Efficacy and Safety of Healsea® Hypertonic Nasal Spray 2.7% in the Treatment of Acute Infectious Rhinitis in Adults
Phase: NA
Conditions: Common Cold
Sponsor: Lallemand Pharma AG

 
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Study Number: LPH-2201 
 Efficacy and safety of Healsea® hypertonic nasal spray 2.7 % in 
the treatment of acute infectious rhinitis in adults  
 
CLINICAL INVESTIGATION PLAN 
 
 
Study Number: LPH-2201 
Short Title: TEACHER 
Version 1.0; 2022.10.03  
 
 
This Clinical Investigation is being sponsored by: 
 
Lallemand Pharma AG 
Via Selva 2 
6900 Massagno 
Switzerland 
 
Represented by Dr Frédéric Durmont 
 
 Principal Investigator:  
Dr Emil Kolev 
Convex 1991 Ltd, Sofia, Bulgaria 
 
 

 
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Study Number: LPH-2201 
HISTORY OF CLINICAL INVESTIGATION PLAN’S UPDATES 
Version 
Date 
Purpose of Update 
Version 1.0 
2022.10.03 
Initial version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Study Number: LPH-2201 
STUDY CONTACT LIST 
PRINCIPAL INVESTIGATOR 
 
 
Dr Emil Kolev 
 
Site No.1 
 
DCC Convex Ltd. 
11A Sinanishko Ezero Str. 
1000 Sofia, Bulgaria 
Tel +359 899526260 
emil@convex.bg 
MONITOR 
Marina Bakalova, CRA 
CONVEX 1991 Ltd. 
6 Tri Ushi Str., Office 2 
1000 Sofia, Bulgaria 
tel:  + 359 2 9863 109 
fax:+ 359 2 9888  700 
marina@convex.bg 
MEDICAL WRITER 
 
Géraldine 
Julou 
Schaeffer, 
PharmD, PhD 
 
BIOMEDICAL AND GLOBAL 
CLINICAL SOLUTION 
Parc Technologique du Canal 
26 rue Hermès 
31520 Ramonville-Saint-Agne, 
France 
Tel: +33 561 531 944 
g.schaeffer@bgclinicals.com 
 
DATA MANAGEMENT / 
STATISTICS  
Benjamin Poirier,  
Biometry Coordinator 
 
 
AXIODIS 
38 Avenue Pierre-Georges 
Latécoère, 31700 Blagnac, 
France 
Tel: +33 680 566 834 
bpoirier@axiodis.com 
 
 
 
 
 
 
 

 
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Study Number: LPH-2201 
APPROVAL FORM 
STUDY: LPH-2201 
CLINICAL INVESTIGATION PLAN Version:  
1.0 – 2022.10.03 
 
Sponsor’s representative: 
 
 
Dr Frédéric Durmont 
 
 
 
 
 
 
 
Principal Investigator: 
 
 
 
Dr Emil Kolev 
 
 
Study’s monitor: 
 
 
Marina Bakalova  
 
 
 
Study’s Statistician: 
 
 
Benjamin Poirier  
 
 
 
Medical Writer 
 
Géraldine Julou-Schaeffer, PharmD,PhD 
 
 
Date: 
Signature: 
 
Date: 
Signature: 
 
Date: 
Signature: 
 
Date: 
Signature: 
 
Date: 
Signature: 
 

 
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Study Number: LPH-2201 
 
Table of Contents 
1. 
Synopsis ......................................................................................................................................... 11 
2. 
Flow Chart ..................................................................................................................................... 16 
3. 
Identification and description of the investigational device and of the Placebo .......................... 17 
3.1 Summary description ................................................................................................................ 17 
3.1.1 
The investigational device ............................................................................................. 17 
3.1.2 
The comparator ............................................................................................................. 18 
3.2 Manufacturer ............................................................................................................................ 18 
3.3 Name or number of the model to permit full identification ..................................................... 18 
3.4 Traceability ................................................................................................................................ 18 
3.5 Intended purpose of the devices in the clinical investigation ................................................... 18 
3.6 Population and indications for which the device is intended ................................................... 18 
3.7 Devices description ................................................................................................................... 19 
3.7.1 
Investigational device .................................................................................................... 19 
3.7.2 
The comparator ............................................................................................................. 20 
3.7.3 
Primary and secondary packaging and labelling ........................................................... 20 
3.8 Investigation Device training/ experience................................................................................. 21 
3.9 Reference to the IFU ................................................................................................................. 22 
4. 
Justification for the design of the clinical investigation ................................................................ 22 
5. 
Risks and Benefits of the Investigational Device and Clinical Investigation .................................. 24 
5.1 Anticipated clinical benefit ........................................................................................................ 24 
5.2 Anticipated adverse device effects ........................................................................................... 24 
5.3 Risk associated with the participation in the clinical investigation ........................................... 24 
5.4 Possible interaction with concomitant treatments as considered under the risk analysis ...... 25 
5.5 Steps that will be taken to control and mitigate the risks ........................................................ 25 
5.5.1 
Healsea Rescue* ............................................................................................................ 25 
5.5.2 
Placebo .......................................................................................................................... 25 
5.5.3 
Mitigation of risk during the clinical investigation ........................................................ 26 
5.6 Rational for the benefit risk ratio .............................................................................................. 26 
6. 
Objectives and hypotheses of the clinical investigation ............................................................... 27 
6.1 Hypothesis ................................................................................................................................. 27 
6.2 Primary Objective ...................................................................................................................... 27 
6.3 Secondary Objectives ................................................................................................................ 27 

 
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6.4 Scientific justification and clinical relevance for effect sizes, non-inferiority margins or 
equivalence ....................................................................................................................................... 27 
6.5 Risks and anticipated adverse effects that are to be assessed ................................................. 27 
7. 
Design of the clinical investigation ................................................................................................ 28 
7.1 General ...................................................................................................................................... 28 
7.1.1 
Design type of clinical investigation .............................................................................. 28 
7.1.2 
Measures to be taken to minimize or avoid bias .......................................................... 28 
7.1.3 
Primary Endpoint with methods and timing for assessing recording and analysing 
variables 29 
7.1.4 
Secondary Endpoints with methods and timing for assessing, recording and analysing 
variables 29 
7.1.5 
Equipment to be used for assessing the clinical investigation variables ...................... 30 
7.1.6 
Any procedures for the replacement of subjects .......................................................... 30 
7.1.7 
Investigation sites: number, location ............................................................................ 30 
7.1.8 
Definition of the completion of the study ..................................................................... 30 
7.2 Investigational device and comparator ..................................................................................... 30 
7.2.1 
Description of the exposure to the investigational device ........................................... 30 
7.2.2 
Description and justification of the choice of the comparator ..................................... 31 
7.3 Subjects ..................................................................................................................................... 31 
7.3.1 
Eligibility Criteria............................................................................................................ 31 
7.3.2 
Point of enrolment and randomization ......................................................................... 33 
7.3.3 
Total expected duration of the clinical investigation .................................................... 33 
7.3.4 
Expected duration of each subject’s participation ........................................................ 33 
7.3.5 
Number of subjects required to be included in the clinical investigation .................... 33 
7.3.6 
Estimated time needed for the enrolment ................................................................... 33 
7.3.7 
Relationship of investigation population to target population ..................................... 33 
7.3.8 
Vulnerable, pregnant and breastfeeding population .................................................... 33 
7.3.9 
Compensation ............................................................................................................... 33 
7.4 Procedures................................................................................................................................. 34 
7.4.1 
Description of clinical investigation-related procedures .............................................. 34 
7.4.2 
Concomitant Medication and/or Treatments ............................................................... 35 
7.4.3 
Activities performed by sponsor representatives (excluding monitoring) ................... 36 
7.4.4 
Any known/foreseeable factors that can compromise the outcome of the clinical 
investigation and methods for addressing these factors .............................................................. 36 
7.4.5 
Follow-up and medical care after completion of the study .......................................... 36 

 
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7.4.6 
Potential use of samples obtained from subjects ......................................................... 36 
7.5 Monitoring plan ......................................................................................................................... 37 
7.5.1 
Initiation visit ................................................................................................................. 37 
7.5.2 
Monitoring ..................................................................................................................... 37 
7.5.3 
Routine Close-out .......................................................................................................... 37 
7.5.4 
Retention of Documentation......................................................................................... 37 
8. 
Statistical design and analysis ....................................................................................................... 38 
8.1 Analysis population ................................................................................................................... 38 
8.2 Baseline Characteristics ............................................................................................................. 38 
8.3 Primary endpoint ....................................................................................................................... 38 
8.4 Secondary endpoints ................................................................................................................. 38 
8.5 Sample Size calculation and justification .................................................................................. 39 
8.6 Rationale for the number of procedures to be performed by a single user ............................. 39 
8.7 Interim analysis ......................................................................................................................... 39 
8.8 Management of bias (randomization, blinding) ........................................................................ 40 
8.9 Management, justification, and documentation of missing data, including drop-outs ........... 40 
8.10 Procedures for reporting any deviation(s) from the original statistical analysis plan .............. 40 
9. 
Data Management ......................................................................................................................... 41 
9.1 Source documents ..................................................................................................................... 41 
9.2 Methods for data entry and collection ..................................................................................... 41 
9.3 Procedure used for CRF tracking, data review, database cleaning and issuing/resolving data 
queries. .............................................................................................................................................. 41 
9.4 Procedures for verification, validation and securing of electronic clinical data system ........... 42 
9.5 Procedures to maintain and protect subject privacy ................................................................ 42 
9.6 Methods for database locking at the start of analysis and storage upon completion of the 
clinical investigation .......................................................................................................................... 43 
9.7 Procedure for data retention .................................................................................................... 43 
10. Amendments to the CIP ................................................................................................................ 43 
11. Deviation from Clinical Investigation Plan..................................................................................... 43 
12. Device accountability .................................................................................................................... 44 
13. Ethical consideration ..................................................................................................................... 44 
13.1 Informed Consent ...................................................................................................................... 44 
13.2 Subject confidentiality ............................................................................................................... 45 
13.3 Insurance policy ......................................................................................................................... 46 
14. Vigilance ........................................................................................................................................ 46 

 
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14.1 General ...................................................................................................................................... 46 
14.2 Definitions ................................................................................................................................. 46 
14.3 Reporting in the eCRF ................................................................................................................ 48 
14.4 Investigator’s responsibilities and processing timelines ........................................................... 48 
14.4.1 
Materiovigilance ............................................................................................................ 48 
14.4.2 
Vigilance reporting according to Article 80 of the MDR ............................................... 48 
14.5 Sponsor responsibilities and processing timelines.................................................................... 49 
14.5.1 
Materiovigilance ............................................................................................................ 49 
14.5.2 
Vigilance according to Article 80 ................................................................................... 49 
15. Suspension, or premature termination of the Clinical Investigation ............................................ 50 
16. Publication policy .......................................................................................................................... 50 
17. References ..................................................................................................................................... 52 
List of Appendix ..................................................................................................................................... 53 
Appendix A: IFU ..................................................................................................................................... 54 
Appendix B: Primary Notification Form ................................................................................................ 56 
Appendix C: SAE form ............................................................................................................................ 59 
 
 
 

 
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Study Number: LPH-2201 
PRINCIPAL INVESTIGATOR STUDY APPROVAL PAGE 
STUDY: TEACHER-LPH 2201 
CLINICAL INVESTIGATION PLAN Version:  
Version 1.0-2022-10-03 
 
By signing the hereinafter form, I hereby confirm that I agree: 
 
To conduct the trial described in the Clinical Investigation Plan (LPH-2201) Version 1 dated 
2022-10-03 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; 
 
To document the delegation of significant study related duties and to notify the sponsor of 
changes in site personnel involved in the study; 
 
To comply with procedures for data recording and reporting; 
 
To permit monitoring, auditing and inspection; 
 
To retain the trial-related essential documents until the sponsor informs these documents are 
no longer needed. 
 
Furthermore, I hereby confirm that I will have and will use the availability of adequate resources, 
personnel, and facilities for the conduct of this trial. 
 
