Assessment of Sino-nasal Microbial Communities Changes in Adult Patients With Chronic Rhinosinusitis by 16 rRNA Gene Amplicon Sequencing Before and After 1-month Treatment Duration With Healsea® Chronic: an Exploratory Study
Conditions: Rhinosinusitis Chronic, Microbiome
Sponsor: Lallemand Pharma AG

 
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Study Number: LPH-2102 
 
CLINICAL INVESTIGATION PLAN 
Assessment of sino-nasal microbial communities changes in adult patients with Chronic 
Rhinosinusitis by 16S rRNA gene amplicon sequencing before and after 1-month treatment 
duration with Healsea® Chronic: an exploratory study 
 
Study Number: LPH-2102 
Short Title : ISONAM 
PMCF investigation for MD CE marked and used in its intended purpose with invasive and/or 
burdensome procedure (MDR Art. 74(1)) 
ID-RCB number: 2021-A01458-33 
Version 1.0; 14 June 2021 
 
 
This Clinical Investigation is being sponsored by: 
 
Lallemand Pharma AG 
Via Selva 2 
6900 Massagno 
Switzerland 
Represented by Dr Frédéric DURMONT 
 
Principal Investigator:  
Pr Guillaume de Bonnecaze 
Department of Otorhinolaryngology and Cervico-Facial Surgery,  
University Hospital of Toulouse (Larrey),  
24 Chemin de Pouvourville, 31400 Toulouse 
France

 
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HISTORY OF CLINICAL INVESTIGATION PLAN’S UPDATES 
Version 
Date 
Purpose of Update 
Version 1.0 
14-06-2021 
Creation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Study Number: LPH-2102 
STUDY CONTACT LIST 
PRINCIPAL INVESTIGATOR  
Pr Guillaume de 
BONNECAZE 
Otorhinolaryngologist 
Department of Otorhinolaryngology 
and Cervico-Facial Surgery, 
University Hospital of Toulouse 
(Larrey), 
24 Chemin de Pouvourville, 31400 
Toulouse 
France 
Tel : +33 567 771 788 
debonnecaze.g@chu-toulouse.fr 
CRO in charge of STUDY 
COORDINATION AND 
MONITORING  
Biomedical and Global 
Clinical Solutions 
represented by Bernard 
GOUT, PharmD, PhD (Study 
coordination) and Corentin 
Roudet, MSc. (monitoring)  
Parc Technologique du Canal 
26 rue Hermès 
31520 Ramonville-Saint-Agne 
France 
Tel : +33 561 531 944 
Fax : +33 561 531 956 
b.gout@bgclinicals.com  
c.roudet@bgclinicals.com  
MEDICAL WRITING 
Géraldine Julou-Schaeffer, 
PharmD, PhD 
Biomedical and Global Clinical 
Solutions 
Parc Technologique du Canal 
26 rue Hermès 
31520 Ramonville-Saint-Agne 
France 
Tel : +33 777 264 808 
Fax : +33 561 531 956 
g.schaeffer@bgclinicals.com  
DATA MANAGEMENT / 
STATISTICS  
Benjamin Poirier, Head of 
biometry 
Axiodis 
38 avenue Pierre Georges Latécoère  
31700 Blagnac, France  
Tel : +33 680 566 834  
bpoirier@axiodis.com  
BIOTECHNOLOGY 
LABORATORY 
VAIOMER represented by 
Benjamin Lelouvier, PhD 
Vaiomer 
516 Rue Pierre et Marie Curie 
31670 LABEGE 
FRANCE 
Tel  +33 561 287 157 
Fax +33 561 287 168 
Benjamin.LELOUVIER@vaiomer.com 
 
 
 

 
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Table of Contents 
1. 
Statement of compliance ................................................................................................................... 8 
2. 
Synopsis ........................................................................................................................................... 11 
3. 
Flow Chart ........................................................................................................................................ 16 
4. 
Identification and description of the investigational Device ........................................................... 17 
4.1 
Summary description of the investigational device................................................................. 17 
4.2 
Manufacturer ........................................................................................................................... 17 
4.3 
Name or number of the model to permit full identification ................................................... 17 
4.4 
Traceability ............................................................................................................................... 18 
4.5 
Intented purpose of the investigational device in the clinical investigation. .......................... 18 
4.6 
Population and indications for which the device is intented .................................................. 18 
4.7 
Device Description ................................................................................................................... 18 
4.8 
Investigation Device Training/Experience ............................................................................... 20 
4.9 
Reference to the IFU ................................................................................................................ 20 
5. 
Justification for the design of the clinical investigation................................................................... 20 
6. 
Risks and Benefits of the Investigational Device and Clinical Investigation .................................... 22 
6.1 
Anticipated clinical benefit ...................................................................................................... 22 
6.2 
Anticipated adverse device effects .......................................................................................... 22 
6.3 
Risks associated with participation in the clinical investigation .............................................. 22 
6.4 
Possible interactions with concomitant medical treatments as considered under the risk 
analysis ................................................................................................................................................. 22 
6.5 
Steps that will taken to control and mitigate the risks ............................................................ 23 
6.6 
Rationale for the benefit-risk ratio .......................................................................................... 23 
7. 
Objectives and hypothesis of the clinical investigation ................................................................... 24 
7.1 
Hypothesis................................................................................................................................ 24 
7.2 
Primary Objective .................................................................................................................... 24 
7.3 
Secondary Objectives ............................................................................................................... 24 
7.4 
Scientific justification and clinical relevance for effect sizes, non inferiority margins or 
equivalence .......................................................................................................................................... 24 
7.5 
Risks and anticipated adverse effects that are to be assessed ................................................ 24 
8. 
Design of the clinical investigation .................................................................................................. 24 
8.1 
General ..................................................................................................................................... 25 
8.1.1 
Design type of clinical investigation ................................................................................. 25 
8.1.2 
Measures to be taken to minimize or avoid bias ............................................................. 25 

 
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8.1.3 
Primary Endpoint ............................................................................................................. 25 
8.1.4 
Secondary Endpoints ....................................................................................................... 25 
8.1.5 
Methods and timing for assessing, recording and analysing variables ........................... 25 
8.1.6 
Arrangements for the monitoring maintenance and calibration of equipment used for 
genomic analysis .............................................................................................................................. 27 
8.1.7 
Any procedures for the replacement of subjects ............................................................ 27 
8.1.8 
Investigation sites: number, location............................................................................... 27 
8.1.9 
Definition of the completion of the study ....................................................................... 27 
8.2 
Investigational device and comparator ................................................................................... 27 
8.3 
Subjects .................................................................................................................................... 27 
8.3.1 
Eligibility criteria............................................................................................................... 28 
8.3.2 
Criteria and procedures for subject withdrawal or lost to follow-up .............................. 28 
8.3.3 
Point of enrolment ........................................................................................................... 29 
8.3.4 
Total expected duration of the clinical investigation ...................................................... 29 
8.3.5 
Expected duration of each subject’s participation .......................................................... 29 
8.3.6 
Number of subjects required to be included in the clinical investigation ....................... 29 
8.3.7 
Estimated time needed for the enrolment ...................................................................... 29 
8.3.8 
Relationship of investigation population to target population ....................................... 30 
8.3.9 
Vulnerable, pregnant and breastfeeding population ...................................................... 30 
8.3.10 
Compensation .................................................................................................................. 30 
8.4 
Procedures ............................................................................................................................... 30 
8.4.1 
Study procedures ............................................................................................................. 30 
8.4.2 
Permitted and forbidden concomitant medications ....................................................... 31 
8.4.3 
Exclusion period ............................................................................................................... 31 
8.4.4 
Activities performed by sponsor representatives (excluding monitoring) ...................... 31 
8.4.5 
Any known/foreseeable factors that can compromise the outcome of the clinical 
investigation and methods for addressing these factors ................................................................ 32 
8.4.6 
Follow-up and medical care after completion of the study............................................. 32 
8.4.7 
Potential use of samples obtained from subjects ............................................................ 32 
8.5 
Monitoring plan ....................................................................................................................... 32 
8.5.1 
Initiation visit ................................................................................................................... 32 
8.5.2 
Monitoring ....................................................................................................................... 32 
9. 
Statistical design and analysis .......................................................................................................... 33 
10. 
Data collection ............................................................................................................................. 33 
10.1 
CRF entry .................................................................................................................................. 33 

 
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10.2 
Source documents ................................................................................................................... 34 
11. 
Data management ....................................................................................................................... 34 
11.1 
Methods for data entry and collection .................................................................................... 34 
11.2 
Data review .............................................................................................................................. 34 
11.3 
Data coding .............................................................................................................................. 34 
11.4 
Procedures for verification, validation and securing of electronic clinical data system ......... 35 
11.5 
Procedures to maintain and protect subject privacy ............................................................... 35 
11.6 
Methods for database locking at the start of analysis and storage upon completion of the 
clinical investigation ............................................................................................................................. 35 
11.7 
Procedure for data retention ................................................................................................... 35 
12. 
Amendments to the CIP ............................................................................................................... 36 
13. 
Deviation from clinical investigation plan .................................................................................... 36 
14. 
Device accountability ................................................................................................................... 36 
15. 
Ethical consideration .................................................................................................................... 36 
15.1 
Informed consent process ....................................................................................................... 37 
15.2 
Subject privacy ......................................................................................................................... 37 
15.3 
Insurance policy ....................................................................................................................... 38 
16. 
Vigilance ....................................................................................................................................... 38 
16.1 
Definitions ................................................................................................................................ 39 
16.2 
Reporting in the CRF ................................................................................................................ 40 
16.3 
Investigator’s responsibilities and processing timelines ......................................................... 40 
16.4 
Sponsor responsibilities and processing time lines ................................................................. 40 
17. 
Suspension, premature termination and routine close out ........................................................ 42 
17.1 
Suspension or Premature Termination of the Clinical Investigation ....................................... 42 
17.2 
Routine close out ..................................................................................................................... 42 
18. 
Publication policy ......................................................................................................................... 42 
19. 
Bibliography ................................................................................................................................. 44 
20. 
List of Appendix............................................................................................................................ 45 
 
