Clinical trial NCT00928135
Conditions: Cystic Fibrosis
Sponsor: Joseph Zabner
Start date: 2013-01-22; Completion date: 2018-04-09
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: 5 ml of 7% saline twice daily arm 2: 5 ml of 15% xylitol twice daily
Interventions: intervention 1: Xylitol intervention 2: Hypertonic saline
Intervention descriptions: intervention 1: 15% xylitol solution for aerosol; Dosage: 5 ml twice a day (BID) intervention 2: 7% hypertonic saline solution for aerosol; Dosage: 5 ml twice a day (BID)

Protocol documents:
Prot_SAP_000.pdf: 
Iowastudyversion1.7March2012, 10/27/20, 3:51 PM  
0 
 
University of Iowa 
SAFETY OF 2-WEEK USE OF AEROSOLIZED 
XYLITOL IN SUBJECTS WITH CYSTIC 
FIBROSIS 
NCT Number 00928135 
durairajl 
3-16-2012 
 


Iowa study version 1.7March2012 
 
1
SAFETY OF 2-WEEK USE OF AEROSOLIZED XYLITOL IN SUBJECTS WITH CYSTIC 
FIBROSIS 
ABSTRACT 
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. 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 is a 5-carbon sugar that can lower the airway surface salt concentration, thus 
enhancing innate immunity.  We recently tested the safety and tolerability of inhaling 
increasing concentrations of single doses of hypertonic xylitol (10% followed by 15%) in 
stable subjects with CF.  All six subjects tolerated both the doses well. There was no 
significant change in FEV1 or respiratory symptom score. In this protocol, we 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 >30% predicted will be randomized  to receive aerosolized 7% hypertonic saline (4 
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 per gram of sputum, 
time to next exacerbation, sputum cytokines and revised CF quality of life questionnaire. 


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2
BACKGROUND 
 
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 [1, 2]. 
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 [3].  
Conversely, their activity is increased by low ionic strength [4-6]. 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 [7].  Xylitol is an artificial sweetener that has been 
successfully used in chewing gums to prevent dental caries [8, 9]; it has been used as an 
oral sugar substitute without significant adverse effects [10].  It has also been shown to 
decrease the incidence of acute otitis media by 20-40% [11]; nasal application to normal 
human subjects was found to decrease colonization with coagulase negative 
staphylococcus [7].   
 


Iowa study version 1.7March2012 
 
3
 
 We found that aerosolized iso-osmolar xylitol was safe in mice and healthy 
volunteers when administered over a single day [12].  We then tested the safety of a 
single dose aerosolized iso-osmotic xylitol in subjects with stable CF and found that it 
was well tolerated [13] In a study of pharmacokinetics of aerosolized xylitol in normal 
volunteers, the terminal half-life of a single dose of iso-osmotic xylitol (10 mL) was 45 
minutes [14]. 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 (safety 
reported submitted to the FDA). 
 
We conducted a 2 week toxicology study under good laboratory practices done in 
rats and dogs in collaboration with Lovelace Respiratory Research Institute (manuscript 
in preparation). Aerosolized xylitol was generated from a 450 mg/mL nebulizer solution 
through two Aerotech II nebulizers.  Exposure levels were defined by time of exposure 
(high, 3 hours; mid, 1.5 hours, and low, 0.5 hours). Mean xylitol aerosol concentrations 
were 3.14 ± 0.19 mg/L for the 3-hour (high) exposure group, 3.03 ± 0.12 for the 1.5-hour 
(mid) exposure group, and 2.91 ± 0.18 for the 0.5-hour (low) exposure group.  Mean 
particle sizes of xylitol were determined to be in the inhalable size range for rodents 
[(range 1–3) μm mass median aerodynamic diameter].  Mean total inhaled doses were 
estimated as 354.2 (target of 394.8), 170.9 (target of 197.4), and 54.7 (target of 65.8) 
mg/kg, for the high, mid, and low exposure groups, respectively.  Mean total deposited 
doses were estimated as 37.55 (target of 55.27), 18.12 (target of 27.64), and 5.80 (target 
of 9.21) mg/kg, for the high, mid, and low exposure groups, respectively. 
 
