muscle ache, chilliness, sore 
throat, blocked nose, runny nose, cough, sneezing according a physician-rated symptom 
score after clinical examination of the child; (scale: 0  3 [0: no symptom, 1 = mild symptoms 
(sign/symptom clearly present, but minimal awareness; easily tolerated), 2 = moderate 
symptoms (definite awareness of sign/symptom that is bothersome but tolerable), 3 = 
severe symptoms (sign/symptom that is hard to tolerate; causes interference with activities 
of daily living and/or sleeping]). This scoring system was developed by Jackson in 1958 and is 
widely used in common cold clinical trials [19],  
Ɣ Verify that eligibility criteria are fulfilled,  
Ɣ Record the patient choice regarding Healsea® Children use (if the patient/parents choose 
nasal symptoms to be treated with Healsea® Children, instructions will be given to the 
patient/parents for getting the test product at the end of the visit), 
Ɣ Explain to the child/parents/legal guardians how to use Healsea® Children if applicable,  
Ɣ Review and detail the questions of the WURSS-K, 
Ɣ Explain how to use the e-diary for WURSS-K recording, how to report adverse events/ 
incidents/expected undesirable side effects, concomitant medications, and contamination of 
relatives in the e-diary. The legal guardians will access the e-diary website 
(https://me.vieodoc.net) using a smartphone and logging in with a randomly assigned 
username and Pin code. Data recorded in the e-diary will be at the same time uploaded in the 
e-CRF. 
D1-D10 (at home):  
The patients will be asked to complete the electronic diary daily (WURSS-K assessed once daily in the 
evening, taking in account the symptoms from the morning to the evening, adverse 
events/incidents/expected undesirable side effects and concomitant medications, contamination of 
relatives) and to report Healsea® Children intake if applicable. For the Healsea® Children treated-
group, compliance will be indirectly assessed by the question: “do you use the nasal spray as 

 
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recommended (1 puff 2 sec in each nostril twice a day)?”. If necessary, the parent(s) will help their 
child in this task. 
D5 (Day 5±2, at home): Telephone call 1 
The Investigator or his/her delegated designee will call the patient to review patient status and study 
progress, adverse event/incidents/expected undesirable side effects and concomitant treatments.  
Visit 2 (V2) – (Day 10±2): end of treatment 
The investigator or his/her delegated designee will: 
● Perform a physical and clinical examination,  
● Record the common cold symptoms if they persist,  
● Validate the adverse events/incidents/expected undesirable side effects and concomitant 
medications reported in the e-CRF through the e-diary and report any new relevant safety 
event.  
 
For patients receiving Healsea® children, the treatment will be stopped at D10. The patients for whom 
common cold symptoms persist, will be instructed to continue to score the WURSS-K until the subject 
feels not sick for two consecutive days. 
D11-D30 (at home):  
After D10, the WURSS-K will be assessed once daily until the subject feels not sick for two consecutive 
days if applicable. The patients will be asked to complete the electronic diary daily (WURSS-K if 
applicable, adverse events, concomitant medications, and contamination of relatives). If necessary, 
the parent(s) will help their child in this task. 
D20 (Day 20±2, at home): Telephone call 2 
The Investigator or his/her delegated designee will call the patient to review patient status and study 
progress, adverse event, and concomitant treatments. 
Visit 3 (V3) – (Day 30±5): end of study 
The investigator or his/her delegated designee will: 
● Perform a physical and clinical examination,  
● Record the common cold symptoms if they persist,  
● Validate the adverse events and concomitant medications reported in the e-CRF through the 
e-diary and report any new relevant safety event.  
8.3.12 Permitted and forbidden concomitant medications 
All concomitant medications are authorized except nasal irrigation for patients who do not choose to 
use Healsea® children. 

 
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8.3.13 Activities performed by sponsor representatives (excluding monitoring) 
The sponsor will implement and write clinical quality procedures to ensure that the clinical 
investigation is conducted and monitored, and that data are generated, documented, recorded, 
evaluated and reported in compliance with the ISO 14155:2020, the CIP, any subsequent 
amendment(s) and any other applicable standards and in accordance with the regulation 
requirements. The sponsor will ensure ongoing risk management throughout the clinical investigation 
and will take all measures to protect rights, safety and well-being of children who participate in the 
study.  
The sponsor is required to report noncompliance trends and safety issues to the Ethics Committee and 
investigators. 
The sponsor shall report on the progress and status of the clinical investigation to the Ethics 
Committee.  
The sponsor will determine the frequency and type of audit to be performed. An audit can be used:  
i) 
As a routine part of the sponsor's quality assurance, 
ii) 
To assess the effectiveness of the monitoring activity, 
iii) 
Whenever there are serious or repeated CIP deviations or suspicion of fraud,  
iv) 
To bring an investigation site into “inspection readiness” (i.e., to prepare the investigation 
site for a potential regulatory inspection),  
v) 
When requested or suggested by a regulatory authority. 
8.3.14 Any known/foreseeable factors that can compromise the outcome of 
the clinical investigation and methods for addressing these factors 
There is no known/foreseeable factor that can compromise the outcome of the clinical investigation. 
8.3.15 Follow-up and medical care after completion of the study 
Neither follow-up nor specific medical care for patients are foreseen after the completion of the study.  
8.3.16 Potential use of samples obtained from subjects 
Not applicable.  
8.4 Monitoring plan 
A risk-based monitoring plan included in a separate document will describe in detail who will conduct 
the monitoring, at what frequency monitoring will be done, at what level of detail monitoring will be 
performed, and the distribution of monitoring reports. Results of the risk assessment will be used to 
develop a risk-based monitoring plan and a supporting rationale. 
8.4.1 Initiation visit 
The study will only start at a site after: 

