Nasal Microbiota Transfer Therapy in Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP)

Study Overview
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Brief Summary
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Chronic Rhinosinusitis (CRS) is a chronic inflammatory condition of the nasal passage and paranasal sinuses that places significant burden on affected patients and global healthcare systems. Current treatments for CRS such as long-term antibiotics, anti-inflammatory drugs, and surgery often reduce symptoms and signs of disease temporarily, however long-term results are much less satisfactory. Recently, the theory of a damaged microbiome (dysbiosis) as a cause or promoting factor behind CRS has gained increasing evidence from the scientific community. A condition of the gut with microbial dysbiosis (c.difficile) has previously employed microbiota transplant treatment with great success in long-term health outcomes. Such treatments are shown to repopulate bacterial microenvironment and restore protective commensal bacterial load. A pilot study conducted by this study team trialed a novel intervention of a Nasal Microbiota Transplant in a small group of participants. Preliminary results suggested significantly improved CRS symptoms after treatment with a healthy donor microbiota transplant, compared to the pre-transplant baseline. The addition of a randomized-control trial with inclusion of a placebo group is the next step. In this study, investigators aim to perform a two-arm, double-blinded, phase II randomized controlled clinical trial in order to assess the efficacy of a Nasal Microbiota Transplant against a placebo in a cohort of CRS patients without Nasal Polyps (CRSsNP).

Detailed Description
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Current treatments for CRS such as long-term antibiotics, anti-inflammatory drugs, and surgery often reduce symptoms and signs of disease temporarily, however long-term results are much less satisfactory. A microbiota therapy, as an alternative treatment to antibiotics, has the potential of improving outcomes for CRS patients long-term, whilst reducing the use of antibiotics in the community. Several attempts of studies to define the role of microbiota of the nose and paranasal sinuses in health and disease have not yet been able to achieve a universal consensus. This is in part due to the significant inter-individual microbiota variation and complexity within humans. Such challenges have also limited the use of probiotic assemblages of one or a combination of few bacterial species in treatment of CRS. The data derived from this study will add to our understanding of the role of the microbiome in the airways and its role in interfering with respiratory pathogens and host immunity. This is likely to have implications for CRS microbiome-based therapies, and also other potentially related respiratory conditions such as asthma, and chronic obstructive pulmonary disease (COPD). In this study, investigators will recruit patients suffering from chronic rhinosinusitis without polyps (CRSsNP) and healthy participants that do not have a history of sinonasal disease. The sinus microbiome transplants will occur over a 2 week period, with regular follow up for up to 6-months post intervention. Main outcomes include change in disease severity, symptom severity, inflammatory changes, and microbial composition across the study period. Successful results from this trial may pave the way for a novel therapeutic for CRS patients. This study has received ethics approval from the Royal Brisbane and Women's Health Human Resource and Ethics Committee (RBWH HREC).

Official Title
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Phase-II Randomized Control Trial of Nasal Microbiota Transplant Therapy in Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP)

Conditions
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Chronic Rhinosinusitis (Diagnosis)

