Lung Inflammation
Conditions
Keywords
randomized, positron emission tomography, lung inflammation, lovastatin, recombinant human activated protein C, endotoxin, fluorodeoxyglucose
Brief summary
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
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.
Interventions
DRUGplacebo pill and placebo IV
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
DRUGLovastatin pill and placebo IV
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
DRUGplacebo pill and recombinant human activated protein C IV
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
BIOLOGICALEndotoxin
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.
Sponsors
Barnes-Jewish Hospital
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
19 Years to 44 Years
Healthy volunteers
Yes
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. *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Ki (Measure of [18F]Fluorodeoxyglucose ([18F]FDG) Uptake Determined by Patlak Graphical Analysis) in the Right Lung 24 Hours After LPS Instillation | 24 hours after endotoxin 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Total Nucleated Cells From Bronchoalveolar Lavage (BAL) Fluid 24 Hours After Endotoxin Instillation | 24 hours after endotoxin instillation | Number of total nucleated cells isolated from the first aliquoe of BAL obtained to correlate with PET data. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Pill and Intravenous (i.v.) Placebo Control group receiving only placebo drug interventions | 7 |
| Lovastatin Pill and i.v. Placebo Group receiving lovastatin as the primary drug intervention | 8 |
| Placebo Pill and Recombinant Human Activated Protein C i.v. Group receiving recombinant human activated protein C (rhAPC) as the drug intervention | 7 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Discovered failed screen after enrolled | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Pill and Intravenous (i.v.) Placebo | Lovastatin Pill and i.v. Placebo | Placebo Pill and Recombinant Human Activated Protein C i.v. | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 7 Participants | 22 Participants |
| Region of Enrollment United States | 7 participants | 8 participants | 7 participants | 22 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 6 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 7 | 5 / 8 | 5 / 7 |
| serious Total, serious adverse events | 1 / 7 | 0 / 8 | 0 / 7 |
Outcome results
Primary
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
Time frame: 24 hours after endotoxin instillation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Pill and Intravenous (i.v.) Placebo | Change in Ki (Measure of [18F]Fluorodeoxyglucose ([18F]FDG) Uptake Determined by Patlak Graphical Analysis) in the Right Lung 24 Hours After LPS Instillation | 18.8 Change in Ki | Standard Deviation 9.2 |
| Lovastatin Pill and i.v. Placebo | Change in Ki (Measure of [18F]Fluorodeoxyglucose ([18F]FDG) Uptake Determined by Patlak Graphical Analysis) in the Right Lung 24 Hours After LPS Instillation | 8.4 Change in Ki | Standard Deviation 4.3 |
| Placebo Pill and Recombinant Human Activated Protein C i.v. | Change in Ki (Measure of [18F]Fluorodeoxyglucose ([18F]FDG) Uptake Determined by Patlak Graphical Analysis) in the Right Lung 24 Hours After LPS Instillation | 14.2 Change in Ki | Standard Deviation 7.4 |
Comparison: One-way analysis of variance was performed to determine whether lovastatin or rhAPC effectively reduced endotoxin-induced lung inflammation.p-value: <0.05ANOVA
Secondary
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.
Time frame: 24 hours after endotoxin instillation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Pill and Intravenous (i.v.) Placebo | Number of Total Nucleated Cells From Bronchoalveolar Lavage (BAL) Fluid 24 Hours After Endotoxin Instillation | 545 cells per cubic mm | Standard Deviation 425 |
| Lovastatin Pill and i.v. Placebo | Number of Total Nucleated Cells From Bronchoalveolar Lavage (BAL) Fluid 24 Hours After Endotoxin Instillation | 311 cells per cubic mm | Standard Deviation 237 |
| Placebo Pill and Recombinant Human Activated Protein C i.v. | Number of Total Nucleated Cells From Bronchoalveolar Lavage (BAL) Fluid 24 Hours After Endotoxin Instillation | 520 cells per cubic mm | Standard Deviation 196 |