Last updated on August 2019

Losartan and Inflammation in Cystic Fibrosis

Brief description of study

The purpose of the study is to examine if a specific drug called losartan (Cozaar ), generally used to treat high blood pressure and to protect kidneys from damage in patients suffering from Diabetes Mellitus, will have any effect on the nasal inflammation in patients with cystic fibrosis (CF). The study will be performed at the Pulmonary Division at the University of Miami, Cincinnati Children's Medical Hospital Center, University of Kansas Medical Center and University of Alabama-Birmingham.

Detailed Study Description

The propose of this study to conduct a proof of concept clinical trial to test if administration of losartan augments CFTR function in vivo in patients who are on Orkambi. The goal of this pilot clinical trial is to examine the ability of losartan on CFTR (primary hypothesis) and possibly BK rescue/augmentation (secondary hypothesis) in patients homozygous for F508del on Orkambi therapy. The additional benefit for Large, Ca 2+ - and voltage-activated K + channels (BK) channels could be important, but is harder to measure in vivo. Towards this end, however, the study will assess calcium-activated chloride channel (CaCC)/BK activity together as the response to adenosine triphosphate (ATP) during nasal potential difference (NPD) measurements, even though this is not an accurate reflection of either channel on its own.

Note that ATP-induced changes in NPD in CF patients are higher than in normal subjects because in vitro data show that this response is increased in the absence of BK activity. Thus, the expectation here is that the rescue of BK activity with losartan will DECREASE NPD (NPD) responses to ATP.

Primary hypothesis: Losartan at 100 mg for 12 weeks will improve CFTR conductance as measured by NPD in patients on Orkambi therapy. It is expected that compared to placebo, NPD in response to 0 Cl-/isoproterenol will change by more than -4 millivolt (mV) using the most polarized nostril each time.

Secondary hypotheses: Losartan 100 mg for 12 weeks will improve BK and CaCC activity as assessed by a decrease of changes in NPD to ATP exposure. Furthermore, losartan will reduce nasal cytokine levels and systemic inflammatory markers.

Study plan: Briefly, 36 patients with CF, > 12 years of age, who are homozygous for F508del and have been on treatment with Orkambi for at least 3 months will be recruited for this trial. This trial will be randomized 1:1 with placebo (n=18 for each group). After signing informed consent at the screening visit, subjects will perform spirometry, determine sweat chloride, take blood, and test for pregnancy where applicable. Eligible patients will complete visits as outlined below. Quality of life will be assessed by CF quality of life questionnaire - revised (CFQ-R), 12). NPD will use standard protocols and so will nasal cell harvest (see below for assessments). Cytokines will be measured from nasal fluid recovered by Leukosorb filter paper (13). There will be two visits for these different nasal assessments to assure that nasal cell fluid and cell collection will not influence NPD and vice versa. After assessing baselines, a daily dose of 50 mg losartan or placebo will be started. A safety visit will occur after 7 days of treatment ( 2 days) and the losartan dose (or placebo) increased to 100 mg daily (higher dose is likely needed to get anti-inflammatory effect in airways if present). Since this trial assesses anti-inflammatory effects of losartan (and lack of placebo), the total duration will be 14 weeks to achieve 12 weeks of treatment with the higher dose of losartan (or placebo).

Clinical Study Identifier: NCT03206788

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