 
 

 
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1. Statement of compliance 
PRINCIPAL INVESTIGATOR STUDY APPROVAL PAGE 
STUDY: LPH-2102 
CLINICAL INVESTIGATION PLAN  
Version 1.0, 14-06-2021 
 
By signing the hereinafter form, I hereby confirm that I agree: 
 
 
To conduct the trial described in the Clinical Investigation Plan (LPH-2102) dated 14 June 2021, 
in accordance with the ethical principles that have their origin in the Declaration of Helsinki, in 
compliance with GCP, with applicable regulatory requirements and with the Clinical 
Investigation Plan agreed upon by the sponsor and given approval/favourable opinion by the 
Ethics Committee and Competent Authority; 
 
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:  
Guillaume de Bonnecaze 
 
Principal Investigator’s Title: 
Professor 
 
Principal Investigator’s Address:  Department of Otorhinolaryngology and Cervico-Facial Surgery  
 
University Hospital of Toulouse (Larrey),  
 
24 Chemin de Pouvourville, 31400 Toulouse, France  
 
 
 
Principal Investigator’s Signature:  
 
 
 
Date of signature:  
14 June 2021 
 
 

 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ANSM 
Agence Nationale de Sécurité du Médicament et des produits de santé 
BoV 
Bag-on-Valve  
CA 
Competent Authority 
CIP 
Clinical Investigation Plan 
CNIL 
Comission Nationale de l’Informatique et des Libertés  
CRA 
Clinical Research Associate  
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRS 
Chronic RhinoSinusitis 
DNA 
Desoxyribo Nucleic Acid 
EC 
Ethics Committee 
EPOS 
European Position Paper on Rhinosinusitis and nasal polyps 
FSCA 
Field Safety Corrective Action 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
IFU 
Instruction For Use 
LPLV 
Last Patient Last Visit  
MDCG 
Medical Device Coordination Group  
MDR 
Medical Device Regulation 
MIR 
Manufacturer Incident Report 
MR 
Méthodologie de Référence  
OTU 
Operational Taxonomic Unit  
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PNF 
Primary Notification Form 
RIPH 
Recherche Interventionnelle chez la Personne Humaine 

 
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Study Number: LPH-2102 
RNA 
Ribo Nucleic Acid 
SAE 
Serious Adverse Event 
SNOT-22 
Sino Nasal Outcome Test-22 
 
 

 
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Study Number: LPH-2102 
 
2. Synopsis 
 
Sponsor: LALLEMAND PHARMA AG 
Principal Investigator Pr. G de Bonnecaze, Department of Otorhinolaryngology and Cervico-Facial 
Surgery, University Hospital of Toulouse (Larrey), France 
Title: Assessment of sino-nasal microbial communities changes in adult patients 
with Chronic Rhinosinusitis by 16S rRNA gene amplicon sequencing before 
and after 1-month treatment duration with Healsea® Chronic: an 
exploratory study 
Short Title ISONAM (Impact of Symbiofilm® On NAsal Microbiota) 
N° ID-RCB 2021-A01458-33 
CIP version: 1.0 
Rationale: Chronic rhinosinusitis (CRS) is an inflammation of the nose and paranasal 
sinuses and is characterized by two or more symptoms, one of which should 
be either nasal blockage/obstruction/congestion or nasal discharge 
(anterior/posterior nasal drip), lasting for 12 weeks or longer. In addition, 
facial pain or pressure and a reduction in the sense of smell can occur [1]. The 
condition can occur with or without nasal polyps. 
Chronic rhinosinusitis (CRS) is a significant health problem and affects 5-12% 
of the general population [1]. 
The physiopathology of CRS is poorly understood with multiple 
environmental, host and microbial factors being implicated. Putative 
pathological factors include changes in the microbiota, imbalance of the local 
or systemic immune system, allergens, toxins and genetic predisposition [2]. 
A dysbiosis mechanism has been proposed as modulating inflammation in 
diseased sinuses. This hypothesis suggests that externally influenced changes 
in the nasal microbiome can result in dysbiosis, i.e. a shift from a “normal” or 
“healthy” microbial community structure and that this shift may be 
responsible for the initiation or maintenance of CRS. For example, the 
disruption of the commensal biofilm during a viral upper respiratory tract 
infection can create a niche for pathogenic species to grow [3]. Despite many 
contradictory statements in the different studies some common trends 
emerge. Less diversity in the microbial community rather than an increased 
overall bacterial load seems to characterize CRS compared to the healthy 
state with no consensus about specific genera indicative of disease [4], [5], 
[6]. However, anaerobes and S. aureus are found to be significantly more 

 
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prevalent and abundant in CRS versus healthy controls [4]. Bacterial biofilm is 
detected on the sinus mucosa in up to 80% of CRS patients and its presence 
does not imply that it is causing mucosal inflammation. However, in the 
context of CRS, there are several possible mechanisms by which biofilms may 
be pro-inflammatory including the release of planktonic organisms and the 
release of superantigens, which can cause ciliary dysfunction and inhibition of 
ciliary clearance. Bacterial biofilms are likely a key modulator of the refractory 
nature of CRS [7].  
Although clinical evidence from well-designed trials is scarce, European 
Guidelines for chronic rhinosinusitis recommend daily nasal saline irrigation 
for reduction of the severity of symptoms of CRS [1]. A recent Cochrane 
analysis has concluded that daily nasal irrigation with hypertonic saline 
solution is more effective than placebo to improve patient symptoms [8]. The 
exact mechanisms by which nasal irrigation works are not known. However, 
most of the experts agree that it is primarily a mechanical intervention 
leading to direct cleansing of the nasal mucosa. Nevertheless, the efficacy of 
such solution remains moderate.  
Healsea® Chronic is a CE marked medical device indicated in adults for the 
treatment of nasal symptoms of chronic rhinosinusitis. This is a seawater-
based nasal spray supplemented with a natural Symbiofilm® extract (0.02%) 
isolated from marine bacteria. The nasal solution is hypertonic (NaCl 2.2%). 
Symbiofilm® is a marine postbiotic comprising active exopolysacharides with 
emulsifying properties and in vitro antibiofilm activity. Antibiofilm properties 
have been demonstrated with the colorimetric microtiter plate assay [9]. In 
this model, a significant inhibition of biofilm formation by Staphylococcus 
aureus and Haemophilus influenzae are 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. Symbiofilm® has no 
bacteriostatic nor bactericidal activities. 
To date, properly designed study to evaluate the effect of topical therapies on 
microbiome are scarce so no definite conclusion can be made. In one study, 
use of saline irrigation with or without budesonideDCI used was not associated 
with significantly distinct microbiota composition among either controls or 
post-operative CRS with polyp patients [10].  
We design this exploratory study aiming at determining if the antibiofilm 
properties of Symbiofilm® may modify sino-nasal microbiota, impacting α 
and/ or β diversities. To this end middle meatus swab specimen will be taken 
from CRS patients before and after treatment with Healsea® Chronic. Bacteria 
colonization will be assessed using quantitative PCR and 16S rRNA gene 
sequencing. 

 
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Objectives: Primary Objective: 
- To characterize the change of sino-nasal microbial communities from adult 
CRS patients via 16S rRNA gene high throughput sequencing before and after 
1-month treatment duration with Healsea® Chronic. 
Secondary objectives: 
-To assess the efficacy of Healsea® Chronic in improving health-related quality 
of life of CRS adult patients.  
-To assess the global satisfaction of patients with the use of Healsea® Chronic 
for CRS.  
- Safety: to assess systemic and local tolerance of Healsea® Chronic over the 
study period. 
 
Endpoints: Primary endpoint: 
Modifications in microbial load and/or profile 
To determine the impact of Healsea® Chronic on the nasal microbiome, the 
microbial load will be evaluated by quantitative PCR and microbiome 
taxonomic profiling by 16S rRNA gene sequencing. Data collected in patients 
before and after 1 month-treatment with Healsea® Chronic will be compared 
using statistical analyses to assess changes in microbial species abundance 
and diversity. Furthermore, special attention will be given to typical sino-nasal 
pathogens 
(e.g. 
Staphylococcus 
aureus, 
Streptococcus 
pneumoniae, 
Haemophilus influenzae, Moraxella catarrhalis) at genus level, and if 
reachable at species level. 
Secondary Endpoints: 
-To measure the clinical performance of Healsea® Chronic, the quality of life 
of CRS patients will be assessed with the Sino-Nasal Outcome Test score-22 
(SNOT-22) [11]. This questionnaire is a disease-specific, quality-of-life-related 
measure of sinonasal function. Patients should rate sino-nasal symptoms and 
their impact from 0 to 5 where 0 means that there is no complaint and 5 
means that there are serious complaints. 
- Patient satisfaction questionnaire assessing medical device usability, sensory 
perception and efficacy in using Healsea® Chronic for CRS. 
- Safety: Assessment of adverse events/incidents/expected side effects 
throughout the study.  
Indication: Treatment of nasal symptoms of chronic rhinosinusitis 
Investigation Design: PMCF investigation for MD CE marked and used in its intended purpose with 
invasive and/or burdensome procedure (MDR Art. 74(1)).  
Non randomized, open and uncontrolled interventional study.  