 
Principal Investigator’s Name:  __________________________________________________ 
 
Principal Investigator’s Title: 
__________________________________________________ 
 
Principal Investigator’s Address: 
 
__________________________________________________ 
 
__________________________________________________ 
 
 
 
Principal Investigator’s Signature: 
 
 
 
Date of signature: 
 
__________________________________________________
 
 
 

 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
CA 
Competent Authority 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
EEC 
European Economic Community 
EC 
Ethics Committee 
FAS 
Full Analysis Set 
GDPR 
General Data Protection Regulation 
GP 
General Practitioner  
IFU 
Instruction For Use 
LPLV 
Last Patient Last Visit 
MDCG 
Medical Devices Coordination Group 
MDR 
Medical Device Regulation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-Steroidal Anti-Inflammatory Drugs 
PI 
Principal Investigator 
PMCF 
Post-Market Clinical Follow-up 
PNF 
Primary Notification Form 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
URTI 
Upper Respiratory Tract Infection 

 
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Study Number: LPH-2201 
1. Synopsis 
Sponsor: LALLEMAND PHARMA AG 
Principal Investigator: Dr Emil Kolev 
Title: Efficacy and safety of Healsea® hypertonic nasal spray 2.7% in the treatment 
of acute infectious rhinitis in adults 
 
Short Title Testing the Efficacy in Adults with Cold of HEalsea Rescue*: TEACHER 
 
CIP version: 2022-10-03 
Competent Authority:  Bulgarian Drug Agency 
Rationale: Upper respiratory tract infections (URTIs) and sino-nasal symptoms are very 
frequent, especially during the fall and the winter. The common cold is caused 
by a variety of viruses such as human rhinoviruses and influenza viruses. The 
incidence of acute rhinitis/rhinosinusitis is very high, estimated to occur from 
2 to 5 times per year in the average adult. However, the natural course of acute 
rhinitis in adults is favorable since 75% of persons have a reduction or 
resolution of symptoms within 7 days. Only 0.5 to 2.0% of subjects develop 
secondary bacterial sinusitis requiring antibiotic prescription. Bacterial over 
infections and progression to a chronic state are favoured by the formation of 
biofilms, which facilitate bacterial growth and persistence as well as reducing 
antibiotic efficacy. The socioeconomic impact of acute rhinitis is well 
established: visits to GP, additional prescriptions and over prescription of 
antibiotics, workdays lost.  
Although clinical evidence from well-designed trials is scarce, European and 
American guidelines for acute rhinosinusitis recommend daily nasal saline 
irrigation for reduction of the severity of symptoms and for speeding recovery. 
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. Hypertonic saline 
solutions are generally considered as more effective than isotonic saline 
solutions in reducing nasal symptoms in the acute phase. Nevertheless, the 
efficacy of such solution remains moderate. 
Healsea® Rescue* is a CE-marked class I medical device. This is a saline-based 
nasal spray supplemented with a natural Symbiofilm™ extract (0.04%) isolated 
from the marine bacteria Bacillus licheniformis T14. The nasal solution is 
hypertonic (NaCl 2.7%). Symbiofilm™ is an exopolysaccharide with emulsifying 
properties and in vitro antibiofilm activity and detachment properties against 
various bacterial pathogens. Symbiofilm™ also protects in vitro human nasal 
epithelial cells viability after Rhinovirus, Adenovirus, Coronavirus OC43 and Flu 
infection. 
The aim of this study is to demonstrate that hypertonic saline solution and 
Symbiofilm™ act in a synergistic manner to alleviate symptoms of the acute 
rhinitis phase resulting in better efficacy than isotonic saline solution without 
Symbiofilm™ used as Placebo. 
 

 
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Study Number: LPH-2201 
Objectives: Primary Objective: 
- To compare the efficacy of Healsea® Rescue* and Placebo to improve the 
Quality of Life through symptoms of acute infectious rhinitis reduction in adults 
during a 7-day treatment period.  
 
Secondary objectives: 
- To compare the efficacy of Healsea® Rescue* and of the Placebo to reduce 
the duration of each infectious rhinitis symptoms rated by the WURSS 21  
- To compare the efficacy of Healsea® Rescue* and of the Placebo to reduce 
the use of concomitant medication (antipyretics, systemic or local mucolytics, 
decongestants, antitussives, antibiotics) 
- To compare the subject overall assessment on efficacy of Healsea® Rescue* 
and of the Placebo. 
- Safety: to assess systemic and local tolerance of Healsea® Rescue* over the 
study period. 
 
Endpoints: Primary Endpoint: 
The primary endpoint is the AUC of Wisconsin Upper Respiratory Symptom 
Survey (WURSS-21) during first 8 days of symptoms. 
The WURSS-21 will be assessed once daily during D1-D8. 
 
Secondary Endpoints: 
- AUC of the symptoms sub-score (items 2-11) and Quality of Life sub-score 
(items 12-20) of the WURSS-21 during first 8 days. 
- Duration of cold symptoms in both groups assessed by means of the WURSS-
21. 
For each item, the duration is defined as the number of symptomatic days 
between D1 and the first day the subject reports not having the symptom for 
two consecutive days.  
Notice that the duration may be censored at day 13-day 15. 
- Frequency and number of days of use of concomitant treatments that may 
affect common cold symptoms (antipyretics, systemic or local mucolytics, 
decongestants, antitussives, antibiotics). 
- Subject satisfaction regarding ease of use, efficacy, local tolerance and taste 
at the end of study visit (V2) using a 4-points categorical scale and of Global 
subject feedback on treatment use (“will you recommend the prescribed 
treatment for treatment of acute rhinitis?”). 
- Safety: Assessment of adverse events/incidents/foreseeable side effects 
throughout the study in both groups 
Indication: Treatment of acute rhinitis 
 
Investigation Design: Double-Blind Placebo controlled randomized trial 
The study will comprise 2 parts: 
- Part 1 (D1-D8): treatment of the acute phase 

 
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Study Number: LPH-2201 
• 
with Healsea® Rescue*, 2 puffs in each nostril 2 times per day during 7 
days (14 intakes of the investigational device).  
or  
• 
with isotonic nasal spray (Placebo), 2 puffs in each nostril 2 times per 
day during 7 days (14 intakes of the Placebo).  
 
- 
Part 2 (D9-D13/15): follow-up phase.  
 
Visit 1 (V1) - (Day 1): Screening/Inclusion/Randomization  
Information and consent, demographic data and medical history, ongoing 
medication, physical and clinical examination (including COVID-19 antigen 
test), inclusion/non-inclusion criteria, randomization, e-diary presentation 
(including the first study questionnaire completion), reporting of adverse 
events, dispensation of Healsea® Rescue* Nasal Spray or Placebo (Isotonic 
nasal spray) (according to randomization list).  
 
D1-D8 (at home):  
Daily 
completion 
of 
the 
electronic 
diary 
(questionnaire, 
adverse 
events/incidents and concomitant medications), Healsea® Rescue* /Placebo 
nasal spray treatment daily administration. 
 
D8 (Telephone call): 
End of Healsea® Rescue*/Placebo nasal spray treatment.  
 
D9-D13/15 (at home): 
Daily completion of the electronic diary (adverse events/incidents, 
concomitant medications, WURSS-21 if applicable, until the subject feels not 
sick for two consecutive days).  
 
Visit 2 (V2) – (Day 13-15): end of study 
Physical and clinical examination (including COVID-19 antigen test), diary 
review, reporting of adverse events and incidents, compliance, subject 
satisfaction, WURSS-21 completion if the patient has not ticked “not sick” for 2 
consecutive days in the previous days.  
 
Number of Subjects: A sample of 180 subjects (90 subjects per group) will be needed to provide 80% 
power with a 1-sided test at a 0.05 significance level to detect a difference 
between Healsea® Rescue* and Placebo groups AUC of 30%.  
Assuming that approximately 10% of subjects may drop-out the study,  200 will 
be randomly assigned at a ratio 1:1 to Healsea® Rescue* and Placebo (100 
subjects per group). 
Target Population: Adults with acute infectious rhinitis 
Permitted and 
prohibited concomitant 
medication 
Permitted concomitant medications during the study: 
o Antipyretics except NSAID  
o Systemic and/or local mucolytics  
o Local decongestants (to be taken away from nasal score 
assessment, 2 hours minimum) 

 
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o Systemic antihistamines only if taken for more than 4 weeks at 
screening 
o Antitussive 
o Antibiotics 
Non-permitted concomitant medications: 
o Local or systemic corticosteroids 
o NSAID 
o Saline nasal spray 
 
Inclusion/Exclusion 
criteria: 
Inclusion Criteria: 
Subjects will be enrolled if they meet all of the following criteria: 
1. Male/Female subjects >18 years  
2. Acute infectious rhinitis/rhinosinusitis for ≤48h before trial entry 
3. Symptoms of headache, muscle ache, chilliness, sore throat, blocked 
nose, runny nose, cough, sneezing with a score ≤9 (according to a self-
rated symptom score; scale: 0 → 3 [0: no symptom to 3: severe 
intensity]) 
4. At least one of these symptoms: sore throat, runny nose or blocked 
nose (i.e. with a score ≥1) 
5. Willingness to participate as evidenced by voluntary written informed 
consent and has received a signed and dated copy of the information 
consent form 
6. Patient with a smartphone and an internet connection. 
 
Non-inclusion Criteria: 
Subjects will not be enrolled if one of the following criteria is present:  
1. Known hypersensitivity/allergy to any component of the test device 
2. Medical history or any current disease that is considered by the 
investigator as a reason for non-inclusion  
3. Severe nasal septum deviation or other condition that could cause 
nasal obstruction such as the presence of nasal polyps 
4. History of nasal or sinus surgery that in the opinion of the investigator 
may influence symptom scores 
5. Antibiotic intake within 2 weeks before screening 
6. Systemic or local corticosteroids (nasal route or inhalation) within 4 
weeks before screening 
7. Antihistamines intake for allergy when treatment was started from 
less than 4 weeks 
8. Chronic decongestant use 
9. Recent (within the previous 2 days) intake of a common cold medicine 
that in the opinion of the investigator may influence symptom score 
at screening (NSAID, nasal decongestants, cough medicines) 
10. Pregnant/Lactating female or absence of efficient contraception 
Number of sites: 1 site in Bulgaria 
Test Device: Healsea® Rescue* nasal spray, class I 

 
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Comparator Device: Isotonic nasal spray used as Placebo 
Duration of 
investigation: 
Duration of inclusion period: 5 months 
Duration of patient’s participation: up to 15 days 
Total study duration: 5.5 months 
Study Start Date: November 2022 
Statistical Analysis: Continuous variables will be summarized using the mean, standard deviation, 
median, minimum, maximum and quartiles. Categorical variables will be 
summarized using frequency counts and percentages. 
All statistical tests will be 1-sided and performed using a 0.05 significance level. 
 
Analysis of Primary endpoint: 
For the primary criterion analysis, AUC for the WURSS-21 will be compared 
between Healsea® Rescue* group and Placebo group using a Student’s t-test. 
If the usual applicability assumptions for the Student’s t-test are not met, a 
Mann-Whitney test will be used. 
 
 
Analyses of Secondary endpoints: 
-The analysis of the primary endpoint will be completed by an analysis of the 
AUC for each of the WURSS-21 components (symptoms and Quality-of-Life). 
-Duration endpoints will be summarized using the medians, with 95% CIs for 
the medians by group. Results for Healsea® Rescue* group and Placebo group 
will be compared using Wilcoxon-Mann-Whitney test. 
-The number of days of use of concomitant treatments in each group will be 
compared by means of chi-square test or exact Fisher test. 
-The subject general satisfaction in each group will be compared by means of 
chi-square test. The global subject feedback on treatment use in each group 
will be compared by means of exact Fisher test. 
-Safety: All adverse events/incidents will be listed, but only treatment-
emergent adverse events (non-serious + serious) will be summarized. 
Adverse events/incidents will be summarized by the number and percentage 
of patients (by treatment group), classified by System Organ Class and 
Preferred Term as defined by MedDRA dictionary. 
For a given treatment group, a given adverse event will be counted treatment 
emergent only once per patient during the treatment period. 
Frequency and percentage of patients with at least one reported adverse 
event/incident will be tabulated by System Organ Class and by treatment 
group. 
 
Expected benefits: Healsea® Rescue* nasal spray is expected to reduce the symptoms of acute 
rhinitis without any safety concern. 

 
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2. Flow Chart 
 
Acute phase 
Telephone call 
Follow-up 
Visit name Screening/Inclusion 
 
At home 
At home 
End of study 
Visit Number 
V1 
 
TC1 
 
V2 
Days/Weeks 
D1 
D1-D8 
D8 
D9-End of study 
visit 
D13-D15 
Informed consent 
X 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
Demography and Medical history 
X 
 
 
 
 
Physical and clinical examination  
X 
 
 
 
X 
COVID-19 antigen test 
X 
 
 
 
X 
Ongoing medication 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Treatment (Healsea® Rescue* or Placebo) 
(14 intakes) 
 
X 
 
 
 
Telephone call (End of Healsea® Rescue* or 
Placebo) 
 
 
X 
 
 
Subject e-diary and WURSS 21 
X* 
X 
 
X$ 
X* 
(Serious) Adverse Events/ (serious) incidents 
and concomitant medication reporting 
X 
X 
 
X 
X 
Satisfaction Questionnaire 
 
 
 
 
X 
Compliance  
 
 
 
 
X 
$ After D8, WURSS-21 until complete resolution of symptoms for 2 consecutive days. 
*WURSS-21 to be completed with the investigator on site at screening and at the end of the study if the patient still has not ticked “not sick” for 2 consecutive days in the 
previous days.

