Sinonasal Microbiome Transplant as a Therapy for Chronic Rhinosinusitis (CRS).

Official title

Sinonasal Microbiome Transplant as a Therapy for Chronic Rhinosinusitis (CRS): A Randomized , Placebo Controlled Cross Over Trial

Overview

Chronic rhinosinusitis (CRS) is a disease associated with impaired quality of life and substantial societal costs. Much is still uncertain regarding the underlying etiology of the disease. Current treatment protocols are based on observed effects rather than a mechanistic understanding of the disease and thus patients often report unsatisfactory symptom reduction despite treatment with maximal medical therapy and even surgery. CRS is subgrouped phenotypically based on whether or not polyps are observed. Recently an endotypical differentiation reflecting the underlying inflammatory profile has been recommended as well, especially for research. Increasing interest in the role of the commensal microbiome inflammatory diseases has followed a growing understanding of its profound impact on the human immune system. Current research indicates that instability and dysfunction of the microbiome is linked to inflammatory disease rather than compositional differences. Previous research has shown that microbiome transplants are effective in restoring the commensal microbiome and reducing inflammation in gastrointestinal disease and in a previous pilot study the investigators showed that sinonasal microbiome transplants are feasible and were associated with reduced symptoms in chronic rhinosinusitis without nasal polyps (CRSsNP). This study will examine if the positive effect on patients symptoms observed in a previous pilot study are sustained in a placebo controlled, blinded study. In addition to this the study will also examine any differences in microbiome structure, stability, and function between patients with CRS and healthy donors as well as any correlation to disease phenotype or inflammatory endotype.

Interventions

• Procedure Sinonasal microbiome transplant procedure.
  A sinonasal microbiome transplant obtained from a healthy donor and administered as a nasal lavage once daily for five consecutive days.
• Other Placebo saline transplant
  Placebo transplant containing saline administered as a nasala lavage once daily for five consecutive days.

Primary outcome measures

• Sino-nasal outcome test 22 (SNOT-22) (min 0 - max 110 higher being worse) [Time frame: 14 days before intervention, on the first day of intervention, 2 and 3 months after intervention and as a follow up 1, 2 and 3 years after the study.]

Secondary outcome measures (6)

• Endoscopy [Time frame: 2 weeks before intervention, 3 months after intervention and as a follow up 1, 2 and 3 years after the study.]
• Total Nasal Symptom Score. (min 0 - max 9) [Time frame: 14 days before intervention, daily during the five days of intervention, 2 and 3 months after intervention and as a follow up 1, 2 and 3 years after the study.]
• Metagenomics [Time frame: 6 and 2 weeks before intervention, 8 and 12 weeks after intervention and as a follow up twice with 4 weeks apart 1, 2 and 3 years after the study.]
• Metabolomics [Time frame: 2 weeks before intervention and 12 weeks after intervention and as a follow up 1, 2 and 3 years after the study.]
• Inflammatory markers [Time frame: 2 weeks before intervention, 12 weeks after intervention and as a follow up 1, 2 and 3 years after the study.]
• Adverse events [Time frame: Entire study duration. Total study duration is 1 year and 5 months for the study and 3 years of follow up.]

Eligibility criteria

Inclusion Criteria (CRS-Patients):

• 2 nasal symptoms, 1 of which must be nasal obstruction or discolored discharge.
• Sinusitis verified by endoscopy or CT scan
• Duration > 12 weeks.
• Signed informed consent to participate in the study.

Exclusion Criteria (CRS-Patients):

• Antibiotic treatment in the last 3 months before study start.
• Ongoing or recent participation in another clinical trial.
• Any medication that might affect the results in an unpredictable manner.
• Treatment with monoclonal antibodies (biologics).
• Immunodeficiency other than low grade MBL deficiency.
• Pregnancy or breastfeeding
• Severe anatomical abnormalities.
• SNOT 22 < 20.

Inclusion Criteria (Donors):

• No history of sinonasal or lower airway disease within the last two years other than the common cold.
• Accepted as a donor by the patient.
• Signed informed consent to participate in the study.

Exclusion Criteria (CRS-Patients):

• Chronic rhinosinusitis.
• Acute rhinosinusitis within the last two years.
• Nasal polyposis
• Antibiotic treatment within the last 3 months before the study start.
• On going or recent participation in another clinical trial.
• Findings in the pre study scan that makes the donor unsuitable.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Crossover

Masking

Double blind

Primary purpose

Treatment

Study locations

Sweden · 1 center

• Departement of ORL — Helsingborg

Publications

• Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, Toppila-Salmi S, Bernal-Sprekelsen M, Mullol J, Alobid I, Terezinha Anselmo-Lima W, Bachert C, Baroody F, von Buchwald C, Cervin A, Cohen N, Constantinidis J, De Gabory L, Desrosiers M, Diamant Z, Douglas RG, Gevaert PH, Hafner A, Harvey RJ, Joos GF, Kalogjera L, Knill A, Kocks JH, Landis BN, Limpens J, Lebeer S, Lourenco O, Meco C, M PMID 32077450
• Rudmik L, Smith TL. Quality of life in patients with chronic rhinosinusitis. Curr Allergy Asthma Rep. 2011 Jun;11(3):247-52. doi: 10.1007/s11882-010-0175-2. PMID 21234819
• Wahid NW, Smith R, Clark A, Salam M, Philpott CM. The socioeconomic cost of chronic rhinosinusitis study. Rhinology. 2020 Apr 1;58(2):112-125. doi: 10.4193/Rhin19.424. PMID 32172284
• McCormick JP, Thompson HM, Cho DY, Woodworth BA, Grayson JW. Phenotypes in Chronic Rhinosinusitis. Curr Allergy Asthma Rep. 2020 May 19;20(7):20. doi: 10.1007/s11882-020-00916-6. PMID 32430653
• Kato A, Peters AT, Stevens WW, Schleimer RP, Tan BK, Kern RC. Endotypes of chronic rhinosinusitis: Relationships to disease phenotypes, pathogenesis, clinical findings, and treatment approaches. Allergy. 2022 Mar;77(3):812-826. doi: 10.1111/all.15074. Epub 2021 Sep 15. PMID 34473358
• Stevens WW, Peters AT, Tan BK, Klingler AI, Poposki JA, Hulse KE, Grammer LC, Welch KC, Smith SS, Conley DB, Kern RC, Schleimer RP, Kato A. Associations Between Inflammatory Endotypes and Clinical Presentations in Chronic Rhinosinusitis. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2812-2820.e3. doi: 10.1016/j.jaip.2019.05.009. Epub 2019 May 22. PMID 31128376
• Foster KR, Schluter J, Coyte KZ, Rakoff-Nahoum S. The evolution of the host microbiome as an ecosystem on a leash. Nature. 2017 Aug 2;548(7665):43-51. doi: 10.1038/nature23292. PMID 28770836
• Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014 Mar 27;157(1):121-41. doi: 10.1016/j.cell.2014.03.011. PMID 24679531

Identifiers

NCT: NCT07184684 · Dnr 2024-03308-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