 
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● The Ethics Committee has granted approval for the conduct of the study,  
● Essential documents are in place, such as CVs of the Investigators and site staff, and the Clinical 
Trial Agreement signed.  
In agreeing to participate, the investigator undertakes to strictly comply with the study protocol, Good 
Clinical Practice, the Polish regulation and to MDR. The investigator also guarantees the authenticity 
of the data collected in the context of the study and agrees to the legal provisions for study sponsor 
quality control.  
8.4.2 Monitoring 
Study monitoring under responsibility of Lallemand Pharma by qualified staff will be performed at 
various stages of the study. Monitoring will include on-site visits and centralized data review to assure 
that the investigation is conducted according to the CIP and comply with applicable regulations and 
deadlines. On-site review of electronic Case Report Form (e-CRFs) will include the review of forms for 
completeness, clarity, and consistency with source documents available for each subject. In case of 
queries, the investigator should respond within agreed timelines. 
The investigator must permit study-related monitoring visits, audits review by the Ethics Committee, 
and allow direct access to source data and source documents provided that subject confidentiality is 
protected. In case of an audit appointed by Lallemand Pharma, the investigator will receive written 
notification in advance.  
 
9. Statistical design and analysis 
9.1 Descriptive statistics 
The cohort is described: continuous variables will be summarized using the mean, standard deviation, 
median, minimum, maximum and quartiles, categorical variables will be summarized using frequency 
counts and percentages.  
Two groups (called treatment groups for a sake of simplicity) will be extracted from the cohort 
according to the treatment chosen by the patient and a description of each group will be performed. 
Details of the statistical analyses, methods and data conventions will be described in the SAP. 
All statistical tests will be 2-sided and performed using a 0.05 significance level.  
 
9.2 Study population 
The study population consists in all the patients included and who do not meet a “major deviation to 
protocol” as defined in section 12. 
The safety population consists in all the patients included in this study. 

 
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The analysis of primary and secondary endpoints will be performed on study population, safety 
endpoint will be performed on safety population. 
 
9.3 Primary endpoint 
The primary objective will be analysed by performing a t-test (or a Wilcoxon test if the normality 
assumption is not acceptable) between the means AUC of WURSS-K score during first 10 days of 
symptoms in each group.  
 
9.4 Secondary endpoints 
The analysis of the secondary endpoints will involve multivariate analysis. 
The selection of variables in multivariate analysis will be performed using a 0.2 significance level and a 
stepwise method. Whole the multivariate analyses specified below involve the treatment and, in order 
to adjust for confounding, all the potential confounding factors as explanatory variables. 
 
The analysis of the impact of the treatment chosen on the primary endpoint will be enriched by means 
of a multivariate regression model with the AUC of the WURSS-K during first 10 days of symptoms as 
dependent variable.  
The impact of the treatment chosen on the cold symptoms’ duration will be analysed by means of a 
Cox model.  
The impact of the treatment chosen on the risk to develop respiratory complication requiring antibiotic 
prescription during a 20-day follow-up period will be analyzed by a multivariate logistic model.  
The impact of the treatment chosen on the intake of conventional common cold medication 
(antibiotics, antipyretics, mucolytics, decongestants, antitussives, systemic and topical corticosteroids) 
will be analyzed by multivariate Poisson regressions for the numbers of days and a multivariate logistic 
regression for the frequency.  
The impact of the treatment chosen on the number of family members in close contact developing 
common cold symptoms after the patient all over the study period will be analyzed by means of a 
multivariate Poisson regression.  
 
9.5 Safety 
All adverse events/incidents/expected side effects will be listed, but only treatment-emergent adverse 
events/incidents (non-serious + serious) will be summarized. 
Two groups (called treatment groups) will be extracted from the cohort according to the treatment 
chosen by the patient. 

 
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Adverse events/incidents/expected side effects will be summarized by the number and percentage of 
patients (by treatment group), classified by System Organ Class and Preferred Term as defined by 
MedDRA dictionary. 
For a given treatment group, a given adverse event will be counted treatment emergent only once per 
patient during the treatment period. 
Frequency and percentage of patients with at least one reported adverse event/ incident / expected 
side effects will be tabulated by System Organ Class and by treatment group.  
 
10. 
Data management 
Subject data will be entered into an electronic case report form. 
 
10.1 Source documents 
The source documents (e.g., medical file, clinical and office charts, laboratory reports…) which contain 
the source of data recorded in the CRF should be specified. The e-diary will be used as source document 
for WURSS-K, compliance, contamination of relatives if applicable.  
Each subject will be assigned and identified by a unique Screening Number. Any reference made to an 
individual subject within the study must be done using the unique Screening Number.  
 
10.2 Methods for data entry and collection 
A validated electronic case report form (eCRF, e-Diary, VIEDOC software) will be used to collect clinical 
data for this study. Some of the study data will be recorded in the e-diary (ViedocMe) by the legal 
guardian after secure logging to the study website (https://me.viedoc.net) and will be automatically 
uploaded in the e-CRF: 
● WURSS-K,  
● Healsea® Children use if applicable,  
● Adverse event/ incidents/ expected side effects and concomitant treatments,  
● Contamination of relative(s) if applicable.  
Lallemand Pharma is responsible for designing the e-CRF. eCRF training will be given to appropriate 
personnel before/at initiation of the investigation site(s). Legal guardians will be instructed how to 
connect to the e-diary at visit 1.  
 