 
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3. Identification and description of the investigational device and of the 
Placebo 
3.1 Summary description  
3.1.1 The investigational device 
Healsea® Rescue* is a CE marked nasal spray composed with a hypertonic saline solution (2.7% NaCl) 
and Symbiofilm® (0.04%) (Table 1). Symbiofilm® is a Lallemand proprietary marine postbiotic 
composition including an exopolysaccharide mainly composed of N-acetyl hexosamines, acidic and 
neutral monosaccharides.  
 
Table 1 : Qualitative and quantitative composition of Healsea Rescue* 
Ingredient 
Concentration (g/L) 
NaCl 
27 g/L 
Symbiofilm® 
0.4 g/L 
Purified Water 
QS 1L 
 
Healsea® Rescue* is a class I medical device (in accordance with the rule 5 of the annex IX of European 
Council Directive 93/42/EEC). 
In accordance with annex IX of European Council Directive 93/42/EEC, the medical device classification 
is based on the following characteristics:  
- Duration of continuous use: Short-term (60 min to 30 days)  
- Type of device: Invasive, with respect to body orifice, non-active, not surgically inserted, no 
implantable device  
- Location of action: Nasal cavity  
 
The primary packaging is a plastic bottle with atmospheric pump in 20 ml format. 
 
Healsea® Rescue* is indicated in adults over 18 years in the treatment of symptoms of acute 
respiratory tract infections: rhinitis or rhinosinusitis, reduces swelling of the nasal mucosa.  
One-two sprays, twice a day in each nostril during 7 days or as recommended by the doctor or 
pharmacist. 
 
The technical performances are summarised below: 
 
Table 2 : Technical performances of Healsea Rescue* 
Component  
Function(s)  
Hypertonic saline solution 2.7 %  
- Improve nasal mucosa function  
- Clean the nasal cavity and eliminate allergens 
and infectious agents  
 
Symbiofilm®  
- Enhancing the cleansing efficacy  
- Reducing biofilm formation  
 
 

 
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3.1.2 The comparator 
The comparator is an isotonic saline nasal spray (same primary and secondary packaging) used as 
Placebo.  
Ingredient 
Concentration (g/L) 
NaCl 
9g/L 
Purified Water 
QS 1L 
 
3.2 Manufacturer 
Healsea® Rescue* is a class I Medical Device manufactured by Lallemand Pharma. The device is CE 
marked (17 MAY 2021). The subcontractor for the manufacturing is C.O.C Farmaceutici Srl, Via Chiesa 
Sud, 156 C/D/E/F/G – 41016 Rovereto s/ Secchia - Novi di Modena (MO) - Italy 
Clinical batches (Healsea® Rescue* and Placebo) are manufactured by C.O.C Farmaceutici and the 
blinding of the investigational devices is ensured by Creapharm, ZA Air-Space Avenue de Magudas, CS 
2007, 33185 Le Haillan, Email : contact@creapharm.com. 
The Lallemand AG identifier numbers are the following: 75015DJMN (20/04/2022) for Healsea Rescue* 
and 75014DJMQ (22/07/2022) for the Placebo (Isotonic saline nasal solution). 
 
3.3 Name or number of the model to permit full identification 
Because the Investigational Device and the Placebo will be used in a blinded manner, a single lot 
number will be attributed to the devices.  
3.4 Traceability 
The traceability of the Investigational Device and of the Placebo will be insured during the clinical study 
according to the SOP “Investigational Products Management” of the CRO.  
3.5 Intended purpose of the devices in the clinical investigation 
This is a post market clinical investigation, and the devices will be used in the treatment of acute 
infectious rhinitis. 
 
3.6 Population and indications for which the device is intended 
The target population of the study is adults with acute infectious rhinitis. The only contraindication is 
hypersensitivity to one or several of the components. This is a non-inclusion criterion. 
 
Healsea® Rescue* will be used within its intended purpose i.e., in adults for the treatment of 
symptoms of acute respiratory tract infections, rhinitis or rhinosinusitis, and for reduction of the 
swelling of the nasal mucosa.  

 
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The comparator is a saline isotonic nasal spray considered as inert Placebo i.e. neutral for the nasal 
mucosa. Nevertheless, nasal irrigation with isotonic saline solution is known to have some efficacy in 
reducing common cold symptomatology. 
 
3.7 Devices description 
3.7.1 Investigational device 
Healsea® Rescue* is a nasal spray (available in 20mL) using the APF (Advanced Preservative-Free) 
technology. This is a spray pump consisting of a white high density polyethylene bottle and a manual 
polyolefine/homopolymer polypropylene actuator holding the nozzle spraying the solution in the 
nostrils. A single activation propels a volume of 100 ± 20 µliters of solution. 
This is a non-sterile device. The primary packaging is described in Figure 1. 
Figure 1 : The spray pump 
 
 
The sponsor certified that the Healsea® Rescue* Medical Device:  
● does not contain any human blood derivative,  
● does not contain any medicinal product,  
● is not manufactured using tissues of animal origin.  
 
As summarized below, Healsea® Rescue* is intended to be used on nasal mucosa. The duration of use 
is 7 days.  
Table 3 : Contact with body and total duration treatment 
Type of contact 
Device in contact with a surface 
Type of tissues 
Mucous membranes  
Total duration treatment 
It can be used for 7 days 
 

 
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Healsea Rescue* and the Placebo need to be indistinguishable in the context of a blinded study. The 
subcontractor in charge of the blinding will remove the label of Healsea® Rescue* and replace it by a 
white label with the mentions requested by the regulation.  
3.7.2 The comparator 
The Placebo is a nasal spray (available in 20mL) using the same technology as those described above 
for the investigational device (Figure 1).  
This is a non-sterile device.  
3.7.3 Primary and secondary packaging and labelling  
The primary packaging is a white vial (Figure 2) 
Figure 2 : primary packaging 
 
The secondary packaging is a white cardboard box.  

 
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A white label is sticked on the primary packaging with the following mentions:  
 
 
A white label is sticked on the secondary packaging with the following mentions:  
 
 
3.8 Investigation Device training/ experience 
In real life setting, there is no need for specific training in using Healsea® Rescue*.  
A usability engineering process test according to the standard EN ISO 62366-1: 2015 was conducted 
with a product from the same range, Healsea® Babykids (same type of pump, worse case because of 
the paediatric population) with 10 people representatives of the parents/legal guardians of the target 

 
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population to ensure that the leaflet and the label were well understood, and that the medical device 
was used correctly to ensure its safe understanding and use.  
The analysis of the results demonstrates that:  
- The information provided by the user interface is readable and understandable by participants: the 
information tested was easy to understand, without interpretation.  
- The observations made during the simulations of use of the device have confirmed that all safety-
related handling steps are properly followed, in accordance with the instructions given in the 
instruction for use.  
 
Nevertheless, Healsea Rescue* and the comparator will be specially conditioned for this controlled 
and blinded study. A IFU leaflet is included in each secondary packaging: on one face, the IFU of 
Healsea® Rescue*, on the other face, the IFU of Healsea® Placebo (see 3.9). During the site initiation 
visit, the investigator will be briefly trained how to use the study devices. After the enrolment, the 
investigator will instruct each patient on how to use the nasal spray. 
 
3.9 Reference to the IFU 
A IFU leaflet is included in each secondary packaging: on one face, the IFU of Healsea® Rescue*, on the 
other face, the IFU of Healsea® Placebo (See appendix 1). 
 
4. Justification for the design of the clinical investigation 
Upper respiratory tract infections (URTIs) and sinonasal symptoms are very frequent, especially during 
the fall and the winter. The common cold is caused by a variety of viruses.  Improvements in viral 
detection techniques during the past two decades, including various viral antigen detection methods 
and particularly the advent of PCR-based assays, have substantially increased the rates of viral 
detection in clinical specimens. The relative proportions of different viruses in the cause of the 
common cold vary depending on several factors, such as age, season, and viral sampling and detection 
methods. However, rhinoviruses have been consistently found to be the most common cause in all age 
groups, irrespective of the viral detection techniques used. Yearly, rhinoviruses account for about 30–
50% of all respiratory illnesses, but during the autumn peak season these viruses can cause up to 80% 
of all upper respiratory infections. Coronaviruses and Influenza viruses account for about 10-15% and 
for 5-15% of common cold respectively. Other viruses such as Respiratory Syncytial virus, Adenoviruses 
and Parainfluenza viruses are less involved [1]. 
Viral upper respiratory infection can extend into the paranasal sinuses and 90% of subjects with viral 
upper respiratory tract infections have concurrent acute sinusitis [2]. The incidence of acute 
rhinitis/rhinosinusitis is very high, estimated to occur from 2 to 5 times per year in the average adult. 
However, the natural course of acute rhinitis in adults is favorable since 75% of persons have a 
reduction or resolution of symptoms within 7 days [2] [3].  Only 0.5 to 2.0% of subjects develop 
secondary bacterial sinusitis requiring antibiotic prescription. The most common pathogens in adults 
with acute bacterial sinusitis are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella 

 
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catarrhalis and Streptococcus aureus [4] [5]. Bacterial over-infections and progression to a chronic 
state are favoured by the formation of biofilms, which facilitate bacterial growth and persistence as 
well as reducing antibiotic efficacy. The socioeconomic impact of acute rhinitis is well established: visits 
to GP, additional prescriptions and over prescription of antibiotics, workdays lost [3].  
Although clinical evidence from well-designed trials is scarce [6], European and American guidelines 
for acute rhinosinusitis recommend daily nasal saline irrigation for reduction of the severity of 
symptoms and for speeding recovery [2] [3]. The exact mechanisms by which nasal irrigation works are 
not fully elucidated. However, most of the experts agree that it is primarily a mechanical intervention 
leading to direct cleansing of the nasal mucosa [7] [8]. The mucus lining the nasal cavity may be 
softened and dislodged. The increase of mucociliary clearance is associated with a decrease of 
pathogens burden. Moreover, inflammatory mediators such as cytokines, prostaglandins and 
leukotrienes can be removed, favoring the resolution of URTIs. Although the impact of the salt 
concentration of the saline solution on all these parameters is still debated, hypertonic saline solutions 
are generally considered as more effective than isotonic saline solutions in reducing nasal symptoms 
in the acute phase [9] [10]. Nevertheless, the efficacy of such saline irrigation remains moderate [6]. 
The Healsea® products are a saline-based nasal spray line supplemented with a natural Symbiofilm™ 
extract (0.02% to 0.04%) isolated from the marine flora of the deep seas of the Panarea Islands, in 
Sicily. Healsea® Rescue* is an hypertonic saline solution (2.7%) with Symbiofilm™ (0.04%). 
Symbiofilm™ is an exopolysaccharide composition secreted by Bacilllus licheniformis LP-T14, a 
Lallemand Pharma proprietary strain, with in vitro antibiofilm activity and detachment properties 
against various bacterial pathogens involved in respiratory tract infections, i.e Haemophilus influenzae 
type b, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and streptococcus 
pneumoniae. Antibiofilm effects of Symbiofilm™ have been reported in vitro, using microtiter plate-
based model and human nasal epithelial cells. The antibiofilm activity of Symbiofilm™ is likely to rely 
on its emulsifying properties. 
Symbiofilm™ (400 µg/ml) has also been demonstrated to protect in vitro human nasal epithelial cells 
viability after Adenovirus, Rhinovirus, Coronavirus OC43 and Flu infections. In vitro data suggest that 
due to its physico-chemical properties, Symbiofilm™ acts in synergy with hypertonic saline solution 
to interfere with the binding of the viruses on the host cell surface. 
The aim of this investigation is to demonstrate that thanks to the antibiofilm and antiviral properties 
of Symbiofilm™, hypertonic saline solution and Symbiofilm™ act in a synergistic manner to alleviate 
symptoms of the acute rhinitis phase resulting in better efficacy than isotonic saline solution without 
Symbiofilm™. 
To demonstrate the efficacy of Healsea® Rescue* in common cold, a Double Blind Randomized 
Controlled Study will be performed. The efficacy of the test product will be assessed by comparison 
with an isotonic saline nasal spray. 