 
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Visit 1 (V1) – (Day 1): Screening/Inclusion  
Information and consent, demographic data and medical history, ongoing 
medication, 
rhinologic 
examination, 
inclusion/non-inclusion 
criteria, 
collection of middle meatus swab specimens, SNOT-22, reporting of adverse 
events, dispensation of Healsea® Chronic Nasal Spray.  
Telephone call 1 (TC1) – (Day 15±3) 
Investigator/nurse telephone call to review patient status and study progress, 
adverse events/incidents/expected undesirable side effects and concomitant 
treatments. 
Visit 2 (V2) – (Day 30±5): end of treatment 
End of Healsea® Chronic nasal spray treatment, physical and clinical 
examination, reporting of adverse events/incidents/expected side effects, 
collection of middle meatus swab specimens, SNOT-22, subject’s satisfaction 
questionnaire.  
Number of Subjects: An arbitrary sample of 20 subjects  
Target Population: Adults with chronic rhinosinusitis according to EPOS criteria [1].  
Permitted and 
prohibited concomitant 
medication 
Permitted concomitant medication:  
Nasal corticosteroids 
Not permitted concomitant medication:  
Other nasal irrigations 
Need for systemic corticosteroids 
Need for nasal application of antibiotics and systemic antibiotics 
Inclusion/Non inclusion 
criteria: 
Inclusion criteria 
In order to be eligible to participate in this study, an individual must meet all 
of the following criteria: 
1. Male or female, aged 18 – 70 years 
2. Provision of signed and dated informed consent form 
3. Stated willingness to comply with all study procedures and availability 
for the duration of the study  
4. Diagnosed with CRS based on the diagnostic criteria of the EPOS 
guideline 
5. Registered with a social security scheme or covered by such a regime 
 
Non inclusion criteria 
An individual who meets any of the following criteria will be excluded from 
participation in this study:  
1. Antibiotics or oral corticosteroids intake in the month prior to the 
study  
2. Endoscopic sinus surgery in the past 6 months 
3. Cystic fibrosis 
4. Wegener's granulomatosis 
5. Immunodeficiency 

 
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6. Defective access to middle meatus 
7. Lidocaine allergy  
8. Known hypersensitivity/allergy to any component of the test device 
9. Pregnant/Lactating female or absence of efficient contraception 
10. Under tutorship or guardianship 
Number of sites: 1 
Test Device: Healsea® Chronic nasal spray will be administered twice a day (1 puff, 1-2 sec) 
in each nostril during 30 days. 
Comparator Device: Not applicable 
Duration of 
investigation: 
Duration of inclusion period: 4 months  
Duration of patient’s participation: 30 days  
Total study duration: 5 months 
Study Start Date: September 2021 
Statistical Analysis: Patients and disease characteristics will be described at baseline. 
 
16S rRNA Gene Sequence Analysis: 
The normal distribution of the values is verified thanks to normality tests (e.g. 
Shapiro-Wilk test). However, it is most likely that the group size will be 
insufficient to apply parametric statistical tests. Significant variations in total 
number of bacterial 16S rRNA gene copies or in alpha diversity are assessed 
using the Kruskal-Wallis test or the Wilcoxon rank-sum test. Multidimensional 
scaling analyses (MDS) are performed on beta diversity distances matrices 
and differences between groups were assessed using PERMANOVA and 
PERMDISP analyses (2000 permutations). LEfSe (Linear discriminant analysis 
Effect Size) analyses, based on non-parametric tests are used to determine 
significant variations in taxa relative abundance [17]. 
Secondary endpoints: 
Values and changes from baseline to D30/end of study of the SNOT-22 total 
score will be described. 
Patients satisfaction will be described at D30/end of study. 
 
Safety: All adverse events/incidents/expected side effects of the device will 
be listed, but only treatment-emergent adverse events/incidents (non-serious 
+ serious) and expected side effects will be summarized by the number and 
percentage of patients, classified by System Organ Class and Preferred Term 
as defined by MedDRA dictionary. 
Frequency and percentage of patients with at least one reported adverse 
event/incident/expected side effect will be tabulated by System Organ Class. 

 
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3. Flow Chart 
Visit name 
Screening/Inclusion 
At home 
Telephone 
call 
At home 
End of 
Treatment 
Visit Number 
V1 
 
TC1 
 
V2 
Days/Weeks 
D1 
D1 – D15± 3 
D15±3 
D15± 3 – D30± 5 
D30 ± 5 
Screening and General Assessments  
Patient information and Consent collection 
X 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
Demography and Medical history 
X 
 
 
 
 
Physical and clinical examination 
X 
 
 
 
X 
Ongoing medication 
X 
 
 
 
 
Treatment  
Healsea® Chronic 
 
X 
 
X 
 
Assessments 
SNOT 22 
X 
 
 
 
X 
Collection of middle meatus swab specimens 
X 
 
 
 
X 
Adverse Events/incidents and concomitant 
medication reporting 
X 
 
X 
 
X 
Satisfaction questionnaire 
 
 
 
 
X 
Compliance to study product 
 
 
 
 
X 

 
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4. Identification and description of the investigational Device 
4.1 Summary description of the investigational device 
Healsea® Chronic is a CE marked nasal spray composed with an hypertonic seawater solution (2.2% 
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. 
Healsea® Chronic is a nasal spray indicated in adults over 18 years in the treatment of nasal 
symptoms of chronic sino-nasal conditions : allergic rhinitis, chronic sinusitis, and/or sensitive nose. It 
can be used also as post-operative nasal care after nasal surgery. 
According to direction of use, one puff (1-2 sec) twice a day in each nostril is to be administered 
during 30 days or as recommended by the physician or the pharmacist.  
 
The technical performances are summarized below:  
Ingredient 
Function(s) 
Hypertonic Seawater solution 2.2% 
- 
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: 
 
Treatment of symptoms of chronic sino-nasal disorders: allergic rhinitis, chronic 
sinusitis and/or sensitive nose..  
 
It can be used also as post-operative nasal care after nasal surgery 
 
4.2 Manufacturer 
Healsea® Chronic is a class IIa Medical Device manufactured by Lallemand Pharma. CE marking has 
been obtained on 30 March 2021. The subcontractor for the manufactoring is AURENA, Fjarrvikvagen 
22, ES-653 50 Karlstad, Sweden.  
 
4.3 Name or number of the model to permit full identification 
The test device is named Healsea® Chronic. It is a nasal spray (150ml presentation), hypertonic 
seawater (2.2%) supplemented with Symbiofilm® (0.02%) identified by the code article: 75012DMMG  
 

 
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4.4 Traceability 
Tracability of the Device will be achieved through the lot number (YYMMXXX, YY for year, MM for 
Month and XXX internal number of the manufacturer).  
 
4.5 Intented purpose of the investigational device in the clinical 
investigation. 
Healsea® Chronic will be used within its intended use in adult patients with CRS according to EPOS 
criteria [1].  
 
4.6 Population and indications for which the device is intented 
Healsea® Chronic will be used in the intended population (adults over 18 years) and within its 
intended indication (CRS) and according to the IFU.  
 
4.7 Device Description 
Healsea® Chronic is a nasal spray (available in 50 or 150mL) 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® 
Chronic 
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 containing the bag and the propellant. 
 
 The Product: Hypertonic Seawater solution (2.2%) 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 1- Packaging description of Healsea® Chronic 

 
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As summarized below, Healsea® Chronic is intended to be used on nasal mucosa. The duration of use 
is 30 days. 
Type of contact 
Device in contact with a surface 
Type of tissues 
Mucous membranes  
Total duration treatment 
It can be used for 30 days 
 
4.8 Investigation Device Training/Experience 
There is no need for specific training in using Healsea® Chronic.  
An usability engineering process test according to the standard EN ISO 62366-1: 2015 was conducted 
with another product using BoV technology from the Healsea® range, Healsea® Children. Ten parents 
were recruited 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 adult 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® Chronic is provided in Appendix A.  
 
5. Justification for the design of the clinical investigation 
Chronic rhinosinusitis (CRS) is an inflammation of the nose and paranasal sinuses and is characterized 
by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or 
nasal discharge (anterior/posterior nasal drip), lasting for 12 weeks or longer. In addition, facial pain 
or pressure and a reduction in the sense of smell can occur [1]. The condition can occur with or 
without nasal polyps. 
The overall prevalence of symptom-based CRS in the population has been found to be between 5% 
and 12% [1]. 
 