10.3 Data review 
The Data Management process includes all activities related to data handling regarding: 

 
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● Set-up of eCRF and database 
● Specification of on-line checks 
● Data entry/Data editing 
● Export of data from e-CRF to SAS 
● Creation of post-entry checks and listings 
● Clean-file process including execution of post-entry checks and listings 
● Post clean-file tasks 
Data entry will be done by investigators and other authorized personnel at the site(s). When entering 
data, on-line checks are encoded in the e-CRF for consistency and validation. Whenever required, 
queries issued from this review will be submitted to the investigator for resolution and then tracked 
until corrections are entered and validated.  
A clean-file review meeting will be held prior to database lock.  
The review process prepared by the clinical research assistant, data manager, study monitor, medical 
manager and statistician will be completed by a meeting (Validation Committee) to be attended by at 
least the following: 
● Coordinating investigator, 
● Study monitor, 
● Sponsor Vigilance representative, 
● Study Coordinator, 
● Data manager, 
● Statistician. 
The review is also required for defining the analysis populations and validating the statistical analysis 
plan.  
The meeting will be documented by written and signed minutes that will act as the basis for data 
processing by the Biometrics Department. 
All decisions on the evaluability of the data from each individual subject for the statistical analysis must 
be made and documented before locking the database.  
Data will be retained for at least 15 years after investigation closure. All data collected in the electronic 
Case Report Forms will be handled and archived under the responsibility of Lallemand Pharma.  
 
10.4 Procedures for verification, validation and securing of electronic clinical 
data system 
The VIEDOC software is installed on a server (secure Data Center) hosted at the VIEDOC company that 
guarantees the security, maintenance, as well as regular antivirus and firewall updates of this 
dedicated server. Any modification to the data is tracked, i.e., creation and changes are timestamped, 
and authors are recorded. Viedoc Technologies complies with the E.U. General Data Protection 
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Backups are taken, encrypted, and replicated to the paired Microsoft Azure region every five minutes. 
One full backup for each instance is encrypted and transferred to cold storage in a third location, read 
back, restored, and tested for integrity every 24 hours.  
The VIEDOC electronic system from PCG Solutions is systematically validated at several levels, from 
program development to actual use in clinical trials: 
● Unit Test / Code Review 
Unit test and code review are validation activities performed by the system developers during the 
programming phase. Unit tests are written by the programmer while they are writing (or modifying) 
the source code. Unit tests are automatic test cases. All Viedoc unit tests are automatically executed 
every time the source code is built. PCG Solutions implements daily builds so these tests are run daily 
(or more often). The results of the unit testing are reported by the build tool, which is integrated into 
the PCG Solutions repository. The build automatically fails if any of the unit tests fail, and the source 
code needs to be corrected and the unit test passed before the next build will pass. Records of all 
builds are kept in TFS so that the history of the release build of any version of Viedoc can be examined, 
as well as the builds leading up to that release. The results of the unit testing are summarized in the 
Validation Report for the release.  
Code review is performed by another member of the development team than the programmer of that 
source code. Code review is mandatory for high-risk implementations and encouraged even for all 
other source code. Risk evaluation is part of the sprint planning process. Code review is performed 
either using pair programming or code review sessions where more members of the team are involved. 
The results of the code review are immediately worked into the source code and are not separately 
documented.  
● Function / System Test 
Function and system testing are different names for the same thing at PCG Solutions. The name 
function test is derived from the fact that the majority of all testing performed at this level is with 
regards to functional requirements. The name system test simply recognizes that occasionally non-
functional requirements are also tested (i.e., performance requirements). The same methodology is 
employed irrespective of whether the requirements are functional or non-functional. 
The goal of function testing is to confirm that the implementation fulfils the requirement, i.e., to 
validate the product implementation against the requirements placed on the product. Function testing 
is performed by a different member of the system development team than the programmer and 
consists of exploratory testing and scripted testing. 
Exploratory tests are not predefined but are rather focused on testing a given requirement using an 
approach of simultaneous learning, test design, test execution and test result documentation. 
Exploratory tests are documented in one test result object in the PCG repository, i.e., the test steps 
and the test results are documented together and linked to the requirement being tested. Exploratory 
testing is often performed first in order for the tester to develop a deeper understanding of the 
requirement before writing the formal scripted tests. 

