Quantifying Airway Inflammation With Radiologic Tests

Study Overview
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Brief Summary
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In this randomized, double-blind, placebo controlled trial we used positron emission tomography to determine if lovastatin or recombinant human activated protein C exhibit anti-inflammatory effects in humans following intrabronchial installation of lipopolysaccharide (LPS or endotoxin).

Detailed Description
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Quantitative, noninvasive biomarkers for lung-specific inflammation have yet to be developed but can potentially contribute significantly to the development of therapies to treat lung inflammation. The purpose of this study was to demonstrate that positron emission tomographic (PET) imaging with [18F}fluorodeoxyglucose (FDG-PET) can be used to quantify the change in lung inflammation in healthy volunteers.

Official Title
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Imaging Biomarkers of Pulmonary Inflammation

Conditions
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Lung Inflammation

Intervention / Treatment
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* Drug: placebo pill and placebo IV
* Drug: Lovastatin pill and placebo IV
* Drug: placebo pill and recombinant human activated protein C IV
* Biological: Endotoxin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, man or woman, any race or ethnicity, age 19 - 44 years old Screening FEV1 and FVC must be > 80% of predicted. Screening oxygen saturation by pulse oximetry is >97% on room air. Research volunteer must be capable of lying still and supine within the PET scanner for  2 ½ hours. Research volunteer must be capable of fasting for 6 hours. Exclusion Criteria: Pregnancy (confirmed by a qualitative urine hCG pregnancy test) Lactation. Actively menstruating at time of randomization History of tobacco use or has smoked other illicit drugs (marijuana, cocaine) in the past year. Research volunteer is currently taking any prescription medications. Research volunteer is at increased risk for radiation exposure (e.g. flight attendants) Research volunteer is enrolled in another research study of an investigational drug. Research volunteer has a known allergy to both trimethoprim/sulfamethoxazole and amoxicillin. Research volunteer has a known allergy to drugs routinely used during bronchoscopy. Research volunteer has a known allergy to lovastatin or rhAPC Fasting glucose at time of PET study > 150 mg/dl. Exclusion criteria related to use of rhAPC: Active or history of internal bleeding within the past 3 months History of hemorrhagic stroke within the past 3 months. History of intracranial or intraspinal surgery, or severe head trauma, within the past 3 months History of trauma with an increased risk of life-threatening bleeding within the past 3 months History of receiving thrombolytic therapy within the past 3 months. History of receiving oral anticoagulants or glycoprotein IIb/IIIa inhibitors within the past 3 months. History of using aspirin > 650 mg/d or other platelet inhibitors within the past 7 days. Any history of intracranial arteriovenous malformation or aneurysm Any history of a known bleeding diathesis Any history of chronic severe hepatic disease Presence of an epidural catheter Any history of intracranial neoplasm or mass lesion or evidence of cerebral herniation Use of heparin during past 7 days Platelet count <100,000 x 106/L Prothrombin time-INR > 1.5 SGOT >47 IU/L, SGPT > 53 IU/L, or bilirubin > 1.1 mg/dl Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location. Exclusion criteria related to use of lovastatin: History of chronic active liver disease or acute liver disease within the past 3 months SGOT >47 IU/L, SGPT > 53 IU/L, or bilirubin > 1.1 mg/dl.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 44 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo pill and placebo IV<br> | Drug: placebo pill and placebo IV<br>* Placebo pill every four hours, starting 16 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS Placebo IV starting 2 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS<br>Biological: Endotoxin<br>* Endotoxin 4 ng/kg instilled bronchoscopically in all volunteers 12 hours after starting lovastatin treatment and 2 hours after starting recombinant human activated protein C treatment.<br>* Other names: lipopolysaccharide;|
| Experimental: Lovastatin pill and placebo IV<br> | Drug: Lovastatin pill and placebo IV<br>* lovastatin pill every four hours, total of 80 milligrams a day, starting 16 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS Placebo IV starting 2 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS<br>* Other names: Mevacor;Biological: Endotoxin<br>* Endotoxin 4 ng/kg instilled bronchoscopically in all volunteers 12 hours after starting lovastatin treatment and 2 hours after starting recombinant human activated protein C treatment.<br>* Other names: lipopolysaccharide;|
| Experimental: Placebo pill and rhAPC IV<br> | Drug: placebo pill and recombinant human activated protein C IV<br>* placebo pill every four hours, total of 80 milligrams a day, starting 16 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS recombinant human activated protein C IV 24 micrograms per kg per hour starting 2 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS<br>* Other names: Xigris;Biological: Endotoxin<br>* Endotoxin 4 ng/kg instilled bronchoscopically in all volunteers 12 hours after starting lovastatin treatment and 2 hours after starting recombinant human activated protein C treatment.<br>* Other names: lipopolysaccharide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ki (Measure of [18F]Fluorodeoxyglucose ([18F]FDG) Uptake Determined by Patlak Graphical Analysis) in the Right Lung 24 Hours After LPS Instillation | Calculated Ki was used to measure the amount of lung inflammation before and after instillation of endotoxin to assess the effect of placebo, lovastatin, and rhAPC treatment | 24 hours after endotoxin instillation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Total Nucleated Cells From Bronchoalveolar Lavage (BAL) Fluid 24 Hours After Endotoxin Instillation | Number of total nucleated cells isolated from the first aliquoe of BAL obtained to correlate with PET data. | 24 hours after endotoxin instillation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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randomized, positron emission tomography, lung inflammation, lovastatin, recombinant human activated protein C, endotoxin, fluorodeoxyglucose