All rats survived to the scheduled necropsy.  Xylitol exposures were generally 
well-tolerated.  No specific xylitol-related findings were observed in clinical signs, body 


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4
weights, organ weights, or histopathology. Single and 14 consecutive-day xylitol 
exposures were associated with a resolvable discoloration of lungs in rats sacrificed prior 
to 24 h after exposure.  Non-specific inflammatory and remodeling responses of the 
upper airway were observed after 14 days of exposure.  The latter is commonly observed 
in rodent inhalation studies and was not determined to be related to any specific chemical 
toxicity of xylitol.  A No Observed Effect Level (NOEL) was not determined based on 
the acute pulmonary findings.  The No Observed Adverse Effect Level (NOAEL) was 
determined to be the low exposure level due to the resolvable nature of the acute gross 
pulmonary findings and the lack of any corroborating pulmonary histopathology in main 
study and recovery animals at all exposure levels.    
 
For the dog study, beagle dogs were exposed to aerosolized xylitol for varying 
durations (high exposure group at 1 hour, mid exposure group at 0.5 hours, and low 
exposure group at 0.25 hours).  A control group was exposed for 1 hour to a nebulized 
normal saline solution. Mean xylitol aerosol concentrations were 3.49 ± 0.15 mg/L for 
the high exposure group, 3.55 ± 0.18 for the mid exposure group, and 3.54 ± 0.18 for the 
low exposure group.  Mean particle sizes of xylitol were determined to be in the inhalable 
size range for dogs [(actual range 2–3) μm mass median aerodynamic diameter].  Mean 
total inhaled doses were estimated as 105, 53, and 27 mg/kg, for the high, mid, and low 
exposure groups, respectively.  Mean total deposited doses to the pulmonary region were 
estimated as 21, 11, and 5 mg/kg, for the high, mid, and low exposure groups, 
respectively. 
 
All dogs survived to the scheduled necropsy and xylitol exposures were generally 
well-tolerated.  No treatment-related findings were observed in clinical signs, body 


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5
weights, physical (with ECGs) and ophthalmic examinations, food consumption, clinical 
pathology, gross pathology, organ weights, or histopathology.  The No Observed Effect 
Level (NOEL) was determined to be the high exposure level. 
 
In this pilot study we propose to test the hypothesis that aerosolized hypertonic 
xylitol given twice 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. In 
addition, hypertonic concentration allows us to deliver adequate amounts of xylitol with 
twice a day dosing which will help with compliance. 


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6
 Protocol  
Randomized Controlled Study of Aerosolized hypertonic xylitol versus hypertonic 
saline in hospitalized patients with exacerbation of cystic fibrosis 
 
 
The study has been approved by the University of Iowa Institutional Review Board as 
well as the Food and Drug Administration.  This will be a randomized, controlled study. 
Blinding is not assured because of ability to taste the sweetness of xylitol.  
 
Inclusion Criteria: Subjects with CF (medical record evidence of 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 with an FEV1 >30% 
predicted (within the last 14 days) and oxygen saturation ≥90% on FiO2 ≤ 50%, admitted 
for an exacerbation, able to provide written informed consent or assent. 
 
Exclusion Criteria:  Pregnancy, 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, known intolerance to hypertonic saline, serum creatinine 2 
mg/dl or more, active malignancy in the last year, on waiting list for lung transplantation, 
received a solid organ transplant, lack of FEV1 data from the last 14 days and previous 
participation in this study.  
 
Experimental Treatment: Aerosolized 15% xylitol, 5 ml twice a day for 2 weeks using 
Pari LC neubulizer with Vios compressor, (Pari Inc, Monterey, CA) .  Xylitol crystals are 


Iowa study version 1.7March2012 
 
7
made as food additives by Danisco Cultor, USA. Aerosol solution is sterile, non-
pyrogenic, preservative-free solution for inhalation made by UI Pharmaceuticals (Iowa 
City, IA). 
 