 
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Scripted tests are predefined test cases with detailed preconditions, steps to be executed and expected 
outcomes listed. Scripted test cases are designed and written by one system developer and executed 
by a different system developer (neither of whom are the programmer who wrote the source code). 
The results of scripted tests are stored in separate test result objects linked to the test cases in the PCG 
repository. 
All test cases and test results are stored in the PCG repository, and are linked such that test cases are 
linked to the requirements they test, while test results are linked to the test case they record the 
results of. 
● Installation Qualification 
The goal of installation qualification is to ensure that the correct versions of all modules that make up 
a release of the product have been installed correctly on the server. There are two types of installation 
qualification: Build Installation Qualification and Instance Installation Qualification. 
Regarding Built Installation Qualification, when a new product or a new version of a product is to be 
released, a build for the version is delivered by the development department. Product operations are 
then responsible for deploying this same build on all production servers. Build installation qualification 
ensures that the exact content released by the development department (in terms of modules and 
versions of the modules) and the exact configuration of the server environment (operating system 
version, database version, other software infrastructure products) are included in the build. This is 
done by ensuring all software components are in place and of the correct version. 
Regarding Instance Installation Qualification, every time a new instance of the product is setup the 
environment is checked to ensure that all prerequisites are met, and all components are installed. 
● Operational Qualification 
After completing the Installation Qualification an Operational Qualification is executed to ensure that 
all core functionality operates as expected. This is performed for every release of a product, and 
Operational Qualification is documented as part of the release documentation for that release of the 
product. 
● Performance Qualification 
The goal of performance qualification is to confirm that the delivered product is fit for use, i.e., that 
the product will work as intended. While function testing will typically find errors where the product 
implemented does not fulfil the requirement as stated, performance qualification will typically identify 
weaknesses where the requirements themselves are faulty (for example have been incorrectly 
analysed or have missed certain conditions). 
Performance qualification is scenario-based, designed around using the product in the same way it will 
be used in a clinical research setting. Performance qualification includes a great deal of regression 
testing, aimed at ensuring that existing functionality is not affected in new releases. Performance 
Qualification is performed and documented per release of the product being validated. These 
documents are stored together with the other release documentation for that product. 

 
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Build Installation Qualification is performed once for every release of a product, and Instance 
Installation Qualification is produced once for every instance of the product. Both are documented as 
part of the release documentation for every release of the product.  
 
10.5 Procedures to maintain and protect subject privacy 
It is the responsibility of the sponsor to maintain a security system that prevents unauthorized access 
to the data, both internally and externally.  
Subject privacy is protected through the VIEDOC system at different levels so as to preclude 
unauthorized access to data:  
● Personal data other than medical are limited to a minimum and under full control of the 
subject.  
In the e-Diary, ViedocMe, there is a possibility for the patient to register their email address and/or 
telephone number to receive reminders, but that information is encrypted within Viedoc and cannot 
be read by any user. The patient can modify or delete this personal data (the email address and 
telephone number) at any time. Each patient will have a username and a PIN code randomly assigned 
for connexion to the e-Diary. 
● Only authorized persons can access the data. 
The permission system is role-based, supporting the principle of least privilege, and restricting access 
to specific pieces of data to users on a need-to-know basis. Multi-factor authentication, as well as a 
sophisticated system for delegated provisioning/deprovisioning of user access, provide an additional 
level of security. 
● The risk of data breaches is minimized by full encryption.  
In addition to encryption-measures in operations environment (only encrypted endpoints served, 
encryption-at-rest on disk), encryption-in-transit is enforced through strict-transport-security headers 
for public endpoints, and sensitive data are encrypted-at-rest in database. The system is also designed 
to use encryption-in-transit internally between sub-systems. 
● External interactions are actively protected.  
Viedoc data communication between client and public endpoint is tuned to standards which in turn 
allows web-application-firewalls to inspect all traffic in prevent mode. Content Delivery Networks 
(CDN) are not used – all content and client-side code libraries are distributed directly from Viedoc 
servers, which is also enforced through content-security-policy headers, to ensure authenticity and 
prevent man-in-the-middle tampering. 
Anti-malware signatures are updated in real-time as released by vendor. Web application firewalls are 
configured with OWASP 3.0 rules in prevent mode. All network segments are protected with firewalls 
that have block-all by default and only allow whitelisted traffic. Only encrypted endpoints are exposed. 
There is a daily review of security bulletins. Each month a black-box vulnerability test (according to PCI-
DSS standard) is performed, along with an encryption-in-transit test. A security meeting is held once a 
month to discuss the current security landscape and review the past month's activity and the plans for 
the upcoming month.  

 
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Once a year, a third-party security team is contracted to perform white-box penetration testing of the 
solution.  
 
10.6 Methods for database locking at the start of analysis and storage upon 
completion of the clinical investigation 
The validated database will be locked upon request of the Data manager following the completion of 
all steps required, i.e., resolution of all queries, validation of the coding, data review meeting.  
 
10.7 Procedure for data retention 
Once the Clinical Investigation Report is signed and validated, the data are archived on a dedicated 
hard disk file with limited access rights. This specific file is mounted on AXIODIS’s OVH server with a 
back-up every two months as well as copied to an external disk that will be stored under seal within 
the premises of AXIODIS. The data are conserved for at least 10 years.  
 
11. 
Amendments to the CIP 
Neither the investigator nor the sponsor may alter the protocol without the authorisation of the other 
party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol.  
Substantial amendments are notified to the EC.  
 
12. 
Deviation from Clinical Investigation Plan 
In this context of observational study, the intervention is not protocolized and the study is restricted 
to the observation of the being of patients during the study. However, we define “Major protocol 
deviations” as deviations liable to prevent or change the interpretation of the results of the study. The 
following deviations are considered major:  
● Non-compliance with the inclusion or exclusion criteria,  
● No assessment of the primary efficacy criterion (WURSS-K) at D1, D5±1 and D10±1 during the 
treatment period,  
● Intake of forbidden medication, i.e., nasal irrigation for patients who choose not to take 
Healsea® children. 
All other cases will, a priori, be considered as minor deviations. 
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A deviation log shall be maintained by the study sites. 
All deviations will be included, as required in the final study report. 
Any major deviation from the protocol that has not been previously approved by the sponsor must be 
reported to the sponsor within 2 working days of the deviation occurrence. Any deviations from the 
clinical investigation plan that are identified during routine monitoring visits will be reported to the 
sponsor within 24 hours of being identified. 
Corrective and preventive actions and principal investigator disqualification criteria will be described 
in the monitoring plan.  
 