 
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5. Risks and Benefits of the Investigational Device and Clinical Investigation 
5.1 Anticipated clinical benefit  
Healsea® Rescue* is a hypertonic saline solution (2.7%) with Symbiofilm™ (0.04%). 
Healsea® Rescue* is indicated in adults over 18 years for the treatment of symptoms of acute 
respiratory tract infections (rhinitis or rhinosinusitis).  
The exact mechanisms by which classic saline nasal irrigation works are not known. However, most of 
the experts agree that it is primarily a mechanical intervention leading to direct cleaning of the nasal 
mucosa. 
The supplementation of the saline solution with Symbiofilm™ impacts the performance of the device. 
Indeed, Symbiofilm™ has also been demonstrated to protect in vitro human nasal epithelial cells 
viability after Adenovirus, Rhinovirus, Coronavirus OC43 and Flu infection.  
Therefore, hypertonic saline solution and Symbiofilm™ may act in a synergistic manner to alleviate 
symptoms of the acute rhinitis phase resulting in better efficacy than isotonic saline solution without 
Symbiofilm™. As a consequence, patients receiving daily administrations of Healsea® Rescue* are 
expected to recover more rapidly from common cold than those receiving the Placebo. 
Subjects who receive Placebo will not benefit from as effective a treatment although nasal 
administrations of isotonic saline are well described as cleansing and hydrating the nasal mucosa. 
Nevertheless, these subjects will receive all concomitant treatments necessary in the context of acute 
rhinitis with the exception of other saline solutions. 
5.2 Anticipated adverse device effects 
The only expected adverse event is the feeling of itching and irritation while initiating the treatment 
with the investigational medical device Healsea® Rescue*. In case of such adverse reaction, the 
patients will be instructed to report the incident into the e-diary and to contact the investigator if the 
patient wishes to stop the nasal spray use. 
No adverse effect is expected with the Placebo. 
5.3 Risk associated with the participation in the clinical investigation 
The assessments of the clinical investigation are questionnaires with no associated risk. 
Two nasopharyngeal swabs are planned for SARS-CoV- 2 antigen detection, at screening and at end of 
study. This sampling method is routinely performed without safety concern. 

 
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5.4 Possible interaction with concomitant treatments as considered under 
the risk analysis 
No interaction is expected. Nevertheless, patients will be instructed to respect a 60-minute minimum 
interval after administration of the investigational medical device before administration of another 
local medication e.g., decongestant or mucolytics (if permitted). 
5.5 Steps that will be taken to control and mitigate the risks  
5.5.1 Healsea Rescue* 
In line with NF EN ISO 14971:2019 standard (Medical Devices – Application of risk management to 
medical devices), a risk analysis has been conducted to estimate the risks associated with each step of 
the device lifecycle. Most of the risk has been mitigated through product design and manufacturing.  
The residual risk to patients who are administered this intervention is low. A list of potential risks 
associated with the device, procedures undertaken to minimise them, and methods used for their 
management is described in the device Risk Management Process File.  
 
Considering:  
- the risk analysis (ISO 14 971 activities) that demonstrates: 
• 
There is no longer High level risk,  
• 
That, the 12 Medium risk level residuals risks have an acceptable benefit-risk balance,  
• 
And all the others residual risks (62) are at Low risk.  
• 
Healsea® Rescue* can be considered as safe and effective  
 
and regarding the evaluation of benefit/risk profile, as detailed in the Clinical evaluation report, 
considering: 
• 
The clinical data of the equivalent device (Hysan® Salin-Spray)  
• 
The currently available data on products use for the treatment of nasal cold and flu symptoms 
and the prevention of upper respiratory tract infections  
 
it can be concluded that the benefit/risk ratio of Healsea Rescue* is acceptable, in compliance with 
essential requirements. 
5.5.2 Placebo 
Isotonic saline nasal solutions are well known for cleansing and hydrating the nasal mucosa without 
any safety concern. No risk analysis has been conducted to estimate the risk associated with each step 
of this device lifecycle. Anyway, the residual risk for the Placebo is expected to be lower than for 
Healsea Rescue* since this latter contains Symbiofilm® and hypertonic saline solution and therefore 
represents the worst case. Thus, the Placebo used during this study can also be considered as safe.  

 
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5.5.3 Mitigation of risk during the clinical investigation 
Although no obvious specific risk is identified for subject participating in the study, and according to 
the requirements of ISO 14155: 2020, some specific points have been identified requiring specific 
attention to guarantee the safety and the well-being of the subject. 
As the study will be conducted in a blinded manner, stringent risk acceptability thresholds are defined 
in the Study Risk Management Plan. Any issue with the dispensation (wrong device delivered) or 
inadequate process to ensure the traceability of the investigational product is deemed unacceptable 
and shall trigger an immediate action plan.  
More generally, the number of unreported incident/serious incident or adverse event/foreseeable 
expected side effect per site, the timelines for materiovigilance/vigilance reporting to sponsor shall be 
tracked according to the risk management plan and risk acceptability threshold are defined. 
Should a potential unanticipated risk be detected, an action plan will be implemented with no delay.  
5.6 Rational for the benefit risk ratio 
Although infectious rhinitis is in most cases self-limiting, it impacts the patient’s quality of life during 
generally about 7 days. Furthermore, bacterial over-infections with worsening of symptoms can occur 
requiring antibiotic prescription. Progression to a chronic state, i.e. chronic rhinosinusitis is also 
observed.  
Conventional therapies for infectious rhinitis are symptomatic and not without side effect. For 
example, decongestant use can increase blood pressure, antihistamine intake is associated with 
drowsiness. Healsea® Rescue* represents an interesting alternative because this nasal spray can 
alleviate infectious rhinitis symptoms but also limit the complication and progression to chronic state. 
Furthermore, apart from feeling of itching and irritation while initiating the treatment, no other 
adverse effect is expected.  
 
 
 

 
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6. Objectives and hypotheses of the clinical investigation 
6.1 Hypothesis  
Our hypothesis is that Healsea® Rescue* nasal spray can improve the symptomatology of acute rhinitis 
with more efficacy than an isotonic saline nasal spray used as Placebo. 
6.2 Primary Objective 
The primary objective is to compare the efficacy of Healsea® Rescue* and of Placebo to improve the 
Quality of Life through symptoms of acute infectious rhinitis reduction in adults during a 7-day 
treatment period. 
6.3 Secondary Objectives 
- To compare the efficacy of Healsea® Rescue* and Placebo to reduce the duration of each infectious 
rhinitis symptoms rated by the WURSS 21.  
- To compare the efficacy of Healsea® Rescue* and Placebo to reduce the use of concomitant 
medication (systemic antibiotics, antipyretics, mucolytics, decongestants).  
- To compare the subject overall assessment on efficacy of Healsea® Rescue*/Placebo. 
- Safety: to assess systemic and local tolerance of Healsea® Rescue* over the study period. 
 
6.4 Scientific justification and clinical relevance for effect sizes, non-
inferiority margins or equivalence 
 A non-pharmaceutical product (Influcid®) used as add-on treatment for Upper Respiratory Tract 
Infections has been demonstrated to reduce from about 30% the WURSS-21 AUC in comparison with 
standard treatment alone [11]. Considering that the Healsea® Rescue* also exerts its action via a non-
pharmacologic mechanism, we consider that a 30% reduction of the WURSS-21 AUC is deemed a 
suitable effect size in this clinical investigation.  
6.5 Risks and anticipated adverse effects that are to be assessed 
No specific risk for subject participating in the study is identified, provided that the eligibility criteria 
are fulfilled. The only expected adverse event is the feeling of itching and irritation while initiating the 
treatment with the investigational medical device Healsea® Rescue*. The safety and well-being of 
subjects will be monitored throughout the study and a Risk Management Plan has defined stringent 
risk acceptability thresholds (see 5.5.3).   
 
 

 
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7. Design of the clinical investigation  
7.1 General 
7.1.1 Design type of clinical investigation 
This is a two-arm, double-blind, parallel group, randomized controlled trial (RCT). 
The primary endpoint will be assessed once daily during the treatment period. After D8, the WURSS-
21 will be assessed once daily until the subject feels not sick for two consecutive days.  
7.1.2 Measures to be taken to minimize or avoid bias 
Randomization: 
The random product attribution will be performed after checking the eligibility criteria are fulfilled, 
thus minimizing the selection bias. During the V1 visit, each subject will be randomly assigned to a 
product (active or placebo) with a 1:1 allocation in accordance with the blocked randomization table 
generated by Axiodis. The investigator or designee will allocate a treatment number according to the 
randomization for eligible subjects via the eCRF.  
 
Blinding and unblinding: 
The randomization list will be drawn up by Axiodis using a validated software and before the beginning 
of the study, by a statistician not involved in the study. The master randomization list will be stored 
confidentially until the study blind is broken at the end of study. 
The randomization list will be: 
- 
Transmitted by Axiodis to the responsible of the product preparation, Creapharm 
- 
Uploaded into the patient enrolment module of the eCRF 
 
In case of dysfunction of the Medical Device, it will be possible to attribute a new randomisation 
number to the patient and a new identical treatment (in a blinded manner) using the eCRF back-up 
randomisation module. 
During the whole study and in the absence of unblinding, neither the investigators nor the subjects 
nor the staff involved (CRO, sponsor…) will be aware whether the product is Healsea® Rescue* or the 
Placebo. Every effort will be made to maintain the blind during the study as well as during the follow-
up period. 
Both Medical Device (Healsea® Rescue* and Placebo) will be indistinguishable: same aspect, same 
packaging and same labelling of the vials.  
The unblinding will occur after the database locking, at the end of the study. The person responsible 
for the randomization list will be in charge of the unblinding.  
 
Emergency Unblinding:  
In case of a medical emergency where knowledge of the blinded treatment is necessary for the 
treatment of an adverse event/incident, the investigator shall perform the unblinding via the 
randomization management interface of the eCRF. The investigator shall send an e-mail informing 

 
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about the unblinding with patient ID, date and reason of unblinding (the name of patient not to be 
communicated for GDPR compliance) to: 
• 
The CRO in charge of the study coordination: etudes@bgclinicals.com 
• 
The sponsor (officelp@lallemand.com and rbelloti@lallemand.com (vigilance manager)) 
• 
The data manager if charge of the randomisation list 
The date and the reason for the unblinding will be indicated in the e-CRF and the source document of 
the study.  
7.1.3 Primary Endpoint with methods and timing for assessing recording and 
analysing variables 
The AUC of Wisconsin Upper Respiratory Symptom Survey (WURSS-21) during first 8 days of 
symptoms will be compared between both groups. 
WURSS-21 is a validated 3-dimensional structure questionnaire [12]. This survey has been 
demonstrated to be responsive, and valid to assessing the severity and functional impact of the 
common cold. It includes 10 items assessing symptoms (symptoms score, (items 2 to 11), 9 items 
assessing functional impairments (quality of life score, (items 12 to 20).) and 2 items assessing 
respectively global severity and global change. Brown et al. [13] support the practice of using, for AUC 
computation, a simply summed daily global illness severity score to represent the overall symptomatic 
and functional impairments arising from acute upper respiratory infection.  
 
The WURSS-21 will be assessed in an e-diary once daily in the evening, taking into account the 
symptoms from the morning to the evening, during D2-D8 (day of the end of treatment). At D1, the 
WURSS-21 will be completed during the visit. After D8, the WURSS-21 will be assessed once daily until 
the subject feels not sick for two consecutive days.  
 
7.1.4 Secondary Endpoints with methods and timing for assessing, recording 
and analysing variables 
--AUC of the symptoms sub-score (items 2-11) and Quality of Life sub-score (items 12-20) of the 
WURSS-21 during first 8 days  
 
- Duration of cold symptoms in both groups assessed by means of the WURSS-21. 
For each item, the duration is defined as the number of symptomatic days between visit V1 and the 
first day the subject reports not to have this symptom for two consecutive days.  
To be noticed that the duration may be censored at the end of study participation (visit V2). Should 
the patient have not ticked “not sick” for 2 consecutive days at the end of study visit, a WURSS-21 will 
be completed by the patient during the visit. 
 

 
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- Frequency and number of days of concomitant treatments use that may affect common cold 
symptoms (antipyretics, systemic or local mucolytics, decongestants, antitussives, antibiotics).  
By reducing duration of common cold symptoms, Healsea® Rescue* will very likely reduce the use of 
common rescue medication. Concomitant treatments use will be reported in the e-diary by the patient 
throughout the study, validated by the investigator at the end of study visit before being reported in 
the e-CRF.  
- Subject satisfaction regarding ease of use, efficacy, local tolerance and taste at end of study visit (V2) 
using a 4-points categorical scale and of the Global subject feedback on treatment use (“will you 
recommend the prescribed treatment for treatment / prevention of acute rhinitis?”). 
Although subjective, these endpoints are pertinent because Healsea® Rescue* is an OTC product which 
does not require physician prescription. 
 
