Prostaglandin Inhibition for Emphysema (PIE)
Primary Purpose
Emphysema
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
600 mg ibuprofen three times daily for 48 weeks
Placebo three times daily
Sponsored by
About this trial
This is an interventional treatment trial for Emphysema focused on measuring Emphysema, Prostaglandin E, Bronchoalveolar lavage
Eligibility Criteria
Inclusion Criteria:
- Age > 45 years
- Emphysema (>5% of voxels <950 Hounsfield Units determined on the CT scan performed as part of the COPDGene study as quantified at the COPDGene radiology center). An equivalent scan as determined by the radiology center is also acceptable.
- Post-bronchodilator FEV1 > 35% predicted)
- Smoker or ex-smoker (10 pack years minimum)
Exclusion Criteria:
- Contraindication to bronchoscopy or other study procedures
- Pregnancy of plans to become pregnant within six months
- Aspirin-sensitive asthma
- Regular use of systemic glucocorticoid
- Regular use of an NSAID (low dose aspirin for cardiac disease is acceptable and subjects taking only this regularly will be eligible)
- Unstable medical condition
- History of myocardial infarction or unstable angina within six months
- Allergy to or history of adverse effect from ibuprofen or other NSAID
- History of gastrointestinal bleeding within one year
- Any condition that, in the opinion of the investigator, places the subject at untoward risk
- Inability to provide informed consent
Sites / Locations
- University of Alabama at Birmingham
- Harbor-UCLA Medical Center
- National Jewish Helath
- The Univerisity of Nebraska Medical Center
- Temple University
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Placebo Comparator
No Intervention
Experimental
Arm Label
COPD, Placebo
Control subject
COPD, ibuprofen
Arm Description
Placebo three times daily
Control subjects, no intervention
600 mg ibuprofen three times daily for 48 weeks
Outcomes
Primary Outcome Measures
Will Ibuprofen, 600 mg Three Times Daily, Decrease PGE Concentration in the Alveolar Portion of BAL Fluid in Subjects With Emphysema in Comparison to Placebo?
PGE will be measured by HPLC in alveolar fluids obtained at randomization (week 0) and again 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group.
Secondary Outcome Measures
Will Ibuprofen, 600 mg Three Times Daily, Increase Pro-collagen Peptide Fragment Concentrations in the Alveolar Portion of BAL Fluid in Subjects With Emphysema in Comparison to Placebo?
Pro-collagen peptide fragments will be measured by ELISA in alveolar fluids obtained at randomization (week 0) and again 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group.
Full Information
NCT ID
NCT02006576
First Posted
December 4, 2013
Last Updated
November 26, 2019
Sponsor
University of Nebraska
Collaborators
National Jewish Health, Temple University, University of California, Los Angeles, University of Alabama at Birmingham
1. Study Identification
Unique Protocol Identification Number
NCT02006576
Brief Title
Prostaglandin Inhibition for Emphysema
Acronym
PIE
Official Title
Proof-of-concept Study to Demonstrate Inhibition of Prostaglandin E (PGE) Production and Associated Biological Effects in the Lower Respiratory Tract by Ibuprofen.
Study Type
Interventional
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
January 2014 (undefined)
Primary Completion Date
March 31, 2018 (Actual)
Study Completion Date
March 31, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Nebraska
Collaborators
National Jewish Health, Temple University, University of California, Los Angeles, University of Alabama at Birmingham
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The Prostaglandin Inhibition for Emphysema (PIE) study will determine if a currently available therapy, ibuprofen 600 mg three times daily, can block PGE production in the lower respiratory tract and if this results in improvement in measures of lung repair function.
Detailed Description
The Prostaglandin Inhibition for Emphysema (PIE) study will determine if a currently available therapy, ibuprofen 600 mg three times daily, can block PGE production in the lower respiratory tract and if this results in improvement in measures of lung repair function. This is a proof-of-concept study. The PIE study will set the stage for novel therapy to modify the course of chronic obstructive pulmonary disease (COPD).
COPD is the third leading cause of death in the United States. No currently available treatment can meaningfully restore lung function that is lost in this disease. Emphysema is a major component of COPD and results when lung damage exceeds the ability of the lung to repair. Recent evidence indicates that the repair processes present in the normal lung are deficient in patients with emphysema and that this is due, in part, to suppression of repair by an inflammatory mediator: prostaglandin E (PGE). Currently available therapies can block PGE production, but whether this can be achieved in the lung in COPD is unknown. The PIE study will answer that question.
