Impact of Symbiofilm On Nasal Microbiota (ISONAM)

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

Healsea® chronic is CE marked medical device indicated in adults for the treatment of nasal symptoms of chronic rhinosinusitis. This is an hypertonic seawater-based nasal spray supplemented with natural Symbiofilm® extract (0.2%) isolated from marine bacteria. In vitro, Symbiofilm® inhibits at early stage biofilm formation from bacteria found to be more prevalent and abundant in CRS patients (e.g. Staphylococcus aureus, Pseudomonas aeruginosa). This exploratory study is designed with aim to determine if the antibiofilm properties of Symbiofilm® may modify sino-nasal microbiota, impacting α and/ or β diversities.

Study Overview

• Status: Completed
• Conditions: Rhinosinusitis Chronic; Microbiome
• Intervention / Treatment: Device: Healsea® Chronic, hypertonic seawater-based nasal spray supplemented with natural Symbiofilm® extract

Detailed Description

Chronic rhinosinusitis (CRS) is an inflammation of the nose and paranasal sinuses and is characterized by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), lasting for 12 weeks or longer. In addition, facial pain or pressure and a reduction in the sense of smell can occur. The condition can occur with or without nasal polyps.

Chronic rhinosinusitis (CRS) is a significant health problem and affects 5-12% of the general population.

The physiopathology of CRS is poorly understood with multiple environmental, host and microbial factors being implicated. Putative pathological factors include changes in the microbiota, imbalance of the local or systemic immune system, allergens, toxins and genetic predisposition.

A dysbiosis mechanism has been proposed as modulating inflammation in diseased sinuses. This hypothesis suggests that externally influenced changes in the nasal microbiome can result in dysbiosis, i.e. a shift from a "normal" or "healthy" microbial community structure and that this shift may be responsible for the initiation or maintenance of CRS. For example, the disruption of the commensal biofilm during a viral upper respiratory tract infection can create a niche for pathogenic species to grow. Despite many contradictory statements in the different studies some common trends emerge. Less diversity in the microbial community rather than an increased overall bacterial load seems to characterize CRS compared to the healthy state with no consensus about specific genera indicative of disease. However, anaerobes and S. aureus are found to be significantly more prevalent and abundant in CRS versus healthy controls. Bacterial biofilm is detected on the sinus mucosa in up to 80% of CRS patients and its presence does not imply that it is causing mucosal inflammation. However, in the context of CRS, there are several possible mechanisms by which biofilms may be pro-inflammatory including the release of planktonic organisms and the release of superantigens, which can cause ciliary dysfunction and inhibition of ciliary clearance. Bacterial biofilms are likely a key modulator of the refractory nature of CRS.

Although clinical evidence from well-designed trials is scarce, European Guidelines for chronic rhinosinusitis recommend daily nasal saline irrigation for reduction of the severity of symptoms of CRS. A recent Cochrane analysis has concluded that daily nasal irrigation with hypertonic saline solution is more effective than placebo to improve patient symptoms. The exact mechanisms by which nasal irrigation works are not known. However, most of the experts agree that it is primarily a mechanical intervention leading to direct cleansing of the nasal mucosa. Nevertheless, the efficacy of such solution remains moderate.

Healsea® Chronic is a CE marked medical device indicated in adults for the treatment of nasal symptoms of chronic rhinosinusitis. This is a seawater-based nasal spray supplemented with a natural Symbiofilm® extract (0.02%) isolated from marine bacteria. The nasal solution is hypertonic (NaCl 2.2%). Symbiofilm® is a marine postbiotic comprising active exopolysaccharides with emulsifying properties and in vitro antibiofilm activity. Antibiofilm properties have been demonstrated with the colorimetric microtiter plate assay. In this model, a significant inhibition of biofilm formation by Staphylococcus aureus and Haemophilus influenzae are observed. Detachment properties from human nasal epithelial cells of Staphylococcus aureus and Pseudomonas aeruginosa has also been demonstrated in vitro, suggesting an inhibition of biofilm formation at early stage in this model. Symbiofilm® has no bacteriostatic nor bactericidal activities.

To date, properly designed studies to evaluate the effect of topical therapies on microbiome are scarce so no definite conclusion can be made. In one study, use of saline irrigation with or without budesonideDCI used was not associated with significantly distinct microbiota composition among either controls or post-operative CRS patients with polyp.

This exploratory study is designed with aim to determine if the antibiofilm properties of Symbiofilm® may modify sino-nasal microbiota, impacting α and/ or β diversities. To this end middle meatus swab specimen will be taken from CRS patients before and after treatment with Healsea® Chronic. Bacteria colonization will be assessed using quantitative PCR and 16S rRNA gene sequencing.

Improvement of nasal symptoms and quality of life will be assessed with the Sino-Nasal Outcome Test score-22 (SNOT-22). Post-market vigilance of Healsea® Chronic and vigilance of study procedures will be assessed throughout the study.