- Safety: Assessment of adverse events and incidents throughout the study in both groups. Adverse 
events/incidents will be reported in the e-diary by the patient, validated by the investigator at the end 
of study visit before being reported in the e-CRF.  
 
7.1.5 Equipment to be used for assessing the clinical investigation variables 
No specific equipment is required for the conduct of the study. 
7.1.6 Any procedures for the replacement of subjects 
Not applicable.  
7.1.7 Investigation sites: number, location 
The clinical investigation will be conducted in 1 site in Bulgaria. All investigators are familiar with acute 
infectious rhinitis and study procedures.  
7.1.8 Definition of the completion of the study 
This is defined as the date of last patient last visit (LPLV). 
 
7.2 Investigational device and comparator  
7.2.1 Description of the exposure to the investigational device 
The investigational device will be Healsea® Rescue*. This is a CE marked Medical Device used for acute 
infectious rhinitis and administered by spraying 2 puffs in each nostril 2 times per day during 7 days 
(14 intakes of the investigational device). 

 
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7.2.2 Description and justification of the choice of the comparator 
Clinical batches are manufactured by C.O.C Farmaceutici and the blinding of the investigational devices 
is ensured by Creapharm, ZA Air-Space Avenue de Magudas CS 200733185 Le Haillan, 
Email: contact@creapharm.com. 
The comparator is an isotonic saline nasal spray indistinguishable from the Healsea® Rescue* product.  
Posology, instructions for use, contraindications, precaution of use and labelling are identical to those 
for Healsea® Rescue*. 
We hypothesize that hypertonic saline solution and Symbiofilm™ will act in a synergistic manner for 
achieving the principal action, i.e. reduction of the duration of acute rhinitis symptoms. Placebo is 
classically defined as a pharmaceutically inert substance. This definition can of course be extended to 
the present study evaluating the Medical Device Healsea® Rescue*. Thus, we have chosen isotonic 
saline solution which can be considered as inert Placebo i.e. neutral for the nasal mucosa. 
Nevertheless, nasal irrigation with isotonic saline solution is known to have some efficacy in reducing 
common cold symptomatology.  
7.3 Subjects 
The target population is subjects with early symptoms of common cold / acute infectious rhinitis. 
7.3.1 Eligibility Criteria 
7.3.1.1 
Inclusion Criteria 
Subjects will be enrolled if they meet all of the following criteria: 
1. Male/Female subjects >18 years  
2. Acute infectious rhinitis/rhinosinusitis for ≤48h before trial entry 
3. Symptoms of headache, muscle ache, chilliness, sore throat, blocked nose, runny nose, 
cough, sneezing with a score ≤9 (according to a self-rated symptom score; scale: 0 → 3 [0: no 
symptom to 3: severe intensity]) 
4. At least one of these symptoms: sore throat, runny nose or blocked nose (i.e., with a score 
≥1) 
5. Willingness to participate as evidenced by voluntary written informed consent and has 
received a signed and dated copy of the information consent form 
6. Patient with a smartphone and an internet connection. 
7.3.1.2 
Non-inclusion Criteria 
Subjects will not be enrolled if one of the following criteria is present:  
1. Known hypersensitivity/allergy to any component of the test device 
2. Medical history or any current disease that is considered by the investigator as a reason for 
non-inclusion,  
3. Severe nasal septum deviation or other condition that could cause nasal obstruction such as 
the presence of nasal polyps 
4. History of nasal or sinus surgery that in the opinion of the investigator may influence symptom 
scores 

 
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5. Antibiotic intake within 2 weeks before screening 
6. Systemic or local corticosteroids (nasal route or inhalation) within 4 weeks before screening 
7. Antihistamines intake for allergy when treatment was started from less than 4 weeks 
8. Chronic decongestant use 
9. Recent (within the previous 2 days) intake of a common cold medicine that in the opinion of 
the investigator may influence symptom score at screening (NSAID, nasal decongestants, 
cough medicines) 
10. Pregnant/Lactating female or absence of efficient contraception  
 
7.3.1.3 
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, incident or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. The monitor will be immediately 
informed by phone or fax. A letter or report explaining the withdrawal will be forwarded to 
the monitor as soon as possible. 
In these cases, a premature end of study visit will be scheduled. Available data will be retained for the 
safety/efficacy analysis.  
It should be noted that COVID-19 is not an exclusion criterion. A SARS-COV-2 test will be performed at 
the beginning and at the end of the study to identify the subpopulation of patients with COVID-19.  
7.3.1.4 
Subject lost to follow-up 
If a patient cannot be contacted to collect follow-up information even beyond the 7 days from visit 2, 
he/she will be considered “lost to follow-up”. But before declaring that a patient is "lost to follow-up", 
the Principal Investigator (or his/her team) must do his/her best effort to contact patients and 
attempts should be made via all available routes. A certified letter should be sent to the permanent 
address on file. 
The methods used to attempt contacting the patient should be noted in the patient medical file. 
7.3.1.5 
Subject replacement  
It is not anticipated to replace withdrawal patients.  

 
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7.3.2 Point of enrolment and randomization 
The site is a healthy volunteer centre. The clinical research center will inform potential subjects 
(identified in the center database) of the objectives and procedures of the clinical investigation by 
sending emails and performing phone calls. Also, flyers describing the clinical trial will be sent and 
displayed in pharmacy stores and in general practitioners’ offices. In case of the onset of acute 
infectious rhinitis, interested subjects will be invited to contact the site and to come for a consultation. 
Before performing any study procedure, the investigator will give all the information pertaining to the 
study and patient will sign the consent form if he/she accepts study participation. The subject will be 
enrolled in the study just after the consent signature. 
7.3.3 Total expected duration of the clinical investigation  
The total study duration is planned to be 5.5 months.  
7.3.4 Expected duration of each subject’s participation 
The duration of each patient’s participation is up to 15 days.  
7.3.5 Number of subjects required to be included in the clinical investigation 
A cohort of 200 patients is expected to participate in the study.  
7.3.6 Estimated time needed for the enrolment 
An enrolment period of 5 months is considered sufficient to enrol the cohort of 200 patients.  
7.3.7 Relationship of investigation population to target population 
Healsea® Rescue* will be used within its intended use, in adults with acute infectious rhinitis. This post-
market clinical investigations aims to demonstrate that hypertonic saline solution and Symbiofilm™ 
act in a synergistic manner to alleviate symptoms of the acute rhinitis phase resulting in better efficacy 
than isotonic saline solution without Symbiofilm™. 
7.3.8 Vulnerable, pregnant and breastfeeding population 
Patient under tutorship or legal guardianship are not eligible.  
Pregnant and breastfeeding women are not eligible although the investigational device is not 
contraindicated in this population.  
7.3.9 Compensation 
A compensation of 310 euros for costs resulting from participation in the clinical investigation 
(transportation, absence of work…) will be paid to each patient who complete the study (e-diary 
completion and availability for visits and telephone call).   

 
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7.4 Procedures  
7.4.1 Description of clinical investigation-related procedures  
The clinical investigation is divided into 2 parts: 
- 
Part 1 (D1-D8): treatment of the acute phase with Healsea® Rescue* or Placebo.  
- 
Part 2 (D9-D13/15): follow-up phase.  
The clinical investigation comprises 2 visits and 1 telephone call.  
Visit 1 (V1) - (Day 1): Screening/Inclusion/Randomization  
Subjects with symptoms of acute infectious rhinitis for ≤48h will go to the site for the 
screening/inclusion visit (visit 1). The investigator will give oral information relative to the study and 
will answer all questions relative to the study participation. The patient will receive the information 
sheet. If the subject agrees to participate in the study, he/she will be asked to give a written consent.  
Each screened subject will be assigned a subject identifier number during screening that will be used 
on all subject documentation. The subject identifier number will contain the site number and the 
subject number and will be assigned in numerical order at the screening visit based on chronological 
order of screening dates (e.g., 001-010 for the 10th subject screened at the Site #001). 
The investigator or his/her delegated designee will: 
• 
Record demographic data, medical history and ongoing medication. 
• 
Perform a physical and clinical examination. A pharyngeal nasal swab will be performed by the 
investigator or by the delegated study nurse to check for absence or presence of SARS-CoV2. 
• 
Verify that eligibility criteria are fulfilled. 
• 
Record the score of the common cold symptoms (headache, muscle ache, chilliness, sore 
throat, blocked nose, runny nose, cough, sneezing according to a physician-rated symptom 
score after clinical examination; (scale: 0 → 3 [0: no symptom, 1 = mild symptoms 
(sign/symptom clearly present, but minimal awareness; easily tolerated), 2 = moderate 
symptoms (definite awareness of sign/symptom that is bothersome but tolerable), 3 = severe 
symptoms (sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping]). This scoring system was developed by Jackson in 1958 and is widely 
used in common cold clinical trials [14]. 
• 
Review and detail the question of the WURSS-21. 
• 
Allocate a treatment number for eligible subjects via the eCRF. 
• 
Explain how to complete every day the e-diary for WURSS-21 recording, how to report 
concomitant medications, adverse events/incidents/expected undesirable side effects. The 
patient will access the e-diary application using a smartphone. 
NB: The first WURSS-21 will be completed by the subject on site during this visit after 
the randomization of the patient.  
• 
Remind the patient to return the device for assessment of compliance to the treatment at V2. 
The investigator will provide the patient with the device according to the treatment number as per 
randomization and explain how to use it. The investigator will also prime the pump bottle to identify a 

 
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possible malfunction before the patient leaves the site. In case of dysfunction, a new randomisation 
number and a new treatment will be attributed to the patient using the eCRF back-up randomisation 
module. 
NB: The first use of the device will be performed in the evening of the Day 1.  
D1-D8 (at home):  
The patient will be asked to complete the electronic diary daily (WURSS-21 assessed once daily in the 
evening, taking into account the symptoms from the morning to the evening, adverse 
events/incidents/expected undesirable side effects and concomitant medications).  
D8 (Telephone Call): 
The investigator or his/her delegated designee will call the patient to remind him/her to stop the 
treatment.  
 NB: The last study nasal spray intake will be performed in the morning of the Day 8. 
D9-D13/15 (at home): 
Patients will continue to complete the electronic diary daily (incidents/adverse events in relation with 
the common cold, concomitant medications). The patient for whom common cold symptoms persist, 
will be instructed to continue to complete the WURSS-21, until the subject feels not sick for two 
consecutive days.  
Visit 2 (V2) – (Day 13-15): end of study 
The investigator or his/her delegated designee will: 
• 
Perform a physical and clinical examination. A pharyngeal nasal swab will be performed by the 
investigator or by the delegated study nurse to check for absence or presence of SARS-CoV2.  
• 
Validate adverse events pertinent in the context of the common cold and of additional study 
procedures /incidents linked to medical device use and concomitant medications reported in 
the e-diary and complete the e-CRF accordingly and report any new relevant safety events. 
• 
Ask the patient to complete the WURSS-21 if he/she still has symptoms. 
• 
Assessed the compliance to the treatment by weighting the device returned by the subject. In 
case of nasal spray dysfunction and attribution of a new treatment using the back-up 
randomization list, the compliance will be assessed by weighting both devices. If a nasal spray 
is lost, the investigator will ask the patient to specify the number of missed nasal spray use and 
will report the data into the e-CRF. 
• 
Ask the patient to complete a satisfaction questionnaire. 
7.4.2 Concomitant Medication and/or Treatments 
7.4.2.1 
Permitted concomitant medications during the study: 
o Antipyretics except NSAID 
o Systemic and/or local mucolytics  

 
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o Local decongestants (to be taken away from nasal score assessment, 2 hours 
minimum) 
o Systemic antihistamines only if taken for more than 4 weeks at screening 
o Antitussive 
o Antibiotics 
7.4.2.2 
Non-permitted concomitant medications: 
o Local or systemic corticosteroids 
o NSAID 
o Saline nasal spray 
 
7.4.3 Activities performed by sponsor representatives (excluding monitoring) 
The sponsor has delegated to the CRO the provision of tasks relative to the project management, 
medical writing, clinical operations, data management and statistics, and site(s) oversight. These 
delegated tasks have been established through a Study Management Plan, signed by both parties.  
The CRO will rely on its in-force Quality Management System to ensure that the clinical investigation 
is conducted and monitored, and that data are generated, documented, recorded, evaluated and 
reported in compliance with the ISO 14155:2020, the CIP, any subsequent amendment(s) and any 
other applicable standards and in accordance with the regulation requirements. The CRO will ensure 
the management of ongoing risk in close collaboration with the sponsor throughout the clinical 
investigation and will take all measures to protect rights, safety and well-being of patients who 
participate in the study.  
Tasks still under sponsor responsibility: 
• 
Reporting of non-compliance trends and safety issues to the Ethics Committee/Competent 
Authorities and investigators. 
• 
Triggering audit to be performed if applicable. 
 
