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Effect of Losartan on Airway Mucociliary Dysfunction in Patients With COPD and Chronic Bronchitis

This study is currently recruiting participants.
See Contacts and Locations
Verified June 2017 by Matthias Salathe, University of Miami
Sponsor:
Information provided by (Responsible Party):
Matthias Salathe, University of Miami
ClinicalTrials.gov Identifier:
NCT02416102
First received: January 16, 2015
Last updated: June 16, 2017
Last verified: June 2017
  Purpose

This is a proof of concept, open label protocol to evaluate the effect of losartan on cigarette smoke-induced lung injury in smokers, ex-smokers with and without chronic obstructive pulmonary disease (COPD), giving 50 mg and subsequently 100 mg losartan for 4 weeks

Aim: To test that inhibition of T-cell growth factor (TGF-ß) with losartan in ex-smokers with COPD and active and passive smokers without COPD will lead to an increase chloride conductance through calcium-activated chloride channel (CACC), as measured by nasal potential difference (NPD).

Study design: The Investigators will assess the consequences of active and passive smoking and the treatment with losartan on CaCC-mediated chloride conductance in human beings using NPD measurements.

NPD is a direct measure of ion transport. It measures CaCC-mediated Cl- secretion and thus serves as an indirect measure of voltage-dependent potassium (BK) channels function. In addition, improvement of NPD measured ion transport was indirectly linked to lung function improvements and clearance in trials with cystic fibrosis patients. Therefore, NPD lends itself as a good surrogate for Mucociliary clearance (MCC), in a proof of concept clinical trial.

The investigators will also measure TGF-ß levels in nasal secretions and cells to correlate these with the level of CaCC-mediated Cl- conductance.


Condition Intervention
COPD Chronic Bronchitis Drug: Losartan 50 mg Drug: losartan 100 mg

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: No masking
Primary Purpose: Basic Science
Official Title: Effect of Losartan on Airway Mucociliary Dysfunction in Patients With COPD and Chronic Bronchitis

Resource links provided by NLM:


Further study details as provided by Matthias Salathe, University of Miami:

Primary Outcome Measures:
  • nasal potential difference (NPD) measurement . [ Time Frame: after 4 weeks of losartan treatment ]
    changes on the NPD measurement after each of the 4-week treatment of losartan( 50 mg and 100 mg) from baseline


Secondary Outcome Measures:
  • inflammatory markers on nasal lavage (IL-8 and TGF-ß) [ Time Frame: after 4 weeks of losartan treatment ]
    changes on IL-8 and TGF-ß concentration on nasal lavage after each of the 4-week treatment of losartan ( 50 mg and 100 mg) from baseline

  • TGF-ß concentration on nasal cells. [ Time Frame: after 4 weeks of losartan treatment ]
    change on TGF-ß concentration on nasal cells after each of the 4-week treatment of losartan ( 50 mg and 100 mg) from baseline


Estimated Enrollment: 60
Actual Study Start Date: October 2015
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: losartan 50 mg
10 COPD ex-smokers (>10 pack-years of cigarette smoking) and 10 active smokers not treated with ARBs will receive 50 mg of losartan for 4 weeks
Drug: Losartan 50 mg
COPD and subjects with chronic bronchitis not on ARB treatment will receive 50 mg for 4 weeks
Other Name: Cozaar
Drug: losartan 100 mg
COPD and subjects with chronic bronchitis not on ARB treatment will receive 100 mg for 4 weeks
Other Name: Cozaar
Experimental: losartan 100 mg
10 COPD ex-smokers (>10 pack-years of cigarette smoking) and 10 active smokers not treated with ARBs will receive 100 mg of losartan for 4 weeks
Drug: Losartan 50 mg
COPD and subjects with chronic bronchitis not on ARB treatment will receive 50 mg for 4 weeks
Other Name: Cozaar
Drug: losartan 100 mg
COPD and subjects with chronic bronchitis not on ARB treatment will receive 100 mg for 4 weeks
Other Name: Cozaar

Detailed Description:

Investigator's preliminary data show that TGF-ß1 and cigarette smoke exposure decrease BK activity and cause airway surface liquid (ASL) volume depletion and losartan partially rescues BK channel function leading to increased ASL volume and ciliary beat frequency (CBF) in airway epithelial cells exposed to smoke.