This will be accomplished by performing a randomized, double blind, placebo-controlled, parallel group study that will compare a widely used and well-tolerated non-steroidal anti-inflammatory drug, ibuprofen 600 mg three times daily, with placebo. PGE will be measured directly in the lower respiratory tract by sampling the lung with the technique of bronchoalveolar lavage. Secondary measures will be made, quantifying PGE in induced sputum and quantifying PGE metabolites in blood and urine. In addition, the current proposal will determine if biochemical measures of lung repair are restored by treatments that block PGE production. Additional outcomes will also be assessed including the effect of treatment on PGD and other eicosanoids and assessing IL-8 and neutrophils in sputum and BAL fluid and selected inflammatory biomarkers present in serum that may be associated with lung function decline. Finally, in an accompanying Ancillary Study, the current proposal will determine if alveolar macrophages over-produce PGE and/or PGD in COPD and will determine if the microRNA miR-146a modulates the production of these prostaglandins, as we have demonstrated for lung fibroblasts. The Ancillary Study will also determine if genetic variation in a miR-146a is related to differential expression.
The proposed research will, therefore, determine if inhibition of PGE production can be achieved in the lung, if this appears to restore lung repair mechanisms and will help determine who would benefit from such a therapeutic approach. This is a highly novel approach to the treatment of emphysema and has the potential to restore lost lung function, a crucial unmet medical need for a major public health problem.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Emphysema
Keywords
Emphysema, Prostaglandin E, Bronchoalveolar lavage
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
118 (Actual)
8. Arms, Groups, and Interventions
Arm Title
COPD, Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo three times daily
Arm Title
Control subject
Arm Type
No Intervention
Arm Description
Control subjects, no intervention
Arm Title
COPD, ibuprofen
Arm Type
Experimental
Arm Description
600 mg ibuprofen three times daily for 48 weeks
Intervention Type
Drug
Intervention Name(s)
600 mg ibuprofen three times daily for 48 weeks
Intervention Type
Other
Intervention Name(s)
Placebo three times daily
Primary Outcome Measure Information:
Title
Will Ibuprofen, 600 mg Three Times Daily, Decrease PGE Concentration in the Alveolar Portion of BAL Fluid in Subjects With Emphysema in Comparison to Placebo?
Description
PGE will be measured by HPLC in alveolar fluids obtained at randomization (week 0) and again 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group.
Time Frame
12 weeks after subject randomization
Secondary Outcome Measure Information:
Title
Will Ibuprofen, 600 mg Three Times Daily, Increase Pro-collagen Peptide Fragment Concentrations in the Alveolar Portion of BAL Fluid in Subjects With Emphysema in Comparison to Placebo?
Description
Pro-collagen peptide fragments will be measured by ELISA in alveolar fluids obtained at randomization (week 0) and again 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group.
Time Frame
12 weeks after subject randomization
Other Pre-specified Outcome Measures:
Title
Will Ibuprofen, 600 mg Three Times Daily, Reduce Prostaglandin E Concentrations in the Alveolar Portion of BAL Fluid in Subjects With Emphysema to Those Present in Smoking, Former Smoking and Healthy Non-smoking Controls?
Description
PGE will be measured by HPLC in alveolar fluids obtained at randomization and again 12 weeks after randomization on subjects taking ibuprofen to compare emphysema subjects, smokers, former smokers and controls.
Time Frame
12 weeks after subject randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce Prostaglandin E Concentrations in the Bronchial Portion of BAL Fluid in Subjects With Emphysema Compared to Placebo?
Description
PGE will be measured by HPLC in bronchial fluids obtained at randomization and again 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
12 weeks after subject randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce Prostaglandin E Concentrations in Induced Sputum From Subjects With Emphysema Compared to Placebo?
Description
PGE will be measured by HPLC in sputum samples obtained prior to randomization and again 10 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smokers and controls.
Time Frame
10 weeks after subject randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce the PGE Metabolite PGEM in the Peripheral Blood of Subjects With Emphysema Compared to Placebo?
Description
PGEM will be measured by HPLC in peripheral blood specimens obtained at randomization, 12 weeks after randomization and 48 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
48 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce the PGE Metabolite PGEM in the Urine of Subjects With Emphysema Compared to Placebo?
Description
PGEM will be measured by HPLC in urine specimens obtained at randomization, 12 weeks after randomization and 48 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
48 weeks after randomization
Title
Will Ibuprofen, 600 mg Three Times Daily, Increase Pro-collagen Peptide Fragment Concentrations in the Alveolar Portion of BAL Fluid in Subjects to the Range Observed in Normal Individuals or to Higher Levels?
Description
Pro-collagen peptide fragment concentrations will be measured by ELISA in alveolar fluids obtained at randomization and again 12 weeks after randomization to determine if levels reach those of normal individuals or reach even higher levels.