7.4.4 Any known/foreseeable factors that can compromise the outcome of the 
clinical investigation and methods for addressing these factors 
There is no known/foreseeable factor that can compromise the outcome of the clinical investigation. 
7.4.5 Follow-up and medical care after completion of the study 
The patients will receive all treatments needed if the common cold is not cured or in case of 
complication or safety issues. In this case, the patient will be followed until the end of the issue.  
7.4.6 Potential use of samples obtained from subjects 
Not applicable.  

 
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7.5 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 what level of detail monitoring will be 
performed, and the distribution of monitoring reports. Results of the risk assessment will be used to 
develop a risk-based monitoring plan and a supporting rationale. 
7.5.1 Initiation visit  
The study will only start at a site after: 
• 
The Ethics Committee has granted approval and the Competent Authority has been notified 
for the conduct of the study,  
• 
Essential documents are in place, such as CVs of the Investigators and site staff, and the Clinical 
Trial Agreement signed.  
In agreeing to participate, the investigator undertakes to strictly comply with the study protocol, Good 
Clinical Practice, the Bulgarian 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.  
7.5.2 Monitoring 
Study monitoring delegated by Lallemand Pharma AG to the CRO will be performed at various stages 
of the study. Monitoring will include on-site visits and centralized data review to ensure that the 
investigation is conducted according to the CIP and comply with applicable regulations and deadlines. 
On-site review of electronic Case Report Form (e-CRFs) will include the review of forms for 
completeness, clarity, and consistency with source documents available for each subject. In case of 
queries, the investigator should respond within agreed timelines. 
The investigator must permit study-related monitoring visits, audits review by the Ethics Committee, 
and allow direct access to source data and source documents provided that subject confidentiality is 
protected. In case of an audit appointed by Lallemand Pharma, the investigator will receive written 
notification in advance.  
7.5.3 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 
disposed of, previously identified issues have been resolved. 
7.5.4 Retention of Documentation 
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 

 
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data be maintained for longer, Lallemand Pharma AG 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 AG with the name and address of the person assuming responsibility for records relating to 
this clinical investigation.  
 
8. Statistical design and analysis 
The statistical analysis will be detailed in the Statistical Analysis Plan. This section provides a summary. 
8.1 Analysis population 
The safety population consists in all the patients included in this study who will have taken at least one 
puff of the nasal spray. 
Full Analysis Set (FAS): all subjects who will have taken at least one puff of nasal spray and with at least 
one post-baseline efficacy data. 
Safety endpoint will be performed on safety population. 
The analysis of primary and secondary endpoints will be performed on the FAS population. 
8.2 Baseline Characteristics 
Continuous variables will be summarized using the mean, standard deviation, median, minimum, 
maximum and quartiles. Categorical variables will be summarized using frequency counts and 
percentages. 
All statistical tests will be 1-sided and performed using a 0.05 significance level. 
8.3 Primary endpoint 
For the primary criterion analysis, AUC for the WURSS-21 will be compared between Healsea® Rescue* 
group and Placebo group using a Student’s t-test. If the usual applicability assumptions for the 
Student’s t-test are not met, a Mann-Whitney test will be used. 
 
8.4 Secondary endpoints 
-The analysis of the primary endpoint will be completed by an analysis of the AUC for each of the 
WURSS-21 components (symptoms and Quality-of-Life). 

 
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-Duration endpoints will be summarized using the medians, with 95% CIs for the medians by group. 
Results for Healsea® Rescue* group and Placebo group will be compared using Wilcoxon-Mann-
Whitney test. 
-The number of days of use of concomitant treatments in each group will be compared by means of 
chi-square test or exact Fisher test. 
-The subject general satisfaction in each group will be compared by means of chi-square test. And the 
global subject feedback on treatment use in each group will be compared by means of exact Fisher 
test. 
-Safety:  
All adverse events/incidents/expected side effects will be listed, but only treatment-emergent 
adverse events/incidents (non-serious + serious) will be summarized. 
 
Adverse events/incidents/expected side effects will be summarized by the number and percentage of 
patients (by treatment group), classified by System Organ Class and Preferred Term as defined by 
MedDRA dictionary. 
For a given treatment group, a given adverse event will be counted treatment emergent only once 
per patient during the treatment period. 
Frequency and percentage of patients with at least one reported adverse event/ incident / expected 
side effects will be tabulated by System Organ Class and by treatment group. 
 
8.5 Sample Size calculation and justification 
A sample of 180 subjects (90 subjects per group) will be needed to provide 80% power with a 1-sided 
test at a 0.05 significance level to detect a difference between Healsea® Rescue* and Placebo groups 
AUC of 30% [12].  
Assuming that approximately 10% of subjects may drop-out the study, 200 subjects will be randomly 
assigned at a ratio 1:1 to Healsea® Rescue* and Placebo (100 subjects per group). 
8.6 Rationale for the number of procedures to be performed by a single 
user 
Only non-burdensome and non-invasive procedures are planned in the study investigation, such as 
quality of life or satisfaction questionnaires. Two visits are scheduled to assess the study criteria. The 
phone call is performed to ensure that the patient has stopped the treatment after 14 continuous 
intakes. 
8.7 Interim analysis 
Not applicable.  

 
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8.8 Management of bias (randomization, blinding)  
See section 7.1.2 
8.9 Management, justification, and documentation of missing data, 
including drop-outs 
 Missing data for the primary endpoint (WURSS-21) will be estimated by interpolation. 
8.10 Procedures for reporting any deviation(s) from the original statistical 
analysis plan 
Any deviation(s) from the original statistical analysis plan will be reported in the statistical analysis plan 
and in the clinical investigation report.  
 
 

 
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9. Data Management 
Subject data will be entered into an electronic case report form.  
9.1 Source documents 
The source documents (e.g., medical file, clinical and office charts, log for compliance data…) which 
contain the source of data recorded in the CRF should be specified. The e-diary will be used as source 
document for WURSS-21, concomitant treatments and adverse events/incidents reported by patient.  
Each subject will be assigned and identified by a unique screening number. Any reference made to an 
individual subject within the study must be done using the unique screening number.  
9.2 Methods for data entry and collection 
A validated electronic case report form (eCRF, 21 CFR Part 11 compliant) will be used to collect clinical 
data for this study. Some of the study data will be recorded in a validated and GCP/GDPR compliant e-
diary by the patient after secure logging to the study website and will be automatically uploaded in 
the e-CRF: 
• 
WURSS-21,  
• 
Adverse event/incidents/expected side effects and concomitant treatments,  
Lallemand Pharma is responsible for designing the e-CRF. eCRF training will be given to appropriate 
personnel before/at initiation of the investigation site. Patients will be instructed how to connect to 
the e-diary at visit 1.  
 
9.3 Procedure used for CRF tracking, data review, database cleaning and 
issuing/resolving data queries.  
The Data Management process includes all activities related to data handling regarding: 
• 
Set-up of eCRF and database 
• 
Specification of on-line checks 
• 
Data entry/Data editing 
• 
Export of data from e-CRF to SAS 
• 
Creation of post-entry checks and listings 
• 
Clean-file process including execution of post-entry checks and listings 
• 
Post clean-file tasks 
Data entry will be done by investigators and other authorized personnel at the site(s). When entering 
data, on-line checks are encoded in the e-CRF for consistency and validation. Whenever required, 
queries issued from this review will be submitted to the investigator for resolution and then tracked 
until corrections are entered and validated.  

 
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A data blind review meeting will be held prior to database lock.  
The review process prepared by the project manager, data manager, study monitor, medical manager 
and statistician will be attended by at least the following: 
• 
Coordinating investigator, 
• 
Study monitor, 
• 
Sponsor Vigilance representative, 
• 
Project managers from the sponsor and from the CRO, 
• 
Data manager, 
• 
Statistician. 
The review is also required for defining the analysis populations and validating the statistical analysis 
plan.  
The meeting will be documented by written and signed minutes that will act as the basis for data 
processing by the Biometrics Department. 
All decisions on the evaluability of the data from each individual subject for the statistical analysis must 
be made and documented before locking the database.  
Data will be retained for at least 10 years after investigation closure. All data collected in the electronic 
Case Report Forms will be handled and archived under the responsibility Lallemand Pharma.  
 
9.4 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. 
 
9.5 Procedures to maintain and protect subject privacy 
It is the responsibility of the sponsor to maintain a security system that prevents unauthorized access 
to the data, both internally and externally.  
Subject privacy is protected through the EXAGIS system at different levels to preclude unauthorized 
access to data:  
• 
Only authorized persons can access the data: 

 
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Access to the database is restricted to authorized users using individual encrypted passwords. For all 
co-workers (from remote or on-site), an identification via a VPN is mandatory. Then, access to each 
server is always done through an authentication with a login and a personal password.  
• 
The risk of data breaches: 
The risk is minimized by full encryption and controlled access. 
  
• 
External/internal interactions are actively protected:  
A standard operating procedure (SOP) details all processes implemented for ensuring network 
security. This SOP mentioned the following subjects: system update, antivirus, antimalware, VPN 
management, user access accounts, password policy, training and awareness of coworkers, and data 
transfer security with partners/clients.  
 
9.6 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. 
 
9.7 Procedure for data retention 
Once the Clinical Investigation Report is signed and validated, the data are archived on a dedicated 
hard disk file with limited access rights. This specific file is mounted on AXIODIS’s OVH server with a 
back-up every two months as well as copied to an external disk that will be stored under seal within 
the premises of AXIODIS. The data are conserved for at least 10 years. 
 
10. Amendments to the CIP 
The investigator should not implement any changes of the protocol without agreement by 
the sponsor. 
All changes to the protocol are subject to an amendment which must be dated and signed by the 
sponsor and the Principal Investigator and must appear as an amendment to the protocol.  
Substantial amendments are notified to the EC and CA.  
11. Deviation from Clinical Investigation Plan 
A major protocol violation is a deviation that has an impact on subject safety, may substantially alter 
risks to subjects, may have an effect on the integrity of the study data, or may affect the subject's 
willingness to participate in the study. In this PMCF study, the following deviations are considered 
major:  

 
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• 
Non-compliance with the inclusion or exclusion criteria,  
• 
No assessment of the primary efficacy criterion (WURSS-21) at D1, D4±1 and D8-1 during the 
treatment period,  
• 
Intake of wrong treatment, i.e, wrong treatment given to the patient after randomization 
• 
A compliance to study product intake below 80% or greater than 120% 
• 
Intake of forbidden medication, i.e., nasal irrigation  
All other cases will, a priori, be considered as minor deviations. 
All protocol deviations will be managed as per the Standard Operating Procedures of the CRO. 
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. 
In case of major deviation, corrective and preventive actions will be implemented as per Study 
Deviation Management plan and Risk management plan.  
 
12. Device accountability 
The device accountability will be performed all over the study according to the SOP “Investigational 
Product Management” of the CRO. Briefly, the site will complete an accountability log after each 
receipt of the Medical Device and delivery to subject. The CRA in charge of the site monitoring will 
check the accountability log at each visit. At V2, the accountability log will be completed with the 
weight of the returned device by the subject.  
Return of unused or expired investigational devices to the sponsor will be tracked using a specific 
record. 
 
13. Ethical consideration 
13.1 Informed Consent 
According to Regulation EU 2017/745, ISO 14155:2020 and applicable Bulgarian regulations, the 
Principal Investigator or his/her authorized designee must explain all aspects of the clinical 
investigation that are relevant to the subject’s decision before any study procedure. In order to ensure 

 
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that the subject is fully informed the investigator must explain to each patient the nature of the clinical 
investigation, including any risks and benefits, its purpose and procedures, and expected duration of 
involvement in the clinical investigation. It must be made clear to the patient that participation in the 
clinical investigation is voluntary and a decision not to participate will not affect their right to the most 
appropriate treatment/care or affect the doctor-patient relationship. 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. Patients reserve 
the right to withdraw from the clinical investigation at any time, irrespective of their initial consent. 
 