13. 
Device accountability 
Not applicable for an observational study. 
 
 
14. 
Ethical consideration 
14.1 Informed consent process  
According to Regulation EU 2017/745, ISO 14155:2020 and applicable Polish regulations, the Principal 
Investigator or his/her authorized designee must explain all aspects of the clinical investigation that 
are relevant to the parents/guardians’ decision for their child participation throughout the clinical 
investigation before any study. Parents/legal guardians will have the opportunity to carefully review 
the information document and ask questions prior to accept or not the participation of their child in 
the study. Although this investigation is observational, the consent will be obtained in writing by both 
parents/legal guardians and the study participation must be documented in the patient medical file. 
In case one parent will not be available for the visit, he/she will be asked to confirm in writing that 
he/she agrees with the participation of the child in the study. Children will also receive an information 
specific to their age and will be invited to sign an assent presented by the investigator. Objections 
raised by a child at any time during a trial should be considered. The child’s will should be respected. 
The child should not be forced to provide reasons. The child should be informed of the possibility to 
freely withdraw from the trial, at any time for any reason, without any disadvantage or prejudice. 
 
14.2 Subject confidentiality 
The present study will be conducted under Regulation 2016/679/EU of the European Parliament and 
of the Council of 27 April 2016 on the protection of natural persons with regard to the personal data 
and free movement of such data (GDPR) and Act on Personal Data Protection dated 10 May 2018, 
effective within the territory of Poland (uniform version - Journal of Laws of 2018, item 1000).  

 
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In accordance with GDPR, the Sponsor is the “Controller” and the participating sites, monitors, data 
managers and statisticians are “Processors”. Lallemand Pharma AG, sponsor of the study, is 
responsible for the processing of the study data. 
Confidentiality of data shall be observed by all parties throughout the clinical investigation. All data 
will be secured against unauthorized access. Subject names will not be sent to the sponsor. Only the 
patient number will be recorded in the e-CRF, and if the patient’s name appears on any document, it 
must be obliterated before a copy of the document is supplied to the sponsor. All subject data that 
appear in reports and publications will be anonymised such that the privacy and confidentiality of each 
subject is maintained. 
No data processing will be performed outside of the European Union, but the data base will be 
transferred to the sponsor at Massagno in Switzerland. Although outside EU, this country is recognized 
by the EU as offering an adequate data privacy protection.  
To fulfil the requirements of source data verification, the PI will be required to obtain consent from 
each subject stating that they agree for their medical records to be accessed (this will form part of the 
consent process). To comply with the Polish Regulation and GDPR, a specific document explaining the 
lawfulness of personal data processing conditions and patients’ rights will be signed before any study 
procedure by the parents/guardians. 
The patients’ rights are the followings:  
● The right to request access to, rectification, deletion or restriction of processing concerning 
personal data collected during the study,  
● The right to get back all data linked to the research and to forward them to another data 
processing manager (portability right),  
● The right to withdraw consent to data collection at any time and to request a restriction of 
processing concerning personal data as mentioned in GDPR’s article 18. However, the data 
processing manager keeps the ability to reject such request should this right likely make 
impossible or seriously compromise the achievement of the research objectives.  
These rights can be exercised with the investigator or his designated representative or by contacting 
the Data Protection Officer appointed by Lallemand Pharma: Yannick Hervy, yhervy@lallemand.com.  
14.3 Insurance policy 
Lallemand Pharma has an insurance policy intended to guarantee against possible damage resulting 
from the investigation (Insurance Policy number). 
It is advisable to underline that non-compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. 
Vigilance 
Non-invasive procedure is planned in this observational study and Healsea® Children will be used in 
the intended use covered by the CE mark. 

 
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Pursuant to (EU)2017/745 Medical Device Regulation, for a post market clinical follow-up investigation 
of a medical device used within the intended use covered by the CE-mark, requirement of MDR articles 
87 to 90 apply.  
 
15.1 Definitions  
Incident means 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 (MDR 
2017/745).  
Serious incident means 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 (MDR 2017/745).  
Serious public health threat means 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 (MDR 2017/745).  
Expected and foreseeable side effects (MEDDEV 2 12-1 rev. 8) 
They meet all the following criteria:  
● Clearly identified in the manufacturer's labelling,  
● Clinically well known as being foreseeable and having a certain qualitative and quantitative 
predictability when the device is used and performs as intended,   
● Documented in the device master record, with an appropriate risk assessment, prior to the 
occurrence of the incident and,  
● Clinically acceptable in terms of the individual patient benefit.  
 
Adverse event means 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 related or not related to the investigational device 
(MDR 2017/745).  
 
Adverse or intercurrent events are graded as follows: 
● Mild:  
Awareness of signs or symptoms but easily tolerated. 
● Moderate:  Uncomfortable enough to cause interference with usual activity. 
● Severe:  
Incapacity with inability to work or do usual activity.  
 

 
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15.2 Reporting in the eCRF  
All serious and non-serious incidents/serious and non-serious risk of incidents/expected side effects 
(except pre-existing condition but allergy) occurring during the clinical investigation will be reported 
in the e-CRF.  
 