• Study Type: Observational
• Enrollment (Actual): 12

Contacts and Locations

Study Locations

• France
  • Toulouse, France, 31400
    • Larrey hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The subjects will be recruited by the site among outpatients coming for routine consultation because of CRS.

Description

Inclusion Criteria:

1. Male or female, aged 18 - 70 years
2. Provision of signed and dated informed consent form
3. Stated willingness to comply with all study procedures and availability for the duration of the study
4. Diagnosed with CRS based on the diagnostic criteria of the EPOS guideline
5. Registered with a social security scheme or covered by such a regime

Exclusion Criteria:

1. Antibiotics or oral corticosteroids intake in the month prior to the study
2. Endoscopic sinus surgery in the past 6 months
3. Cystic fibrosis
4. Wegener's granulomatosis
5. Immunodeficiency
6. Defective access to middle meatus
7. Lidocaine allergy
8. Known hypersensitivity/allergy to any component of the test device
9. Pregnant/Lactating female or absence of efficient contraception
10. Under tutorship or guardianship

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Test Medical Device; Healsea Chronic nasal spray will be administered twice daily (1 puff, 1-2 sec) in each nostril during 30 days	Device: Healsea® Chronic, hypertonic seawater-based nasal spray supplemented with natural Symbiofilm® extract; Healsea® Chronic nasal spray will be administered twice daily (1 puff, 1-2 sec) in each nostril during 30 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparaison of Alpha-diversity of Sino-nasal Microbiota Before and After Treatment (Visit 1 and Visit 2)	Comparaison of the values of alpha diversity of bacterial species assessed by the Shannon index at baseline and after the treatment period	At baseline (V1) and at end of the 30-day treatment period (V2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of Healsea® Chronic on Quality of Life Assessed by the Sino-Nasal Outcome Test Score-22	Change of SNOT-22 total score at the end of the 30-day treatment period versus baseline . A change >-9 is deemed clinically meaningful.	End of treatment (Visit 2(V2)-Day 30) versus screening/inclusion (Visit 1(V1)-Day 1)
Patient Satisfaction Questionnaire (Usability)	To assess patient 's satisfaction regarding the medical device usability	Visit 2(V2)-Day 30 (end of treatment)
Patient Satisfaction Questionnaire (Taste)	To assess patient 's satisfaction regarding the sensory perception (residual taste after spraying)	Visit 2(V2)-Day 30 (end of treatment)
Patient Satisfaction Questionnaire (Efficacy)	To assess patient 's satisfaction regarding product efficacy for chronic Rhinosinusitis (Cleansing and Moistening of nasal mucosa)	Visit 2(V2)-Day 30 (end of treatment)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reporting of Adverse Events, Incidents and Expected Side Effects	Assessment of materiovigilance from the medical device (incidents, expected side effects) and reporting of adverse reactions related to the additional invasive procedure (swab of the nasal meatus)	During the intervention, up to 30 days

Collaborators and Investigators

• Sponsor: Lallemand Pharma AG
• Investigators: Principal Investigator: Pr Guillaume de Bonnecaze, MD, PhD, Department of Otorhinolaryngology , University Hospital of Toulouse (Larrey), France