 
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The physiopathology of CRS is poorly understood with multiple environmental, host and microbial 
factors being implicated. Putative pathological factors include changes in the microbiota, imbalance 
of the local or systemic immune system, allergens, toxins and genetic predisposition [2]. 
A dysbiosis mechanism has been proposed as modulating inflammation in diseased sinuses. This 
hypothesis suggests that externally influenced changes in the nasal microbiome can result in 
dysbiosis, i.e. a shift from a “normal” or “healthy” microbial community structure and that this shift 
may be responsible for the initiation or maintenance of CRS. For example, the disruption of the 
commensal biofilm during a viral upper respiratory tract infection can create a niche for pathogenic 
species to grow [3]. Despite many contradictory statements in the different studies some common 
trends emerge. Less diversity in the microbial community rather than an increased overall bacterial 
load seems to characterize CRS compared to the healthy state with no consensus about specific 
genera indicative of disease [4], [5], [6]. However, anaerobes and S. aureus are found to be 
significantly more prevalent and abundant in CRS versus healthy controls [4]. Bacterial biofilm is 
detected on the sinus mucosa in up to 80% of CRS patients and its presence does not imply that it is 
causing mucosal inflammation. However, in the context of CRS, there are several possible 
mechanisms by which biofilms may be pro-inflammatory including the release of planktonic 
organisms and the release of superantigens, which can cause ciliary dysfunction and inhibition of 
ciliary clearance. Bacterial biofilms are likely a key modulator of the refractory nature of CRS [7].  
Although clinical evidence from well-designed trials is scarce, European guidelines for chronic 
rhinosinusitis recommend daily nasal saline irrigation for reduction of the severity of symptoms of 
CRS [1]. A recent Cochrane analysis has concluded that daily nasal irrigation with hypertonic saline 
solution is more effective than placebo to improve patient symptoms [8]. The exact mechanisms by 
which nasal irrigation works are not known. However, most of the experts agree that it is primarily a 
mechanical intervention leading to direct cleansing of the nasal mucosa. Nevertheless, the efficacy of 
such solution remains moderate.  
Healsea® Chronic is a CE marked medical device indicated in adults for the treatment of nasal 
symptoms of chronic rhinosinusitis. This is a seawater-based nasal spray supplemented with a 
natural Symbiofilm® extract (0.02%) isolated from marine bacteria. The nasal solution is hypertonic 
(NaCl 2.2%). Symbiofilm® is a marine postbiotic comprising active exopolysacharides with emulsifying 
properties and in vitro antibiofilm activity. Antibiofilm properties have been demonstrated with the 
colorimetric microtiter plate assay [9]. In this model, a significant inhibition of Staphylococcus aureus 
and Haemophilus influenzae biofilms are 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. Symbiofilm® has no 
bacteriostatic nor bactericidal activities. 
To date, properly designed study to evaluate for the effect of topical therapies on microbiome are 
scarce so no definite conclusion can be made. In one study, use of saline irrigation with or without 
budesonideDCI used was not associated with significantly distinct microbiota composition among 
either controls or post-operative CRS with polyp patients [10].  
We design this exploratory study aiming at determining if the antibiofilm properties of Symbiofilm 
may modify sino-nasal microbiota, impacting α and/or β diversities. To this end middle meatus swab 
specimen will be taken from CRS patients before and after treatment with Healsea ® Chronic. 
Bacteria colonization will be assessed using quantitative PCR and 16S rRNA gene sequencing.  

 
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6. Risks and Benefits of the Investigational Device and Clinical Investigation 
6.1 Anticipated clinical benefit 
Healsea® Chronic is a CE marked class IIa medical device indicated in the treatment of nasal 
symptoms of sino-nasal conditions of which CRS. The clinical benefit of nasal irrigation with saline 
solution used during several weeks to improve CRS symptomatology is well known. Due to its 
technical performances, Symbiofilm® may enhance the cleansing activity of the device.  
 
6.2 Anticipated adverse device effects 
The only anticipated adverse device effect is the feeling of itching and irritation while initiating the 
treatment with the medical device Healsea® Chronic. In case of such adverse reaction, the participant 
will be instructed to contact the investigator if wishing to stop the nasal spray use. 
Furthermore, as mentionned in the IFU, patients with known hypersensitivity/allergy to any 
component of the test device will not be enrolled in the study.  
 
6.3 Risks associated with participation in the clinical investigation 
The collection of middle meatus specimen will be performed by the Principal Investigator or co-
investigator who are familiar with this medical procedure. This additional procedure is invasive 
(MDCG 2021-6-Regulation (EU) 2017/745) but no expected risk is associated with this procedure. 
This procedure is definitely comparable to nasopharyngeal swab which is routinely performed for 
Sars-CoV-2 detections without safety concern. Furthermore, nasopharyngeal swabs were mentioned 
in the « Arrêté du 12 avril 2018 fixant la liste des recherches mentionnées au 2° de l'article L. 1121-1 
du code de la santé publique » previously applicable for RIPH-2 with medical device. Additionally, in 
order to avoid any inconvenience, patients with defective access to the middle meatus, e.g. with 
deviated nasal septum, will not be enrolled (non-inclusion criterion) and a topical anesthesia with a 
lidocaine spray will be proposed to the eligible patients. 
 
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 
nasal spray e.g. decongestant or mucolytics if prescribed.  
 

 
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6.5 Steps that will 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 14971 activities) that demonstrates:  
o There is no longer High-level risk,  
o That, the 41 Medium risk level residual risks have an acceptable benefit-risk balance.  
o And all of the other residual risks (85) are at Low risk  
 
The fact that the device Healsea® Chronic 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® 
Chronic is mainly performed by LALLEMAND PHARMA AG in compliance with 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 assumed to be not 
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.  
 
6.6 Rationale for the benefit-risk ratio 
Chronic rhinosinusitis is a painful disease that impacts the quality of life. Orbital and intracaranial 
complications are rare but potentially serious. 
Nasal saline irrigation are recommended by European and American guidelines as adjuvant 
treatment for CRS. The addition of Symbiofilm® to nasal saline irrigation may improve the clinical 
performances of the device. Furthermore, apart from feeling of itching and irritation while initiating 
the treatment, no adverse effect is anticipated.  
The analysis of middle meatus swabs is expected to provide first insights on the in vivo mechanism of 
action of Healsea® Chronic. If an improvement of nasal microbiota is observed in the present study, 
this could justify to further study the impact of Symbiofilm® in a larger population of patients with 
CRS but also in other diseases with reported sino-nasal dysbiosis, e.g. asthma,  especially in the 
paediatric population [12].  
 

 
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7. Objectives and hypothesis of the clinical investigation 
7.1 Hypothesis 
Our hypothesis is that a one month-course of Healsea® Chronic nasal spray could modify the sino-
nasal microbiota diversity, impacting α and/or β diversities. Although performed on a small cohort of 
CRS patients, this clinical investigation is expected to provide first insights into the mechanism of 
action of Healsea® Chronic nasal spray in vivo.  
 
7.2 Primary Objective 
To characterize the change of sino-nasal microbial communities from adult CRS patients via 16S rRNA 
gene high throughput sequencing before and after 1-month treatment duration with Healsea® 
Chronic.  
 
7.3 Secondary Objectives 
-To assess the efficacy of Healsea® Chronic in improving health-related quality of life of CRS adult 
patients.  
-To assess the global satisfaction of patients in using Healsea® Chronic nasal spray for CRS.  
-Safety: to assess systemic and local tolerance of Healsea® Chronic over the study period. 
 
7.4 Scientific justification and clinical relevance for effect sizes, non 
inferiority margins or equivalence 
Not applicable. This is an exploratory clinical investigation. 
 
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. Expected and foreseeable side effects are feeling of itching and irritation while 
initiating the treatment. Nevertheless, the safety according to post market safety regulations (see 
paragraph 16) and well being of subjects will be monitored throughout the study.  
 
8. Design of the clinical investigation 

 
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8.1 General 
8.1.1 Design type of clinical investigation 
This is an exploratory study, open label in one site, in France. No control group is deemed necessary 
at this stage.  
8.1.2 Measures to be taken to minimize or avoid bias 
Not applicable.  
8.1.3 Primary Endpoint 
Modifications in microbial load and/or profile 
To determine the impact of Healsea® Chronic on the nasal microbiome, the microbial load will be 
evaluated by quantitative PCR and the microbiome taxonomic profiling by 16S rRNA gene 
sequencing. Data collected in patients before and after 1 month-treatment with Healsea® Chronic 
will be compared using statistical analyses to assess changes in microbial species abundance and 
diversity. Furthermore, special attention will be given to typical sino-nasal pathogens (e.g. 
Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) 
at genus level, and if reachable at species level. 
8.1.4 Secondary Endpoints 
To measure the clinical performance of Healsea® Chronic, the quality of life of CRS patients will be 
assessed with the Sino-Nasal Outcome Test 22 score (SNOT-22) [13]. This questionnaire is a disease-
specific, quality-of-life-related measure of sinonasal function. Patients should rate sino-nasal 
symptoms and their impact from 0 to 5 where 0 means that there is no complaint and 5 means that 
there are serious complaints (Appendix B). 
Patient satisfaction questionnaire assessing medical device usability, sensory perception and efficacy 
in using Healsea® Chronic for CRS (Appendix C). 
Safety: Assessment of adverse events/incidents/expected side effects throughout the study.  
8.1.5 Methods and timing for assessing, recording and analysing variables 
8.1.5.1 
Middle meatus swab specimen 
Collection of middle meatus swab specimens will be performed at V1 and V2. A sterile stick swab 
(reference MW940; Medical Wire) will be introduced deeply within the middle meatus rotated at 
least 5 turns until visibly saturated. Immediately after collection, the swab will be placed in a dry tube 
(reference 62 554502; Sarstedt) and immediately stored in a freezer at -20°C. 
8.1.5.2 
SNOT-22 
SNOT-22 (Appendix B) will be self-evaluated by the patient at V1 and V2 during the visit. 
8.1.5.3 
Assessment of sino-nasal microbial communities by 16S rRNA gene amplicon sequencing 
DNA extraction 

 
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Genomic DNA (gDNA) is extracted using an optimized tissue-specific technique as previously 
described [14], [15]. This technique was carefully designed to maximize the recovery of bacterial DNA 
and to minimize any risk of contamination from the environment and the reagents. The quality and 
quantity of extracted gDNA are monitored by gel electrophoresis (1% w/w agarose in 0.5× TBE 
buffer) and NanoDrop 2000 UV spectrophotometer (ThermoFisher Scientific). All gDNA samples are 
stored at −20 °C until further processing.  
 
Bacterial quantification by quantitative PCR (qPCR) 
Total number of bacterial 16S rRNA gene copies is evaluated by real-time PCR amplification targeting 
the hypervariable regions V3-V4 with the primers: EUBF 5ʹ-TCCTACGGGAGGCAGCAGT-3ʹ and EUBR 
5ʹ-GGACTACCAGGGTATCTAATCCTGTT-3ʹ. The qPCR is realized in triplicate on a VIIA 7 PCR system 
(Life Technologies) using SYBR Green technology and the specificity of all qPCR products is assessed 
by systematic analysis of a post-PCR dissociation curve performed between 60°C and 95°C. The 
absolute number of copies of the 16S rRNA gene is determined by comparison with a quantitative 
standard curve generated by serial dilution of linearized plasmid standards. 
 
