Losartan and Inflammation in Cystic Fibrosis

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03206788

Enrollment

Registered

2017-07-02

Start date

2017-11-11

Completion date

2019-12-30

Last updated

2020-11-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cystic Fibrosis

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.

Interventions

DRUGLosartan

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.

DRUGplacebo

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

12 Years to No maximum

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

Design outcomes

Primary

Measure	Time frame	Description
Change in Nasal Potential Difference (NPD) to Assess CFTR Activity	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

Measure	Time frame	Description
Change in NPD to Assess BK Activity	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.
Change in FEV1	Baseline, 12 weeks	Forced Expiratory Volume in 1 second (FEV1) assessed in liters will be measured using spirometry.
Change in Sweat Chloride Concentration	Baseline, 12 weeks	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	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.
Change in Cytokine Levels	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.
Change in hsCRP	Baseline, 12 weeks	Serum samples will be analyzed for High sensitivity C-Reactive Protein (hsCRP) values in mg/L.
Change in Blood Count Values	Baseline, 12 weeks	Serum blood count values including white blood count (WBC) and Absolute Neutrophil Counts (ANC) will be evaluated in units/uL.
Change in NPD to Assess CaCC Activity	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.
Change in SAA Values	Baseline, 12 weeks	Serum samples will be analyzed for Serum Amyloid A (SAA) values in mg/L.
Change in Calprotectin Values	Baseline, 12 weeks	Serum samples will be analyzed for calprotectin values in ug/mg.
Change in GM-CSF Values	Baseline, 12 weeks	Serum samples will be analyzed for % Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) values in pg/mL.
Change in TGF-beta Values	Baseline, 12 weeks	Serum samples will be analyzed for TGF-beta values in ng/mL.
Change in mRNA Expression	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).
Change in Losartan Metabolites Levels	Baseline, 12 weeks	Change in serum blood levels of Losartan and Losartan metabolites EXP3179 & EXP3174.
Change in %PMN Values	Baseline, 12 weeks	Serum samples will be analyzed for % Polymorphonuclear (PMN) cells.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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).	2
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.	5
Total	7

Withdrawals & dropouts

Period	Reason	FG001
Overall Study	Adverse Event	1
Overall Study	Physician Decision	1
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Losartan Group	Placebo Group	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	2 Participants	5 Participants	7 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants	4 Participants	6 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	2 Participants	5 Participants	7 Participants
Sex: Female, Male Female	0 Participants	2 Participants	2 Participants
Sex: Female, Male Male	2 Participants	3 Participants	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 2	0 / 5
other Total, other adverse events	2 / 2	5 / 5
serious Total, serious adverse events	0 / 2	0 / 5

Outcome results

Primary

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.