Clinical trial NCT05400616: Nasal Microbiota Transfer Therapy in Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP)
Official title: Phase-II Randomized Control Trial of Nasal Microbiota Transplant Therapy in Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Chronic Rhinosinusitis (Diagnosis)
Keywords: microbiota
transplant
paranasal sinuses
nasal lavage
Lead sponsor: The University of Queensland
Sponsor class: OTHER
Collaborators: name: Royal Brisbane and Women's Hospital
name: Monash Health
name: Queensland University of Technology
First posted: 2022-06-01
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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:-

  1. females must use contraceptive pill or Intra-uterine device (IUD) or similar and condoms
  2. 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.

Primary outcomes:
measure: Sino-Nasal Outcome Test (SNOT-22) - 22 Item Questionnaire
timeFrame: Week 1 (Day 1) to Week 20
Secondary outcomes:
measure: Lund-Kennedy endoscopic assessment score
timeFrame: Week 1 (Day 1) to Week 20
measure: Characterisation of nasal microbiome in study participants
timeFrame: Week 1 (Day 1) to Week 20
measure: Characterisation of microbiome within effective donors as compared to ineffective donors
timeFrame: Week 1 (Day 1) - Week 2 (Day 9)
measure: Adverse events of Participating Patients
timeFrame: 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).
measure: Cytokine level - Interleukin 5 or (IL-5)
timeFrame: Week 1 (Day 1) to Week 20
measure: Cytokine level - Interleukin 13 (IL-13)
timeFrame: Week 1 (Day 1) to Week 20
measure: Cytokine level - Interleukin 2 (IL-2)
timeFrame: Week 1 (Day 1) to Week 20
measure: Cytokine level - Interleukin 6 (IL-6)
timeFrame: Week 1 (Day 1) to Week 20
measure: Cytokine level - Interleukin 10 (IL-10)
timeFrame: Week 1 (Day 1) to Week 20
measure: Cytokine level - Interferon gamma (IFN-γ)
timeFrame: Week 1 (Day 1) to Week 20
measure: Cytokine level - Interleukin 4 (IL-4)
timeFrame: Week 1 (Day 1) to Week 20
Other outcomes:
Locations:
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: University of Queensland
state: Queensland
city: Melbourne
country: Australia
facility: Monash Health
Study officials:
affiliation: University of Queensland/Royal Brisbane and Women's Hospital
name: Anders Cervin, MD,FRACS
role: STUDY_DIRECTOR
References:
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citation: Cho DY, Hunter RC, Ramakrishnan VR. The Microbiome and Chronic Rhinosinusitis. Immunol Allergy Clin North Am. 2020 May;40(2):251-263. doi: 10.1016/j.iac.2019.12.009. Epub 2020 Jan 16.
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citation: Mahdavinia M, Keshavarzian A, Tobin MC, Landay AL, Schleimer RP. A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS). Clin Exp Allergy. 2016 Jan;46(1):21-41. doi: 10.1111/cea.12666.
citation: Buckland JR, Thomas S, Harries PG. Can the Sino-nasal Outcome Test (SNOT-22) be used as a reliable outcome measure for successful septal surgery? Clin Otolaryngol Allied Sci. 2003 Feb;28(1):43-7. doi: 10.1046/j.1365-2273.2003.00663.x.
citation: Rudmik L. Economics of Chronic Rhinosinusitis. Curr Allergy Asthma Rep. 2017 Apr;17(4):20. doi: 10.1007/s11882-017-0690-5.
citation: Wagner Mackenzie B, Waite DW, Hoggard M, Douglas RG, Taylor MW, Biswas K. Bacterial community collapse: a meta-analysis of the sinonasal microbiota in chronic rhinosinusitis. Environ Microbiol. 2017 Jan;19(1):381-392. doi: 10.1111/1462-2920.13632. Epub 2017 Jan 18.