Sinus Disease, Sinus Infection, Sinus Infection Chronic, Sinusitis, Chronic
Conditions
Keywords
Microbiota Transplant, Chronic Rhinosinusitis
Brief summary
Chronic sinusitis (CRS) is a common inflammatory condition of the sinuses that affects up to 2.5% of the Canadian population, and is thought to be caused by bacterial infection, resistant biofilms, chronic inflammation and possibly an unhealthy population of sinus microbes (or microbiota). Symptoms include nasal obstruction and discharge, facial pain, loss of smell and sleep disturbance, which all strongly impact quality of life. CRS treatment involves nasal or oral steroids, repeated rounds of antibiotic, and sinus surgery. Despite maximal treatment, some recalcitrant patients suffer with CRS for years. The lack of new, effective therapies to treat CRS leads the investigators to test whether a SinoNasal Microbiota Transfer (SNMT) could trigger CRS recovery. SNMT is defined as the endoscopic transfer of a healthy sinus microbiota from a fully screened donor's sinus to a CRS patient's sinus(es). Similar to a fecal transplant used to treat Clostridioides difficile diarrhea, the sinonasal microbiota transfer may eliminate sinus pathogens and restore the sinus microbiota to a healthy state. SNMT will be combined with a one-time, high volume, high pressure "sinus power wash" pre-treatment to temporarily clear the way for the donor microbiota to establish itself. The investigators will conduct a proof-of-principle, randomized, double-blind, placebo-controlled trial of 80 subjects to test whether a sinus power wash plus SNMT improves clinical outcomes in CRS patients.
Detailed description
Chronic rhinosinusitis (CRS) is a common inflammatory condition of the paranasal sinuses. CRS patients experience persistent facial pain/pressure, nasal discharge, nasal obstruction, and loss of smell. Initial treatment includes topical and systemic steroids and (often multiple rounds of) antibiotics; however, two thirds of patients remain symptomatic despite medical therapy and require endoscopic sinus surgery. Direct medical and indirect social costs of CRS are substantial, with 57% of patients reporting absenteeism and poor health and 28% experiencing associated anxiety and depression. These hard-to-treat patients are classified as recalcitrant CRS (rCRS), have limited treatment options available, and are the focus of this trial. CRS was thought to occur due to impaired sinus ventilation and drainage however new evidence suggests that sinus mucosal inflammation, driven in part by microbiota disruptions and pathogen carriage, is the etiological factor behind CRS. Type of inflammation varies and cannot be predicted based on clinical variables alone. Several studies show that the microbiome composition of CRS patients is less diverse compared to healthy subjects, suggesting that community-level disruptions, and not individual opportunistic pathogens, may contribute to persistent inflammation. The investigators will conduct a proof-of-principle, randomized, double-blind, placebo-controlled trial of 80 subjects to test whether a sinus power wash plus SNMT improves clinical outcomes in CRS patients within 45 days compared to a sinus power wash and sham SNMT. The investigators will investigate the safety profile of SNMT and determine if SNMT-related CRS symptom improvement lasts up to 6 months. Finally, the investigators will investigate how SNMT contributes to CRS recovery, by tracking changes in the sinus microbiota and inflammation pre- and post-treatment. Results from our pilot study shows that SNMT produced CRS symptom improvement in 75% of patients. SNMT therapy may be a transformative strategy to address CRS, a chronic and debilitating illness.
Interventions
PROCEDURESinonasal Microbiota Transfer
Pre-screened donor mucus, up to 15mL, will be transplanted into each diseased sinus via nasal lavage.
PROCEDURESham Sinonasal Microbiota Transfer
Saline, up to 15mL, will be transplanted into each diseased sinus via nasal lavage.
Sponsors
Amin Javer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
for Patients: * Recalcitrant CRS patients * Able to provide informed consent * Diagnosed with CRS (with/without polyps) and have previously undergone functional endoscopic sinus surgery (Post-FESS) * Continued to fail despite receiving "maximal and adequate medical treatment" This is defined as patients who: * Have received topical nasal steroids in any form (Spray/ Rinse/ Atomized) for at least 3 months or at least one course of oral corticosteroids treatment (\>0.5 mg/kg for 2 weeks tapering dose); * Had at least one course of antibiotic treatment either based on culture and sensitivity of nasal sinus secretions or as long-term low dose macrolide therapy (clarithromycin 500mg twice a day for 2 weeks then 250 mg once a day for 4 weeks) for at least one trial or have received a course of itraconazole 100mg twice daily for 6 weeks * Have deteriorating SNOT-22 Scores (≥20) or do not improve after surgery and appropriate maximal medical management (MLK score ≥ 2, with at least 2 points on the discharge subdomain)
Exclusion criteria
for Patients: * Diagnosed with sinonasal tumors * Autoimmune diseases affecting the upper airway (e.g., systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis) * Immune-compromised patients * Impairment in mucociliary function (e.g., cystic fibrosis, Kartagener syndrome) * Pregnant or planning to become pregnant or breastfeeding * Severe underlying disease with anticipated survival less than 6 months * Unable to tolerate SNMT for any reason Inclusion Criteria for Donors: * 19 years of age or older * Able to provide informed consent, complete donor screening, and adhere to SNMT mucus collection and testing procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Lund-Kennedy (MLK) endoscopic scoring | Baseline to 45 days | Change in endoscopic score, where points to each sinus are assigned based on discharge (0 - no discharge; 1 - clear discharge; 2 - purulent discharge), edema (0 - edema; 1 - mild edema; 2 - severe edema), and polyps (0 - no polyps; 1 - confined to the middle meatus; 2 - beyond the middle meatus) for a maximum of 6 points per side (12 total). A 1-point difference in the total MLK score is considered clinically meaningful since it signifies a change in either polyp size, edema severity, or type of discharge. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sinonasal Outcome Test (SNOT-22) questionnaire | Baseline to 45 days, 90 days, 180 days | Disease specific quality of life improvement, which includes 22 questions that encompass 4 subdomains of CRS (nasal, sleep, otologic/facial pain, and emotional symptoms). |
| Smell Test | Baseline to 45 days, 90 days, 180 days | Smell test using Sniffin' Sticks (scores range from 0-48). |
| Adverse and serious adverse events | Baseline to any time until the end of the study period | The safety of SNMT will be examined by identifying any adverse events, including serious adverse events. |
| Microbiome analysis of patients and donor samples | Baseline to 45 days, 90 days, 180 days | Metagenome sequencing will be performed to construct metagenome-assembled genomes of CRS pathogens in donor and recipient mucus, to unambiguously describe strain-specific eradication or reinfection; determine donor sinus microbiota engraftment; detect evidence for (or not) resistance gene and resistant organism transfer via SNMT from donor to recipient; and investigate microbiome compositional and functional features associated with SNMT success or failure. |
| Immune markers | Baseline to 45 days, 90 days, 180 days | To assess immune activation and inflammation-related responses to SNMT CRS-specific structured histological analysis will be performed to detect a reduction in tissue eosinophilia and/or neutrophilia, mucosal ulceration, and squamous metaplasia; cytokine/chemokine testing to detect a decrease in inflammation; and antibody testing and blood work to measure sustained reductions in serum eosinophils and IgE levels |
Countries
Canada
Contacts
STUDY_DIRECTORAmin Javer, MD
University of British Columbia
Outcome results
None listed