Aerosolized Hypertonic Xylitol Versus Hypertonic Saline in Cystic Fibrosis (CF) Subjects

Randomized Controlled Study of Aerosolized Hypertonic Xylitol Versus Hypertonic Saline in Hospitalized Patients With Exacerbation of Cystic Fibrosis

Cystic fibrosis (CF) lung disease is characterized by chronic bacterial colonization and recurrent infection of the airways. Lowering the airway surface liquid (ASL) salt concentration has been shown to increase activity of salt sensitive antimicrobial peptides.

Xylitol is a 5-carbon sugar that can lower the ASL salt concentration, thus enhancing innate immunity. In this study, the investigators propose to test the safety and tolerability of aerosolized xylitol used daily for 2 weeks in subjects with cystic fibrosis. In a pilot, 2-week study, 60 subjects with cystic fibrosis with an FEV1(Forced expiratory volume in 1 second ) >30% predicted will be randomized to receive aerosolized 7% hypertonic saline (5 ml) or 15% xylitol, (5 ml) twice a day for 14 days. The primary outcomes will be safety as assessed by FEV1 change from baseline, adverse events and respiratory symptom score. Outcomes for trend in efficacy include density of colonization of sputum, time to next exacerbation, sputum cytokines and revised CF quality of life questionnaire.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Hypertonic saline; Drug: Xylitol

Detailed Description

Cystic fibrosis (CF) lung disease is characterized by chronic bacterial colonization and recurrent infection of the airways. Disruption of the cystic fibrosis transmembrane conductance regulator chloride channels in subjects with CF results in altered fluid and electrolyte transport across the airway epithelium thereby initiating infections.

These infections eventually destroy the lungs and contribute to significant morbidity and mortality in patients with CF. It is well known that antibacterial activity of innate immune mediators such as lysozyme and beta defensins in human airway surface liquid (ASL) is salt-sensitive; an increase in salt concentration inhibits their activity.

Conversely, their activity is increased by low ionic strength. Lowering the ASL salt concentration and increasing the ASL volume might therefore potentiate innate immunity and therefore decrease or prevent airway infections in subjects with CF.

Xylitol, a five-carbon sugar with low transepithelial permeability, which is poorly metabolized by bacteria can lower the salt concentration of both cystic fibrosis (CF) and non-CF epithelia in vitro. Xylitol is an artificial sweetener that has been successfully used in chewing gums to prevent dental caries; it has been used as an oral sugar substitute without significant adverse effects. It has also been shown to decrease the incidence of acute otitis media by 20-40%; nasal application to normal human subjects was found to decrease colonization with coagulase negative staphylococcus. We found that aerosolized iso-osmolar xylitol was safe in mice, healthy volunteers and stable subjects with CF when administered over a single day. In a recent study, we observed that single doses of 10% followed by 15% xylitol was well tolerated by subjects with cystic fibrosis who were stable. In this pilot study we propose to test the hypothesis that aerosolized hypertonic xylitol given daily for 2 weeks, will be safe and well tolerated and potentially lower the density of colonization in subjects with CF compared to hypertonic saline. We chose hypertonic concentration of xylitol to be comparable in part to hypertonic saline which is being offered as a routine treatment in hospitalized patients with CF exacerbation.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with CF (medical record evidence of CFTR(Cystic fibrosis transmembrane conductance regulator) mutation or sweat chloride test or nasal voltage difference, and 1 or more clinical findings of CF),
• Age 12 or greater
• FEV1 > 30% predicted(within the last 14 days and oxygen saturation > 90% on FiO2(fraction of inspired oxygen) ≤ 50%,
• Admitted for an exacerbation,
• Use of effective contraception in women,
• Able to provide written informed consent.

