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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Dr. Steven M Rowe, University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT01348204
First received: June 1, 2010
Last updated: January 27, 2012
Last verified: January 2012
  Purpose

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.


Condition Intervention Phase
Cystic Fibrosis
Other: quercetin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Nasal Potential Studies Utilizing CFTR Modulators (UAB Center for Clinical and Translational Science)

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • NPD Biomarker [ Time Frame: patients enroll for a single 2-4 hour visit ] [ Designated as safety issue: No ]
    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


Secondary Outcome Measures:
  • Residual CFTR activity [ Time Frame: patients enroll for a single 2-4 hour visit ] [ Designated as safety issue: No ]
    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.


Enrollment: 32
Study Start Date: March 2010
Study Completion Date: November 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: quercetin
health food supplement
Other: quercetin
health food supplement
Other Name: quercetin

Detailed 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.

  Eligibility

Ages Eligible for Study:   8 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01348204

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
Principal Investigator: Steven M Rowe, MD University of Alabama at Birmingham
  More Information

No publications provided

Responsible Party: Dr. Steven M Rowe, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT01348204     History of Changes
Other Study ID Numbers: F100107002
Study First Received: June 1, 2010
Last Updated: January 27, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by University of Alabama at Birmingham:
Cystic Fibrosis

Additional relevant MeSH terms:
Cystic Fibrosis
Fibrosis
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Pathologic Processes
Quercetin
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 29, 2014