Losartan Effects on Emphysema Progression (LEEP)

A randomized, parallel, placebo controlled trial to evaluate the effect of 100mg/day losartan on the progression of emphysema as measured by quantitative HRCT compared to placebo

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Study Overview

• Status: Completed
• Conditions: Emphysema
• Intervention / Treatment: Drug: Losartan; Drug: Placebo

Detailed Description

This is a trial designed to test if a treatment, losartan, may decrease the progression of Chronic Obstructive Pulmonary Disease (COPD). Losartan is an angiotensin receptor blocking agent, commonly used as an antihypertensive agent, which has been shown to alter cardiac remodeling after myocardial infarction and renovascular remodeling in diabetes-mellitus. In this trial participants with mild to severe COPD, with Computed Tomography (CT) evidence of emphysema (5-35% of voxels with < -950 Hounsfield Units), will be randomly assigned to receive 100mg/day of losartan or placebo for 48 weeks. The primary outcome measure will be the rate of progression of emphysema, quantified as the percent of lung voxels with a density less than -950 HU as measured by High Resolution CT (HRCT, from baseline to 48 weeks.

• Study Type: Interventional
• Enrollment (Actual): 220
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • San Diego, California, United States, 92103
      • University of California at San Diego
    • San Francisco, California, United States, 94143
      • University of California at San Francisco
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Medical and Research Center
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Western Connecticut Health Network
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine
    • Tampa, Florida, United States, 33613
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60608
      • University of Illinois at Chicago
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospitals
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Hospital And Health Care Center, Inc.
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Louisiana State University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5360
      • University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • St. Louis University School of Medicine
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Asthma Clinical Research Center - Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • New York University School of Medicine
    • New York, New York, United States, 10021
      • Weill Cornell Medicine
    • New York, New York, United States, 10029
      • Mount Sinai National Jewish Health Respiratory Institute; Icahn School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Vermont
    • Colchester, Vermont, United States, 05466
      • Vermont Lung Center at The University of Vermont
  • Washington
    • Seattle, Washington, United States, 98108
      • Pacific Northwest Airways - VA Puget Sound Healthcare System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Mild to severe COPD: Ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) less than or equal to 0.70, FEV1 20-80% of predicted
• Current or former smoker
• HRCT scan with 5-35% of voxels with density less than -950 Hounsfield Units (HU)
• Ability to understand and willingness to sign consent documents

Exclusion Criteria:

