Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Effect of Losartan in Cystic Fibrosis (CF)-NIH Grant #133240

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03435939
Recruitment Status : Not yet recruiting
First Posted : February 19, 2018
Last Update Posted : September 1, 2020
Sponsor:
Information provided by (Responsible Party):
Matthias Salathe, MD, University of Kansas Medical Center

Brief Summary:
The goal of this study is to execute a small clinical proof of concept trial: To examine the effects of losartan on mucociliary clearance (MCC) in patients not eligible for CFTR rescue therapies

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: Losartan Early Phase 1

Detailed Description:

CF is the most common inherited disease causing a shortened life span, affecting ~30,000 people in the United States with annual health care costs of at least $1.8 billion. The median age of predicted survival of these patients has improved and is now almost 40 years in the US. Over the last two decades, investigators have identified ~2,000 mutations in the CF transmembrane conductance regulator (CFTR) gene. These mutations are imperfectly classified into 5 groups, and small molecules are being developed that rescue group-specific CFTR mutants. These agents have produced remarkable improvements in some patients. The CFTR potentiator ivacaftor (Kalydeco™), approved by the FDA mainly for class III mutations especially G551D, improves ion transport (large decrease in sweat chloride), clinical outcome (increased FEV1 and weight, decreased exacerbations), and quality of life. Furthermore, the FDA recently approved Orkambi™ (a corrector and potentiator: lumacaftor plus ivacaftor) because it reduced exacerbation rates by up to 39% in patients homozygous for F508del.

It has been demonstrated in vitro that improvements in airway surface liquid (ASL) volume are highly predictive of changes seen in clinical studies and track with tracheal mucus velocities measured in sheep in vivo using the CFTR potentiator ivacaftor, inhaled hypertonic saline and other interventions (preliminary data). ASL volume is regulated by ion fluxes through ENaC, CFTR, CaCC, and BK channels, and TGF-β1-mediated inflammation in CF cells decreases activities of CaCC (8) and BK. These findings suggest that effective and safe anti-inflammatory therapy has the potential to improve mucociliary dysfunction in CF patients, even in the absence of small molecule therapy. Currently used anti-inflammatory therapies such as high-dose ibuprofen and steroids produce unwanted side effects that negate their effectiveness. Other medications showed severe side effects in clinical trials. However, experiments proposed in this application will test the hypothesis that losartan provides a safe and effective anti-inflammatory therapy needed to improve outcomes in CF patients.

Briefly, 16 patients with CF, >18 years of age, who are not on CFTR augmentation therapy will be recruited for this trial (4 per year). After signing informed consent at the screening visit, spirometry will be performed, take blood for safety and inflammatory markers, and test for pregnancy where applicable. Since losartan has teratogenic effects, strict birth control in female participants will be enforced. Eligible patients will complete visits as following:

Quality of life will be assessed by CF quality of life questionnaire - revised (CFQ-R). Cytokines will be measured from nasal fluid collected by Leukosorb filter paper. After assessing baselines, a daily dose of 50 mg losartan will be started, followed by a safety visit 7 days after treatment start (± 2 days). Then, the losartan dose will be increased to 100 mg daily until week 14. Since this trial assesses anti-inflammatory effects of 100 mg losartan, the total duration will be 14 weeks to achieve >12 weeks of treatment with losartan.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Anti-Inflammatory Therapy to Augment CFTR Rescue in CF Patients
Estimated Study Start Date : November 1, 2020
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

Arm Intervention/treatment
Experimental: losartan
a daily dose of 50 mg losartan for 7 days (for tolerability). Then, the losartan dose will be increased to 100 mg daily for 12 weeks.
Drug: Losartan
50 mg/day for 7 days followed by 100 mg/day for 12 weeks
Other Name: Cozaar




Primary Outcome Measures :
  1. Improvement of mucociliary clearance ( MCC) and cough clearance (CC) [ Time Frame: 12 weeks treatment ]
    Losartan (100 mg for >12 weeks) will improve MCC+CC clearance in CF patients not on CFTR augmentation therapy in % of baseline


Secondary Outcome Measures :
  1. Improvement on pulmonary function tests (in %predicted) [ Time Frame: 12 weeks of treatment ]
    forced expiratory volume at one second (FEV1) in %predicted

  2. Improvement on pulmonary function tests (in L) [ Time Frame: 12 weeks of treatment ]
    forced expiratory volume at one second (FEV1) in liters