Control Treatment: Hypertonic 7% saline (UIHC pharmacy) 4 ml twice a day for 2 
weeks using the same kind of nebulizer. 
 
Screening and Baseline Visit: On the day of admission for exacerbation, informed 
consent obtained in subjects whose admission spirometry (or spirometry within the last 
14 days prior to admit date) shows an FEV1 >30% predicted. Once consented, subjects 
will be randomized to either xylitol or saline group as per the randomization code 
previously generated by the statistician. Demographics, current medications use and the 
revised CF quality of life questionnaire (CFQ-R) will be completed. Spontaneously 
expectorated sputum will be collected and processed for cell count and cytokines and 
quantitative cultures.  Blood will be collected for chemistry and liver function tests 
(LFT). Pregnancy test will be done in women. All medication use during hospitalization 
will be recorded. Treatment will begin the day after admission for an exacerbation. 
Results from spirometry that is routinely done twice a week for inpatients will be 
recorded. All spirometry testing will follow the 2005 American Thoracic Society 
guidelines.  
 
First dose pre and post spirometry: All subjects will undergo spirometry before and 20 
minutes after the first study drug dose as follows.  


Iowa study version 1.7March2012 
 
8
 
Perform baseline spirometry and measure SpO2. Multiply the patient’s best FEV1 
by 0.80 to obtain 20% fall in FEV1 value. 
 
Premedicate subject with 4 puffs albuterol and wait 15-30 min.  
 
Begin study drug nebulization.  
 
Wait for 15-30 minutes and repeat spirometry and SpO2. 
 
Subject is excluded from the study of SpO2 is <89% or FEV1 declines by 20% or 
greater from baseline. 
 
Administration: Subjects will take their routine inhaled medicines followed by chest 
physical therapy. All subjects will then receive 2-4 puffs of albuterol metered dose 
inhaler 15-30 minutes before the study drug. Finally the study drug will be inhaled.  All 
empty, unused and partially used study drug containers will be tracked by the 
investigators. Subjects will be required not to use any new treatments if not medically 
indicated during the study period. 
 
Day 14 follow-up: Subjects will undergo spirometry and sputum collection and answer 
CFQ-R questionnaire. Blood draw for LFTS and electrolytes will be done if not done for 
clinical reasons. If subjects are discharged prior to 14 days of xylitol use, nebulizer 
solutions will be sent home. They will be asked to keep a log of nebulizer use and bring 
back empty and unused vials on follow-up visit (Day 10-15, preferably day 14). They 
will undergo spirometry and sputum collection and questionnaire administration on that 
day. If subjects don’t return on this day, they will have a phone follow-up for adverse 
events and compliance. 


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9
 
Phone follow-up: Week 1, Day 90 and Day 180 after discharge: Subjects will be 
contacted by phone at these time points to enquire about further pulmonary 
exacerbations, admissions, and other AEs. 
 
In the event of bronchospasm:  Subjects will alert the nurses or study team members. 
Nebulized bronchodilators will be immediately administered. Once symptoms resolve, 
they will undergo spirometry using a portable handheld spirometer by a trained user. 
If the subjects dropped FEV1 by 20% or greater from their baseline, they will not receive 
further study drug. However, they will remain in the study for completion of data 
collection. 
Endpoints: Primary outcome will be FEV1 change from baseline. Other safety 
assessments include vital signs within 30 minutes after nebulization, withdrawal from the 
study, rescue bronchodilator use, incidence of treatment related adverse events, and 
laboratory tests (chemistry and liver function tests). Efficacy outcomes include difference 
in density of colonization per gram of sputum from baseline to day 14, time to next 
hospitalization, difference in CFQ-R, sputum cytokine levels and cell counts.  
 
Adverse events such as cough, chest tightness, and headache will be scored on a visual 
analog scale. Other variables collected include antibiotic and other medication use during 
the hospitalization, demographics, organ involvement with CF, genotype data from 
medical records. Follow-up phone calls will be made 1 week, 3 months and 6 months 


Iowa study version 1.7March2012 
 
10 
after study completion for any complications and to assess the time to next 
hospitalization. 
 
Adverse events: Any untoward medical occurrence (abnormal symptom, sign or 
laboratory value) in a study subject that is temporally associated with the study drug will 
be reported as an adverse event. The event does not have to have a causal relationship 
with the treatment. The event will be classified by the investigator as mild, moderate or 
severe. The relationship of an adverse event to the study drug will be determined by the 
investigator to be ‘unlikely to be related, possibly related, probably related or definitely 
related’. 
Future Use of Stored Specimens 
Subjects will be asked for permission to keep any remaining unlinked sputum and blood 
specimens for possible use in future research studies.  Samples may be shared with other 
investigators at other institutions. The samples will not be sold or used directly for 
production of any commercial product. No human genetic tests will be performed on 
samples.  Each sample will be labeled only with a study ID to protect subject’s 
confidentiality.  
There are no benefits to subjects in the future research use of their specimens. Reports 
about future research done with these samples will not be kept in their health records.  
Subjects can decide if they want their samples to be used for future research or have their 
samples destroyed at the end of the study. A subject’s decision can be changed at any 
time prior to the end of the study by notifying the study investigators in writing. 


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However, if a subject consents to future use and some of their specimens have already 
been used for research purposes, the information from that research may still be used.  
 
Statistical analysis: We plan to enroll a total of 60 subjects for this study.  These 
subjects will be randomly assigned to the treatment (xylitol) and control (saline) groups, 
with a goal of 30 subjects in each group.  Since this is a pilot safety study, it has been 
primarily powered to detect common adverse events.  Assuming that the likelihood of a 
subject experiencing an adverse event is no less than 5%, a sample size of 30 subjects 
ensures 80% power towards event detection [16].  (In other words, with a group sample 
size of 30, the probability of observing at least one adverse event in the group is at least 
80%.)   
Study Performance 
Accrual will be assessed be on a monthly basis. We will examine the number of screened 
subjects, those meeting eligibility criteria, the number of persons consenting to 
participate and the number of randomized. The rate of accrual will be tracked versus the 
expected number to achieve the target of 60 participants randomized. 
We will also track the completion number and proportion by time. The number of study 
terminations and reason for termination will be measured. The subject will undergo a 
spirometry and if the FEV1 has declined by 20%, the subject will be terminated from the 
study.  
Baseline  
The composition of the study sample will be described in aggregate. Comparison of 
randomized participants of baseline characteristics will be analyzed using 2 sample t-test, 


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12 
Wilcoxon rank sum test, and analysis of variance (ANOVA) as indicated by the type and 
characteristics of the variable. 
Outcomes 
To assess the adequacy of these group sample sizes for testing a trend in efficacy, we 
consider the outcome of log CFU.  We assume an average density of colonization of 6.5 
log CFU with a SD of 1.5 log CFU among CF subjects.  To detect a reduction of 1.5 log 
CFU in the xylitol group with 80% power, the required sample size is 17 subjects per 
group.  (This computation is based on a two-sided, two-sample t-test conducted at the 
0.05 level of significance.) Data from all patients who have received at least one dose of 
the drug or placebo will be analyzed.  Thus, the analysis will be based on intention to 
treat.  All tests will be two-sided, and conducted using a significance level of 0.05. 
 
The primary outcome is FEV1 change from baseline.  To test for a difference in the mean 
change between the treatment group and the control group, a two-sample t-test will be 
conducted.  To estimate the difference in the mean change, the equivalent confidence 
interval procedure will be used.  Prior to conducting the test, normality will be assessed 
for each group based on normal probability plots.   If gross departures from normality are 
observed, a Wilcoxon rank sum test will be performed instead of the t-test.  (With group 
sample sizes of 30, the t-test is fairly robust to departures from normality.) 
 
The same analytical approach will be used to assess differences in the group means for 
the following variables: the primary outcome of change in respiratory symptom score, 
and the efficacy outcomes of change in density of colonization (per gram of sputum), 


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change in sputum cytokines and cell counts, and responses to all Likert-scale questions 
on the CFQ-R.   
 
