Impact of Highly Effective Modulator Therapy on the Cystic Fibrosis Microbiome

Official title

Impact of Highly Effective Modulator Therapy on Sinonasal Microbial Communities, Host Mucosal Inflammatory Environment and Quality of Life in Adults With Cystic Fibrosis

Overview

The goal of this observational study is to learn about the effects of a specific cystic fibrosis therapy (Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy) on chronic sinonasal disease. The main questions it aims to answer are: 1. How does this therapy impact bacterial communities in the paranasal sinuses? 2. How does this therapy impact inflammation in the paranasal sinuses and olfactory cleft? 3. How does this therapy impact sense of smell and sinonasal disease burden in individuals with cystic fibrosis? 4. How does this therapy impact disease-specific and general quality of life of individuals with cystic fibrosis? Participants will be asked to provide samples from their nose, complete testing of their sense of smell, and complete surveys about their quality of life and sense of smell in this study. Researchers will compare study results between patients who are currently undergoing Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy and patients who are not currently undergoing therapy.

Detailed description

The goal of this study is to characterize the effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy on the sinonasal microbial communities and inflammatory profiles in adults with cystic fibrosis. Participants will be asked to complete the below research activities on a 6-month basis over the course of two years to total 5 research visits (0 months, 6 months, 12 months, 18 months, 24 months).

A mucus sample from the middle meatus will be obtained and stored at 4ºC until culture analysis. Semi-quantitative bacterial cultures will be performed. Bacterial community composition will be quantified using 16S rRNA variable region (V4) amplicon sequencing and qPCR. Data preprocessing and taxonomic assignment will be performed using QIIME 2 (v 2023.2) and the SILVA 138.1 rRNA database. Abundance data will be further processed in R (v 4.3.0) using packages decontam, phyloseq, and vegan.

Samples from the middle meatus and olfactory cleft will be analyzed to investigate the inflammatory profiles of patients with cystic fibrosis. Both samples will be centrifuged at 4°C, 10,000 rpm for 10 minutes to extract the entire sample from the material. Samples will be transferred by pipette to cryovials, flash-frozen in liquid nitrogen, and stored in a -80°C environment until time of laboratory assay. The study will assess changes in immune status through cytokine arrays. To assess innate immune responses, a Bioplex Pro Human Inflammation Assay for 37 human cytokines (BD Biosciences) will be employed.

The study will also investigate if alterations in nasal microbiome and inflammatory profile correlate with changes in cystic fibrosis-specific quality of life (QOL) and olfaction outcomes. Participants will be asked to complete olfactory function testing using the Sniffin' Sticks extended test kit (MediSense, NL) and/or the University of Pennsylvania Smell Identification Test (UPSIT). Additionally, participants will be asked to complete the four following surveys to assess their quality of life as it relates to sinus symptom severity, disease control, and sense of smell: Cystic Fibrosis Questionnaire-Revised, Sino-nasal Outcome Test-22, Sinus Control Test, and Questionnaire of Olfactory Disorders.

Interventions

• Other Nasal endoscopy with microbiome swab and mucus collection through filter paper and sponge
  A CultureSwab MaxV(+) (BD, Franklin Lakes, NJ) will be placed under endoscopic visualization to the middle meatus through a sterile sheath (red rubber urinary catheter) and gently rotated 5 full turns or until the tip is saturated with mucus (no more than 20 seconds). Under direct visualization, a sterile Leukosorb sponge (Leukosorb; Pall Scientific, Port Washington, NY) will be placed in the middle meatus. A piece of Leukosorb filter paper will additionally be placed in the olfactory cleft. Th
• Other Olfactory Function Testing
  Olfactory function will be tested using the Sniffin' Sticks extended test kit (MediSense, NL) using the established threshold, discrimination, and identification (TDI) scoring system. Odors will be delivered using felt-tip pens (Sniffin' Sticks, MediSense, NL). The pen cap will be removed from the pen for approximately 3 seconds, and the pen's tip will be brought in front of the subject's nose and carefully moved from left to right nostril. Threshold testing will be obtained by asking the subjec
• Other Survey Completion
  Participants will be asked to complete the validated Cystic Fibrosis Questionnaire-Revised (CFQ-R) survey. This survey evaluates Cystic Fibrosis-specific and general quality of life metrics. Participants will also be asked to complete the validated Sino-nasal Outcome Test-22 (SNOT-22) which is the most commonly used survey for evaluating outcomes in patients with chronic rhinosinusitis. Participants will also be asked to complete the validated Sinus Control Test (SCT) - a 4-question questionna

Primary outcome measures

• Difference in nasal bacterial community composition between CFTR-MT cohort and Non-CFTR-MT cohort [Time frame: Baseline, 6 months, 12 months, 18 months, 24 months]
• Difference in inflammatory profiles between CFTR-MT cohort and Non-CFTR-MT cohort [Time frame: Baseline, 6 months, 12 months, 18 months, 24 months]

Secondary outcome measures (6)

• Difference in Sniffin' Sticks test scores between the CFTR-MT cohort and Non-CFTR-MT cohort [Time frame: Baseline, 6 months, 12 months, 18 months, 24 months]
• Difference in the University of Pennsylvania Smell Identification Test scores between the CFTR-MT cohort and Non-CFTR-MT cohort [Time frame: Baseline, 6 months, 12 months, 18 months, 24 months]
• Difference in Cystic Fibrosis Questionnaire-Revised survey responses between CFTR-MT cohort and Non-CFTR-MT cohort [Time frame: Baseline, 6 months, 12 months, 18 months, 24 months]
• Difference in Sino-nasal Outcome Test-22 (SNOT-22) survey scores between CFTR-MT cohort and Non-CFTR-MT cohort [Time frame: Baseline, 6 months, 12 months, 18 months, 24 months]
• Difference in Sinus Control Test survey scores between CFTR-MT cohort and Non-CFTR-MT cohort [Time frame: Baseline, 6 months, 12 months, 18 months, 24 months]
• Difference in Questionnaire of Olfactory Disorder survey scores between CFTR-MT cohort and Non-CFTR-MT cohort [Time frame: Baseline, 6 months, 12 months, 18 months, 24 months]

Eligibility criteria

Inclusion criteria

• Subjects between the ages of 18 years old (inclusive) and 99 years old (inclusive)
• English-speaking
• Diagnosed with CF as established by genetic testing combined with clinical assessment and/or sweat chloride
• Patients being seen at the New Hampshire Cystic Fibrosis Center
• Adults able to sign informed consent

Exclusion criteria

• Adults unable to consent
• Individuals who are not yet adults
• Prisoners

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

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 1 center

• Dartmouth-Hitchcock Medical Center — Lebanon

Identifiers

NCT: NCT05982795 · STUDY02001953

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