Bacterial 16S rRNA gene sequencing 
The V3-V4 hypervariable regions of the 16S rRNA gene are amplified by PCR using universal primer 
Vaiomer 1F (CTTTCCCTACACGACGCTCTTCCGATCT–TCCTACGGGAGGCAGCAGT, partial P5 adapter–
primer) 
and 
universal 
primer 
Vaiomer 
1R 
(GGAGTTCAGACGTGTGCTCTTCCGATCT–
GGACTACCAGGGTATCTAATCCTGTT, partial P7 adapter–primer), which are fusion primers based on 
the qPCR primers with sequencing adapters. The first PCR reaction is carried out on a Veriti Thermal 
Cycler (Life Technologies) as follows: an initial denaturation step (94°C for 10 min), 35 cycles of 
amplification (94°C for 1 min, 68°C for 1 min and 72°C for 1 min) and a final elongation step at 72°C 
for 10 min. Amplicons (467 bp on the Escherichia coli reference genome) are then purified using the 
magnetic beads CleanNGS for DNA clean-up (CleanNA). A second PCR reaction for sample 
multiplexing is performed using tailor-made 6-bp unique index sequences with the forward primer 
Vaiomer 2F (AATGATACGGCGACCACCGAGATCTACACT–CTTTCCCTACACGAC, partial P5 adapter–
primer targeting primer 1F) and reverse primer Vaiomer 2R (CAAGCAGAAGACGGCATACGAGAT–
index–GTGACT–GGAGTTCAGACGTGT, partial P7 adapter including index–primer targeting primer 1R). 
This second PCR step is run as follows: an initial denaturation step (94°C for 10 min), 12 cycles of 
amplification (94°C for 1 min, 65°C for 1 min and 72°C for 1 min) and a final elongation step at 72°C 
for 10 min. Amplicons are purified as described for the first PCR round. All libraries are pooled in the 
same quantity to generate an equivalent number of raw reads and are sequenced on a MiSeq 
Illumina platform (2 x 300 bp paired-end MiSeq kit v3, Illumina). 
 
16S rRNA Gene Sequence Analysis 
The targeted metagenomic sequences are analyzed using a bioinformatics pipeline based on ‘find, 
rapidly, OTUs with Galaxy solution’ (FROGS) guidelines [16]. In brief, after demultiplexing of barcoded 
Illumina paired reads, single-read sequences were cleaned and paired into longer fragments. OTUs 
are produced with single-linkage clustering. The taxonomic assignment is performed by BLAST 
against SILVA database to determine bacterial profiles from phylum to genus, and when reachable to 
species level. The following filters are applied: amplicons with a length of <350 nt or a length of 

 
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>490 nt are removed and OTUs with abundance lower than 0.005% and that appear less than twice 
in the entire dataset are removed. Alpha and beta diversity analyses are conducted on the OTU table. 
8.1.5.4 
Safety  
Adverse events, incidents and expected side effects of the medical device will be reported in the CRF 
at each visit/telephone call.  
8.1.6 Arrangements for the monitoring maintenance and calibration of 
equipment used for genomic analysis  
Annual maintenance by the manufacturer is performed on the Freedom EVO 150 (Tecan) and 
pipetting volumes are regularly controlled. The ViiA 7 Real-Time PCR System (ThermoFisher 
Scientific) is monthly controlled by Vaiomer staff and annually calibrated by the manufacturer. All 
handling, measurement and safety equipment (e.g. pipettes, scale, Captair Biocap PCR Workstations, 
spectrophotometers, safety and fume hoods) is annually controlled by specialized providers.  
8.1.7 Any procedures for the replacement of subjects 
No replacement of subjects is planned. 
8.1.8  Investigation sites: number, location 
The clinical investigation will be undertaken in 1 site in France. The principal investigator, Pr G de 
Bonnecaze is Otorhinolaryngologist and familiar with study procedures.  
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® Chronic (nasal spray; 150 mL presentation) is a CE 
marked Medical Device. As this is an interventional study, the device will be provided to the patient. 
No specific labelling is required as the device will be used within its intended use in this post-market 
clinical investigation. 
No comparator is used in this study.  
 
8.3 Subjects 
The target population is adult patients patients over 18 years diagnosed with CRS according to EPOS 
criteria [1]. According to these criteria, chronic rhinosinusitis (with or without nasal polyps) in adults 
is defined as presence of two or more symptoms one of which should be either nasal 
blockage/obstruction/ congestion or nasal discharge (anterior/posterior nasal drip), ± Facial 
pain/pressure ± reduction or loss of smell, lasting for 12 weeks or longer.  

 
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The subjects will be recruited by the site among outpatients coming for routine consultation because 
of CRS.  
8.3.1 Eligibility criteria 
8.3.1.1 
Inclusion criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Male or female, aged ≥18 – ≤70 years 
2. Provision of signed and dated informed consent form 
3. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
4. Diagnosed with CRS based on the diagnostic criteria of the EPOS guideline 
5. Registered with a social security scheme or covered by such a regime 
8.3.1.2 
Non-inclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study:  
1. Antibiotics or oral corticosteroids intake in the month prior to the study 
2. Endoscopic sinus surgery in the 6 past months 
3. Cystic fibrosis 
4. Wegener's granulomatosis 
5. Immunodeficiency 
6. Defective access to the middle meatus  
7. Lidocaine allergy 
8. Known hypersensitivity/allergy to any component of the test device 
9. Pregnant/Lactating female or absence of efficient contraception 
10. Under tutorship or guardianship 
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 subject can withdraw his/her consent 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: 
 
Significant study product non-compliance,  
 
If any clinical adverse event (AE)/incident, 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,  

 
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 
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 data at the end of the treatment period after repeated 
unsuccessful attempts including sending through a registered letter, he/she will be considered “lost 
to follow-up”. But before declaring that a patient is "lost to follow-up", the investigator (or his/her 
team) must do his/her best effort to contact the patient and attempts should be made via all 
available routes. A registered 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  
No subject replacement is planned. 
8.3.3  Point of enrolment 
The subjects will be recruited by the site among outpatients coming for routine consultation because 
of CRS. 
In order to facilate the enrolment, a study nurse or a CRA will contact patients before the 
consultation in order to explain the study aim and design. This will allow the patient to have a period 
for though before the consultation with the investigator.  
When coming for the consultation, the patient will be informed again about the study by the 
investigator. All questions relative to the study will be answered by the investigator. If the patient 
agrees study participation, he/she will sign/date the Informed Consent Form before any study 
procedure. 
8.3.4 Total expected duration of the clinical investigation 
The total study duration is planned to be 5 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 
An arbitrary sample of 20 patients completing the investigation without major protocol deviation has 
been chosen.  
8.3.7 Estimated time needed for the enrolment 
It is expected to enrol 20 patients within 4 months. 

 
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8.3.8 Relationship of investigation population to target population 
Patients with CRS have two or more symptoms, one of which should be either nasal 
blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), lasting for 12 
weeks or longer. Healsea® Chronic is indicated in adults over 18 years in the treatment of nasal 
symptoms of sinonasal conditions. The investigation population is thus a target population of 
Healsea® Chronic. 
 
8.3.9 Vulnerable, pregnant and breastfeeding population 
Patient under tutorship or guardianship are not eligible. 
Pregnant and breastfeeding women are not eligible too. 
8.3.10 Compensation 
A compensation of 200 euros for costs resulting from participation in the clinical investigation 
(transportation, absence of work..) will be paid to each patient who complete the study.  
 
8.4 Procedures 
8.4.1 Study procedures 
The study will comprise 2 visits and 1 telephone call. 
Visit 1 (V1) – (Day 1): Screening/Inclusion  
The investigator will give oral information relative to the study to the participant and answer to all 
the questions raised by the patient. If he/she agrees to participate in the study, he/she will be asked 
to sign and date a consent form. 
Each screened subject will be assigned a subject identifier number during screening. The subject 
identifier number will contain the site number (01) and the subject number assigned in numerical 
order at the screening visit based on chronological order of screening dates (e.g., 01-10 for the 10th 
subject screened at the Site #01). 
The investigator or his/her delegated designee will: 
 
Record demographic data and medical history and ongoing medication,  
 
Perform a rhinologic examination,  
 
Verify that eligibility criteria are fulfilled,  
 
Proceed with the middle meatus swab collection, 
 
Detail the questions of the SNOT-22 and record the patient’s score,  
 
Record adverse events if applicable, 
 
Explain how to collect adverse events/incidents/expected side effects and concomitant 
medications for reporting at the telephone call/visit,   
 
Deliver Healsea® Chronic and explain to the patient how to use it.  
The patient will be ask to bring back the container at the end of the treatment period. 

