Losartan and Inflammation in Cystic Fibrosis

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

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.

Study Overview

• Status: Terminated
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Losartan; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Miller School of Medicine
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Losartan group; 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; 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.; Other Names: Cozaar
Placebo Comparator: Placebo group; 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; 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.; Other Names: matching placebo twice daily

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: University of Alabama at Birmingham; University of Kansas Medical Center; Children's Hospital Medical Center, Cincinnati; Cystic Fibrosis Foundation
• Investigators: Principal Investigator: Matthias Salathe, MD, University of Miami

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2017
• Primary Completion (Actual): October 24, 2019
• Study Completion (Actual): December 30, 2019

Study Registration Dates

• First Submitted: June 29, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): November 27, 2020
• Last Update Submitted That Met QC Criteria: November 12, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: 20170397; 20170333 (Other Identifier: Human Subject Research Office at University of Miami)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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