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.
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:
1. 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.
2. 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:
1. Eligibility determination period (Day 0)
2. Treatment period (Day 1 to Day 14): Probiorinse or Saline solution
3. 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.
Other: Probiorinse
Nasal irrigations with probiotic twice-daily for a period of fourteen days
Other Name: Array
Other: Saline solution
Nasal irrigations with saline-only twice-daily for a period of fourteen days
Other Name: Natural health product
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
Centre Hospitalier de l'Université de Montréal (CHUM)
Montreal, Quebec, Canada
Martin Y Desrosiers, MD, Principal Investigator
Centre hospitalier de l'Université de Montréal (CHUM)