13.2 Subject confidentiality 
The present study will be conducted under Regulation 2016/679/EU of the European Parliament and 
of the Council of 27 April 2016 on the protection of natural persons about the personal data and free 
movement of such data (GDPR) and PERSONAL DATA PROTECTION ACT, in force as from 1 January 2002.  
In accordance with GDPR, the Sponsor is the “Controller” and the participating sites, monitors, data 
managers and statisticians are “Processors”. Lallemand Pharma AG, sponsor of the study, is 
responsible for the processing of the study data. 
Confidentiality of data shall be observed by all parties throughout the clinical investigation. All data 
will be secured against unauthorized access. Subject names will not be sent to the sponsor. Only the 
patient number will be recorded in the e-CRF, and if the patient’s name appears on any document, it 
must be obliterated before a copy of the document is supplied to the sponsor. All subject data that 
appear in reports and publications will be anonymised such that the privacy and confidentiality of each 
subject is maintained. 
No data processing will be performed outside of the European Union. 
To fulfil the requirements of source data verification, the PI will be required to obtain consent from 
each subject stating that they agree for their medical records to be accessed (this will form part of the 
consent process). To comply with GDPR, a specific document explaining the lawfulness of personal 
data processing conditions and patients’ rights will be signed before any study procedure by the 
parents/guardians. 
The patients’ rights are the followings:  
• 
The right to request access to, rectification, deletion or restriction of processing concerning 
personal data collected during the study,  
• 
The right to get back all data linked to the research and to forward them to another data 
processing manager (portability right),  
• 
The right to withdraw consent to data collection at any time and to request a restriction of 
processing concerning personal data as mentioned in GDPR’s article 18. However, the data 

 
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processing manager keeps the ability to reject such request should this right likely make 
impossible or seriously compromise the achievement of the research objectives.  
These rights can be exercised with the investigator or his designated representative or by contacting 
the Data Protection Officer appointed by Lallemand Pharma: Yannick Hervy, yhervy@lallemand.com. 
13.3 Insurance policy 
Lallemand Pharma AG has an insurance policy intended to guarantee against possible damage resulting 
from the investigation. 
It is advisable to underline that non-compliance with the Research Legal Conditions is a cause for 
guaranteed exclusion. 
 
14. Vigilance 
14.1 General 
Healsea® Rescue* will be used in the intended use covered by the CE mark in this PMCF study. 
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).  
Nevertheless, if a causal relationship between a serious adverse event and an investigational 
procedure has been established, the safety reporting laid down in Article 80 of the MDR. Since the 
electronic system referred to in Article 73 (Eudamed) will not be available and fully functional at the 
date of study start, the procedures for safety reporting will be performed according to modalities 
described in the MDCG 2020-10/1 and -10/2. 
All modalities of safety reporting will be detailed in a Safety Management Plan signed by the sponsor 
vigilant, the Principal Investigators, the local CRA in charge of the monitoring and a representant of the 
CRO. 
 
14.2 Definitions  
Incident means any malfunction or deterioration in the characteristics or performance of a device 
made available on the market, including use-error due to ergonomic features, as well as any 
inadequacy in the information supplied by the manufacturer and any undesirable side-effect (MDR 
2017/745).  
Serious incident means any incident that directly or indirectly led, might have led or might lead to any 
of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent 

 
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serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health 
threat (MDR 2017/745).  
Serious public health threat means an event which could result in imminent risk of death, serious 
deterioration in a person's state of health, or serious illness, that may require prompt remedial action, 
and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for 
the given place and time (MDR 2017/745).  
Expected and foreseeable side effects (MEDDEV 2 12-1 rev. 8) 
They meet all the following criteria:  
• 
Clearly identified in the manufacturer's labelling,  
• 
Clinically well known as being foreseeable and having a certain qualitative and quantitative 
predictability when the device is used and performs as intended,   
• 
Documented in the device master record, with an appropriate risk assessment, prior to the 
occurrence of the incident and,  
• 
Clinically acceptable in terms of the individual patient benefit.  
 
Adverse event means any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, 
in the context of a clinical investigation, whether related or not related to the investigational device 
(MDR 2017/745).  
 
Adverse or intercurrent events are graded as follows: 
• 
Mild:  
Awareness of signs or symptoms but easily tolerated. 
• 
Moderate:  Uncomfortable enough to cause interference with usual activity. 
• 
Severe:  
Incapacity with inability to work or do usual activity.  
 
Serious adverse event (SAE) (MDR Article 2(58): 
Any adverse event that led to any of the following: 
a) death, 
b) serious deterioration in the health of the subject, that resulted in any of the following: 
i. 
life-threatening illness or injury, 
ii. 
permanent impairment of a body structure or a body function, 
iii. 
hospitalisation or prolongation of patient hospitalisation, 
iv. 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
v. 
chronic disease, 
c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect  

 
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14.3 Reporting in the eCRF  
At V2, the investigator will validate the adverse events/incidents and concomitant medications 
reported in the e-diary by questioning the patient.        
All serious and non-serious incidents/serious and non-serious risk of incidents/expected side effects 
/serious and non-serious adverse event (pertinent in the context of the common cold, additional study 
procedures and of the medical device use) occurring during the clinical investigation will be reported 
in the e-CRF.  
 
14.4 Investigator’s responsibilities and processing timelines 
14.4.1 Materiovigilance  
All incidents and expected undesirable side effects will be reported to LP vigilance manager according 
to MDR, MEDDEV 2.12 rev 8 modalities, national requirements, ISO 14155:2020 and Lallemand Pharma 
procedures which are described in the safety management plan. This document will be signed by the 
Principal Investigator, representants of the Clinical Research Organization (CRO), CRA in charge of the 
monitoring and the Vigilant Manager, before the study start. 
As soon as the investigator will be informed of the event, he/she will complete a Primary Notification 
Form template (PNF, appendix B) and send it to the sponsor ( officelp@lallemand.com and/or fax +41 
91 980 
4615 
(as 
back-up 
method) 
and 
to 
the 
Vigilance 
manager 
Roberta 
Belotti 
(rbelotti@lallemand.com), to the CRO (etudes@bgclinicals.com and/or fax: +33 561 561 956), to the 
EU 
representative 
Michel 
Huc 
(michel.huc@aspe-conseil.eu), 
and 
to 
the 
local 
CRA 
(marina@convex.bg) 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.  
14.4.2 Vigilance reporting according to Article 80 of the MDR 
The following events are considered reportable events in accordance with MDR Art. 80(2): 
- 
any serious adverse event that has a causal relationship with the investigation procedure or where 
such causal relationship is reasonably possible. 
 
For the purpose of harmonizing reports, each SAE will be classified according to four different levels of 
causality as per definitions of the MDCG 2020-10/1 specified in the safety management plan:  
1. Not related  
2. Possible  
3. Probable  
4. Causal relationship 
Only causality level 1 (i.e. “not related”) is excluded from reporting. 

 
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Any serious adverse event that has a causal relationship with an investigational procedure will be 
reported by the investigator to the sponsor (officelp@lallemand.com and/or fax +41 91 980 4615 (as 
back-up method) and to the Vigilance manager Roberta Belotti (rbelotti@lallemand.com), to the CRO 
(etudes@bgclinicals.com and/or fax: +33 561 561 956), to the EU representative Michel Huc 
(michel.huc@aspe-conseil.eu), and to the local CRA (marina@convex.bg) 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 C).  
 
14.5 Sponsor responsibilities and processing timelines 
14.5.1 Materiovigilance 
The vigilance manager of Lallemand Pharma is responsible for the reporting to the Bulgarian 
Competent Authority.  
Briefly, for serious incidents or risk of serious incident, the vigilance manager will complete a 
Manufacturer Incident Report. 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 Corrective Action 
(FSCA) and of a Field Safety Notice. These documents will be transmitted to the Bulgarian Competent 
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 status of health 
Report immediately but not more than 10 days 
Others (could have led to death or serious 
deterioration in health) 
Report immediately but not more than 15 days 
Every FSCA 
Immediately 
before 
the 
measure 
is 
implemented except in case of emergency, when 
the vigilance manager of the sponsor has to 
immediately take a safety corrective action 
 
Increase rate or severity of expected undesirable side effects and non-serious incidents will be 
reported to the Bulgarian Competent Authority in Trend reports as per regulation requirements.  
Responsibilities of sponsor are detailed in the Safety Management Plan. 
14.5.2 Vigilance according to Article 80 
Any serious adverse event that has a causal relationship with an additional procedure or a causal 
relationship reasonably possible, will be reported by the sponsor to the Bulgarian CA and the Ethics 
Committee if applicable as follows: 

 
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Any serious adverse event that has a causal 
relationship with the additional procedure or 
a causal relationship reasonably possible, 
will be reported to the Bulgarian CA 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. The excel file provided by 
the MDCG 2020-10/2 is to be used. 
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. The excel 
file provided by the MDCG 2020-10/2 is to be used. 
 
15. Suspension, or premature termination of the Clinical Investigation 
Lallemand Pharma AG may suspend or prematurely terminate the clinical investigation. The reasons 
shall be documented.  Reasons for suspension or premature termination at an investigation site may 
include occurrences where monitoring or auditing identifies serious or repeated deviations on the part 
of an investigator. Lallemand Pharma AG will notify the Regulatory Authority as appropriate and 
ensure that the EC is notified of any suspension or early termination of the clinical investigation. 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or when so 
instructed by the EC or Regulatory Authority, Lallemand Pharma AG will suspend the clinical 
investigation while the risk is assessed. The sponsor will terminate the clinical investigation if an 
unacceptable risk is confirmed. The decision to maintain or to unblind the study will be taken in 
consultation with the Regulatory Authority.  Should the risk not be confirmed Lallemand Pharma AG 
will, in accordance with regulations, provide relevant persons with justification and data supporting 
the decision to resume the clinical investigation.  
EC or Regulatory Authority may suspend or prematurely terminate participation of one site or of all 
the participating sites. 
The patients will receive all treatments needed in case of complication or safety issues. In this case, 
the patient will be followed until the end of the issue.  
 
16. Publication policy  
The information and data collected during the conduct of this clinical study are considered confidential 
and are used by the sponsor in connection with the development of the study treatment. This 
information will be disclosed by the sponsor depending on current regulations. 

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

 
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17. References 
Medical Device Directive 93/42/EEC (MDD) 
“Clinical Investigation of medical devices for human subjects” – Good clinical practice ISO 14155:2020 
[1] 
T. Heikkinen and A. Järvinen, “The common cold,” in Lancet, 2003, vol. 361, no. 9351, pp. 51–
59. 
[2] 
R. M. Rosenfeld et al., “Clinical practice guideline (update): Adult sinusitis,” Otolaryngol. - Head 
Neck Surg. (United States), vol. 152, pp. S1–S39, Apr. 2015. 
[3] 
W. J. Fokkens et al., “European Position Paper on Rhinosinusitis and Nasal Polyps 2020,” 
Rhinology, vol. 58, pp. 1–464, Feb. 2020. 
[4] 
R. M. Rosenfeld, “Acute sinusitis in adults,” N. Engl. J. Med., vol. 375, no. 10, pp. 962–970, Sep. 
2016. 
[5] 
N. Rabin, Y. Zheng, C. Opoku-Temeng, Y. Du, E. Bonsu, and H. O. Sintim, “Biofilm formation 
mechanisms and targets for developing antibiofilm agents,” Future Medicinal Chemistry, vol. 7, 
no. 4. Future Science, pp. 493–512, 01-Mar-2015. 
[6] 
D. King, B. Mitchell, C. P. Williams, and G. K. P. Spurling, “Saline nasal irrigation for acute upper 
respiratory tract infections,” Cochrane Database of Systematic Reviews, vol. 2015, no. 4. John 
Wiley and Sons Ltd, 20-Apr-2015. 
[7] 
N. Principi and S. Esposito, “Nasal irrigation: An imprecisely defined medical procedure,” 
International Journal of Environmental Research and Public Health, vol. 14, no. 5. MDPI AG, 11-
May-2017. 
[8] 
A. R. Talbot, T. M. Herr, and D. S. Parsons, “Mucociliary clearance and buffered hypertonic saline 
solution,” Laryngoscope, vol. 107, no. 4, pp. 500–503, Apr. 1997. 
[9] 
C. L. Brown and S. M. Graham, “Nasal irrigations: Good or bad?,” Current Opinion in 
Otolaryngology and Head and Neck Surgery, vol. 12, no. 1. pp. 9–13, 2004. 
[10] 
D. Rabago, A. Zgierska, M. Mundt, B. Barrett, J. Bobula, and R. Maberry, “Efficacy of daily 
hypertonic saline nasal irrigation among patients with sinusitis: A randomized controlled trial,” 
J. Fam. Pract., vol. 51, no. 12, pp. 1049–1055, Dec. 2002. 
[11] 
R. Haselen et al., “The effectiveness and safety of a homeopathic medicinal product in pediatric 
upper respiratory tract infections with fever: A randomized controlled trial,” Pediatriya, vol. 57, 
no. 3, pp. 51–52, 2017. 
[12] 
B. Barrett et al., “Validation of a short form Wisconsin upper respiratory symptom survey 
(WURSS-21),” Health Qual. Life Outcomes, vol. 7, p. 76, Aug. 2009. 
[13] 
B. Brown, Roger L and Obasi, Chidi N and Barrett, “Rasch Analysis of The WURSS-21 Dimensional 
Validation and Assessment of Invariance,” J. Lung, Pulm. Respir. Res., vol. 3, no. 2, Apr. 2016. 
[14] 
G. G. Jackson, H. F. Dowling, I. G. Spiesman, and A. V. Boand, “Transmission of the Common 
Cold to Volunteers Under Controlled Conditions: I. The Common Cold as a Clinical Entity,” A.M.A 
Arch. Intern. Med., vol. 101, no. 2, pp. 267–278, 1958. 