• Current therapy with angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)
• Known intolerance to ACE inhibitor or ARB
• History of angioedema
• Conventional indication for ACE inhibitor or ARB (e.g., history of myocardial infarction, known cardiomyopathy)
• Renal insufficiency (GFR <30 mL/min by Cockcroft-Gault calculation)
• Current regular use of NSAIDs defined as daily use 5 or more days of the week for more than one month
• Potassium supplementation or serum potassium level of 5.0 milliequivalents (mEq)/dL or higher at V1
• Current use of a potassium sparing diuretic
• COPD exacerbation requiring treatment within 6 weeks at V1
• Chronic systemic corticosteroid use of more than 10mg/day of prednisone
• Resting SpO2 <89% on 2 L nasal cannula continuous flow; unless at altitude > 4,000 feet, then resting oxygen saturation (SpO2) <89% on 4 L N C continuous flow
• Untreated arterial hypertension (systolic blood pressure greater than140 mm Hg, diastolic blood pressure greater than 90 mm Hg)
• Blood pressure less than 90 mm Hg systolic or 60 mm Hg diastolic while standing or sitting
• Known unilateral or bilateral renal artery stenosis higher than 70%
• Previous lung resection surgery
• Evidence of interstitial, occupational or chronic infectious lung disease
• Changes to chest that preclude adequate HRCT imaging (e.g. Metallic objects in the chest such as shrapnel or pacemaker leads)
• For women of child bearing potential, positive pregnancy test or unwillingness to use two methods of birth control or abstinence for the duration of the study
• Major chronic illnesses which in the judgment of the study physician would interfere with participation in the study e.g. including but not limited to: cardiac, renal, hepatic (LFTs more than 2.5x normal upper limit), neurological, psychiatric, endocrine or neoplastic diseases, uncontrolled diabetes, uncontrolled HIV infection or other immune system disorder, hyperthyroidism, seizure disorders, non-skin cancer, rheumatic diseases
• Failure to keep screening appointments or other indicators of non-adherence
• Inability to be contacted by telephone
• Intention to leave area within 12 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Losartan; At randomization participants will start with a dose of 50mg (one capsule) once a day for 2 weeks. If this dose is well tolerated and systolic BP is >90 mm Hg and diastolic BP is > 60 mm Hg, the dose will be increased to 100 mg (2 capsules) once a day for the remaining 46 weeks.	Drug: Losartan; 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated
Placebo Comparator: placebo; At randomization participants will start with a dose of one capsule (inactive) once a day for 2 weeks. After two weeks, if systolic BP is >90 mm Hg and diastolic BP is > 60 mm Hg, the dose will be increased to 2 capsules once a day for the remaining 46 weeks.	Drug: Placebo; one capsule per day for two weeks, followed by two capsules per day for 46 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean pct950	change in percentage of voxels with density less than -950 Hounsfield Units	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Pre-bronchodilator FEV1 Percent Predicted	Change from the first visit to the final visit in a spirometry (breathing test) measure: forced expiratory volume in one second (FEV1). The test is administered without the participant taking any bronchodilator medication. The FEV1 is compared to standard predicted values in the US population for each individual based on their height, gender, and ethnic group; the result is given as percent of predicted value.	48 weeks
Change From Baseline in Post-bronchodilator FEV1 Percent Predicted	Change from the first visit to the final visit in a spirometry (breathing test) measure: forced expiratory volume in one second (FEV1). This test is performed after the participant is given bronchodilator medications. The FEV1 is compared to standard predicted values in the US population for each individual based on their height, gender, and ethnic group; the result is given as percent of predicted value.	48 weeks
Change From Baseline in CAT Score	Change from the first visit to the final visit in the participant's COPD Assessment Test (CAT) score. The CAT is an 8-item questionnaire assessing the impact of COPD on health status. CAT scores range from 0 to 40, with higher scores indicating a more severe impact of COPD on a patient's life.	48 weeks
Change From Baseline in SGRQ Score: Total	Change from the first visit to the final visit in participants' score on the St George's Respiratory Questionnaire - COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.	48 weeks
Change From Baseline in SGRQ Score: Symptoms	Change from the first visit to the final visit in participants' scores on the symptom-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.	48 weeks
Change From Baseline in SGRQ Score: Activity	Change from the first visit to the final visit in participants' scores on the activity-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.	48 weeks
Change in SGRQ Score: Impact	Change from the first visit to the final visit in participants' scores on the impact-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.	48 weeks
Change From Baseline in mMRC Dyspnea Scale	Change from the first visit to the final visit in participants' scores on the modified Medical Research Council dyspnea scale. The modified Medical Research Council dyspnea scale (mMRC) is a self-rating tool to measure how much breathlessness affects someone's day to day activities. Scores are between 0 and 4, with higher scores indicating more severe breathlessness.	48 weeks
Change From Baseline in PROMIS-20a T-score	Change from the first visit to the final visit in participants' scores on the Patient-Reported Outcome Measures Information System (PROMIS) Physical Function assessment. The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a is a 20-item questionnaire used to indicate a patient's ability to perform activities of daily living, such as bathing, dressing, and commuting. Raw scores from this questionnaire are compared to a reference population to create a "T-score". The general US population is the reference population. In this T-score metric, 50 indicates the population mean with a standard deviation of 10. Higher scores mean better outcomes (more ability to do activities of daily living)	48 weeks

Collaborators and Investigators

• Sponsor: JHSPH Center for Clinical Trials
• Collaborators: University of Pittsburgh

Publications and helpful links

General Publications

• Wise RA, Holbrook JT, Brown RH, Criner GJ, Dransfield MT, He J, Henderson RJ, Kaminsky DA, Kaner RJ, Lazarus SC, Make BJ, McCormack MC, Neptune ER, Que LG. Clinical Trial of Losartan for Pulmonary Emphysema: Pulmonary Trials Cooperative Losartan Effects on Emphysema Progression Clinical Trial. Am J Respir Crit Care Med. 2022 Oct 1;206(7):838-845. doi: 10.1164/rccm.202201-0206OC.

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2017
• Primary Completion (Actual): March 31, 2021
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: February 25, 2016
• First Submitted That Met QC Criteria: February 25, 2016
• First Posted (Estimate): March 2, 2016

Study Record Updates

• Last Update Posted (Actual): June 1, 2022
• Last Update Submitted That Met QC Criteria: May 4, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: COPD; emphysema; losartan; HRCT
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Emphysema; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: U01HL128951 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No