Therefore the investigators propose that smoke exposure, via TGF-ß1 production, leads to apical BK channel dysfunction to cause ASL volume depletion and mucociliary dysfunction in smokers and ex-smokers with COPD. Clinically used Angiotensin II Receptor Blockers (ARBs) are known to inhibit TGF-ß signaling and present a "low-hanging-fruit" approach (medication already in clinical use) for intervention in COPD. In a murine model, losartan has previously been shown to attenuate cigarette smoke-induced lung injury and to rescue lung architecture.

The long-term goal of this study is evaluate the effect of currently available and clinically useful TGF-ß1 signaling inhibitors (ARBs) on mucociliary function in individuals with smoke-associated airway diseases, such as chronic bronchitis and COPD.

To test that hypothesis, subjects with COPD will be given four weeks of 50 mg of losartan daily and consequently an additional four weeks of 100 mg of losartan (divided in two doses of 50 mg twice daily).

  Eligibility

Ages Eligible for Study:   35 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Fulfill one of the group definitions above
  2. Age between 35 and 75 years old
  3. Clinical diagnosis of chronic bronchitis, defined as productive cough for at least 3 months per year for at least two consecutive years
  4. Stable maintenance of all current medication therapy for 3 months, including ARBs for treated groups

Exclusion criteria

  1. Current therapy with ACE inhibitor,or Intolerance to ARB
  2. Women of child bearing potential
  3. Current use of nonsteroidal antiinflammatory drugs or potassium supplementation, treatment with aliskiren, anticoagulation
  4. COPD exacerbation requiring treatment within 6 weeks of the screening visit
  5. Oral corticosteroid use within 6 weeks of the screening visit
  6. Significant hypoxemia (oxygen saturation <90% on room air), chronic respiratory failure by history (pCO2 > 45 mmHg) and forced expiratory volume in 1 second (FEV1) below 40%, clinical evidence of cor pulmonale
  7. Untreated arterial hypertension (systolic blood pressure >140 mm Hg, diastolic blood pressure > 90 mm Hg)
  8. Ability to understand and willingness to sign consent documents
  9. Blood pressure less than 100 mm Hg systolic or 70 mm Hg diastolic while standing at the screening visit
  10. Cardiac, renal, hepatic (LFTs > 3x normal upper limit), neurological, psychiatric, endocrine or neoplastic diseases that are at the discretion of the investigator, to interfere with participation in study
  11. History of renal artery stenosis
  12. Concomitant airway disorders other than COPD and chronic bronchitis, such as bronchiectasis and asthma (history and reversible airflow obstruction by American Thoracic Society (ATS) criteria)
  13. History of pulmonary malignancies, and any other malignancies in the last 5 years
  14. History of thoracic surgery.
  15. Acute pulmonary exacerbation within 6 weeks from the Screening Visit.
  16. Subjects with no airflow obstruction by spirometry but with a decrease in diffusing capacity of lung for carbon monoxide(DLco) possibly indicating emphysema.
  17. Significant exposure to environmental tobacco smoke or atmospheric or occupational pollutants
  18. Urine pregnancy positive test at the Screening Visit.
  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: NCT02416102

Contacts
Contact: Matthias Salathe, MD (305)243-2568 msalathe@med.miami.edu
Contact: Eliana Mendes (305)243-2568 emendes@med.miami.edu

Locations
United States, Florida
Pulmonary Human Research Laboratory, University of Miami, Miller School of Medicine Recruiting
Miami, Florida, United States, 33136
Contact: Eliana Mendes, MD    305-243-2568    emendes@med.miami.edu   
Contact: Carolina Aguiar    (305) 243-5545    caguiar2@miami.edu   
Principal Investigator: Matthias Salathe, MD         
Sponsors and Collaborators
University of Miami
Investigators
Principal Investigator: Matthias Salathe, MD University of Miami
  More Information

Responsible Party: Matthias Salathe, Professor of Medicine, University of Miami
ClinicalTrials.gov Identifier: NCT02416102     History of Changes
Other Study ID Numbers: 20140722
Study First Received: January 16, 2015
Last Updated: June 16, 2017
Individual Participant Data  
Plan to Share IPD: No
Plan Description: individual participant data will be use for analysis only. This is a proof of concept protocol. Results are for research purpose only.

Additional relevant MeSH terms:
Bronchitis
Acute Disease
Bronchitis, Chronic
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Infections
Disease Attributes
Pathologic Processes
Pulmonary Disease, Chronic Obstructive
Losartan
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 23, 2017