Nasal Inflammation Following Endotoxin Challenge in Patients With Asthma (Nasal-LPS)

Nasal Endotoxin Challenge to Study Mucosal Inflammation in Patients With Asthma

A phase I clinical research study aimed at determining mechanisms that regulate airway mucosal inflammation in asthma endotypes using intranasal administration of endotoxin (lipopolysaccharide from E. coli) in healthy controls and subjects diagnosed with asthma.

Study Overview

• Status: Not yet recruiting
• Conditions: Asthma; Asthma; Eosinophilic
• Intervention / Treatment: Drug: Lipopolysaccharides

Detailed Description

Patients with severe asthma can be broadly classified into three endotypes (T2, T1, and T17) based on inflammatory cell and cytokine profiles. Within these endotypes, many patients have high levels of neutrophils in the airways and mucosal epithelium. Our preliminary data suggest that neutrophils in the airways and blood of patients with severe asthma are heterogenous and that subsets exist. The nature of these subsets appears to differ between T2, T1, and T17 asthma endotypes.

In order to advance the field and determine the mechanisms that underpin severe neutrophilic asthma, investigators plan to longitudinally assess transcriptional profiles and functional properties of neutrophil subsets that migrate to the nasal cavity following exposure to a standardized dose of Clinical Reference Center endotoxin (IRB#HS-3131-528, IND 018580).

Investigators will recruit 15 subjects of each asthma endotype (45 total participants with asthma) and 15 healthy controls. LPS will be used to elicit migration of neutrophils into the nasal cavities. Neutrophils will be isolated from the nasal cavities using both nasal lavage and nasal brushes 20 minutes, 1 day and 3 days after endotoxin challenge. Neutrophil biology will be assessed using single-cell RNAseq and ex vivo functional assays.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
      • Contact: William J Janssen, MD; Phone Number: 303-398-1366
      • Contact: Olivia M VerBurg, BA; Phone Number: 303-398-1201
      • Principal Investigator: William J Janssen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participants will have asthma diagnosed by a health care provider. Healthy controls are individuals without asthma.
• Written informed consent

Exclusion Criteria:

• Current or recent illness (in the past 4 weeks)
• Recent asthma exacerbation (past 4 weeks)
• History of nasal perforation or nasal surgery
• Nasal polyposis
• Presence or prior history of cardiac or systemic disease
• Bleeding disorder, use of systemic anticoagulants, or antiplatelet therapy
• Immunocompromised state (HIV, immunoglobulin deficiency, systemic immunosuppressants excluding corticosteroids)
• Use of tobacco or marijuana in the past 2 months or greater than a 10 pack-year smoking history
• Currently pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Asthma Group; Subjects diagnosed with one of the three asthma endotypes being studied (T2, T1, or T17).	Drug: Lipopolysaccharides; LPS aka endotoxin is a component of bacterial cell walls and is ubiquitous in the environment. It is found in pet dander, house dust and environmental dusts and has been heavily studied in asthma.; Other Names: LPS; Endotoxin; Clinical reference center lipopolysaccharide; LPS E. Coli O:113
Active Comparator: Control Group; Subjects with no diagnosis of asthma or other respiratory disease and are deemed healthy.	Drug: Lipopolysaccharides; LPS aka endotoxin is a component of bacterial cell walls and is ubiquitous in the environment. It is found in pet dander, house dust and environmental dusts and has been heavily studied in asthma.; Other Names: LPS; Endotoxin; Clinical reference center lipopolysaccharide; LPS E. Coli O:113

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neutrophil heterogeneity using single cell RNA sequencing	Neutrophil subset composition as determined by single cell RNAseq is compared to endotype groups using a multivariate linear regression framework for compositional data, employing the additive log ratio transformation. Models will include indicator variables for whether a sample is T1 high, T2 high, T17 high or non-asthmatic and will control for age, sex, and smoking status. AM subset gene expression matrices from scRNAseq will be compared between endotypes using the pseudo bulk approach to account for clustering of cells within subjects. To identify global gene expression programs underlying each endotype, bulk RNAseq gene expression data will be normalized using DESeq2's variance stabilizing transformation and similarly compared between endotypes using linear regression models. A Benjamini-Hochberg adjustment will be used to control the false discovery rate.	We anticipate that the study will run over 5 years

Collaborators and Investigators

• Sponsor: National Jewish Health

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: January 30, 2024
• First Submitted That Met QC Criteria: February 13, 2024
• First Posted (Estimated): February 21, 2024

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Hematologic Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Leukocyte Disorders; Eosinophilia; Hypereosinophilic Syndrome; Inflammation; Asthma; Pulmonary Eosinophilia
• Other Study ID Numbers: HS3131

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No