Time Frame
12 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Increase the Procollagen III Amino Peptide Excreted Into the Urine of Subjects With Emphysema Compared to Placebo?
Description
Procollagen III amino peptide will be measured by ELISA in urine specimens obtained at randomization, 12 weeks after randomization and 48 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group.
Time Frame
48 weeks after randomization
Title
Will Ibuprofen, 600 mg Three Times Daily, Decrease IL-8 Concentrations in the Alveolar Portion of BAL Fluid in Subjects With Emphysema in Comparison to Placebo?
Description
IL-8 will be measured by ELISA in alveolar specimens obtained at randomization and 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
12 weeks after randomization
Title
Will Ibuprofen, 600 mg Three Times Daily, Decrease Neutrophil Concentrations in the Alveolar Portion of BAL Fluid in Subjects With Emphysema in Comparison to Placebo?
Description
Neutrophils will be measured by 500 cell differentials in alveolar specimens obtained at randomization and 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
12 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce IL-8 Concentrations in the Bronchial Portion of BAL Fluid in Subjects With Emphysema Compared to Placebo?
Description
IL-8 will be measured by ELISA in bronchial specimens obtained at randomization and 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
12 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce IL-8 Concentrations in Induced Sputum From Subjects With Emphysema Compared to Placebo?
Description
IL-8 will be measured by ELISA in sputum specimens obtained prior to randomization and 10 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
10 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce PMN Concentrations in the Bronchial Portion of BAL Fluid in Subjects With Emphysema Compared to Placebo?
Description
Neutrophils will be measured by 500 cell differentials in bronchial specimens obtained at randomization and 12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
12 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce PMN Concentrations in Induced Sputum From Subjects With Emphysema Compared to Placebo?
Description
Neutrophils will be measured by 500 cell differentials in bronchial specimens obtained prior to randomization and 10 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
10 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Alter LTB4 Concentrations in Subjects With Emphysema Compared to Placebo in the Alveolar Portion of BAL, Bronchial Portion of BAL and Induced Sputum?
Description
LTB4 will be measured by HPLC in alveolar fluids, bronchial fluids and induced sputums obtained at randomization and again 10-12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
12 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce Concentrations of CC-16 in Serum From Subjects With Emphysema Compared to Placebo?
Description
CC-16 will be measured by ELISA in serum specimens obtained at randomization, 12 weeks after randomization and 48 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group.
Time Frame
48 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce Concentrations of CRP in Serum From Subjects With Emphysema Compared to Placebo?
Description
CRP will be measured by ELISA in serum specimens obtained at randomization, 12 weeks after randomization and 48 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group.
Time Frame
48 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce Concentrations of SP-d in Serum From Subjects With Emphysema Compared to Placebo?
Description
SP-d will be measured by ELISA in serum specimens obtained at randomization, 12 weeks after randomization and 48 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group.
Time Frame
48 weeks after randomization
Title
Are Levels of PGD Increased in the Alveolar Component of BAL Fluid in Patients With COPD? Are Levels of PGD in Alveolar Lavage Fluid Related to FEV1 and/or Severity of Emphysema?
Description
PGD will be measured by HPLC in alveolar fluids obtained at randomization and again 10-12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls. PGD levels will be compared against FEV1 and severity of emphysema.
Time Frame
12 weeks after randomization
Title
Are Levels of TXB2 (the Primary Metabolite of Thromboxane) Increased in the Alveolar Component of BAL Fluid in Patients With COPD? Are the Levels Related to FEV1 and/or Severity of Emphysema?
Description
TXB2 will be measured by HPLC in alveolar fluids obtained at randomization and again 10-12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls. TXB2 levels will be compared against FEV1 and severity of emphysema.
Time Frame
12 weeks after randomization
Title
Are Levels of 6kPGF1a (the Primary Metabolite of Prostacyclin) Increased in the Alveolar Component of BAL Fluid in Patients With COPD? Are the Levels Related to FEV1 and/or Severity of Emphysema?
Description
6kPGF1a will be measured by HPLC in alveolar fluids obtained at randomization and again 10-12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls. 6kPGF1a levels will be compared against FEV1 and severity of emphysema.
Time Frame
12 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Reduce the Eicosanoids Other Than PGE in Subjects With Emphysema Compared to Placebo in BAL and Induced Sputum?
Description
LTB4, PGD, TXB2, and 6kPGF1a will be measured by HPLC in induced sputums and BAL's obtained prior to randomization and again 10-12 weeks after randomization on emphysema subjects taking placebo and emphysema subjects taking ibuprofen to compare control group versus treatment group. The emphysema group will also be compared to smokers, former smoker, and controls.
