Losartan and Inflammation in Cystic Fibrosis

Study Overview
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Brief Summary
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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.

Official Title
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Losartan as Anti-inflammatory Therapy to Augment F508del Cystic Fibrosis Transmembrane (CFTR) Recovery

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Losartan
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CF patients homozygous for F508del and on current treatment with Orkambi™ for at least 3 months Age >12 years Forced expiratory volume at one second (FEV1) >/= 40% of predicted Exclusion Criteria: Female patients not willing to adhere to strict birth control (combination of two methods) Pregnancy History of intolerance to angiotensin receptor blockers (ARBs) Treatment with angiotensin converting enzyme (ACE) inhibitor NPD response to zero chloride (0Cl)/isoproterenol of > - 6.6 mV at screening (evidence of detectable CFTR activity at baseline) Regular use of NSAIDs or potassium supplementation, treatment with aliskiren, on anticoagulation Oral corticosteroid use within 6 weeks Exacerbation requiring treatment within 6 weeks Active treatment for mycobacterial infections Significant hypoxemia (oxygen saturation <90% 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 (ABPA). Subjects with prior thoracic surgery

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losartan group<br>Participant will receive the Losartan intervention and will take 50 mg losartan orally once daily for week 1, followed by 50 mg orally twice daily on weeks 2-12 (unless weight adjustment needed). | Drug: Losartan<br>* 25 mg or 50 mg (based on patient's weight) Losartan tablets taken by mouth daily in the morning for week 1 followed by twice daily (one in the morning and one in the evening) on Weeks 2-12.<br>* Other names: Cozaar;|
| Placebo Comparator: Placebo group<br>Participant will receive the placebo intervention, matching the Losartan intervention, once daily for week 1, followed by twice daily on weeks 2-12. | Drug: placebo<br>* Placebo tablets, matching the Losartan intervention, taken by mouth daily in the morning for week 1 followed by twice daily (one in the morning and one in the evening) on Weeks 2-12.<br>* Other names: matching placebo twice daily;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Nasal Potential Difference (NPD) to Assess CFTR Activity | Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) activity will be measured as the change in NPD in response to apical perfusion with 0 Cl-/isoproterenol. NPD will be measured at the nasal epithelium via a voltmeter. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in NPD to Assess CaCC Activity | Potential difference of Calcium dependent Chloride Channels (CaCC) will be measured as the change in NPD on on Adenosine Triphosphate (ATP) stimulation. NPD will be measured at the nasal epithelium via a voltmeter. | Baseline, 12 weeks | 
| Change in NPD to Assess BK Activity | Big Potassium (BK) activity will be measured as the change in NPD on Adenosine Triphosphate (ATP) stimulation. NPD will be assessed from nasal epithelium samples and analyzed via a voltmeter. | Baseline, 12 weeks | 
| Change in FEV1 | Forced Expiratory Volume in 1 second (FEV1) assessed in liters will be measured using spirometry. | Baseline, 12 weeks | 
| Change in Sweat Chloride Concentration | Sweat chloride concentration will be analyzed from participant sweat samples analyzed in millimoles per liter (mmol/l) | Baseline, 12 weeks | 
| Change in Quality of Life (QoL) Scores as Assessed by the CFQ-R | Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a quality of life questionnaire with a total score ranging from 0-100 with a higher score indicating increased quality of life. | Baseline, 12 weeks | 
| Change in Cytokine Levels | Nasal airway epithelial cells taken by brush will be assessed for cytokine levels including Interleukin IL-1beta, Transforming Growth Factor (TGF-beta) active and total, IL-6, IL-8 and IL-13 in pg/mL. | Baseline, 12 weeks | 
| Change in hsCRP | Serum samples will be analyzed for High sensitivity C-Reactive Protein (hsCRP) values in mg/L. | Baseline, 12 weeks | 
| Change in Blood Count Values | Serum blood count values including white blood count (WBC) and Absolute Neutrophil Counts (ANC) will be evaluated in units/uL. | Baseline, 12 weeks | 
| Change in %PMN Values | Serum samples will be analyzed for % Polymorphonuclear (PMN) cells. | Baseline, 12 weeks | 
| Change in SAA Values | Serum samples will be analyzed for Serum Amyloid A (SAA) values in mg/L. | Baseline, 12 weeks | 
| Change in Calprotectin Values | Serum samples will be analyzed for calprotectin values in ug/mg. | Baseline, 12 weeks | 
| Change in GM-CSF Values | Serum samples will be analyzed for % Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) values in pg/mL. | Baseline, 12 weeks | 
| Change in TGF-beta Values | Serum samples will be analyzed for TGF-beta values in ng/mL. | Baseline, 12 weeks | 
| Change in mRNA Expression | Change in messenger ribonucleic acid (mRNA) expression from nasal cells evaluated via quantitative polymerase chain reaction (qPCR) for Leucine Rich Repeating Protein 26 (LRRC26) and TGF-Beta). | Baseline, 12 weeks | 
| Change in Losartan Metabolites Levels | Change in serum blood levels of Losartan and Losartan metabolites EXP3179 & EXP3174. | Baseline, 12 weeks |