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Microbiota Transfer for Chronic Rhinosinusitis (SNMT)

Primary Purpose

Sinusitis, Chronic, Sinus Disease, Sinus Infection

Status

Recruiting

Phase

Not Applicable

Locations

Canada

Study Type

Interventional

Intervention

Sinonasal Microbiota Transfer

Sham Sinonasal Microbiota Transfer

About this trial

This is an interventional treatment trial for Sinusitis, Chronic focused on measuring Microbiota Transplant, Chronic Rhinosinusitis

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Exclusion Criteria for Donors:

If they are positive for any of the following: (i) from blood or mucus testing, human Immunodeficiency virus (HIV) I/II, hepatitis A IgM, hepatitis B surface antigen (HBsAg), hepatitis C, human T- lymphotropic virus (HTLV) I/II, methicillin-resistant Staphylococcus aureus, multidrug resistant bacteria, and/or SARS-CoV-2
A history of sinonasal or lower airway disease within the last 2 years other than the common cold; diagnosed with CRS; diagnosed with acute rhinosinusitis within the last six months; asthma; and/or clinical findings of sinonasal disease at the inclusion visit and immunodeficiency; any history of active cancer, or risk factors for acquisition of HIV, syphilis, hepatitis A, hepatitis B, hepatitis C, prion, or relevant neurological disease, receipt of blood transfusion from a country other than Canada in the preceding 6 months, any type of antibiotic treatment or any systemic immunosuppressive agents in the 3 months prior to the donation, or any current or previous medical or psychosocial condition or behaviours, which in the opinion of the investigator, may pose a risk to the recipient or the donor

Sites / Locations

St. Paul's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Sinonasal Microbiota Transfer

Sham Sinonasal Microbiota Transfer

Arm Description

The transfer site for patients will be prepared by endoscopically removing any visible crusting, mucin, and purulent discharge from the sinuses and via manual high-volume (>60 ml), high-pressure saline wash on day 0. The donor mucus sample will be homogenized using sterile, disposable rotor-stator homogenizer tips for 30 seconds and 5 ml of donor mucus will be instilled into the affected sinus cavity(ies) using a masked syringe under endoscopic visualization, with the recipient's head in a dependent position. Patients will remain in this position for 15 minutes to facilitate transfer.

Sterile saline will replace the SNMT donor mucus in the masked syringe and will be delivered in an identical manner to the SNMT intervention.

Outcomes

Primary Outcome Measures

Modified Lund-Kennedy (MLK) endoscopic scoring

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 Outcome Measures

Sinonasal Outcome Test (SNOT-22) questionnaire

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

Smell test using Sniffin' Sticks (scores range from 0-48).

Adverse and serious adverse events

The safety of SNMT will be examined by identifying any adverse events, including serious adverse events.

Microbiome analysis of patients and donor samples

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

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

Full Information

NCT ID

NCT05454072

First Posted

July 7, 2022

Last Updated

July 15, 2022

Sponsor

Amin Javer

1. Study Identification

Unique Protocol Identification Number

NCT05454072

Brief Title

Microbiota Transfer for Chronic Rhinosinusitis

Acronym

SNMT

Official Title

SinoNasal Microbiota Transfer (SNMT) to Treat Chronic Rhinosinusitis: A Randomized, Double-blind, Placebo-controlled Trial

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Recruiting

Study Start Date

June 15, 2022 (Actual)

Primary Completion Date

June 2024 (Anticipated)

Study Completion Date

June 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Amin Javer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sinusitis, Chronic, Sinus Disease, Sinus Infection, Sinus Infection Chronic

Keywords

Microbiota Transplant, Chronic Rhinosinusitis

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sinonasal Microbiota Transfer

Arm Type

Experimental

Arm Description

Arm Title

Sham Sinonasal Microbiota Transfer

Arm Type

Sham Comparator

Arm Description

Sterile saline will replace the SNMT donor mucus in the masked syringe and will be delivered in an identical manner to the SNMT intervention.

Intervention Type

Procedure

Intervention Name(s)

Sinonasal Microbiota Transfer

Intervention Description

Pre-screened donor mucus, up to 15mL, will be transplanted into each diseased sinus via nasal lavage.

Intervention Type

Procedure

Intervention Name(s)

Sham Sinonasal Microbiota Transfer

Intervention Description

Saline, up to 15mL, will be transplanted into each diseased sinus via nasal lavage.