15.3 Investigator’s responsibilities and processing timelines 
All incidents and expected undesirable side effects will be reported to LP vigilance manager according 
to MDR, MEDDEV 2.12 rev 8 modalities, national requirements, ISO 14155:20 and Lallemand Pharma 
procedures which are described in the safety management plan. This document will be signed by the 
Principal Investigator, representants of the Clinical Research Organization (CRO) before study start. 
As soon as the investigator will be informed of the event, he will complete a Primary Notification Form 
template (PNF, appendix C) and send it to LP vigilant manager and to the CRO with any relevant 
supportive documentation within the same day (<24h) for serious (risk)incident and within two 
calendar days (<48h) for non-serious incidents and expected side effects.  
 
15.4 Sponsor responsibilities and processing timelines 
The vigilance manager of Lallemand Pharma is responsible for the reporting to the Polish Health 
Authority (URPL) and to Ethics Committees according to local requirements.  
Briefly, for serious incidents or risk of serious incident, the vigilance manager will complete a 
Manufacturer Incident Report (MIR). The result of the investigation conducted by the sponsor may 
lead to the implementation of a safety corrective action and completion of a Field Safety Correction 
Action (FSCA) and of a Field Safety Notice. These documents will be transmitted to the URPL in 
accordance with the timelines provided in the table below:  
Serious Public Health Threat 
Report immediately but not more than 2 days 
 
Death or UNANTICIPATED Serious Deterioration 
in State of Health 
Report immediately but not more than 10 days 
Others (could have led to death or serious 
deterioration in health) 
Report immediately but not more than 15 days 
Every FSCA 
Immediately 
before 
the 
measure 
is 
implemented except in case of emergency, when 
the vigilance manager of the sponsor has to 
immediately take a safety corrective action 
 
Increase rate or severity of expected undesirable side effects and non-serious incidents will be 
reported to the URPL in Trend reports as per regulation requirements.  
 

 
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16. 
Suspension, premature termination and routine close out 
16.1 Suspension or Premature Termination of the Clinical Investigation 
Lallemand Pharma may suspend or prematurely terminate either the clinical investigation in an 
individual investigation site or the entire clinical investigation. The reasons will be documented. 
Reasons for suspension or premature termination at an investigation site may include incidences 
where monitoring or auditing identifies serious or repeated deviations done by an investigator. 
Lallemand Pharma will notify the EC of any suspension or early termination of the clinical investigation, 
it will also notify all other principal investigators in the event that the suspension or termination was 
due to safety issues. 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or when so 
instructed by the EC, Lallemand Pharma will suspend the clinical investigation while the risk is assessed. 
The sponsor will terminate the clinical investigation if an unacceptable risk is confirmed. Should the 
risk not be confirmed Lallemand Pharma will, in accordance with regulations, supply relevant persons 
with justification and data supporting the decision to resume the clinical investigation.  
 
16.2 Routine close out 
Routine close-out procedures will be conducted ensuring that the Patients’ records are complete, all 
documents needed for the sponsor files are retrieved, remaining clinical investigation materials are 
returned to the sponsor, previously identified issues have been resolved. 
The expected duration of the trial is ca. 4 months from recruitment of the first participant. The end of 
trial is the date of the last follow up visit of the last participant. 
The Principal Investigator will retain all copies of the records for a period of 15 years from the 
completion of the clinical investigation. In any circumstances, the Principal Investigator must contact 
the sponsor prior to disposing of any records related to the clinical investigation. Should the data be 
no longer required for regulatory purposes then the confidential destruction of said documents will be 
approved. Should the data be maintained for longer Lallemand Pharma will make this information 
available to all appropriate bodies in the same way. A list of essential documents to be maintained will 
be provided to each site at initiation. 
Should the Principal Investigator have to move/retire, or otherwise leaves his(her) position, he(she) 
will provide Lallemand Pharma with the name and address of the person assuming responsibility for 
retention of records relating to this clinical investigation.  
 
17. 
Publication policy 
The information and data collected during the conduct of this clinical study are considered confidential 
and are used by the sponsor in connection with the development of the study treatment. This 
information will be disclosed by the sponsor depending on current regulations. 

 
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To allow use of the information derived from this clinical study and to ensure compliance with current 
regulations, the investigator must provide the sponsor with complete test results and all data collected 
during the study. 
Only the sponsor may make study information available to physicians and to Regulatory Agencies, 
except as required by current regulations. 
All the results of this study including data and reports are the property of the sponsor. 
In the event that the sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) investigator(s) shall withhold publication for an additional 60 days, to 
allow the filing of a patent application, or to allow the sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a publication of 
the study results obtained by all sites performing the protocol, once the study is completed and 
finalised. 
A description of the clinical investigation is registered in https://www.clinicaltrials.gov/. The content 
will be updated throughout the conduct of the clinical investigation and the results entered at 
completion of the clinical investigation and made publicly available. 

