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Losartan and Inflammation in Cystic Fibrosis

Primary Purpose

Cystic Fibrosis

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Losartan
placebo
Sponsored by
University of Miami
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cystic Fibrosis

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham
  • University of Miami, Miller School of Medicine
  • University of Kansas
  • Cincinnati Children's Hospital Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Losartan group

Placebo group

Arm Description

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).

Participant will receive the placebo intervention, matching the Losartan intervention, once daily for week 1, followed by twice daily on weeks 2-12.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
Change in FEV1
Forced Expiratory Volume in 1 second (FEV1) assessed in liters will be measured using spirometry.
Change in Sweat Chloride Concentration
Sweat chloride concentration will be analyzed from participant sweat samples analyzed in millimoles per liter (mmol/l)
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.
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.
Change in hsCRP
Serum samples will be analyzed for High sensitivity C-Reactive Protein (hsCRP) values in mg/L.
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.
Change in %PMN Values
Serum samples will be analyzed for % Polymorphonuclear (PMN) cells.
Change in SAA Values
Serum samples will be analyzed for Serum Amyloid A (SAA) values in mg/L.
Change in Calprotectin Values
Serum samples will be analyzed for calprotectin values in ug/mg.
Change in GM-CSF Values
Serum samples will be analyzed for % Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) values in pg/mL.
Change in TGF-beta Values
Serum samples will be analyzed for TGF-beta values in ng/mL.
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).
Change in Losartan Metabolites Levels
Change in serum blood levels of Losartan and Losartan metabolites EXP3179 & EXP3174.

Full Information

First Posted
June 29, 2017
Last Updated
November 12, 2020
Sponsor
University of Miami
Collaborators
University of Alabama at Birmingham, Children's Hospital Medical Center, Cincinnati, University of Kansas Medical Center, Cystic Fibrosis Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT03206788
Brief Title
Losartan and Inflammation in Cystic Fibrosis
Official Title
Losartan as Anti-inflammatory Therapy to Augment F508del Cystic Fibrosis Transmembrane (CFTR) Recovery
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Terminated
Why Stopped
due to slow enrollment and approval of the Trikafta for CF patients
Study Start Date
November 11, 2017 (Actual)
Primary Completion Date
October 24, 2019 (Actual)
Study Completion Date
December 30, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Miami
Collaborators
University of Alabama at Birmingham, Children's Hospital Medical Center, Cincinnati, University of Kansas Medical Center, Cystic Fibrosis Foundation

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Losartan group
Arm Type
Experimental
Arm Description
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).
Arm Title
Placebo group
Arm Type
Placebo Comparator
Arm Description
Participant will receive the placebo intervention, matching the Losartan intervention, once daily for week 1, followed by twice daily on weeks 2-12.
Intervention Type
Drug
Intervention Name(s)
Losartan
Other Intervention Name(s)
Cozaar
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
placebo
Other Intervention Name(s)
matching placebo twice daily
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in Nasal Potential Difference (NPD) to Assess CFTR Activity
Description
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.
Time Frame
Baseline, 12 weeks
Secondary Outcome Measure Information:
Title
Change in NPD to Assess CaCC Activity
Description
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.
Time Frame
Baseline, 12 weeks
Title
Change in NPD to Assess BK Activity
Description
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.
Time Frame
Baseline, 12 weeks
Title
Change in FEV1
Description
Forced Expiratory Volume in 1 second (FEV1) assessed in liters will be measured using spirometry.
Time Frame
Baseline, 12 weeks
Title
Change in Sweat Chloride Concentration
Description
Sweat chloride concentration will be analyzed from participant sweat samples analyzed in millimoles per liter (mmol/l)
Time Frame
Baseline, 12 weeks
Title
Change in Quality of Life (QoL) Scores as Assessed by the CFQ-R
Description
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.
Time Frame
Baseline, 12 weeks
Title
Change in Cytokine Levels
Description
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.
Time Frame
Baseline, 12 weeks
Title
Change in hsCRP
Description
Serum samples will be analyzed for High sensitivity C-Reactive Protein (hsCRP) values in mg/L.
Time Frame
Baseline, 12 weeks
Title
Change in Blood Count Values
Description
Serum blood count values including white blood count (WBC) and Absolute Neutrophil Counts (ANC) will be evaluated in units/uL.
Time Frame
Baseline, 12 weeks
Title
Change in %PMN Values
Description
Serum samples will be analyzed for % Polymorphonuclear (PMN) cells.
Time Frame
Baseline, 12 weeks
Title
Change in SAA Values
Description
Serum samples will be analyzed for Serum Amyloid A (SAA) values in mg/L.
Time Frame
Baseline, 12 weeks
Title
Change in Calprotectin Values
Description
Serum samples will be analyzed for calprotectin values in ug/mg.
Time Frame
Baseline, 12 weeks
Title
Change in GM-CSF Values
Description
Serum samples will be analyzed for % Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) values in pg/mL.
Time Frame
Baseline, 12 weeks
Title
Change in TGF-beta Values
Description
Serum samples will be analyzed for TGF-beta values in ng/mL.
Time Frame
Baseline, 12 weeks
Title
Change in mRNA Expression
Description
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).
Time Frame
Baseline, 12 weeks
Title
Change in Losartan Metabolites Levels
Description
Change in serum blood levels of Losartan and Losartan metabolites EXP3179 & EXP3174.
Time Frame
Baseline, 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthias Salathe, MD
Organizational Affiliation
University of Miami
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
University of Miami, Miller School of Medicine
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
University of Kansas
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Losartan and Inflammation in Cystic Fibrosis

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