Clinical trial NCT02006576: Prostaglandin Inhibition for Emphysema
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Emphysema
Keywords: Emphysema
Prostaglandin E
Bronchoalveolar lavage
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Jewish Health
name: Temple University
name: University of California, Los Angeles
name: University of Alabama at Birmingham
First posted: 2013-12-10
Enrollment: 118
Sex: ALL
Minimum age (years): 46
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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?
timeFrame: 12 weeks after subject randomization
Secondary outcomes:
measure: 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?
timeFrame: 12 weeks after subject randomization
Other outcomes:
measure: Prostaglandin E Concentrations n Participants With Emphysema v in Smoking, Former Smoking and Healthy Non-smoking Controls After Ibuprofen Three Times Daily
timeFrame: 12 weeks after subject randomization
measure: 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?
timeFrame: 12 weeks after subject randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce Prostaglandin E Concentrations in Induced Sputum From Subjects With Emphysema Compared to Placebo?
timeFrame: 10 weeks after subject randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce the PGE Metabolite PGEM in the Peripheral Blood of Subjects With Emphysema Compared to Placebo?
timeFrame: 48 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce the PGE Metabolite PGEM in the Urine of Subjects With Emphysema Compared to Placebo?
timeFrame: 48 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Increase the Procollagen III Amino Peptide Excreted Into the Urine of Subjects With Emphysema Compared to Placebo?
timeFrame: 48 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce IL-8 Concentrations in Induced Sputum From Subjects With Emphysema Compared to Placebo?
timeFrame: 10 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce PMN Concentrations in the Bronchial Portion of BAL Fluid in Subjects With Emphysema Compared to Placebo?
timeFrame: 12 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce PMN Concentrations in Induced Sputum From Subjects With Emphysema Compared to Placebo?
timeFrame: 10 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce Concentrations of CC-16 in Serum From Subjects With Emphysema Compared to Placebo?
timeFrame: 48 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce Concentrations of CRP in Serum From Subjects With Emphysema Compared to Placebo?
timeFrame: 48 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily, Reduce Concentrations of SP-d in Serum From Subjects With Emphysema Compared to Placebo?
timeFrame: 48 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: 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?
timeFrame: 12 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily Alter the Rate of Change of Emphysema Progression as Assessed by CT Scan?
timeFrame: 48 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily Alter the Rate of Change of DLCO?
timeFrame: 48 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily Alter the Rate of Change of FEV1?
timeFrame: 48 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily Alter the Rate of COPD Exacerbations?
timeFrame: 48 weeks after randomization
measure: Will Ibuprofen 600 mg Three Times Daily Alter Health Status Assessed by the SGRQ or COPD Status Assessed by the CAT in Participants With Emphysema ?
timeFrame: 48 weeks after randomization
measure: Are There Differences Between Subjects With Upper Lobe vs. Lower Lobe Emphysema?
timeFrame: 48 weeks after randomization
measure: Are There Differences Between Subjects With Clustered vs. Diffuse Emphysema?
timeFrame: 48 weeks after randomization
measure: Will BAL PGE Levels be Related to the Rate of Emphysema Progression Determined by the Change in Computed Tomography (CT) Quantified Lung Density in COPDGene?
timeFrame: 3-6 years from initial CT scan
measure: 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?
timeFrame: 3-6 years from initial FEV1 assessment
measure: Will Measures of Prostanoids be Related to the Rate of Emphysema Progression Determined by the Change in CT Quantified Lung Density in COPDGene?
timeFrame: 3-6 years from initial CT scan
measure: 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
timeFrame: 3-6 years after initial FEV1 assessment
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Omaha
country: United States
facility: Univerisity of Nebraska Medical Center
state: Nebraska
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
Study officials:
affiliation: University of Nebraska
name: Stephen I Rennard, MD
role: STUDY_CHAIR
References: