Nasal Potential Studies Utilizing Cystic Fibrosis Transmembrane Regulator (CFTR) Modulators

Cystic Fibrosis Clinical Trial

Official title:

Nasal Potential Studies Utilizing CFTR Modulators (UAB Center for Clinical and Translational Science)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01348204
• Other study ID #: F100107002
• Status: Completed
• Phase: Phase 2
• First received: June 1, 2010
• Last updated: January 27, 2012
• Start date: March 2010
• Est. completion date: November 2011

Study information

• Verified date: January 2012
• Source: University of Alabama at Birmingham
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to develop new biomarkers for studies of cystic fibrosis (CF). Defects in the gene encoding Cystic Fibrosis Transmembrane Regulator (CFTR) cause CF, an autosomal recessive disorder affecting mainly the pulmonary and digestive tract, leading to early death largely due to progressive loss of pulmonary function. In vitro experiments show that quercetin - a dietary supplement with a well-established safety profile for human use, including clinical trials in a variety of disorders encompassing cancer, heart disease, and as an anti-inflammatory agent - induces activation of CFTR. The nasal potential difference (NPD) test is a measurement of voltage across the nasal membrane and as a fundamental biomarker for CFTR activity in vivo. The NPD is a useful, well-established tool in CF research to determine both diagnoses as well as to measure the effect of new therapies. In vitro experiments show that quercetin induces activation of CFTR additive to that seen with current NPD reagents. In addition, it activates rescued mutant CFTR in vitro (∆F508 CFTR the most common cause of CF), whereas conventional agonists do not. Preliminary in vivo experiments mirrored these results and show that quercetin activates CFTR in human (n=12) NPD tests. Importantly, quercetin perfusion was well-tolerated by a validated sinus questionnaire and physician assessed nasal examination rating. These studies provide strong support for use of quercetin as potentiator of CFTR Cl- channel function by nasal administration. By adding quercetin to the sequence of perfusion solutions for NPD, the investigators may be better suited to detect ∆F508 CFTR activity of rescued mutant protein in the CF patient population.

Description:

Flavonoids are a large group of naturally occurring polyphenolic compounds which are ubiquitous throughout the plant kingdom and are bio-available in fruits, vegetables, nuts, seeds, flowers, and bark. Quercetin has raised particular interest as it is not only a major component of the naturally occurring dietary flavonols, but it also seems to have anti-oxidant, anti-carcinogenic, anti-inflammatory, as well as cardioprotective functions. Recently, our laboratory and others have reported that quercetin, in addition to its other functions, plays a role in improving the function of chloride (Cl-) transport in the (CFTR).

It is well established that genistein, a flavone related to quercetin, increases mutant and wild-type CFTR channel activity. Genistein is now widely used in various cell systems, tissues, and species as a robust CFTR activator. Although it has been extremely helpful in laboratory experiments, Genistein translates poorly into human experiments as it has poor dissolution in solvent. As almost all flavonoids activate CFTR, deeper examination of other members of this family is important for both clinical use as well as a tool for future clinical studies. Quercetin is now available in health food stores as a dietary supplement in both pill as well as beverage form. It may also be beneficial for the treatment of CF and for use as a direct activator of CFTR for use in clinical trials where measurements of CFTR activity are important.

Through a better understanding of CFTR biogenesis and activation, new therapeutic approaches that restore activity to mutant CFTR molecules in vitro and in vivo are being developed. Biomarkers that can detect activity of rescued CFTR are required to measure therapeutic effects of new compounds. Current methods have yet to show consistent rescue of CFTR activity, raising the importance of optimizing detection strategies, including the most effective NPD endpoint. This may be particularly important for subjects harboring the ∆F508 mutation which in addition to its cell processing abnormality, also exhibits a channel gating defect (it does not activate with the conventional NPD agonist isoproterenol) thereby reducing detection of rescued protein. The investigators have previous experience evaluating alternative CFTR activating agents, both in CF animal models, and in human subjects. By adding quercetin to the sequence of perfusion solutions for NPD, the investigators may be better suited to detect CFTR activity of rescued mutant protein. In vitro experiments show that quercetin induces activation of CFTR additive to that seen with current NPD reagents. Preliminary in vivo experiments of non-CF individuals mirrored these results and show that quercetin activates CFTR in human NPD tests (n=12). Importantly, quercetin perfusion was well-tolerated by a validated sinus questionnaire and physician assessed nasal examination rating. As preliminary data suggest perfusion of quercetin may improve defective CFTR activation in surface localized ΔF508, use of this agent within an NPD protocol is likely to improve detection of ΔF508 CFTR resident at the cell surface, representing a potential means to identify new candidates for systemic CFTR potentiator therapies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: November 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 8 Years to 65 Years

Eligibility

Inclusion Criteria:

• 8-65 years old

• absence of pulmonary exacerbation in the last 2 weeks

• willingness to perform nasal potential difference measurement

Exclusion Criteria:

• Need for chronic oxygen supplementation

• positive for B. cepecia within the last year

• active participation in another interventional trial utilizing ion transport modulators

• interfering medical conditions

• pregnant females

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Other:
• quercetin
health food supplement

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama

Sponsors (2)

Lead Sponsor	Collaborator
University of Alabama at Birmingham	National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	NPD Biomarker	Determine whether the NPD biomarker can be improved by including the potentiator quercetin to activate CFTR dependent ion channel activity among CF individuals with surface localized CFTR mutations	patients enroll for a single 2-4 hour visit	No
Secondary	Residual CFTR activity	Determine the relationship between quercetin induced residual CFTR activity (detected in CF patients by the NPD biomarker) and stimulated short circuit currents (Isc) in primary airway cultures harvested from CF tissue donors.	patients enroll for a single 2-4 hour visit	No