 
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D1-D30 (at home):  
The patient will be instructed to self administer Healsea® Chronic nasal spray twice a day (1 puff, 1-2 
sec) in each nostril during 30 days. 
D15±3 (at home): Telephone call  
The Investigator or his/her delegated designee will call the patient to review patient status and study 
progress, adverse events/incidents/expected side effects and concomitant treatments.  
Visit 2 (V2) – (Day 30 ±5): end of treatment 
The investigator or his/her delegated designee will: 
 
Perform a physical and clinical examination,  
 
Record the SNOT 22 score in the CRF,  
 
Proceed with the middle meatus swab collection,  
 
Report the adverse events/incidents/expected side effects and concomitant medications in 
the CRF,  
 
Ask the patient to complete the satisfaction questionnaire and report the result in the CRF,  
 
Measure compliance to Healsea® Chronic intake.  
8.4.2 Permitted and forbidden concomitant medications 
All concomitant medications are authorized during the investigation, except nasal irrigation, systemic 
corticosteroids, topical (nasal mucosa) and systemic antibiotics. 
8.4.3 Exclusion period 
The patients will be asked to not participate in another study during their study participation. 
8.4.4 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 regulatory 
requirements. The sponsor will ensure ongoing risk management throughout the clinical 
investigation and will take all measures to protect rights, safety and weel-being of children who 
participate in the study.  
The sponsor is required to report noncompliance trends and safety issues to the CA and 
investigators. 
The sponsor shall report on the progress and status of the clinical investigation to the CA.  
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),  

 
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v) 
When requested or suggested by a regulatory authority. 
8.4.5 Any known/foreseeable factors that can compromise the outcome of 
the clinical investigation and methods for addressing these factors 
No known or foreseeable factors that can compromise the outcome of the clinical investigation is 
anticipated.  
8.4.6 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. Nevertheless, routine care for CRS will be provided to the patients.  
8.4.7 Potential use of samples obtained from subjects 
Patients’ samples will be used to assess sino-nasal microbiota through 16S RNA gene amplicon 
sequencing only as per approved protoocol.  
 
8.5 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 which 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. 
8.5.1 Initiation visit 
The study will only start at a site after: 
 
The Ethics Committee has granted approval for the conduct of the study,  
 
ANSM approval,  
 
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 French 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. 
8.5.2 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 Case Report Form (paper 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. 

 
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The investigator must permit study-related monitoring visits, audits review by the Ethic Committee 
and ANSM, 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 
Patients and disease characteristics will be described at baseline. 
 
16S rRNA Gene Sequence Analysis 
The normal distribution of the values is verified thanks to normality tests (e.g. Shapiro-Wilk test). 
However, it is most likely that the group size will be insufficient to apply parametric statistical tests. 
Significant variations in total number of bacterial 16S rRNA gene copies or in alpha diversity are 
assessed using the Kruskal-Wallis test or the Wilcoxon rank-sum test. Multidimensional scaling 
analyses (MDS) are performed on beta diversity distances matrices and differences between groups 
were assessed using PERMANOVA and PERMDISP analyses (2000 permutations). LEfSe (Linear 
discriminant analysis Effect Size) analyses, based on non-parametric tests are used to determine 
significant variations in taxa relative abundance [17]. 
Secondary endpoints 
Values and changes from baseline to D30/end of study of the SNOT-22 total score will be described. 
Patients satisfaction will be described at D30/end of study. 
Safety 
All adverse events/incidents/expected side effects will be listed, but only treatment-emergent 
adverse events/incidents (non-serious + serious) and expected side effects will be summarized by the 
number and percentage of patients, classified by System Organ Class and Preferred Term as defined 
by MedDRA dictionary. 
Frequency and percentage of patients with at least one reported adverse event/incident/expected 
side effect will be tabulated by System Organ Class. 
 
10. Data collection 
10.1 CRF entry 
All the data provided in the protocol and collected by the investigator are to be reported in the case 
report forms (CRF). 
The case report forms will consist of triplicate self-copying sheets (Carbonless copy paper): 
 
The white sheet (original) is intended for the data entry, 
 
The blue sheet (median copy) is a working document for reference purpose, 
 
The yellow sheet (bottom copy) is retained by the investigator. 
The CRFs will be completed and signed by the investigator. Each correction will also be initialled and 
dated by the investigator or his designee.  

 
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10.2 Source documents 
The investigator is asked to report in the patient’s medical record: 
 
Mention of the subject’s participation in the study 
 
Demographic data (date of birth, sex, name) 
 
Past medical and surgical history 
 
Recent past treatments 
 
Concomitant treatments 
 
Clinical assessment 
 
Date of each study visit 
 
Change in any of the concomitant treatment 
 
Any adverse event/incident 
and all relevant data according to the investigator’s opinion. 
In case of computerized medical file, a printout will be edited, dated and signed by the investigator. 
Source data are documented on the “source data agreement form”.  
 
11. Data management 
11.1 Methods for data entry and collection 
Clinical data related to the study will be collected and saved into a computerized database by the 
Data Management Department of AXIODIS using the EXAGIS e-CRF software. In order to ensure 
maximum data quality, the paper CRF will be transcribed into the electronic database using double 
data entry.  
 
11.2 Data review 
After double data entry, a computerized data review will be performed by AXIODIS according to the 
Data Validation Plan. 
Results of this data review will be sent to the Study CRA and/or Study Manager. Whenever required, 
queries issued from this review will be submitted to the investigator for resolution and signature and 
then tracked until corrections are entered and validated.  
 
11.3 Data coding 
Adverse events, concomitant diseases, medical/surgical histories will be coded by AXIODIS using the 
MedDRA dictionary (last version in use). 
Concomitant medication will be coded using the WHO-DD dictionary (last version in use). 
The study manager and/or other relevant sponsor representative will validate the coding.  
 

 
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11.4 Procedures for verification, validation and securing of electronic clinical 
data system 
The EXAGIS software is installed on a Linux server (secure Data Center) hosted at the OVH 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. Software access is restricted to authorized users using individual 
encrypted passwords. Data processing via SAS software (SAS Institute, Cary, NC, USA) is carried out 
on a Windows 2012 R2 production server at OVH, using direct access by SAS or MySQL Workbench.  
 
11.5 Procedures to maintain and protect subject privacy 
Data privacy is ensured through restricted access to the anonymized data located in a dedicated 
separate database.  
 
11.6 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. 
The review process prepared by the clinical research assistant, data manager, study monitor, medical 
manager and statistician will be concluded during 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.  
 
11.7 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 

 
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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.  
 
12. 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 submitted to the EC and ANSM for approval.  
 
13. Deviation from clinical investigation plan 
All protocol deviations will be managed as per the Standard Operating Procedures of the CRO in 
charge of the study coordination. 
A deviation log shall be maintained by the study site. 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.  
Major protocol deviations are defined 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  
 
Non-compliance with treatment  
 
No collection of middle meatus swab sample at any visit 
 
Intake of forbidden medication  
All other cases will, a priori, be considered as minor deviations.  
 
14. Device accountability 
Not applicable for this post market interventional study.   
 
15. Ethical consideration  

 
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15.1 Informed consent process  
According to Regulation UE 2017/745, ISO 14155:2020 and articles L1122-1 and L1122-2 of Code de 
la Santé Publique, the Princial Investigator or his/her authorized designee must given all pertinent 
information relative to all aspects of the research before any study procedure. Participants will have 
the opportunity to carefully review the information document and ask questions prior to accepting 
or not to participate in the study. As this investigation is interventional, the consent shall be obtained 
in writing and the study participation must be documented in the patient medical file.  
 
15.2 Subject privacy 
This research falls within the scope of the reference methodology MR-001 relating to the processing 
of personal health data carried out in the context of a research involving the subject’s consent 
collection. The sponsor has signed  a commitment to comply with the provisions of MR-001 (CNIL 
receipt number: 2222437v0 dated from 21st May 2021). 
All records identifying directly and/or indirectly the subject will be kept confidential according to the 
French law n°78-17 relative to data processing, files and liberties and the European Regulation 
2016/679 effective as of 25 May 2018 (hereafter the “GDPR”) and will not be made publicly available.  
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).  
In accordance with GDPR, the Sponsor is the “Controller” and the participating sites, monitors, data 
managers and statisticians are “Processors”. Lallemand Pharma, sponsor of the study, is responsible 
for the processing of the study data. The Data Protection Officer appointed by Lallemand Pharma: Ms 
Yannick Hervy, yhervy@lallemand.com. 
Confidentiality of data shall be observed by all parties involved 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 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.  
To characterize the nasal microbiome by quantitative PCR and 16S rRNA gene sequencing, VAIOMER 
will receive patient biological samples identified by anonymized sample codes. To ensure that 
personal data cannot be attributed to specific samples, the decoding index will not be communicated 
to Vaiomer at any time. Moreover, to protect the integrity and the confidentiality of the data 
generated by Vaiomer, below are the relevant actions in place: 
 
Physical location 
Vaiomer will produce data derived from the biological samples which will be stored on Vaiomer local 
servers (no cloud storage). As Vaiomer does not own the sequencing machines (MiSeq), the 
sequencing step itself is performed on a public genomic platform (INRAE) in our close environment. 
This is realized by Vaiomer staff who is validated beforehand by the platform. Sequencing data is 

 
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transferred by encrypted download links to Vaiomer server after data acquisition and purged from 
the data provider disk after 3 months. 
 
Data backup 
Vaiomer storage server is backed up externally daily to a secured data center fully owned by our 
subcontractor. 
 
Access control 
Access to these data is restricted to Vaiomer staff via a password-protected personal account. The 
computer and storage servers are located in a restricted area through badge access control. 
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 fullfil 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). The information document and the consent form provided to patient will 
include a specific paragraphe relative to data privacy explaining the lawfulness of personal data 
processing conditions and patients rights.  
The patients’s 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: 
Ms 
Yannick 
Hervy, 
yhervy@lallemand.com  
 
15.3 Insurance policy 
In accordance with the provisions of the French law n° 2012-300 du 5 mars 2012 et son décret 
d’application n°2016-1537 du 16 novembre 2016, Lallemand Pharma, has an insurance policy 
intended to guarantee against possible damage resulting from the investigation (appendix D).  
It is advisable to underline that non-compliance with the Research Legal Conditions is a cause for 
guarantee exclusion.  
 