 
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List of Appendix  
Appendix A:  Instructions for Use (IFU) 
Appendix B: Primary Notification Form (PNF) 
Appendix C: Serious Adverse Event (SAE) form 
 
 

 
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Appendix A: IFU 
HEALSEA® RESCUE 
MPOS 
INDICATION 
Healsea® RESCUE is a nasal spray indicated in adults 
over 18 years in the treatment of nasal symptoms of 
acute rhinitis and rhinosinusitis, reduces swelling of 
the nasal mucosa. 
 
UNDESIDERABLE EFFECTS 
Feeling of itching and irritation can occur while 
initiating the treatment. 
In case of undesirable effects, contact your doctor. 
COMPOSITION 
Hypertonic saline solution (salinity 2.7%), 
Symbiofilm®. 
 
STORAGE AND WASTE RECOMMENDATION 
Store at room temperature and not above 30°C. 
See the expiry date on the box or the bottle. 
Ask your pharmacist to throw out the bottle after use. 
These measures contribute to protect the 
environment. 
DIRECTION OF USE 
One-two sprays twice a day in each nostril for 7 days 
or as recommended by your doctor or pharmacist. 
TECHNOLOGY 
The spray pump APF (Advanced Preservative Free) 
uses a technology that permits to dispense a 
preservative free solution. 
PRECAUTION OF USE 
- Keep out of reach of children. 
-If symptoms persist more than 7 days, ask for 
advices to your doctor or pharmacist. 
-The bottle shall be used by only one person for 
hygiene reason and to avoid the transmission of 
pathogenic agents that could be in contact with the 
nozzle. 
HOW TO USE HEALSEA® RESCUE? 
1. Place the nozzle smoothly into the nostril while 
keeping head straight. 
2. Once the nozzle is placed, press on the nozzle in 
each nostril. Let flow the excess of solution and 
wipe. 
3. Clean the nozzle with tissue, soapy water, rinse 
and dry after every use. 
CONTRAINDICATION 
Do not use in children and adolescents under 18 
years. 
Do not use in case of hypersensitivity or allergy to one 
or several components. 
 
 
Healsea® RESCUE is a nasal spray containing hypertonic saline solution mixed with an innovative 
extract, Symbiofilm®, isolated from the marine biosphere. 
Healsea® RESCUE is a natural care preservative free allowing to treat nasal symptoms of acute rhinitis 
and rhinosinusitis. 
Symbiofilm® is a marine postbiotic, which contains exopolymeric substances, that enhances 
mechanically the cleansing efficiency of hypertonic water. 
Symbiofilm® reduces the development of biofilm from respiratory pathogenic microorganisms by 
mechanical action as well as the mucosal adhesion and helps reducing the spreading of viruses in-vitro. 
Healsea® RESCUE is the ideal solution to ensure an efficient cleansing, moisturizing and 
decongestion of the nasal mucosa by osmotic action. 
 
                Lallemand Pharma AG                                               
                Via Selva 2  
                6900 Massagno  
                             Learn more about                                      Publication date: 
Switzerland                                                        biofilms by flashing                                   2021/12/10_R1                                
                                                                                             this QR code!           
 
 
 
 
 
 
 
 
 
 
                         
                    
      
ASPE CONSEIL 
21, chemin de la Favasse 
31140 Aucamville – FRANCE  
 

 
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PLACEBO 
 
INDICATION 
The Medical Device is a nasal spray indicated in adults 
over 18 years in the treatment of nasal symptoms of 
acute rhinitis and rhinosinusitis, reduces swelling of 
the nasal mucosa. 
 
UNDESIDERABLE EFFECTS 
Feeling of itching and irritation can occur while 
initiating the treatment. 
In case of undesirable effects, contact your doctor. 
COMPOSITION 
Isotonic saline solution (salinity 0.9%) 
STORAGE AND WASTE RECOMMENDATION 
Store at room temperature and not above 30°C. 
See the expiry date on the box or the bottle. 
Ask your pharmacist to throw out the bottle after use. 
These measures contribute to protect the environment. 
DIRECTION OF USE 
One-two sprays twice a day in each nostril for 7 days 
or as recommended by your doctor or pharmacist. 
TECHNOLOGY 
The spray pump APF (Advanced Preservative Free) 
uses a technology that permits to dispense a 
preservative free solution. 
PRECAUTION OF USE 
- Keep out of reach of children. 
-If symptoms persist more than 7 days, ask for 
advices to your doctor or pharmacist. 
-The bottle shall be used by only one person for 
hygiene reason and to avoid the transmission of 
pathogenic agents that could be in contact with the 
nozzle. 
HOW TO USE HEALSEA® PLACEBO? 
1. Place the nozzle smoothly into the nostril while 
keeping head straight. 
2. Once the nozzle is placed, press on the nozzle in 
each nostril. Let flow the excess of solution and 
wipe. 
3. Clean the nozzle with tissue, soapy water, rinse 
and dry after every use. 
CONTRAINDICATION 
Do not use in children and adolescents under 18 
years. 
Do not use in case of hypersensitivity or allergy to one 
or several components. 
 
 
 
 
 
 
             Lallemand Pharma AG                                               
               Via Selva 2  
               6900 Massagno  
Switzerland      
 
 
 
 
 
 
 
 
 
 
                 
                    
      
ASPE CONSEIL 
21, chemin de la Favasse 
31140 Aucamville – FRANCE  
 

 
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Appendix B: Primary Notification Form 
This form is to be completed immediately and no later than 24h (in case of any SERIOUS 
safety issue) or 48h (in case of any NON-SERIOUS safety issue). 
Protocol title: [to be completed] 
Acronym: [to be completed] 
Sponsor code: [to be completed] 
Site number:  
Country:  
 
 
 
 
Competent authority(ies) reference number: 
[to be completed] 
 
Transmission date:  
 
 
 
  
 
  
 
ddmmyy 
 
1. Date, type and classification of incident report 
Incident codification:  
 
First notification: 
 
Follow-up: 
 
Final: 
 
Date of the incident 
 
 
 
 
  
 
  
 
ddmmyy 
Reporter awareness date 
 
 
  
 
  
 
ddmmyy 
Classification/type 
of 
the 
incident 
 
Serious 
public 
health threat 
 Death 
Expected 
undesirable side effect 
 Unanticipated serious deterioration 
in state of health 
 Non serious incident 
 
2. Patient information 
Birthdate:  
 
Height: 
 
 
 
  
 
 
 
mmyyyy 
 
 
 
cm 
Gender: Male 
 Female 
 Unknown 
  
Non applicable 
  
 
Weight:  
 
 
 
 
, 
 
Kg 
List any of the patient’s prior condition of medication that may be relevant to this incident: 
 

 
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3. Medical Device information 
UDI device identifier / 
Eudamed ID: 
 not applicable 
Basic UDI-DI/Eudamed-DI: 
 not applicable 
UDI production identifier: 
 not applicable 
Medical device name (brand, trade, 
proprietary or common name) & SKU: 
 
Class of risk: 
 
Batch number 
 
Expiry date (yyyy/mm): 
 
/  
 
 
Other details: 
 
4. Incident information 
Intended use of the medical device: 
 
Date of first use:  
 
Date of last use:  
 
Frequency of use:________________________ 
 
Description of the incident: Provide a comprehensive description of the incident, including (1) what 
went wrong with device (if applicable) and (2) a description of health effects (if applicable), i.e. 
clinical signs, symptoms …): 
 
 
 
 
 
 
 
 
 
Outcome & Health Impact: 
 
 death 
 life threatening 
 hospitalization (initial or prolonged)  
 required intervention to prevent permanent damage 
 disability or permanent damage 
 congenital abnormality/birth defect  
 
 no serious outcome 
 
 other, please specify:  
 
 
 
 
 
 
  
 
  
 
ddmmyy 
 
 
  
 
  
 
ddmmyy 
Remedial actions taken by investigator, patient, or user subsequent:  
 
 
 
 

 
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5. Reporter information 
 Distributor 
 Patient  
 Healthcare professional: ___________________ 
 Investigator (in case of the safety issue has been occurred during a clinical investigation) 
 Other, please specify: _______________________________ 
 
 
For any follow-up please kindly indicate the contact details: 
 
Name and Surname: ___________________ 
 
Email: ___________________ 
 
Phone number:___________________ 
 
Fax: ___________________ 
 
 
Date:                                                                                          Signature: 
 
 
 
___________________________                                         ___________________________ 
 
 
 
 

 
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Appendix C: SAE form  
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 personnel 
have been made aware of the event and sent immediately to the Clinical Study Monitor by mail 
marina@convex.bg and to BG ClinicalS etudes@bgclinicals.com, FAX: no +33 561 531 956, to the 
sponsor officelp@lallemand.com and/or fax: +41 91 980 4615 (as back-up method) and to the Vigilance 
Manager Roberta Belotti (rbelotti@lallemand.com) and the EU representative (michel.huc@aspe-
conseil.eu). 
 
Protocol title:  
Efficacy and safety of Healsea® hypertonic nasal spray 
2.7 % in the treatment of acute infectious rhinitis in 
adults  
 
Acronym: TEACHER 
Sponsor code: LPH-2201 
Competent Authority(ies) reference 
number:  
 
 
Transmission date:  
 
 
 
  
 
  
 
ddmmyy 
 
 
SAE# 
(to be completed by the 
sponsor) 
 
 
First notification: 
 
Follow-up: 
 
Final: 
 
 
1. Subject information 
 
Birthdate:  
 
Height:  
 
 
 
  
 
 
 
mmyyyy 
 
 
 
cm 
 
Gender: Male 
 Female 
 Other 
 
 
Weight:  
 
 
 
 
,  
Kg 
Investigational arm: 
Healsea® 
Rescue 
Placebo 
blinded 
 
2. Description of the SAE 
The serious adverse event resulted in: 
 Death (whatever may be the cause) 
Serious deterioration in the health of the 
subject, that resulted in any of the following: 
 In-patient hospitalisation or prolongation of  
existing hospitalisation (*) 
 Life threatening illness or injury 
 Permanent impairment to a body structure 
or a body function 
 Medical or surgical intervention to prevent 
life threatening illness or injury or permanent 
impairment to a body structure or a body 
function 
 Chronic disease 
 Foetal distress, foetal death or congenital 
physical or mental impairment or birth defect 
 
Description of the SAE: (if clinical nature, indicate the diagnosis or the major symptoms) 
  

 
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Date of the procedure leading to the SAE:  
 
 
 
  
 
  
 
ddmmyy 
SAE onset date:  
 
 
 
  
 
  
 
ddmmyy 
 
 not capture 
 
SAE stop date: 
 
 
 
  
 
  
 
ddmmyy 
 
 on going 
Or date of death if SAE “fatal” 
 
 
 
  
 
  
 
ddmmyy 
 
Summary description (study procedure, significant medical history, progression of event, available 
laboratory results, study procedure): 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goal planned in the protocol or scheduled before 
study participation 
 
3. Mesures taken following the SAE 
The event led to: 
 Prescription of corrective or symptomatic medication / medical device (specify name, dosage): 
………………………………………………………………………………………………………………….. 
 Other,specify: 
.............................................................................................................................................. 
………………………………………………………………………………………………………………………………………... 
 
 
4. Outcome 
 
 
 Not recovered/Not resolved 
 Recovering/Resolving 
 Recovered/Resolved 
 Recovered/Resolved with 
sequelae 
 Unknown 
 
 Fatal: in case of death, has an autopsy been conducted? 
 Yes 
 No 
 
5. Investigator causality assessment with the study procedure (investigator’s assessment to 
be done as soon as possible) 
 Not related 
 Possible 
 Probable 
 Causal relationship 
 
Comments: 
………………………………………………………………………………………………………. 
 
Enclose in the notification the results of carried out examination, reports of hospitalisation, etc… 
6. Submitter information 
 

 
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 Investigator 
 Other, please specify: _______________________________ 
 
Name: _____________________________ 
 
e-mail: _____________________________ 
 
Phone number: _______________________________________ 
 
Fax: _________________________________________________ 
 
Date:  
 
Signature: 
 
 
  
 
  
 
ddmmyy