Assessing NOS Uptake With PET Imaging in Lung Inflammation

Early Phase 1

Completed

• Conditions: Lung Inflammation
• Interventions: Drug: [18F](+/-)NOS

• Registration Number: NCT02151552
• Lead Sponsor: Washington University School of Medicine

Brief Summary

The purpose of this study is to learn more about the basic responses of the lungs to inflammation using positron emission tomography, or PET, imaging scans of the lungs. PET is a machine that detects radiation and generates pictures using a donut-shaped scanner similar in appearance to an x-ray "CAT" or computed tomography (CT) scan or an MRI. Inflammation is the way our bodies react to irritation or injury, and involves red, warm, and often painful swelling of the affected tissue. An enzyme called inducible nitric oxide synthase (iNOS) contributes to the development of lung inflammation.

Detailed Description

The investigators plan to use three radioactive tracers to produce the PET images for measuring lung inflammation: \[18F\](+/-)NOS (the F stands for fluorine and NOS stands for Nitric Oxide Synthase, which targets iNOS), O-15 carbon monoxide (\[15O\]CO), and O-15 water (\[15O\]H2O). The NOS tracer gives information specifically about lung inflammation, while the carbon monoxide and water tracers give information about whether the lung inflammation causes more blood or water to be retained in the area of lung inflammation.

In order to show that \[18F\](+/-)NOS-PET is related to the amount of inflammation, the investigators first need to create a state of controlled lung inflammation that can be measured and quantified. "Controlled lung inflammation" means a reaction in the lungs that is similar to that which occurs during lung infection (increased respiratory secretions and cough). It is "controlled" because the investigators will not be using anything alive or contagious (it does not spread from one part of the body to another, and cannot spread to another person), and a small area in only one lung will be affected. In order to created this state of controlled lung inflammation, the investigators plan to place a small amount of a purified bacterial substance called endotoxin into a single small section of the lung using a bronchoscope (a long, flexible narrow tube that is passed through the mouth into the airways of the lung). This use of endotoxin is considered investigational, and the investigators have received permission from the FDA to use endotoxin in this research study.

Study Timeline

• Study Start: 2014-05
• Study First Submitted: 2014-05-28
• Study First Submitted QC: 2014-05-28
• Study First Posted: 2014-05-30
• Primary Completion: 2018-02
• Study Completion: 2018-02
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-19
• Last Update Posted: 2018-07-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 3

Inclusion Criteria

• Healthy man or woman, any race or ethnicity, age 19-44 years old
• Screening FEV1 and FVC greater than or equal to 90% of predicted
• Screening oxygen saturation by pulse oximetry greater than or equal to 97% on room air
• Capable of lying still and supine with arms raised above the head within PET/CT scanner for 2-2.5 hours
• Capable of following instructions for breathing protocol during CT portion of PET/CT scans
• Able and willing to give informed consent
• Body Mass Index (BMI) < 35

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Exclusion Criteria

• Pregnancy (confirmed by qualitative serum hCG pregnancy test)
• Lactation
• History of cardiopulmonary disease
• Currently taking any prescription medications
• History of tobacco use or illicit drug use within the past year
• Presence of implanted electronic medical device
• Enrollment in another research study of an investigational drug
• Known allergy to both trimethoprim/sulfamethoxazole and amoxicillin, Penicillin, Lidocaine, Demerol, Versed, and/or Fentanyl
• Inability to lie flat for 2-2.5 hours for PET/CT scans or follow breathing protocol instructions for the CT portion of the PET/CT
• Prior research-related radiation exposure within the past year such that participation in this study would result in exposures that exceed the limits as defined by the FDA RDRC regulations (21 CFR 361.1)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Endotoxin and [18F](+/-)NOS	[18F](+/-)NOS	All volunteers in this study will receive endotoxin in a single segment of the lung to induce mild, self-limited inflammation. They will also be imaged before and after endotoxin instillation with the novel PET tracer \[18F\](+/-)NOS.

Primary Outcome Measures

Name	Time	Method
Distribution volume ratio (DVR), determined by Logan plot analysis, in the right middle lobe	Change in DVR on post-endotoxin PET scan (Day 2) from baseline (Day 1)	Comparison of DVR by Logan plot for \[18F\](+/-)NOS uptake, pulmonary blood flow (PBF) and extravascular lung water (EVLW) in the regions of interest generated from scans obtained before and after endotoxin instillation and in the right and left lungs will be compared using a repeated-measures t-test, with statistical significance set at p\<0.05. The DVR determined for \[18F\](+/-)NOS normalized for either PBF or EVLW will also be compared using a repeated-measures t-test before and after endotoxin as well as in the right and left lungs to determine whether differences in \[18F\](+/-)NOS uptake depend on either PBF or EVLW.

Secondary Outcome Measures

Name	Time	Method
Change in DVR in right middle lobe	post-endotoxin scan (Day 2) from baseline (Day 1) scan
Mean Hounsfield units (HU), measure of density on CT images, in right middle lobe and lingula	baseline PET/CT scan on Day 1 to post-endotoxin scan on Day 2
Change in HU in right middle lobe and lingula	before and after endotoxin instillation (Day 1 to Day 2)
Bronchoalveolar lavage (BAL) cell counts (including total nucleated and neutrophil counts)	6 hours post-endotoxin instillation
Number and percent of iNOS-stained BAL cells by flow cytometry	6 hours post-endotoxin instillation
Number and percent of 3-nitrotyrosine-stained cells on biopsy	6 hours post-endotoxin instillation
Change in exhaled nitric oxide (ENO) levels	before and after endotoxin instillation (Day 1 to Day 2)
Regional PBF and EVLW in right middle lobe and lingula	before and after endotoxin (Day 1 to Day 2)
Number of iNOS positive cells from brushing cytospins	6 hours post-endotoxin instillation

Trial Locations

Locations (1)

Washington University School of Medicine / Barnes-Jewish Hospital; 🇺🇸 Saint Louis, Missouri, United States