16. Vigilance 
Healsea® Chronic will be used within 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 (materiovigilance).  
This additional procedure “collection of middle meatus swab specimens “ is invasive (MDCG 2021-6 
Regulation (EU) 2017/745) but no expected risk is associated with this procedure. However, should a 
serious adverse event related to this additional procedure occur, MDR article 80 shall apply. 
 
16.1 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, article 2 (64)).  
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, article 2(65)).  
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, article 2(66)).  
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, article 2(57)). 
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.  
Serious Adverse Event means any adverse event that led to any of the following: 
(a) death,  
(b) serious deterioration in the health of the subject, that resulted in any of the following:  
(i) life-threatening illness or injury,  
(ii) permanent impairment of a body structure or a body function, 

 
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(iii) hospitalisation or prolongation of patient hospitalisation, 
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
(v) chronic disease,  
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect (MDR 
2017/745 Article 2(58)). 
 
16.2 Reporting in the CRF  
All serious and non serious incidents/serious and non serious risk of incidents/expected side 
effects/adverse events (except pre-existing condition but CRS) occurring during the clinical 
investigation will be reported in the CRF.  
 
16.3 Investigator’s responsibilities and processing timelines 
16.3.1 Materiovigilance (art 87 to 90) 
All incidents and expected side effects will be reported to Lallemand Pharma vigilance manager 
according to MDR, MEDDEV 2.12 rev 8 modalities, national requirements, ISO 14155:20 and 
Lallemand Pharma procedures which are described in a 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 E) and send it to LP vigilant manager (officelp@lallemand.com) and to 
the clinical 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. 
16.3.2 Vigilance according to article 80 for the invasive procedure 
Any serious adverse event that has a causal relationship with the additional procedure or a causal 
relationship reasonably possible, will be reported by the investigator to the sponsor 
(officelp@lallemand.com) and to the CRO (etudes@bgclinicals.com) immediately, but not later than 
3 calendar days after investigation site study personnel’s awareness of the event. To this end, the 
investigator will complete the SAE form (appendix F).  
 
 
16.4 Sponsor responsibilities and processing time lines 
16.4.1 Materiovigilance (art 87 to 90) 
The vigilance manager of Lallemand Pharma is responsible for the reporting to the French Health 
Authority (ANSM).  

 
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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 French Health 
Authority 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 
deteriation 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 take immediate safety corrective action 
 
Increase rate or severity of expected undesirable side effects and non serious incidents will be 
reported to the ANSM in Trend reports as per regulation requirements.  
16.4.2 Vigilance according to article 80 for the invasive procedure 
Any serious adverse event that has a causal relationship with the additional procedure or a causal 
relationship reasonably possible, will be reported to the ANSM by the sponsor as follows:  
Imminent risk of death, serious injury, or 
serious illness and that requires prompt 
remedial action for patients/subjects or a new 
finding to it 
Immediately, but not later than 2 calendar days 
after awareness by sponsor of a new reportable 
event or of new information in relation with an 
already reported event. 
Other 
reportable 
events 
or 
a 
new 
finding/update to it 
Immediately, but not later than 7 calendar days 
following the date of awareness by the sponsor 
of the new reportable event or of new 
information in relation with an already reported 
event. 
 
In the absence of a fully functional electronic system referred to in Article 73, the sponsor will 
complete the « Investigation summary safety report form » (MDCG-2020-10/2):  
https://ec.europa.eu/health/sites/health/files/md_sector/docs/md_mdcg_2020-10-
2_guidance_safety_report_form_en.xlsx. 
 
Where an investigator assessment is not available and/or the sponsor remains uncertain about 
classifying the serious adverse event, the sponsor should not exclude the relatedness; the event 
should be classified as “possible” and the reporting not be delayed. 
 

 
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17. Suspension, premature termination and routine close out 
17.1 Suspension or Premature Termination of the Clinical Investigation 
Lallemand Pharma may suspend or prematurely terminate the clinical investigation. The reasons will 
be documented. Reasons for suspension or premature termination may include occurrences where 
monitoring or auditing identifies serious or repeated deviations done by an investigator. Lallemand 
Pharma will notify the ANSM as appropriate and ensure that the EC is notified of any suspension or 
early termination of the clinical investigation. 
A principal investigator, EC, or ANSM may suspend or prematurely terminate participation in the 
clinical investigation at the investigation site. 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or when so 
instructed by the EC or ANSM, 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, provide 
relevant persons with justification and data supporting the decision to resume the clinical 
investigation.  
 
17.2 Routine close out 
Routine close-out procedures will be conducted ensuring that the PIs records are complete, all 
documents needed for the sponsor files are retrieved, remaining clinical investigation materials are 
returned to th sponsor, previously identified issues have been resolved. 
The Principal Investigator will retain all copies of the records for a period of 10 years from the 
completion of the clinical investigation. In any circumstances, the PI 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 PI 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 records 
relating to this clinical investigation.  
 
18. 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 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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19. Bibliography 
[1] 
W. J. Fokkens et al., “European Position Paper on Rhinosinusitis and Nasal Polyps 2020,” 
Rhinology, vol. 58, no. Suppl S29, pp. 1–464, Feb. 2020. 
[2] 
R. Sivasubramaniam and R. Douglas, “The microbiome and chronic rhinosinusitis,” World J. 
Otorhinolaryngol. - Head Neck Surg., vol. 4, no. 3, pp. 216–221, Sep. 2018. 
[3] 
S. Boase et al., “The microbiome of chronic rhinosinusitis: Culture, molecular diagnostics and 
biofilm detection,” BMC Infect. Dis., vol. 13, no. 1, May 2013. 
[4] 
V. R. Ramakrishnan, L. J. Hauser, and D. N. Frank, “The sinonasal bacterial microbiome in 
health and disease,” Current Opinion in Otolaryngology and Head and Neck Surgery, vol. 24, 
no. 1. Lippincott Williams and Wilkins, pp. 20–25, 01-Feb-2016. 
[5] 
M. Hoggard, B. W. Mackenzie, R. Jain, M. W. Taylor, K. Biswas, and R. G. Douglas, “Chronic 
rhinosinusitis and the evolving understanding of microbial ecology in chronic inflammatory 
mucosal disease,” Clin. Microbiol. Rev., vol. 30, no. 1, pp. 321–348, Jan. 2017. 
[6] 
K. Koeller et al., “Microbiome and culture based analysis of chronic rhinosinusitis compared to 
healthy sinus mucosa,” Front. Microbiol., vol. 9, no. APR, p. 643, Apr. 2018. 
[7] 
J. H. Fastenberg, W. D. Hsueh, A. Mustafa, N. A. Akbar, and W. M. Abuzeid, “Biofilms in 
chronic 
rhinosinusitis: 
Pathophysiology 
and 
therapeutic 
strategies,” 
World 
J. 
Otorhinolaryngol. - Head Neck Surg., vol. 2, no. 4, pp. 219–229, Dec. 2016. 
[8] 
L. Y. Chong et al., “Saline irrigation for chronic rhinosinusitis,” Cochrane Database of 
Systematic Reviews, vol. 2016, no. 4. John Wiley and Sons Ltd, 26-Apr-2016. 
[9] 
G. A. O’Toole, “Microtiter dish Biofilm formation assay,” J. Vis. Exp., no. 47, 2010. 
[10] 
C. M. Liu et al., “Impact of saline irrigation and topical corticosteroids on the postsurgical 
sinonasal microbiota,” Int. Forum Allergy Rhinol., vol. 5, no. 3, pp. 185–190, Mar. 2015. 
[11] 
C. Hopkins, S. Gillett, R. Slack, V. J. Lund, and J. P. Browne, “Psychometric validity of the 22-
item Sinonasal Outcome Test,” Clin. Otolaryngol., vol. 34, no. 5, pp. 447–454, Oct. 2009. 
[12] 
K. F. Chung, “Airway microbial dysbiosis in asthmatic patients: A target for prevention and 
treatment?,” 2017. 
[13] 
J. L. Kennedy, M. A. Hubbard, P. Huyett, J. T. Patrie, L. Borish, and S. C. Payne, “Sino-nasal 
outcome test (SNOT-22): A predictor of postsurgical improvement in patients with chronic 
sinusitis,” Ann. Allergy, Asthma Immunol., vol. 111, no. 4, pp. 246-251.e2, Oct. 2013. 
[14] 
J. Lluch et al., “The characterization of novel tissue microbiota using an optimized 16S 
metagenomic sequencing pipeline,” PLoS One, vol. 10, no. 11, p. e0142334, Nov. 2015. 
[15] 
F. F. Anhê et al., “Type 2 diabetes influences bacterial tissue compartmentalisation in human 
obesity,” Nat. Metab., vol. 2, no. 3, pp. 233–242, Mar. 2020. 
[16] 
F. Escudié et al., “FROGS: Find, Rapidly, OTUs with Galaxy Solution,” Bioinformatics, vol. 34, 
no. 8, pp. 1287–1294, Apr. 2018. 
[17] 
N. Segata et al., “Metagenomic biomarker discovery and explanation,” Genome Biol., vol. 12, 
no. 6, pp. 1–18, Jun. 2011. 
 
