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

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ClinicalTrials.gov Identifier: NCT02416102
Recruitment Status : Terminated (slow enrollment)
First Posted : April 14, 2015
Last Update Posted : August 12, 2019
Sponsor:
Information provided by (Responsible Party):
Rafael Calderon Candelario, University of Miami

Brief Summary:

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 or disease Intervention/treatment Phase
COPD Chronic Bronchitis Drug: Losartan 50 mg Drug: losartan 100 mg Not Applicable

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Effect of Losartan on Airway Mucociliary Dysfunction in Patients With COPD and Chronic Bronchitis
Actual Study Start Date : October 2015
Actual Primary Completion Date : April 3, 2017
Actual Study Completion Date : April 3, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: healthy non-smokers
10 healthy non-smokers will receive 50 mg of losartan for 4 weeks followed by 100 mg of losartan for 4 weeks
Drug: Losartan 50 mg
50 mg QD for 4 weeks
Other Name: Cozaar

Drug: losartan 100 mg
50 mg BID for 4 weeks
Other Name: Cozaar

Experimental: smokers without COPD
10 smokers without COPD will receive 50 mg of losartan for 4 weeks followed by 100 mg of losartan for 4 weeks
Drug: Losartan 50 mg
50 mg QD for 4 weeks
Other Name: Cozaar

Drug: losartan 100 mg
50 mg BID for 4 weeks
Other Name: Cozaar

Experimental: ex-smokers with COPD
10 ex-smokers with COPD will receive 50 mg of losartan for 4 weeks followed by 100 mg of losartan for 4 weeks
Drug: Losartan 50 mg
50 mg QD for 4 weeks
Other Name: Cozaar

Drug: losartan 100 mg
50 mg BID for 4 weeks
Other Name: Cozaar




Primary Outcome Measures :
  1. 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 :
  1. 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

  2. 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



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Ages Eligible for Study:   35 Years to 75 Years   (Adult, Older Adult)
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02416102


Locations
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United States, Florida
Pulmonary Human Research Laboratory, University of Miami, Miller School of Medicine
Miami, Florida, United States, 33136
Sponsors and Collaborators
University of Miami
Investigators
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Principal Investigator: Rafael Calderon, MD University of Miami

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Responsible Party: Rafael Calderon Candelario, Assistant Professor, University of Miami
ClinicalTrials.gov Identifier: NCT02416102    
Other Study ID Numbers: 20140722
First Posted: April 14, 2015    Key Record Dates
Last Update Posted: August 12, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Bronchitis
Bronchitis, Chronic
Acute Disease
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