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Losartan and Inflammation in Cystic Fibrosis

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ClinicalTrials.gov Identifier: NCT03206788
Recruitment Status : Terminated (due to slow enrollment and approval of the Trikafta for CF patients)
First Posted : July 2, 2017
Results First Posted : November 13, 2020
Last Update Posted : November 27, 2020
Sponsor:
Collaborators:
University of Alabama at Birmingham
Children's Hospital Medical Center, Cincinnati
University of Kansas Medical Center
Cystic Fibrosis Foundation
Information provided by (Responsible Party):
Matthias Salathe, University of Miami

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: Losartan Drug: placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Losartan as Anti-inflammatory Therapy to Augment F508del Cystic Fibrosis Transmembrane (CFTR) Recovery
Actual Study Start Date : November 11, 2017
Actual Primary Completion Date : October 24, 2019
Actual Study Completion Date : December 30, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

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 Name: 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 Name: matching placebo twice daily




Primary Outcome Measures :
  1. Change in Nasal Potential Difference (NPD) to Assess CFTR Activity [ Time Frame: Baseline, 12 weeks ]
    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.


Secondary Outcome Measures :
  1. Change in NPD to Assess CaCC Activity [ Time Frame: Baseline, 12 weeks ]
    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.

  2. Change in NPD to Assess BK Activity [ Time Frame: Baseline, 12 weeks ]
    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.

  3. Change in FEV1 [ Time Frame: Baseline, 12 weeks ]
    Forced Expiratory Volume in 1 second (FEV1) assessed in liters will be measured using spirometry.

  4. Change in Sweat Chloride Concentration [ Time Frame: Baseline, 12 weeks ]
    Sweat chloride concentration will be analyzed from participant sweat samples analyzed in millimoles per liter (mmol/l)

  5. Change in Quality of Life (QoL) Scores as Assessed by the CFQ-R [ Time Frame: Baseline, 12 weeks ]
    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.

  6. Change in Cytokine Levels [ Time Frame: Baseline, 12 weeks ]
    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.

  7. Change in hsCRP [ Time Frame: Baseline, 12 weeks ]
    Serum samples will be analyzed for High sensitivity C-Reactive Protein (hsCRP) values in mg/L.

  8. Change in Blood Count Values [ Time Frame: Baseline, 12 weeks ]
    Serum blood count values including white blood count (WBC) and Absolute Neutrophil Counts (ANC) will be evaluated in units/uL.

  9. Change in %PMN Values [ Time Frame: Baseline, 12 weeks ]
    Serum samples will be analyzed for % Polymorphonuclear (PMN) cells.

  10. Change in SAA Values [ Time Frame: Baseline, 12 weeks ]
    Serum samples will be analyzed for Serum Amyloid A (SAA) values in mg/L.

  11. Change in Calprotectin Values [ Time Frame: Baseline, 12 weeks ]
    Serum samples will be analyzed for calprotectin values in ug/mg.

  12. Change in GM-CSF Values [ Time Frame: Baseline, 12 weeks ]
    Serum samples will be analyzed for % Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) values in pg/mL.

  13. Change in TGF-beta Values [ Time Frame: Baseline, 12 weeks ]
    Serum samples will be analyzed for TGF-beta values in ng/mL.

  14. Change in mRNA Expression [ Time Frame: Baseline, 12 weeks ]
    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).

  15. Change in Losartan Metabolites Levels [ Time Frame: Baseline, 12 weeks ]
    Change in serum blood levels of Losartan and Losartan metabolites EXP3179 & EXP3174.



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT03206788


Locations
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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, Florida
University of Miami, Miller School of Medicine
Miami, Florida, United States, 33136
United States, Kansas
University of Kansas
Kansas City, Kansas, United States, 66160
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Sponsors and Collaborators
University of Miami
University of Alabama at Birmingham
Children's Hospital Medical Center, Cincinnati
University of Kansas Medical Center
Cystic Fibrosis Foundation
Investigators
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Principal Investigator: Matthias Salathe, MD University of Miami
  Study Documents (Full-Text)

Documents provided by Matthias Salathe, University of Miami:
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Responsible Party: Matthias Salathe, Emeritus Professor, University of Miami
ClinicalTrials.gov Identifier: NCT03206788    
Other Study ID Numbers: 20170397
20170333 ( Other Identifier: Human Subject Research Office at University of Miami )
First Posted: July 2, 2017    Key Record Dates
Results First Posted: November 13, 2020
Last Update Posted: November 27, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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