Effect of Losartan in Cystic Fibrosis (CF)-NIH Grant #133240
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|ClinicalTrials.gov Identifier: NCT03435939|
Recruitment Status : Not yet recruiting
First Posted : February 19, 2018
Last Update Posted : September 1, 2020
|Condition or disease||Intervention/treatment||Phase|
|Cystic Fibrosis||Drug: Losartan||Early Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||16 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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.
50 mg/day for 7 days followed by 100 mg/day for 12 weeks
Other Name: Cozaar
- 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
- Improvement on pulmonary function tests (in %predicted) [ Time Frame: 12 weeks of treatment ]forced expiratory volume at one second (FEV1) in %predicted
- Improvement on pulmonary function tests (in L) [ Time Frame: 12 weeks of treatment ]forced expiratory volume at one second (FEV1) in liters
- 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)
- 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)
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
|Contact: Matthias Salathe, MDfirstname.lastname@example.org|
|United States, Kansas|
|University of Kansas Medical Center|
|Kansas City, Kansas, United States, 66160|
|Contact: Matthias Salathe, MD 913-588-6000 email@example.com|
|Principal Investigator:||Matthias Salathe, MD||University of Kansas|