Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Preventing Fucose-dependent Binding of Aspergillus and Pseudomonas to Lung Mucin (CADET)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2016 by University of California, San Francisco
Sponsor:
Information provided by (Responsible Party):
John V. Fahy, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01533636
First received: February 10, 2012
Last updated: May 24, 2016
Last verified: May 2016
  Purpose

The investigators will collect samples of sputum from healthy volunteers and patients with cystic fibrosis for the purpose of: a) purifying airway mucins for plate-based binding studies and; b) assessment of the effects of carbohydrates on the rheologic properties of the sputum.

This study has two hypotheses:

  1. Lectins from Pseudomonas aeruginosa and Aspergillus fumigatus bind to airway mucins in a fucose-dependent manner, and this binding can be inhibited by fucosyl glycomimetic compounds.
  2. Fucosyl glycomimetics will compete with Pseudomonas aeruginosa lectin (PA-IIL) and Aspergillus fumigatus lectin (AFL) and disrupt lectin-driven mucin cross-linking in CF sputum.

Condition
Cystic Fibrosis

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Cross-Sectional
Official Title: Preventing Fucose-dependent Binding of Aspergillus and Pseudomonas to Lung Mucin

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Mucus viscosity [ Time Frame: Up to one hour ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA
Samples of induced and expectorated sputum and blood for DNA and RNA extraction, plasma, and serum will be banked in the UCSF Airway Tissue Bank.

Estimated Enrollment: 50
Study Start Date: July 2012
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Groups/Cohorts
Healthy Control
This group will be comprised of healthy individuals without evidence of lung disease.
Cystic Fibrosis
This group will be comprised of individuals who have been diagnosed with cystic fibrosis.

Detailed Description:

Pseudomonas lung infection is a major cause of morbidity and mortality occurring in multiple clinical settings. Patients with cystic fibrosis have lung colonization with Pseudomonas from an early age, and overwhelming pseudomonal lung infection is the most common cause of death in these patients. In addition, Pseudomonas pneumonia is common in immunocompromised patients and in patients intubated for management of respiratory failure. Particularly worrisome is the increasing frequency of P. aeruginosa isolates that are resistant to all or most currently available antibiotics. The mechanism of virulence of P. aeruginosa includes soluble lectins that recognize host oligosaccharides on mucins and the cell glycocalyx. P. aeruginosa has two soluble lectins - LecA, also known as PA-IL and LecB, also known as PA-IIL. PA-IL binds galactose and PA-IIL binds fucose. Notably, PA-IIL binds the fucose containing Lewis a oligosaccharide with very high affinity and the role of PA-IIL in biofilm formation is shown by the absence of biofilm formation in Pseudomonas mutants lacking PA-IIL and by the efficacy of multivalent fucosyl-peptide dendrimers in preventing and disrupting Pseudomonas biofilm formation. D-galactose and L-fucose have been successfully used to treat P. aeruginosa infection in a case report, which hints at the potential for glycomimetic therapy in CF. These monosaccharides are weak inhibitors of PA-IIL, however, and multivalent glycomimetics will be needed for more effective inhibition.

Aspergillus fumigatusinfection is responsible for the majority of human and animal aspergillosis disease, even though air sampling studies show that its conidia usually comprise only a small percentage of total airborne fungal challenge. It is both a primary and opportunistic pathogen, and it is particularly troublesome for patients with cystic fibrosis. It causes multiple lung diseases, includingchronic pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, and invasive pulmonary aspergillosis. Aspergillomas also occur in patients with cavitary lung diseases. Together, these diseases cause significant morbidity and mortality, and available treatments are suboptimal. Most patients with chronic pulmonary aspergillosis require antifungal therapy for many months or years, many experience significant drug side effects, and some experience drug resistance. Patients with either allergic bronchopulmonary aspergillosis (ABPA) or severe asthma with fungal sensitization can improve with itraconazole treatment, but relapses are common, and itraconazole affects corticosteroid metabolism and has the potential to worsen steroid side effects. ABPA requires long-term treatment because Aspergillus airway colonization is difficult to eradicate and quickly recurs when treatment is stopped. Immunocompromised patients are especially vulnerable to invasive aspergillosis where the mortality rate is often 50%, even with antifungal treatment. Clearly, therefore, new treatment approaches are needed for lung diseases caused by A. fumigatus, and we are proposing an approach based on prevention of binding to airway mucins. Adherence of A. fumigatus conidia to host tissues has been the subject of extensive research, but little attention has been directed to Aspergillus/mucin interactions, a surprising deficiency given the role mucins play in airway biology.

This study is an ex-vivo study in which we will collect samples of sputum from healthy volunteers and patients with cystic fibrosis for the purpose of: a) purifying airway mucins for plate-based binding studies and; b) ex-vivo assessment of the effects of carbohydrates on the rheologic properties of the sputum.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Cystic Fibrosis and Healthy Controls
Criteria

Inclusion Criteria:

  • Healthy control subjects:

    • Age 18-65
    • No history of lung disease
  • Cystic fibrosis subjects:

    • Age 18-65
    • No history of lung disease other than cystic fibrosis
    • Diagnosis of CF if sweat chloride values > 60 mM on two separate pilocarpine iontophoresis sweat tests and/or two allelic CF-producing mutations in genetic analysis

Exclusion Criteria:

  • Use of recreational drugs within 30 days prior to enrollment
  • Use of tobacco within 30 days prior to enrollment, or > 10 pack-year tobacco history
  • Pregnant or lactating 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: NCT01533636

Contacts
Contact: Ariana Baum, BA 415-514-1539 ariana.baum@ucsf.edu

Locations
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Ariana Baum, BA    415-514-1539    ariana.baum@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: John V Fahy, MD University of California, San Francisco
  More Information

Additional Information:
Responsible Party: John V. Fahy, Professor in Residence, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01533636     History of Changes
Other Study ID Numbers: 10-04834 
Study First Received: February 10, 2012
Last Updated: May 24, 2016
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
Cystic Fibrosis, Healthy

Additional relevant MeSH terms:
Fibrosis
Cystic Fibrosis
Pseudomonas Infections
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Gram-Negative Bacterial Infections
Bacterial Infections

ClinicalTrials.gov processed this record on September 30, 2016