Intervention / Treatment
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* Procedure: Microbiome Transplant
* Procedure: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria (patient): Diagnosis of Chronic Rhinosinusitis as defined by the presence of 2 or more major sinonasal symptoms (nasal blockage, nasal discharge, loss of smell, and facial pain/ fullness) for a minimum of 12 weeks Endoscopic confirmation of middle meatus inflammation or presence of mucopurulence, and /or CT confirmation of paranasal sinus inflammation. Previous nasal surgery with patent ostia to the diseased ethmoids and maxillary sinuses Signed written informed consent Inclusion criteria (donor): No history of sinonasal or lower airway disease for the last 2 years other than the common cold. No clinical findings of sinonasal disease at the inclusion visit. Accepted as a donor by the patient. Signed informed consent to participate in the study. Exclusion Criteria: Exclusion criteria (patient): Aged <18 or >80 years Allergy to amoxicillin or clavulanate potassium and Clarithromycin. Excessive Nasal polyposis Antibiotic treatment in the last 4 weeks Patients with a history supporting a diagnosis of immune deficiency will be tested (Immunoglobulin A (IgA), Immunoglobulin M (IgM), Immunoglobulin G (IgG) and IgG subclasses, MBL) and /or are immunocompromised due to disease and / or medication ( e.g., insulin dependent diabetes mellitis, systemic corticosteroids) Patients who live with someone who is severly immunocompromised. Patients with cystic fibrosis or ciliary dyskinesia Patients who have been on an active investigational therapy within 2 months of screening Patients who have clinically significant laboratory abnormalities Patients who are pregnant, breast feeding or planning to become pregnant during the study Patients who are not willing to use a double barrier method of contraception during the study that is:- females must use contraceptive pill or Intra-uterine device (IUD) or similar and condoms males must use condoms and spermicidal gel Patients currently on any medication that may affect the results in an unpredictable manner The patient does not agree to comply with or is unable to meet all study requirements for the duration of the study period Patients deemed by the investigator to be unsuitable for participation in the study Patients who have had Coronavirus-19 (COVID-19) within the last month. Exclusion criteria (donor): Findings in the prestudy pathogen scan that makes the donor unsuitable. Prestudy pathogen scan: Prior to first donation, the donors will be tested for HIV, Human T-lymphotropic virus 1 and 2, Hepatitis B and C, Syphilis, Tuberculosis, Herpes Simplex (HSV 1 and 2), Varicella Zoster (VZV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Methicillin-resistant Staphylococcus aureus (MRSA) and a standard panel for sinonasal pathogens (Pneumococci, H. Influenza, Beta-streptococci and M. Catarrhalis). Donors who have had COVID-19 within the last 2 months. If the donor is positive for Herpes Simplex, CMV or EBV they will be considered unsuitable as a donor for a patient negative for the same pathogen. If the donor is positive for any other pathogen they will be considered unsuitable as a donor entirely.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible patient participants will be randomly assigned to intervention or control group (1:1 ratio) as per a computer-generated randomisation schedule using permuted blocks of random sizes. The block sizes will not be disclosed, to ensure concealment. Both groups will receive two weeks of antibiotic treatment between recruitment and allocation to a study arm. The study team will work with each patient participant to find a suitable donor. Some patient participants will prefer a donor that is known to them other patients will prefer a donor that is an unknown volunteer. Potential donors who consent to participating in this study will be screened and be classified as donor-participants in the study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>For each nostril, the donated nasal wash sample is quiesced to 15 mls with saline Nasal Microbiota Transplant therapy. | Procedure: Microbiome Transplant<br>* A raw microbiome, is collected from a donor without any sinonasal health problems, as a nasal lavage.<br>|
| Placebo Comparator: Control<br>For each nostril, 15 mls of saline will be used as the placebo therapy. | Procedure: Placebo<br>* Normal saline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sino-Nasal Outcome Test (SNOT-22) - 22 Item Questionnaire | Change of burden of disease as measured by the SNOT-22 (22 item sinonasal outcome test) questionnaire in patients. Each item graded 0-5. Minimum score 0, Maximum 105 Interpretation: Higher score indicates poorer disease control. | Week 1 (Day 1) to Week 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lund-Kennedy endoscopic assessment score | Change of grading of disease severity using the Lund-Kennedy endoscopy score based on clinical assessment of the middle meatus. 4-item criteria, with score of 0-2 Minimum score: 0, Maximum 8 Interpretation: Higher score indicates a higher degree of disease severity based on clinical assessment. | Week 1 (Day 1) to Week 20 | 
| Characterisation of nasal microbiome in study participants | Change in nasal microbiome associated with clinical outcomes such as decrease in presence, absence or abundance of bacterial pathogens. | Week 1 (Day 1) to Week 20 | 
| Characterisation of microbiome within effective donors as compared to ineffective donors | Analysis of microbes (bacterial strains, viruses and fungi), and human cell types within donor specimens. | Week 1 (Day 1) - Week 2 (Day 9) | 
| Adverse events of Participating Patients | Any adverse event | From the day participating patients give signed consent (2-4 weeks before baseline) until the day of their End of study visit (Up to 33 weeks). | 
| Cytokine level - Interleukin 5 or (IL-5) | Change of lL-5 in nasal secretion/swab markers across duration of study. Each cytokine will be quantified using a highly sensitive immunoassay which will use biotinylated antibodies specific to each cytokine to bind the cytokine molecules in the sample. Interactions measured on a flow cytometer and compared against its relevant standard. this will result in a measure of the total concentration of the cytokine in the sample (pg/ml). | Week 1 (Day 1) to Week 20 | 
| Cytokine level - Interleukin 13 (IL-13) | Change of lL-13 in nasal secretion/swab markers across duration of study. Each cytokine will be quantified using a highly sensitive immunoassay which will use biotinylated antibodies specific to each cytokine to bind the cytokine molecules in the sample. Interactions measured on a flow cytometer and compared against its relevant standard. this will result in a measure of the total concentration of the cytokine in the sample (pg/ml). | Week 1 (Day 1) to Week 20 | 
| Cytokine level - Interleukin 2 (IL-2) | Change of lL-2 in nasal secretion/swab markers across duration of study. Each cytokine will be quantified using a highly sensitive immunoassay which will use biotinylated antibodies specific to each cytokine to bind the cytokine molecules in the sample. Interactions measured on a flow cytometer and compared against its relevant standard. this will result in a measure of the total concentration of the cytokine in the sample (pg/ml). | Week 1 (Day 1) to Week 20 | 
| Cytokine level - Interleukin 6 (IL-6) | Change of lL-6 in nasal secretion/swab markers across duration of study.Each cytokine will be quantified using a highly sensitive immunoassay which will use biotinylated antibodies specific to each cytokine to bind the cytokine molecules in the sample. Interactions measured on a flow cytometer and compared against its relevant standard. this will result in a measure of the total concentration of the cytokine in the sample (pg/ml). | Week 1 (Day 1) to Week 20 | 
| Cytokine level - Interleukin 10 (IL-10) | Change of lL-10 in nasal secretion/swab markers across duration of study.Each cytokine will be quantified using a highly sensitive immunoassay which will use biotinylated antibodies specific to each cytokine to bind the cytokine molecules in the sample. Interactions measured on a flow cytometer and compared against its relevant standard. this will result in a measure of the total concentration of the cytokine in the sample (pg/ml). | Week 1 (Day 1) to Week 20 | 
| Cytokine level - Interferon gamma (IFN-γ) | Change of IFN-Y in nasal secretion/swab markers across duration of study.Each cytokine will be quantified using a highly sensitive immunoassay which will use biotinylated antibodies specific to each cytokine to bind the cytokine molecules in the sample. Interactions measured on a flow cytometer and compared against its relevant standard. this will result in a measure of the total concentration of the cytokine in the sample (pg/ml). | Week 1 (Day 1) to Week 20 | 
| Cytokine level - Interleukin 4 (IL-4) | Change of IL-4 in nasal secretion/swab markers across duration of study.Each cytokine will be quantified using a highly sensitive immunoassay which will use biotinylated antibodies specific to each cytokine to bind the cytokine molecules in the sample. Interactions measured on a flow cytometer and compared against its relevant standard. this will result in a measure of the total concentration of the cytokine in the sample (pg/ml). | Week 1 (Day 1) to Week 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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microbiota, transplant, paranasal sinuses, nasal lavage