Topical Probiotic Sinus Irrigations for Treating Chronic Sinusitis

Study Overview
=================
Brief Summary
-----------------
The purpose of this non-randomized study will be to determine whether topical probiotic sinus irrigations are more effective compared to saline sinus irrigation controls in the treatment of active CRS in patients who have had prior sinus surgery based on subjective and objective outcome measures.

Detailed Description
-----------------
CRS is a common clinical entity with estimated prevalence ranging from 14-16% in the community. The most commonly implicated pathogenic bacteria in recalcitrant patients are Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa). In recent years, there has been an increasing focus on the commensal sinonasal microbiome and its role in the development of a functional immune system. It has been theorized that infections in CRS may be related to a decrease in diversity of the commensal microbiome and an increase in these pathogenic bacteria. The concept behind the therapeutic potential of topical probiotics is that they outcompete pathogenic bacteria via a variety of mechanisms, including creating suboptimal environmental conditions, competing for cell surface receptors and thus limiting pathogen adherence, and producing antibacterial metabolites. In doing so, topical probiotics restore the commensal microbiome. For this study, after being informed about the study and potential risks, all patients meeting eligibility criteria and giving written informed consent will be randomized in a double blind manner (participant and investigator) in a 1:1 ratio to Lactobacillus sakei (1×10(9) CFU L. Sakei nasal irrigation in 240 ml water/irrigation) or Isotonic saline solution in 240 ml of water for nasal irrigation, twice a day for 14 days. Patient assessments will occur before treatments begin, immediately after the completion of nasal irrigations, and 6 weeks after initial enrollment. Assessments will be based on patient history, endoscopic exams, CT scan assessments using Lund-MacKay CT staging system, culture swab of the sinuses (bacterial burden and number of taxa, SNOT-22 survey, and a visual analog scale to record pain scores.

Official Title
-----------------
Topical Probiotic Sinus Irrigations for the Treatment of Chronic Rhinosinusitis: a Double Blinded Randomized Controlled Trial

Conditions
-----------------
Chronic Rhinosinusitis (Diagnosis)

Intervention / Treatment
-----------------
* Drug: Lactobacillus sakei proBio65
* Other: Isotonic Saline Solution


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female patients 18 years of age or older. Patients diagnosed with acute exacerbation of CRS, defined by worsening of 1 or more sinonasal symptoms (nasal obstruction/congestion, nasal discharge, facial pain/pressure, reduced sense of smell) and inflammatory and/or infectious changes on sinus endoscopy. Patients that have undergone functional endoscopic sinus surgery > 12 weeks prior to enrollment as documented in the patients electronic medical record, with patent sinuses deemed suitable for trial on investigator's discretion. Patients must be willing to follow study related procedures for the duration of the study. Patients must understand the purpose and procedures and be willing to sign the study informed consent document. All adult men and women with active CRS will be considered for participation in this study without regard to race, gender, or socioeconomic status. Exclusion Criteria: Male and female patients under 18 years of age. Patients who have not been diagnosed with CRS or acute exacerbation of CRS, defined by worsening of 1 or more sinonasal symptoms (nasal obstruction/congestion, nasal discharge, facial pain/pressure, reduced sense of smell) and inflammatory and/or infectious changes on sinus endoscopy. Patients that have undergone functional endoscopic sinus surgery < 12 weeks prior to enrollment with patent sinuses deemed unsuitable for trial on investigator's discretion. Patients unwilling to follow study related procedures for the duration of the study. Patients who are unable to independently understand the study purpose and procedures and who are not willing to sign the study informed consent document. Patients who are taking topical antibiotic irrigations and state they are unwilling to stop them. Patients who are unable to complete self-administered questionnaires because of cognitive impairment, language barrier, or severe medical conditions. Patients who have a terminal illness, immunocompromised or systemic disease (e.g. granulomatosis polyangiitis, cystic fibrosis). Patients who have severe or emergent complications from CRS or presence of a sinus tumor. Female patients who are pregnant or breastfeeding. Patients who are taking oral corticosteroids or who have taken oral antibiotics in the previous 2 weeks or on oral corticosteroids.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Adult patients of the PI's or co-investigator's with a diagnosis of active CRS and who meet the inclusion and exclusion criteria will be eligible to participate. A total of 60 subjects will be randomize evenly into 2 study groups: 30 patients in the saline group (SAL) and 30 patient in the Lactobacillus sakei group (LAC). Patients will asked to do nasal irrigations 2 times/day for 14 days. Patient history, sinus exams, culture swabs, surveys (SNOT-22) and pain scale will access pre and post treatment results. Patients will be assessed and compared prior to beginning sinus irrigations, the week after irrigations are completed, and 6 weeks after initial assessment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Saline Nasal Irrigation (Control)<br>Patients will perform nasal irrigation with an isotonic saline solution, using a 240ml NeilMed sinus rinse bottle, 2 times/day for 14 days. A blinded vial supplied by IDS containing a premeasured amount of saline to be mixed with 240ml of distilled water will be provided to patients for each irrigation. | Other: Isotonic Saline Solution<br>* Saline sinus irrigations (SAL group): NeilMed® Isotonic Sinus Rinse™ is marketed as a saline sinus irrigation formula. Subjects will be given instructions to mix one unlabeled vial (containing NeilMed® premixed buffered salt powder) with lukewarm distilled or boiled water in 240mL NeilMed® sinus rinse bottle.<br>* Other names: NeilMed Isotonic Sinus Rinse;|
| Experimental: Lactobacillus sakei nasal irrigation<br>Patients will perform nasal irrigation with 1 gram of product 2 times/day for 14 days. Each gram of product contains 1×10(9) CFU L. Sakei that will be dissolved in 240 ml water using a 240ml NeilMed sinus rinse bottle. A blinded vial provided by IDS containing a premeasured amount of Lactobacillus sakei to be mixed with 240ml of distilled water will be provided to patients for each irrigation. | Drug: Lactobacillus sakei proBio65<br>* Lanto Sinus probiotic Lactobacillus sakei is a currently available over the counter supplement from the common source kimchi and produced in South Korea. The product contains 17 billion total CFU of Lactobacillus sakei/gram at the time of manufacture. Lanto Sinus is produced using Good Manufacturing Practice standards. The probiotic is packaged as a powder in PE plastic bottles with 15 grams of product in each bottle. IDS will aliquot 1 gram of product/unlabeled vial, 28 vials/patient. Patients will be instructed to mix 1 vail with 240 mls of distilled water.<br>* Other names: Lanto Sinus Probiotic Powder;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sinonasal Outcome Test-22 (SNOT-22) | It is expected that topical probiotic irrigations will result in a clinically significant change in symptom severity score (SNOT-22) (a change of 9 on a scale 0-110) compared to saline irrigations (primary outcome). | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sinus microbiota | Nasal swab samples will be assessed for the number of bacteria present before and after treatment. Bacterial DNA will be extracted from nasal swabs. The purified DNA will be quantified for concentration using a Qubit fluorometer (Invitrogen, CA, USA) before storing at -20°C until further use. Bacterial burden will be determined by quantitative PCR (qPCR) using universal 16S ribosomal RNA primers. Additionally, each nasal swab will be assessed for bacteria taxonomic distribution by NGS using the MiSeq NGS platform (Illumina) before and after treatment. MiSeq paired-end sequencing of the hypervariable V3-V4 regions of the 16S rRNA gene (primers 341F/785R) will be performed. | 6 weeks |