Time Frame
12 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily Alter the Rate of Change of Emphysema Progression as Assessed by CT Scan?
Time Frame
48 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily Alter the Rate of Change of DLCO?
Time Frame
48 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily Alter the Rate of Change of FEV1?
Time Frame
48 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily Alter the Rate of COPD Exacerbations?
Time Frame
48 weeks after randomization
Title
Will Ibuprofen 600 mg Three Times Daily, Alter Health Status Assessed by the SGRQ or COPD Status Assessed by the CAT in Subjects With Emphysema ?
Time Frame
48 weeks after randomization
Title
Are There Differences Between Subjects With Upper Lobe vs. Lower Lobe Emphysema?
Description
PGE levels in BAL fluid, sputum and metabolites in blood and urine will be evaluated for differences between subjects with upper lobe vs. lower lobe emphysema. Procollagen peptides will be evaluated in BAL fluid between subjects with upper lobe vs. lower lobe emphysema. Eicosanoids (PGD, 6kPGF1a, TXB2) urine will be evaluated between subjects with upper lobe vs. lower lobe emphysema. Measures of inflammation will be evaluated between subjects with upper vs. lower lobe emphysema. Does the response of PGE, measures of repair, response of other eicosanoids, and response of measures of inflammation change as a result of 600 mg three times daily of ibuprofen.
Time Frame
48 weeks after randomization
Title
Are There Differences Between Subjects With Clustered vs. Diffuse Emphysema?
Description
PGE levels in BAL fluid, sputum and metabolites in blood and urine will be evaluated for differences between subjects with clustered versus diffuse emphysema. Procollagen peptides will be evaluated in BAL fluid between subjects with clustered versus diffuse emphysema. Eicosanoids (PGD, 6kPGF1a, TXB2) urine will be evaluated between subjects with clustered versus diffuse emphysema. Measures of inflammation will be evaluated between subjects with clustered versus diffuse emphysema. Does the response of PGE, measures of repair, response of other eicosanoids, and response of measures of inflammation change as a result of 600 mg three times daily of ibuprofen.
Time Frame
48 weeks after randomization
Title
Will BAL PGE Levels Assessed at Study Initiation be Related to the Rate of Emphysema Progression Determined by the Change in CT Quantified Lung Density From the Time of Assessment in COPDGene to the Current Study (Estimated 3-6 Years)?
Time Frame
3-6 years from initial CT scan
Title
Will BAL PGE Levels Assessed at Study Initiation be Related to the Rate of Emphysema Progression Determined by the Change in FEV1 From the Time of Assessment in COPDGene to the Current Study (Estimated 3-6 Years)?
Time Frame
3-6 years from initial FEV1 assessment
Title
Will Measures of Prostanoids Other Than PGE Assessed at Study Initiation be Related to the Rate of Emphysema Progression Determined by the Change in CT Quantified Lung Density From the Time of Assessment in COPDGene to the Current Study?
Time Frame
3-6 years from initial CT scan
Title
Will Measures of Inflammation Assessed at Study Initiation be Related to the Rate of Emphysema Progression Determined by the Change in FEV1 From the Time of Assessment in COPDGene to the Current Study (Estimated 3-6 Years)?
Time Frame
3-6 years after initial FEV1 assessment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
46 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Age > 45 years
Emphysema (>5% of voxels <950 Hounsfield Units determined on the CT scan performed as part of the COPDGene study as quantified at the COPDGene radiology center). An equivalent scan as determined by the radiology center is also acceptable.
Post-bronchodilator FEV1 > 35% predicted)
Smoker or ex-smoker (10 pack years minimum)
Exclusion Criteria:
Contraindication to bronchoscopy or other study procedures
Pregnancy of plans to become pregnant within six months
Aspirin-sensitive asthma
Regular use of systemic glucocorticoid
Regular use of an NSAID (low dose aspirin for cardiac disease is acceptable and subjects taking only this regularly will be eligible)
Unstable medical condition
History of myocardial infarction or unstable angina within six months
Allergy to or history of adverse effect from ibuprofen or other NSAID
History of gastrointestinal bleeding within one year
Any condition that, in the opinion of the investigator, places the subject at untoward risk
Inability to provide informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen I Rennard, M.D.
Organizational Affiliation
The University of Nebraska Medical Center
Official's Role
Study Chair
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Harbor-UCLA Medical Center
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
Facility Name
National Jewish Helath
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
The Univerisity of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68105
Country
United States
Facility Name
Temple University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Prostaglandin Inhibition for Emphysema
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