To analyze group differences in the efficacy outcome of time to next exacerbation, a 
time-to-event analysis will be conducted.  Kaplan-Meier estimates will be obtained for 
each survival curve (where failure is defined by exacerbation).  To compare the survival 
distributions, a log rank test will be employed.   
 
To compare the proportion of subjects in each group who have experienced any adverse 
events, Fisher’s exact test will be used.  Since certain subjects may experience multiple 
adverse events, we will also compare the incidence of adverse events in each group.  For 
this comparison, a test will be conducted to contrast the mean number of events in each 
group, where the two samples of event counts are treated as arising from independent 
Poisson distributions.  To estimate the difference in group proportions and the difference 
in group means, equivalent confidence interval procedures will be employed. 
 
The preceding inferential procedures will be conducted for individual types of adverse 
events (e.g., cough, chest tightness, headache), as well as the aggregate of all adverse 
events. Fisher’s exact test will also be used to compare the compliance proportion and the 
proportion of rescue bronchodilator use in each group. 
 
Since this study is a randomized, controlled clinical trial, we expect the treatment group 
and the control group to be balanced with respect to factors that could affect the primary 


Iowa study version 1.7March2012 
 
14 
and efficacy outcomes, such as age and gender.  For such variables, descriptive statistics 
will be compiled for each group to ensure that the randomization has been effective.  If a 
marked difference is observed in the distribution of any variables, an analytical approach 
will be utilized that will allow us to control for these variables.  Specifically, the t-test can 
be replaced with an analysis of covariance model, the log-rank test can be replaced with a 
Cox proportional hazards model, Fisher’s exact test can be replaced with a logistic 
regression model, and the two-sample Poisson test can be replaced with a Poisson 
regression model. 
All analyses will be performed by the study statistician using SAS version 9.2 (SAS 
Institute, NC). 
 
Risks: Exposure to xylitol and hypertonic saline is expected to not elicit any significant 
symptoms other than some cough; however we recognize that there may be a possibility 
of bronchospasm with the hyperosmolar xylitol in a subgroup of subjects with CF who 
have bronchial hyperresponsiveness that was not known previously.  
Blood draw and spirometry are a part of standard care and will not pose added risks.  
With the admission labs that are routinely done, we will collect another red top tube for 
liver function tests if they were not planned. Answering questions may involve some 
concentration and may be boring.  
 
Risks are minimized as follows: In the event of bronchospasm with the study drug, 
immediate treatment with bronchodilators is available. The subject will undergo a 
spirometry and if the FEV1 has declined by 20%, the subject will be terminated from the 


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study. Blood draw will be performed by trained nurses or the hospital IV team with 
minimal discomfort. Spirometry will be done by experienced respiratory therapists. 
Symptom questionnaire will be administered by well-trained interviewers and will be as 
brief as possible.  
 
Confidentiality: All the test results and questionnaire will be stored in the research office 
under lock and key with access only to the investigators. Once all testing is complete and 
data is entered for analysis, there will be no identifiers connecting the subject to the data. 
All results will be reported in summary without identifying the subjects. Blood and urine 
specimens will not be stored for future use. 
 
Stopping criteria: If any subject drops his/her FEV1 % predicted by 20%, we will stop 
further exposures. If 3 subjects drop their FEV1 by 20% the treatment assignment will be 
unblinded and they were all in the xylitol group, the study will be closed for further 
recruitment. 
 
Safety Monitoring: Any unexpected fatal or life-threatening adverse event will be 
reported to the Food and Drug Administration (FDA) by phone, fax or email no later than 
7 days of occurrence. Any other serious and unexpected adverse event associated with the 
use of xylitol will be reported to the FDA within 15 days of occurrence. Please see 
DSMP for a detailed safety plan. 
 


Iowa study version 1.7March2012 
 
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[16] 
O'Neill, Robert T. The Assessment of Safety. Biopharmaceutical Statistics for 
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