Primary Outcome Measure Information:

Title

Modified Lund-Kennedy (MLK) endoscopic scoring

Description

Time Frame

Baseline to 45 days

Secondary Outcome Measure Information:

Title

Sinonasal Outcome Test (SNOT-22) questionnaire

Description

Disease specific quality of life improvement, which includes 22 questions that encompass 4 subdomains of CRS (nasal, sleep, otologic/facial pain, and emotional symptoms).

Time Frame

Baseline to 45 days, 90 days, 180 days

Title

Smell Test

Description

Smell test using Sniffin' Sticks (scores range from 0-48).

Time Frame

Baseline to 45 days, 90 days, 180 days

Title

Adverse and serious adverse events

Description

The safety of SNMT will be examined by identifying any adverse events, including serious adverse events.

Time Frame

Baseline to any time until the end of the study period

Title

Microbiome analysis of patients and donor samples

Description

Time Frame

Baseline to 45 days, 90 days, 180 days

Title

Immune markers

Description

Time Frame

Baseline to 45 days, 90 days, 180 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

19 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 Exclusion Criteria for Donors: If they are positive for any of the following: (i) from blood or mucus testing, human Immunodeficiency virus (HIV) I/II, hepatitis A IgM, hepatitis B surface antigen (HBsAg), hepatitis C, human T- lymphotropic virus (HTLV) I/II, methicillin-resistant Staphylococcus aureus, multidrug resistant bacteria, and/or SARS-CoV-2 A history of sinonasal or lower airway disease within the last 2 years other than the common cold; diagnosed with CRS; diagnosed with acute rhinosinusitis within the last six months; asthma; and/or clinical findings of sinonasal disease at the inclusion visit and immunodeficiency; any history of active cancer, or risk factors for acquisition of HIV, syphilis, hepatitis A, hepatitis B, hepatitis C, prion, or relevant neurological disease, receipt of blood transfusion from a country other than Canada in the preceding 6 months, any type of antibiotic treatment or any systemic immunosuppressive agents in the 3 months prior to the donation, or any current or previous medical or psychosocial condition or behaviours, which in the opinion of the investigator, may pose a risk to the recipient or the donor

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Amin Javer, MD

Phone

(604) 806-9926

sinusdoc@me.com

First Name & Middle Initial & Last Name or Official Title & Degree

Amee Manges, PhD

Phone

(604) 822-9203

amee.manges@ubc.ca

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Amin Javer, MD

Organizational Affiliation

University of British Columbia

Official's Role

Study Director

Facility Information:

Facility Name

St. Paul's Hospital

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V6Z 1Y6

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Amin Javer, MD

Phone

(604) 806-9926

sinusdoc@me.com

First Name & Middle Initial & Last Name & Degree

Amee Manges, PhD

Phone

(604) 822-9203

amee.manges@ubc.ca

First Name & Middle Initial & Last Name & Degree

Amin Javer, MD

First Name & Middle Initial & Last Name & Degree

Amee Manges, PhD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

24131818

Citation

Lange B, Holst R, Thilsing T, Baelum J, Kjeldsen A. Quality of life and associated factors in persons with chronic rhinosinusitis in the general population: a prospective questionnaire and clinical cross-sectional study. Clin Otolaryngol. 2013 Dec;38(6):474-80. doi: 10.1111/coa.12189.

Results Reference

background

PubMed Identifier

25640115

Citation

Smith KA, Orlandi RR, Rudmik L. Cost of adult chronic rhinosinusitis: A systematic review. Laryngoscope. 2015 Jul;125(7):1547-56. doi: 10.1002/lary.25180. Epub 2015 Jan 30.

Results Reference

background

PubMed Identifier

19117310

Citation

Macdonald KI, McNally JD, Massoud E. The health and resource utilization of Canadians with chronic rhinosinusitis. Laryngoscope. 2009 Jan;119(1):184-9. doi: 10.1002/lary.20034.

Results Reference

background

PubMed Identifier

24610673

Citation

Baguley C, Brownlow A, Yeung K, Pratt E, Sacks R, Harvey R. The fate of chronic rhinosinusitis sufferers after maximal medical therapy. Int Forum Allergy Rhinol. 2014 Jul;4(7):525-32. doi: 10.1002/alr.21315. Epub 2014 Mar 7.

Results Reference

background

PubMed Identifier

28688189

Citation

Stein NR, Jafari A, DeConde AS. Revision rates and time to revision following endoscopic sinus surgery: A large database analysis. Laryngoscope. 2018 Jan;128(1):31-36. doi: 10.1002/lary.26741. Epub 2017 Jul 8.

Results Reference

background

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Microbiota Transfer for Chronic Rhinosinusitis

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