Publications and helpful links

General Publications

• Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 2009 Oct;34(5):447-54. doi: 10.1111/j.1749-4486.2009.01995.x.
• Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, Toppila-Salmi S, Bernal-Sprekelsen M, Mullol J, Alobid I, Terezinha Anselmo-Lima W, Bachert C, Baroody F, von Buchwald C, Cervin A, Cohen N, Constantinidis J, De Gabory L, Desrosiers M, Diamant Z, Douglas RG, Gevaert PH, Hafner A, Harvey RJ, Joos GF, Kalogjera L, Knill A, Kocks JH, Landis BN, Limpens J, Lebeer S, Lourenco O, Meco C, Matricardi PM, O'Mahony L, Philpott CM, Ryan D, Schlosser R, Senior B, Smith TL, Teeling T, Tomazic PV, Wang DY, Wang D, Zhang L, Agius AM, Ahlstrom-Emanuelsson C, Alabri R, Albu S, Alhabash S, Aleksic A, Aloulah M, Al-Qudah M, Alsaleh S, Baban MA, Baudoin T, Balvers T, Battaglia P, Bedoya JD, Beule A, Bofares KM, Braverman I, Brozek-Madry E, Richard B, Callejas C, Carrie S, Caulley L, Chussi D, de Corso E, Coste A, El Hadi U, Elfarouk A, Eloy PH, Farrokhi S, Felisati G, Ferrari MD, Fishchuk R, Grayson W, Goncalves PM, Grdinic B, Grgic V, Hamizan AW, Heinichen JV, Husain S, Ping TI, Ivaska J, Jakimovska F, Jovancevic L, Kakande E, Kamel R, Karpischenko S, Kariyawasam HH, Kawauchi H, Kjeldsen A, Klimek L, Krzeski A, Kopacheva Barsova G, Kim SW, Lal D, Letort JJ, Lopatin A, Mahdjoubi A, Mesbahi A, Netkovski J, Nyenbue Tshipukane D, Obando-Valverde A, Okano M, Onerci M, Ong YK, Orlandi R, Otori N, Ouennoughy K, Ozkan M, Peric A, Plzak J, Prokopakis E, Prepageran N, Psaltis A, Pugin B, Raftopulos M, Rombaux P, Riechelmann H, Sahtout S, Sarafoleanu CC, Searyoh K, Rhee CS, Shi J, Shkoukani M, Shukuryan AK, Sicak M, Smyth D, Sindvongs K, Soklic Kosak T, Stjarne P, Sutikno B, Steinsvag S, Tantilipikorn P, Thanaviratananich S, Tran T, Urbancic J, Valiulius A, Vasquez de Aparicio C, Vicheva D, Virkkula PM, Vicente G, Voegels R, Wagenmann MM, Wardani RS, Welge-Lussen A, Witterick I, Wright E, Zabolotniy D, Zsolt B, Zwetsloot CP. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020 Feb 20;58(Suppl S29):1-464. doi: 10.4193/Rhin20.600.
• Sivasubramaniam R, Douglas R. The microbiome and chronic rhinosinusitis. World J Otorhinolaryngol Head Neck Surg. 2018 Oct 31;4(3):216-221. doi: 10.1016/j.wjorl.2018.08.004. eCollection 2018 Sep.
• Boase S, Foreman A, Cleland E, Tan L, Melton-Kreft R, Pant H, Hu FZ, Ehrlich GD, Wormald PJ. The microbiome of chronic rhinosinusitis: culture, molecular diagnostics and biofilm detection. BMC Infect Dis. 2013 May 8;13:210. doi: 10.1186/1471-2334-13-210.
• Ramakrishnan VR, Hauser LJ, Frank DN. The sinonasal bacterial microbiome in health and disease. Curr Opin Otolaryngol Head Neck Surg. 2016 Feb;24(1):20-5. doi: 10.1097/MOO.0000000000000221.
• Hoggard M, Wagner Mackenzie B, Jain R, Taylor MW, Biswas K, Douglas RG. Chronic Rhinosinusitis and the Evolving Understanding of Microbial Ecology in Chronic Inflammatory Mucosal Disease. Clin Microbiol Rev. 2017 Jan;30(1):321-348. doi: 10.1128/CMR.00060-16.
• Koeller K, Herlemann DPR, Schuldt T, Ovari A, Guder E, Podbielski A, Kreikemeyer B, Olzowy B. Microbiome and Culture Based Analysis of Chronic Rhinosinusitis Compared to Healthy Sinus Mucosa. Front Microbiol. 2018 Apr 17;9:643. doi: 10.3389/fmicb.2018.00643. eCollection 2018.
• Fastenberg JH, Hsueh WD, Mustafa A, Akbar NA, Abuzeid WM. Biofilms in chronic rhinosinusitis: Pathophysiology and therapeutic strategies. World J Otorhinolaryngol Head Neck Surg. 2016 May 5;2(4):219-229. doi: 10.1016/j.wjorl.2016.03.002. eCollection 2016 Dec.
• Chong LY, Head K, Hopkins C, Philpott C, Glew S, Scadding G, Burton MJ, Schilder AG. Saline irrigation for chronic rhinosinusitis. Cochrane Database Syst Rev. 2016 Apr 26;4(4):CD011995. doi: 10.1002/14651858.CD011995.pub2.
• O'Toole GA. Microtiter dish biofilm formation assay. J Vis Exp. 2011 Jan 30;(47):2437. doi: 10.3791/2437.
• Liu CM, Kohanski MA, Mendiola M, Soldanova K, Dwan MG, Lester R, Nordstrom L, Price LB, Lane AP. Impact of saline irrigation and topical corticosteroids on the postsurgical sinonasal microbiota. Int Forum Allergy Rhinol. 2015 Mar;5(3):185-90. doi: 10.1002/alr.21467. Epub 2014 Dec 29.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2022
• Primary Completion (Actual): May 19, 2023
• Study Completion (Actual): May 19, 2023

Study Registration Dates

• First Submitted: August 12, 2021
• First Submitted That Met QC Criteria: August 19, 2021
• First Posted (Actual): August 20, 2021

Study Record Updates

• Last Update Posted (Estimated): November 8, 2024
• Last Update Submitted That Met QC Criteria: August 29, 2024
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Microbiome; Biofilm; Adult; Nasal spray; Rhinosinusitis chronic; 16S rRNA sequencing
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Nose Diseases; Otorhinolaryngologic Diseases; Rhinitis; Sinusitis; Paranasal Sinus Diseases; Rhinosinusitis
• Other Study ID Numbers: LPH-2102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No