 
 

 
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20. List of Appendix  
Appendix A: Instruction for Use 
Appendix B: SNOT-22 
Appendix C: Satisfaction questionnaire 
Appendix D : Insurance certificate  
Appendix E: Primary Notification Form (PNF) 
Appendix F: SAE form 
 
  
 
 
 
 
 
 

 
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Annexe A: Instructions for use 
English version: 
 
 
 
 

 
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French version: 
 
 
 
 
 
 
 

 
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Appendix B: SNOT-22 
 
 
 

 
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Appendix C: Satisfaction questionnaire  
 
 Please score from 0 to 3 your satisfaction regarding the following 
points: 
0 
1 
2 
3 
How would you characterize the use of Healsea® Chronic nasal spray? 
(0 : not easy; 1 : pretty easy ; 2 : easy ; 3 : very easy) 
 
 
 
 
How would you characterize the residual taste after spraying Healsea® 
Chronic? 
(0 : not pleasant ; 1 : neutral ; 2 : pleasant ; 3 : very pleasant 
 
 
 
 
How would you characterize the cleansing and moistening of nasal 
mucosa with Healsea® Chronic ? 
(0 : no improvement ; 1 : slight improvement ; 2 : moderate improvement; 3 : 
very clear improvement) 
 
 
 
 
Total :   
 
 
 

 
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Appendix D: Insurance certificate 
 

HDI Global SE 
Tour Opus 12 – Défense 9 
77 Esplanade du Général de Gaulle 
92914 PARIS LA DEFENSE CEDEX 
478 913 882 RCS Nanterre 
N° SIRET : 478 913 882 000 54 
 
HDI Global SE 
HDI-Platz 1, 30659 Hannover, Germany 
www.hdi.global 
 
Handelsregister: Registered office Hannover 
HR Hannover B 60320 
VAT registration ID DE 219828782 
 
Chairman of the Supervisory Board: Torsten Leue 
Executive Board: Dr. Edgar Puls (Chairman), Yves Betz, 
Dr Mukadder Erdönmez, Dr Christian Hermelingmeier, David 
Hullin, Dr Thomas Kuhnt, Andreas Luberichs, Jens Wohlthat 
ATTESTATION D’ASSURANCE RESPONSABILITE CIVILE 
PROMOTEUR DE RECHERCHE IMPLIQUANT LA PERSONNE HUMAINE 
 
 
Nous soussignés HDI Global SE - TOUR OPUS 12 – LA DEFENSE 9 - 77, Esplanade du Général de Gaulle F.92914 
PARIS LA DEFENSE CEDEX, certifions que la société : 
 
LALLEMAND PHARMA AG 
VIA SELVA 2 
6900 MASSAGNO - SUISSE 
 
a souscrit un contrat de Responsabilité Civile Promoteur de Recherche impliquant la personne humaine sous 
le numéro 01005345-14058 210068 conforme aux dispositions légales et réglementaires françaises sur les 
recherches impliquant la personne humaine et notamment de la loi n° 88.1138 du 20.12.1988, modifiée par 
les textes subséquents notamment la loi n° 2012-300 du 5 mars 2012 et son décret d’application n° 2016-1537 
du 16 novembre 2016, ainsi que le règlement européen (UE) 2017/745 sur le dispositif médical du 26 Mai 2021  
pour la recherche impliquant la personne humaine dénommée ci-après : 
 
Nom du promoteur : 
 
LALLEMAND PHARMA AG 
Numéro d’enregistrement : 
(EUDRACT ou n° fourni par l’ANSM) 
 
2021-A01458-33 
 
Titre de la recherche :  
 
Assessment of sino-nasal microbial communities changes in adult 
patients with Chronic Rhinosinusitis by 16S rRNA gene amplicon 
sequencing before and after 1-month treatment duration with Healsea® 
Chronic: an exploratory study (Study ISONAM) 
 
Protocole LPH-2102 
 
Nombre de patients : 
 
20 
Début et fin prévisionnels  de la 
recherche : 
 
DU 01/09/2021 AU 31/01/2022 
La garantie est conforme à l’obligation d’assurance instituée par les textes de loi précités ainsi que l’article 
L1121-10 du code de la santé publique et à la charge du promoteur, tant pour sa responsabilité que pour 
celle des intervenants au titre de la recherche impliquant la personne humaine. 
 
La garantie prévue au contrat restera acquise à l’Assuré en cas de modification affectant la date de prise 
d’effet de la recherche. 
 
La présente attestation est valable pour la durée de la recherche assurée et sa présentation vaut présomption 
de garantie à la charge de l’Assureur. Elle est délivrée, sous réserve du paiement de la prime, pour servir et 
valoir ce que de droit et ne peut en aucun cas engager l’Assureur au-delà des clauses et conditions du contrat 
auquel elle se réfère. 
 
Fait à Paris, le 17 juin 2021 
Pour l’Assureur 
 

 
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Appendix E: 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 :  
  

 
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Date of the incident occurred:  
Seriousness criteria :  Incident 
description narrative:  
Usage of the medical 
Device/frequency of use :  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
INVESTIGATION  
 Date : ……………..  
 Manager : ……….……….……….……….……….……….  
  
  
  
  
Elements to control during 
investigation :  
  
  
  
  
  
  
  
  
  
Risks identification :   
  
  
  
  
  
  
  
  
Recurrence study /  
  
  

 
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Impact on other batches ?  
  
  
  
  
  
  
Field Safety Corrective Action (FSCA), preventive actions, corrections, and corrective 
actions  
FSCA  
  
 Date : ……………..  
 Manager : ……….……….……….……….……….……….  
  
  
  
Nature of the FSCA :  
  
 
Control of the FSCA 
implemantation :  
  
  
  
  
  
  
  
  
  
Control of the FSCA  
effectiveness:  
  
  
  
  
  
  
  
  
  
Preventive actions  
  
 Date : ……………..  
 Manager : ……….……….……….……….……….……….  
  
  
  
Nature of preventives actions :  
  

 
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Control of the preventive 
actions’ implementation :   
  
 
Control of the preventives 
actions’ effectiveness :  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Corrective actions  
  
 Date : ……………..  
 Manager : ……….……….……….……….……….……….  
  
  
  
Nature of corrective actions :  
  
 
Control of the corrective 
actions’ execution :   
  
  
Control of the corrective  
actions’ implementation :  
  
  
  
  
  
  
  
  
  
  
  
  
  
Corrections  :  
  
 Date : ……………..  
 Manager : ……….……….……….……….……….……….  
  

 
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Nature of corrections :  
  
  
  
  
  
  
  
Closure  
  
 Date of investigation conclusion  :     ……………..  
 Manager : ……….……….……….……….……….……….  
 Signature :  
  
 
 

 
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Appendix F: SAE form 
Serious Adverse Event (SAE) notification form 
Post market clinical investigation with invasive/burdensome additional 
procedure(s) (art 74 MDR) 
Box reserved for 
sponsor, internal 
reference. 
 
 
 
This form is to be used when a causal relationship between the serious adverse event and the 
additional investigational procedure is suspected (art 80.5 and 80.6).  
 
This form is to be completed immediately and no later than 3 days after the investigation site 
study personnel have been made aware of the event and sent immediately by e-mail to the 
vigilance manager of the sponsor (e-mail: officelp@lallemand.com) and to the CRO (e-mail: 
etudes@bgclinicals.com) 
 
Study title: 
 
 
Assessment of sino-nasal microbial communities changes in adult 
patients with Chronic Rhinosinusitis by 16S rRNA gene amplicon 
sequencing before and after 1-month treatment duration with Healsea® 
Chronic: an exploratory study.  
 
Study number: 
LPH-2102 
 
 
 
1. Type of report: 
☐  Initial report 
☐  Follow-up report 
☐  Final report 
 
2. Date of report 
3. Date of initial notification to sponsor 
 
 
 
4. Investigator’s name: 
 
Report 
Investigator site 

 
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5. Investigator’s address: 
 
 
 
 
 
 
6. Phone number:  
 
7. Fax number: 
 
 
 
 
8. Email:  
 
 
 
 
 
9. Patient ID: 
10. Age: 
11.  Gender: 
 
 
 
 
12. Consent signature date: 
 
13. Relevant medical history: 
 
 
 
 
 
Subject 

 
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14. Date of occurrence: 
15. Place (e.g., hospital): 
 
 
 
 
16. Event description:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serious Adverse Event 

 
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17. Relation with invasive/burdensome procedures: 
☐  1. Not related  
☐  2. Possible  
☐  3. Probable  
☐  4. Causal relationship 
 
18. SAE: Any adverse event that led to any of the following:  
 
☐  a. Death 
 
☐  b. Serious deterioration in the health of the subject, that resulted in any of 
the following: 
 
☐  i. Life-threatening illness or injury 
 
☐  ii. Permanent impairment of a body structure or a body function 
 
☐  iii. Hospitalisation or prolongation of patient hospitalisation 
 
☐  iv. Medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure or a body function 
 
☐  v. Chronic disease 
 
☐  c. Fetal distress, fetal death or congenital physical or mental or birth 
defect 
 
19. Action/treatment/outcome: 
 
 
 
 
 
 
 
 
 
20. Investigational arm:  
 
☐  Test group 
 
☐  Comparison group 
 
☐  Blinded 
 
☐  Not applicable 
 
21. Event status: 

 
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☐  Resolved 
 
☐  Resolved with sequelae 
 
☐  Ongoing 
 
☐  Death  
 
22. Date and time of resolution (if applicable):  
23. Date and time of death: 
 
 
24. Had subject been excluded from the study because of the event?  
☐  Yes 
☐  No 
 
 

 
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Please give any necessary contact(s) if complementary information should be needed: 
 
25. Person to contact: 
 
26. Phone number: 
 
27. Email address:  
 
 
 
 
............................................................................................ 
 ............................................................................................. 
Signature (person who completed the form) 
Name (capital letter), First Name 
 
Date:  
 
 
....................................................................... 
(JJ/MMM/YYYY) 
 
 
 
............................................................................................ 
 ............................................................................................. 
Signature of investigator if he/she does not complete the 
form 
Name (capital letter), First Name 
 
Date:  
 
 
....................................................................... 
(JJ/MMM/YYYY) 
 
 
 
 
 
Contact and Signatures