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

• Sponsor: Joseph Zabner (Other)
• Overall Status: Completed
• CT.gov ID: NCT00928135
• Collaborator: (none)
• Enrollment: 63
• Location: 1
• Arms: 2
• Actual Duration (Months): 62.5
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Xylitol; Drug: Hypertonic saline	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Other
• Official Title: Randomized Controlled Study of Aerosolized Hypertonic Xylitol Versus Hypertonic Saline in Hospitalized Patients With Exacerbation of Cystic Fibrosis
• Actual Study Start Date: Jan 22, 2013
• Actual Primary Completion Date: Apr 9, 2018
• Actual Study Completion Date: Apr 9, 2018

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures

1. Change in FEV1 Percentage Predicted From Baseline [14 days]

   Change in lung function (forced expiratory volume in 1 second) between baseline and Day 14

Secondary Outcome Measures

1. Density of Colonization of Pseudomonas Aeruginosa Per Gram of Sputum [14 days]

   Mean difference from baseline of Sputum density expressed as log colony forming units between baseline and Day 14

2. Exacerbations During 6 Months Follow-up [6 months]

   numbers of subjects that experienced an exacerbation during the 6 months follow-up

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242

Sponsors and Collaborators

• 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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 16, 2012

More Information

Publications

• 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.
• 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;5:13.
• 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. 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;7:27.
• 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.

• Responsible Party: Joseph Zabner, Professor, University of Iowa
• ClinicalTrials.gov Identifier: NCT00928135
• Other Study ID Numbers: 200901713
• First Posted: Jun 25, 2009
• Last Update Posted: Jun 25, 2021
• Last Verified: Oct 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis

Study Results

Participant Flow

Recruitment Details	subject screen failed due to intolerance to hypertonic saline subjects failed xylitol trial inhalation

Arm/Group Title	7% Hypertonic Saline	Hypertonic Xylitol
Arm/Group Description	5 ml of 7% saline twice daily Saline: 7% hypertonic saline solution for aerosol; Dosage: 5 ml twice a day (BID)	5 ml of 15% xylitol twice daily Xylitol: 15% xylitol solution for aerosol; Dosage: 5 ml twice a day (BID)
Period Title: Overall Study
STARTED	30	30
COMPLETED	29	30
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Hypertonic Saline	Xylitol	Total
Arm/Group Description	7% hypertonic saline given twice daily for 14 days	Xylitol given twice daily for 14 days	Total of all reporting groups
Overall Participants	29	30	59
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.4 (12.8)	29.7 (12.3)	30.1 (12.4)
Sex: Female, Male (Count of Participants)
Female	12 41.4%	15 50%	27 45.8%
Male	17 58.6%	15 50%	32 54.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	28 96.6%	30 100%	58 98.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 3.4%	0 0%	1 1.7%
Forced Expiratory volume % predicted (Percentage predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage predicted]	53.3 (18.8)	58.8 (20.1)	56.1 (19.5)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	7% Hypertonic Saline	Hypertonic Xylitol
Arm/Group Description	5 ml of 7% saline twice daily Saline: 7% hypertonic saline solution for aerosol; Dosage: 5 ml twice a day (BID)	5 ml of 15% xylitol twice daily Xylitol: 15% xylitol solution for aerosol; Dosage: 5 ml twice a day (BID)
Measure Participants	29	30
Mean (95% Confidence Interval) [percentage of predicted]	11.8	8.8

2. Secondary Outcome

Title	Density of Colonization of Pseudomonas Aeruginosa Per Gram of Sputum
Description	Mean difference from baseline of Sputum density expressed as log colony forming units between baseline and Day 14
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

Subjects who were able to produce sputum at baseline and day 14

Arm/Group Title	7% Hypertonic Saline	Hypertonic Xylitol
Arm/Group Description	5 ml of 7% saline twice daily Saline: 7% hypertonic saline solution for aerosol; Dosage: 5 ml twice a day (BID)	5 ml of 15% xylitol twice daily Xylitol: 15% xylitol solution for aerosol; Dosage: 5 ml twice a day (BID)
Measure Participants	18	22
Mean (95% Confidence Interval) [log CFU/ml]	-1.4	-0.9

3. Secondary Outcome

Title	Exacerbations During 6 Months Follow-up
Description	numbers of subjects that experienced an exacerbation during the 6 months follow-up
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	7% Hypertonic Saline	Hypertonic Xylitol
Arm/Group Description	5 ml of 7% saline twice daily Saline: 7% hypertonic saline solution for aerosol; Dosage: 5 ml twice a day (BID)	5 ml of 15% xylitol twice daily Xylitol: 15% xylitol solution for aerosol; Dosage: 5 ml twice a day (BID)
Measure Participants	29	30
Count of Participants [Participants]	15 51.7%	11 36.7%

Adverse Events

Time Frame	For the duration of the study treatment (up tp 14 days) and Up to 7 days after last study drug inhalation for a total of up to 21 days
Arm/Group Title	7% Hypertonic Saline		Hypertonic Xylitol
Arm/Group Description	5 ml of 7% saline twice daily Saline: 7% hypertonic saline solution for aerosol; Dosage: 5 ml twice a day (BID)		5 ml of 15% xylitol twice daily Xylitol: 15% xylitol solution for aerosol; Dosage: 5 ml twice a day (BID)
All Cause Mortality
	7% Hypertonic Saline		Hypertonic Xylitol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/30 (0%)
Serious Adverse Events
	7% Hypertonic Saline		Hypertonic Xylitol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/29 (6.9%)		0/30 (0%)
Gastrointestinal disorders
Distal intestinal obstruction syndrome	2/29 (6.9%)	2	0/30 (0%)	0
Other (Not Including Serious) Adverse Events
	7% Hypertonic Saline		Hypertonic Xylitol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/29 (37.9%)		8/30 (26.7%)
Gastrointestinal disorders
Bowel obstruction	3/29 (10.3%)	3	0/30 (0%)	0
Hepatobiliary disorders
abnormal laboratory values	5/29 (17.2%)	5	4/30 (13.3%)	4
Respiratory, thoracic and mediastinal disorders
bronchospasm	0/29 (0%)	0	2/30 (6.7%)	2
Hemoptysis	2/29 (6.9%)	2	1/30 (3.3%)	1
flu	1/29 (3.4%)	1	0/30 (0%)	0
Vascular disorders
deep vein thrombosis	0/29 (0%)	0	1/30 (3.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.