Prostaglandin Inhibition for Emphysema (PIE)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Nebraska
Sponsor:
Collaborators:
National Jewish Health
Temple University
University of California, Los Angeles
Information provided by (Responsible Party):
Stephen I. Rennard, MD, University of Nebraska
ClinicalTrials.gov Identifier:
NCT02006576
First received: December 4, 2013
Last updated: May 9, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Emphysema
Drug: 600 mg ibuprofen three times daily for 48 weeks
Other: Placebo three times daily
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

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? [ Time Frame: 12 weeks after subject randomization ] [ Designated as safety issue: No ]
    PGE will be measured by HPLC in alveolar 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.


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? [ Time Frame: 12 weeks after subject randomization ] [ Designated as safety issue: No ]
    Pro-collagen peptide fragments will be measured by ELISA in alveolar 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.


Other Outcome Measures:
  • 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? [ Time Frame: 12 weeks after subject randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after subject randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce prostaglandin E concentrations in induced sputum from subjects with emphysema compared to placebo? [ Time Frame: 10 weeks after subject randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce the PGE metabolite PGEM in the peripheral blood of subjects with emphysema compared to placebo? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce the PGE metabolite PGEM in the urine of subjects with emphysema compared to placebo? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, increase the procollagen III amino peptide excreted into the urine of subjects with emphysema compared to placebo? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce IL-8 concentrations in induced sputum from subjects with emphysema compared to placebo? [ Time Frame: 10 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce PMN concentrations in the bronchial portion of BAL fluid in subjects with emphysema compared to placebo? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce PMN concentrations in induced sputum from subjects with emphysema compared to placebo? [ Time Frame: 10 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce concentrations of CC-16 in serum from subjects with emphysema compared to placebo? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce concentrations of CRP in serum from subjects with emphysema compared to placebo? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Will ibuprofen 600 mg three times daily, reduce concentrations of SP-d in serum from subjects with emphysema compared to placebo? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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? [ Time Frame: 12 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
  • Will ibuprofen 600 mg three times daily alter the rate of change of DLCO? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
  • Will ibuprofen 600 mg three times daily alter the rate of change of FEV1? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
  • Will ibuprofen 600 mg three times daily alter the rate of COPD exacerbations? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Are there differences between subjects with upper lobe vs. lower lobe emphysema? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • Are there differences between subjects with clustered vs. diffuse emphysema? [ Time Frame: 48 weeks after randomization ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 200
Study Start Date: January 2014
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: COPD, Placebo
Placebo three times daily
Other: Placebo three times daily
No Intervention: Control subject
Control subjects, no intervention
Experimental: COPD, ibuprofen
600 mg ibuprofen three times daily for 48 weeks
Drug: 600 mg ibuprofen three times daily for 48 weeks

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

Ages Eligible for Study:   46 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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)
  • COPD of GOLD stage 0, 1, 2 or 3 (post-bronchodilator FEV1/FVC < 0.7 and 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02006576

Locations
United States, California
Harbor-UCLA Medical Center Recruiting
Torrance, California, United States, 90502
Contact: Rafi Kiledjian    310-222-8249    rkiledjian@labiomed.org   
Principal Investigator: Richard Casauri, M.D.         
Sub-Investigator: David Hsia, M.D.         
Sub-Investigator: William Stringer, M.D.         
United States, Colorado
National Jewish Helath Recruiting
Denver, Colorado, United States, 80206
Contact: Jennifer Underwood    303-398-1558    underwoodj@njhealth.org   
Contact: Christina Schnell, BA, CCRC    (303) 398-1772    schnellc@njhealth.org   
Principal Investigator: Barry Make, M.D.         
United States, Pennsylvania
Temple University Recruiting
Philadelphia, Pennsylvania, United States, 19140
Contact: Delores Fehrle, RN    215-707-4261    Dolores.Fehrle@tuhs.temple.edu   
Contact: Lanping Hao, RA    (215) 707-2664    Lanping.Hao@tuhs.temple.edu   
Principal Investigator: Gerald Criner, M.D.         
Sponsors and Collaborators
University of Nebraska
National Jewish Health
Temple University
University of California, Los Angeles
Investigators
Study Chair: Stephen I Rennard, M.D. The University of Nebraska Medical Center
  More Information

No publications provided

Responsible Party: Stephen I. Rennard, MD, Principal Investigator, University of Nebraska
ClinicalTrials.gov Identifier: NCT02006576     History of Changes
Other Study ID Numbers: 503-13-ET
Study First Received: December 4, 2013
Last Updated: May 9, 2014
Health Authority: United States: Food and Drug Administration
United States: National Heart, Lung and Blood Institute

Keywords provided by University of Nebraska:
Emphysema
Prostaglandin E
Bronchoalveolar lavage

Additional relevant MeSH terms:
Emphysema
Pulmonary Emphysema
Pathologic Processes
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Diseases
Ibuprofen
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Central Nervous System Agents

ClinicalTrials.gov processed this record on September 16, 2014