 
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18. Bibliography 
[1] 
D. King, B. Mitchell, C. P. Williams, and G. K. P. Spurling, “Saline nasal irrigation for acute upper 
respiratory tract infections,” Cochrane Database of Systematic Reviews, vol. 2015, no. 4. John 
Wiley and Sons Ltd, 20-Apr-2015. 
[2] 
W. J. Fokkens et al., “European Position Paper on Rhinosinusitis and Nasal Polyps 2020,” 
Rhinology, vol. 58, pp. 1–464, Feb. 2020. 
[3] 
N. Principi and S. Esposito, “Nasal irrigation: An imprecisely defined medical procedure,” 
International Journal of Environmental Research and Public Health, vol. 14, no. 5. MDPI AG, 11-
May-2017. 
[4] 
C. L. Brown and S. M. Graham, “Nasal irrigations: Good or bad?,” Current Opinion in 
Otolaryngology and Head and Neck Surgery, vol. 12, no. 1. pp. 9–13, 2004. 
[5] 
G. A. O’Toole, “Microtiter dish Biofilm formation assay,” J. Vis. Exp., no. 47, 2010. 
[6] 
M. Passioti, P. Maggina, S. Megremis, and N. G. Papadopoulos, “The common cold: Potential 
for future prevention or cure topical collection on rhinosinusitis,” Curr. Allergy Asthma Rep., 
vol. 14, no. 2, Feb. 2014. 
[7] 
T. Heikkinen and A. Järvinen, “The common cold,” in Lancet, 2003, vol. 361, no. 9351, pp. 51–
59. 
[8] 
J. Yan and B. L. Bassler, “Surviving as a Community: Antibiotic Tolerance and Persistence in 
Bacterial Biofilms,” Cell Host and Microbe, vol. 26, no. 1. Cell Press, pp. 15–21, 10-Jul-2019. 
[9] 
N. Rabin, Y. Zheng, C. Opoku-Temeng, Y. Du, E. Bonsu, and H. O. Sintim, “Biofilm formation 
mechanisms and targets for developing antibiofilm agents,” Future Medicinal Chemistry, vol. 7, 
no. 4. Future Science, pp. 493–512, 01-Mar-2015. 
[10] 
A. Varricchio, I. La Mantia, F. P. Brunese, and G. Ciprandi, “Inflammation, infection, and allergy 
of upper airways: New insights from national and real-world studies,” Italian Journal of 
Pediatrics, vol. 46, no. 1. BioMed Central Ltd., 10-Feb-2020. 
[11] 
G. Ciprandi, M. A. Tosca, and L. Fasce, “Allergic children have more numerous and severe 
respiratory infections than non-allergic children,” Pediatr. Allergy Immunol., vol. 17, no. 5, pp. 
389–391, Aug. 2006. 
[12] 
I. Cirillo, G. Marseglia, C. Klersy, and G. Ciprandi, “Allergic patients have more numerous and 
prolonged respiratory infections than nonallergic subjects,” Allergy Eur. J. Allergy Clin. 
Immunol., vol. 62, no. 9, pp. 1087–1090, Sep. 2007. 
[13] 
J. Bousquet et al., “Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines 
for allergic rhinitis based on Grading of Recommendations Assessment, Development and 
Evaluation (GRADE) and real-world evidence,” Journal of Allergy and Clinical Immunology, vol. 
145, no. 1. Mosby Inc., pp. 70-80.e3, 01-Jan-2020. 
[14] 
A. O. Eifan and S. R. Durham, “Pathogenesis of rhinitis,” Clinical and Experimental Allergy, vol. 
46, no. 9. Blackwell Publishing Ltd, pp. 1139–1151, 01-Sep-2016. 
[15] 
E. De Corso et al., “Clinical Evidence and Biomarkers Linking Allergy and Acute or Chronic 
Rhinosinusitis in Children: a Systematic Review,” Current Allergy and Asthma Reports, vol. 20, 
no. 11. Springer, 01-Nov-2020. 

 
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[16] 
S. W. Lin, S. K. Wang, M. C. Lu, C. L. Wang, and M. Koo, “Acute rhinosinusitis among pediatric 
patients with allergic rhinitis: A nationwide, population-based cohort study,” PLoS One, vol. 14, 
no. 2, Feb. 2019. 
[17] 
J. Fashner, K. Ericson, and S. Werner, “Treatment of the common cold in children and adults,” 
Am. Fam. Physician, vol. 86, no. 2, pp. 153–159, 2012. 
[18] 
K. M. Schmit et al., “Wisconsin Upper Respiratory Symptom Survey for Kids: Validation of an 
Illness-specific Quality of Life Instrument,” Pediatr. Res., 2021. 
[19] 
G. G. Jackson, H. F. Dowling, I. G. Spiesman, and A. V. Boand, “Transmission of the Common 
Cold to Volunteers Under Controlled Conditions: I. The Common Cold as a Clinical Entity,” A.M.A 
Arch. Intern. Med., vol. 101, no. 2, pp. 267–278, 1958. 
 
 
 

 
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19. List of Appendix  
Appendix A: Instruction for Use of Healsea® Children 
Appendix B: WURSS-K 
Appendix C: PNF 
 
 

 
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Appendix A: Instruction For Use 
 
 
 
 

 
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Appendix B: WURSS-K (English version) 
 
Wisconsin Upper Respiratory Symptom Survey For Kids 
Daily Symptom Report 
Day:  
Date:  
Time:  
ID:  
  
Please fill in one circle for each question:  
                                                                Not 
sick  
                                              
A little sick  
  
Sick  
  
Very sick  
  
How sick do you feel today?                         O  
O  
O  
O  
  
How bad are your cold symptoms?          (Overall, since yesterday)  
   
Do not have this 
                            
  
A little bad  
  
Bad  
  
Very bad  
  
Runny nose  
O  
O  
O  
O  
Stuffy nose   
O  
O  
O  
O  
Sneezing   
O  
O  
O  
O  
Sore throat (hurts to swallow)  
O  
O  
O  
O  
Cough  
O  
O  
O  
O  
Feeling tired  
O  
O  
O  
O  
  
Since yesterday, how hard has it been to:  
  
