Efficacy of Intranasal Probiotic Treatment to Reduce Severity of Symptoms in COVID19 Infection

Study Overview
=================
Brief Summary
-----------------
Randomised, single-blinded trial. Patients with a diagnosis of COVID-19 infection within the past 96 hours and not requiring hospitalization will be recruited into a trial of BID Nasal irrigation for 14 days, followed by a 14 day observation period. Irrigation will be performed with either Probiorinse probiotic nasal irrigation solution or NeilMed Sinus rinse. Patients will be able to identify their treatments, but study staff will be blinded as to assignment.

Detailed Description
-----------------
BACKGROUND/OBJECTIVE The potential role of the microbiome in COVID-19 disease remains little explored, yert may offer an unique therapeutic opportunity for its treatment. Airway inflammation and microbiome dysbiosis is present in COVID-19 patients and is related to evolution. The limited information on airway inflammation in COVID-19 suggests greater inflammation, as assessed by serum markers of inflammation, is associated by more severe disease. Late cell-mediated T-cell activation is paradoxically accompanied by TLR expression downregulation, which contributes to dysfunctional immune regulation. Individual predisposition to heightened inflammatory responses may contribute to this. The investigators believe this early TLR downregulation is an important feature of the disease, allowing the disease to reproduce unchecked and spread during a prolonged asymptomatic shedding period. Immune-evasion strategies are common to several viral infections such as influenza, respiratory syncytial virus, and human rhinovirus, COVID-19 may exploit this as well. Lung microbiome data in COVID-19 is limited, but a small dataset of 8 hospitalised cases has been reported from China suggests pulmonary inflammation can be influenced by the microbiome at the time of intubation, arguing the need for a more favorable upper airway microbiome. Based on the above information, the investigators believe that administration of probiotic bacteria directly to the upper airway via irrigation to patients receiving a diagnosis of COVID-19 will improve the status of the upper airway microbiome and reduce symptom severity and disease in patients with COVID-19 disease not requiring ICU admission or intubation. The investigators believe intranasally applied 'health-inducing' bacteria will favorably modulate the response to COVID-19 infection, reducing its severity and complications. Probiorinse may exert potentially beneficial effects in COVID-19 infection via two potential and distinct mechanisms: Activation of the innate immune system via enhanced TLR signalling: - Abundant TLR ligands present on the probiotic bacterial capsule may counter the downregulation in TLR expression and function seen with COVID-19 infection. Promotion of a 'healthy' microbiome profile in the nasopharynx: Reducing seeding the lower respiratory tract with inappropriate bacteria or pathogens. Conditioning inappropriate or excessive immune responses of the airway The purpose of this clinical trial is thus to compare the safety and validity of intranasal irrigation with Lactococcus lactis W136 with saline nasal irrigation alone in patients with mild COVID-19 infection. METHODOLOGY Consent process in the current context of the COVID-19 pandemic: Verbal consent and confirmation of consent in writing or electronically. Participants will be recruited via posted signs in the COVID-19 clinic and hospital Intranet advertising a research project for individuals diagnosed with COVID-19 infection. This study will include three (3) periods, which will take the form of telephone calls / email contacts: Eligibility determination period (Day 0) Treatment period (Day 1 to Day 14): Probiorinse or Saline solution Follow-up period (Day 21 and Day 28) STATISTICAL ANALYSIS Analysis population: The primary analysis population for the efficacy endpoints will be the randomized ITT population which includes all patients who have been allocated to a randomized treatment regardless of whether the treatment kit was used or not. The efficacy analyses will be conducted according to the treatment to which they were randomized. The analysis population for safety endpoints is defined as all patients exposed to study medication, regardless of the amount of treatment administered. The safety analyses will be conducted according to the treatment patients actually received. The treatment emergent period is defined as the time from the first administration of study medication to Day 14 of post treatment period. Data Analysis: The following null hypothesis and alternative will be tested for the Probiorinse arm against NeilMed Sinus Rinse: H0: No treatment difference between Probiorinse and NeilMed Sinus Rinse. H1: There is a treatment difference between Probiorinse and NeilMed Sinus Rinse Descriptive statistics including number of subjects mean, standard error, and least squares (LS) means will be provided. In addition, difference in LS means and the corresponding 95% confidence intervals (CI) will be provided along with the p-values.

Official Title
-----------------
Randomised Single Blinded Clinical Study of Efficacy of Intranasal Probiotic Treatment to Reduce Severity of Symptoms in COVID19 Infection

Conditions
-----------------
COVID-19 Infection

Intervention / Treatment
-----------------
* Other: Probiorinse
* Other: Saline solution


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females aged 18-59 years Positive diagnosis of COVID-19 infection less than 96 hours Characteristic respiratory symptoms present but no more than mild to moderate No need for oxygen Temperature less than 38.0 ºC Not presently being considered for hospitalisation or ICU admission Able to perform nasal irrigation Able to provide consent Able to communicate with the study team by phone, text or email Exclusion Criteria: Patients with pre-existing conditions or demographic features placing them at increased risk of complications from COVID10 infection will not be included in this study. These will be considered exclusion factors, thus individuals will be questioned as to the presence or these factors during their telephone screening. Respiratory disorders: Asthma, Pre-existing COPD, bronchiectasis or cystic fibrosis Hypertension Cardiovascular disease: Rhythm disturbances, recent (less than 6 months), angina pectoris cardiac insufficiency Diabetes Immunosuppressed patients (other than COVID-19 induced) Primary immune deficiencies such as hypogammaglobulinemia or common variable immune deficiency (CVID) Chemotherapy depressing the immune system Immune suppressing medications such as prednisone, Imuran, or TNF inhibitors, or anti-rejection transplant drugs. Solid organ transplant Cancer under treatment or within five years (except basocellular skin cancers) Pregnant or breastfeeding women or women unwilling to practice contraception as outlined in the study protocol for the duration of the study period. Allergy to milk or its derivatives

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 59 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: Single-blinded, randomized, prospective trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiorinse<br>Nasal irrigations with Probiorinse (2.4 Billion CFU (Colony-Forming Units) of Lactococcus Lactis W136, (NPN: 80085895)) twice-daily for a period of fourteen days | Other: Probiorinse<br>* Nasal irrigations with probiotic twice-daily for a period of fourteen days<br>* Other names: Probiotic;|
| Active Comparator: Saline solution<br>Nasal irrigations with saline (NeilMed Sinus Rinse, (NPN: 80027142)) twice-daily for a period of fourteen days | Other: Saline solution<br>* Nasal irrigations with saline-only twice-daily for a period of fourteen days<br>* Other names: Natural health product;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in severity of COVID-19 infection | Change in severity of COVID-19 infection as assessed by number of days with any symptoms of COVID-19 infection greater than or equal to 35 as measured on VAS scale as assessed at the 28 day endpoint. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of days with any symptom of anosmia | Number of days with any symptom of anosmia | 4 weeks | 
| Maximal intensity attained in overall assessment of symptoms of COVID-19 infection as measured on Visual Analogue Scale (VAS). | Maximal intensity attained in overall assessment of symptoms of COVID-19 infection as measured on Visual Analogue Scale (VAS). VAS scale from 0 to 100, with a higher score indicating a worse outcome. | 4 weeks | 
| Number of days where rescue medication is required | Number of days where rescue medication is required | 4 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, Nasal irrigation, Probiotic, Microbiome, Lactococcus lactis W136