  3. Decrease of inflammatory markers [ Time Frame: 12 weeks ]
    Changes in serum inflammatory markers (hsCRP, WBC including absolute neutrophil count, %PMNs, serum amyloid A or SAA, calprotectin, GM-CSF, TGF-β active and total)

  4. Nasal cytokine changes [ Time Frame: 12 weeks ]
    Nasal cytokine changes (TGF-β1 active and total, TNF-α, IL-1β, IL-6, IL-8, IL-13, COX-2)



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • CF patients with any known mutation combination not on CFTR augmentation therapy
  • ≥18 years of age
  • Severity of the Disease: Suitable patients will have mild to moderate lung disease, as defined by:

    • Pulmonary Function: Each patient must have an FEV1 ≥40% of predicted at the screening visit.
    • Hemoglobin saturation: Patients must have an oxygen saturation of >92% on room air as determined by pulse oximetry at the screening visit.
    • Produces sputum regularly (daily basis, at minimum)
  • FEV1 40-80%
  • Able to sign Informed consent

Exclusion Criteria:

  • When enrolling female patients
  • Not willing to adhere to strict birth control (combination of two methods)
  • If female, patient must be non-pregnant and non-lactating, and those of childbearing potential must be using an acceptable method of birth control (i.e., an Intrauterine Contraceptive Device with a failure rate of <1%, hormonal contraceptives or a barrier method). If a female patient is abstinent, she must agree to use one of the acceptable methods if she becomes sexually active.
  • Unstable lung disease: As defined by a change in medical regimen during the preceding 2 weeks or an FEV1 ≥15% below value within 3 months
  • Received an investigational drug or therapy during the preceding 30 days
  • Active or former smokers with less than 1 year since quitting, or >10 pack-year smoking history
  • Unable to adequately complete study measures, including spirometry and travel to University of North Carolina (UNC)
  • Intolerance to angiotensin receptor blockers (ARB)
  • Treatment with angiotensin converting enzyme (ACE) inhibitor
  • Regular use of NSAIDs or potassium supplementation, treatment with aliskiren, on anticoagulation
  • Oral corticosteroid use within 6 weeks
  • Exacerbation requiring treatment within 6 weeks
  • Treatment of mycobacterial infections
  • Significant hypoxemia (oxygen saturation <92% on room air and rest or use of continuous oxygen treatment), chronic respiratory failure by history (pCO2 > 45 mmHg), clinical evidence of cor pulmonale
  • Untreated arterial hypertension (systolic blood pressure >140 mm Hg, diastolic blood pressure > 90 mmHg)
  • Blood pressure less than 90 mm Hg systolic while standing
  • Cardiac, renal (creatinine 1.5 times normal limit), hepatic (LFTs > 3x normal upper limit), neurological, psychiatric, endocrine or neoplastic diseases that are judged to interfere with participation in study
  • Known renal artery stenosis
  • Concomitant airway disorders other than CF, such as allergic bronchopulmonary aspergillosis or asthma
  • Subjects with prior thoracic surgery
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or may interfere with the interpretation of trial results and, in the judgment of the PI, would make the subject inappropriate for enrollment.
  • Patients using intermittent inhaled or oral antibiotics will be allowed to participate in this trial. Patients on chronic, cycling antibiotics will be required to have completed at least 2 full cycles of the prescribed antibiotic prior to enrollment and should be studied during the same phase of treatment (on or off) during each study period.
  • Have had radiation exposure within the past year that would cause them to exceed Federal Regulations by participating in this study.

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): NCT03435939


Contacts
Layout table for location contacts
Contact: Matthias Salathe, MD 913-588-6000 msalathe@kumc.edu

Locations
Layout table for location information
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
Contact: Matthias Salathe, MD    913-588-6000    msalathe@kumc.edu   
Sponsors and Collaborators
University of Kansas Medical Center
Investigators
Layout table for investigator information
Principal Investigator: Matthias Salathe, MD University of Kansas
Layout table for additonal information
Responsible Party: Matthias Salathe, MD, Chairperson-Professor- Internal Medicine, University of Kansas Medical Center
ClinicalTrials.gov Identifier: NCT03435939    
Other Study ID Numbers: 20170522
First Posted: February 19, 2018    Key Record Dates
Last Update Posted: September 1, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: since this study is a pilot study, participant data will not be shared to other researchers.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Cystic Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Losartan
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action