                      Not at all  
                            
  
A little 
hard  
Hard  
  
Very hard  
  
Think  
O  
O  
O  
O  
Sleep   
O  
O  
O  
O  

 
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Breathe   
O  
O  
O  
O  
Talk  
O  
O  
O  
O  
Walk, climb stairs, exercise  
O  
O  
O  
O  
Go to school  
O  
O  
O  
O  
Play with friends  
O  
O  
O  
O  
  
Compared to yesterday, I feel my cold is…  
A lot better  
  
A little better  
 
 
  
The same  
A little worse  
  
A lot worse  
  
O  
O  
O  
O  
O  
  
I completed this page:   ☐ all by myself     ☐ with some help    ☐ with a lot of help  
Who helped you? ___________________________ 
  
WURSS-K© (Wisconsin Upper Respiratory Symptom Survey) 2014  
Created by Bruce Barrett MD PhD et al, UW Department of Family Medicine, Madison, WI 53715, USA  
 
 

 
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Appendix C: Primary Notification Form 
 
Date of the report: ……………………  
Type of report: initial/Follow up  
Recorded by (name and position) : ……….……….……….……….……….……….  
Reference number:  
Information on reporter:   
  
Contact name :  
  
 
Health professional :  
Address :  
Country :  
Phone :  
Fax : Email 
:  
 
 
YES           
 NO  
  
 
  
 
  
 
  
 
  
 
  
Support : Mail / Phone / Fax / Email / Other  
(1) Delete as appropriate  
  
Product concerned by notification :   
  
Product Name :  
  
Country :  
Batch number :  
Expiry date :  
Classification : 
Quantity concerned :  
  
  
  
  
  
  
Consumer information :  
Age :  
Gender :  
Remedial action :  
Outcome :  
  
Detailed description the incident :  
  
Date of the incident occurred:    
  

 
Strictl y C o nfi d e nti al  
 
 
V ersi o n: 2. 0; 0 8 S e p 2 0 2 1  
 
P a g e 5 9  of 6 1  
St u dy N u m b er: L P H-2 1 0 1  
S eri o us n ess crit eri a :  I nci d e nt 
d escri pti o n n arr ati v e :  
Us a g e of t h e m e dic al 
D e vic e/fr e q u e nc y of us e :  
  
  
 
 
 
I N V E S TI G A TI O N  
🡺 D at e : … … … … …..  
🡺 M a n a g er : … … …. … … …. … … …. … … …. … … …. … … ….  
  
  
  
  
El e m e nts t o c o ntr ol d uri n g 
i n v esti g ati o n :  
  
  
  
  
  
  
  
  
  
Ris ks i d e ntific ati o n :   
  
  
  
  
  
  
  
  
R ec urr e nc e st u d y /  
I m p act o n ot h er b atc h es ?  
  
  
  
  
  
  
  
  
Fi el d S af et y C orr ectiv e Acti o n ( F S C A), pr ev e ntiv e acti o ns, c orr ecti o ns, a n d c orr ectiv e 
acti o ns  
F S C A   
  
🡺 D at e : … … … … …..  

 
Strictl y C o nfi d e nti al  
 
 
V ersi o n: 2. 0; 0 8 S e p 2 0 2 1  
 
P a g e 6 0  of 6 1  
St u dy N u m b er: L P H-2 1 0 1  
🡺 M a n a g er : … … …. … … …. … … …. … … …. … … …. … … ….  
  
  
  
N at ur e of t h e F S C A :  
  
 
C o ntr ol of t h e F S C A 
i m pl e m a nt ati o n :  
  
  
  
  
  
  
  
  
  
C o ntr ol of t h e F S C A  
eff ecti v e n ess:  
  
  
  
  
  
  
  
  
  
Pr e v e nti v e acti o ns   
  
🡺 D at e : … … … … …..  
🡺 M a n a g er : … … …. … … …. … … …. … … …. … … …. … … ….  
  
  
  
N at ur e of pr e v e nti v es acti o ns :  
  
  
C o ntr ol of t h e pr e v e nti v e 
acti o ns’ i m pl e m e nt ati o n :   
  
 
C o ntr ol of t h e pr e v e nti v es 
acti o ns’ eff ecti v e n ess :  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C orr ecti v e acti o ns   
  

 
Strictl y C o nfi d e nti al  
 
 
V ersi o n: 2. 0; 0 8 S e p 2 0 2 1  
 
P a g e 6 1  of 6 1  
St u dy N u m b er: L P H-2 1 0 1  
🡺 D at e : … … … … …..  
🡺 M a n a g er : … … …. … … …. … … …. … … …. … … …. … … ….  
  
  
  
N at ur e of c orr ecti v e acti o ns :  
  
 
C o ntr ol of t h e c orr ecti v e 
acti o ns’ e x ec uti o n :   
  
  
C o ntr ol of t h e c orr ecti v e  
acti o ns’ i m pl e m e nt ati o n :  
  
  
  
  
  
  
  
  
  
  
  
  
  
C orr ecti o ns  :  
  
🡺 D at e : … … … … …..  
🡺 M a n a g er : … … …. … … …. … … …. … … …. … … …. … … ….  
   
N at ur e of c orr ecti o ns :  
  
  
  
  
  
  
  
Cl os ur e  
  
🡺 D at e of i n v esti g ati o n c o ncl usi o n  :     … … … … …..  
🡺 M a n a g er : … … …. … … …. … … …. … … …. … … …. … … ….  
🡺 Si g n at ur e :