Exclusion Criteria:

• Pregnancy,
• History of asthma based on methacholine challenge or bronchial hyperresponsiveness on PFTS(Pulmonary Function Test),
• Hemoptysis more than 60 mL within the last 30 days,
• Use of any investigational study drug within the last 30 days,
• Initiation of hypertonic saline within the last 30 days,
• A serum creatinine 2 mg/dl or more
• Active malignancy in the last year
• Antibiotics for CF exacerbation as an outpatient in the last 2 weeks
• B cepacia colonization
• Waiting list for lung transplant
• Lack of FEV1 data from the last 14 days
• Previous participation in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 7% Hypertonic saline; 5 ml of 7% saline twice daily	Drug: Hypertonic saline; 7% hypertonic saline solution for aerosol; Dosage: 5 ml twice a day (BID)
Experimental: Hypertonic xylitol; 5 ml of 15% xylitol twice daily	Drug: Xylitol; 15% xylitol solution for aerosol; Dosage: 5 ml twice a day (BID)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FEV1 Percentage Predicted From Baseline	Change in lung function (forced expiratory volume in 1 second) between baseline and Day 14	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Density of Colonization of Pseudomonas Aeruginosa Per Gram of Sputum	Mean difference from baseline of Sputum density expressed as log colony forming units between baseline and Day 14	14 days
Exacerbations During 6 Months Follow-up	numbers of subjects that experienced an exacerbation during the 6 months follow-up	6 months

Collaborators and Investigators

• Sponsor: Joseph Zabner
• Investigators: Principal Investigator: Joseph Zabner, M.D., PMID: 16781897; Study Director: Lakshmi Durairaj, M.D., PMID: 16781897; Study Chair: Jan L Launspach, R.N., CCRC, PMID: 16781897

Publications and helpful links

General Publications

• Hurley MN, Smith S, Forrester DL, Smyth AR. Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis. Cochrane Database Syst Rev. 2020 Jul 16;7(7):CD008037. doi: 10.1002/14651858.CD008037.pub4.
• Durairaj L, Launspach J, Watt JL, Mohamad Z, Kline J, Zabner J. Safety assessment of inhaled xylitol in subjects with cystic fibrosis. J Cyst Fibros. 2007 Jan;6(1):31-4. doi: 10.1016/j.jcf.2006.05.002. Epub 2006 Jun 15.
• Durairaj L, Neelakantan S, Launspach J, Watt JL, Allaman MM, Kearney WR, Veng-Pedersen P, Zabner J. Bronchoscopic assessment of airway retention time of aerosolized xylitol. Respir Res. 2006 Feb 16;7(1):27. doi: 10.1186/1465-9921-7-27.
• Brown CL, Graham SM, Cable BB, Ozer EA, Taft PJ, Zabner J. Xylitol enhances bacterial killing in the rabbit maxillary sinus. Laryngoscope. 2004 Nov;114(11):2021-4. doi: 10.1097/01.mlg.0000147939.90249.47.
• Durairaj L, Launspach J, Watt JL, Businga TR, Kline JN, Thorne PS, Zabner J. Safety assessment of inhaled xylitol in mice and healthy volunteers. Respir Res. 2004 Sep 16;5(1):13. doi: 10.1186/1465-9921-5-13.
• Zabner J, Seiler MP, Launspach JL, Karp PH, Kearney WR, Look DC, Smith JJ, Welsh MJ. The osmolyte xylitol reduces the salt concentration of airway surface liquid and may enhance bacterial killing. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11614-9. doi: 10.1073/pnas.97.21.11614.
• Holliday ZM, Launspach JL, Durairaj L, Singh PK, Zabner J, Stoltz DA. Effects of Tham Nasal Alkalinization on Airway Microbial Communities: A Pilot Study in Non-CF and CF Adults. Ann Otol Rhinol Laryngol. 2022 Sep;131(9):1013-1020. doi: 10.1177/00034894211051814. Epub 2021 Oct 21.
• Singh S, Hornick D, Fedler J, Launspach JL, Teresi ME, Santacroce TR, Cavanaugh JE, Horan R, Nelson G, Starner TD, Zabner J, Durairaj L. Randomized controlled study of aerosolized hypertonic xylitol versus hypertonic saline in hospitalized patients with pulmonary exacerbation of cystic fibrosis. J Cyst Fibros. 2020 Jan;19(1):108-113. doi: 10.1016/j.jcf.2019.06.016. Epub 2019 Jul 18.

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2013
• Primary Completion (Actual): April 9, 2018
• Study Completion (Actual): April 9, 2018

Study Registration Dates

• First Submitted: June 18, 2009
• First Submitted That Met QC Criteria: June 23, 2009
• First Posted (Estimate): June 25, 2009

Study Record Updates

• Last Update Posted (Actual): June 25, 2021
• Last Update Submitted That Met QC Criteria: June 3, 2021
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: 200901713

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No