Inhaled Xylitol Versus Saline in Stable Subjects With Cystic Fibrosis

NCT ID: NCT01355796

Last Updated: 2018-10-24

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

30 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-05-31

Study Completion Date

2015-02-28

Brief Summary

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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 plan to study the safety and efficacy of 2 weeks of inhaled xylitol compared to 2 weeks of hypertonic saline in a randomized crossover design in stable subjects with cystic fibrosis

Detailed Description

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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. The investigators 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, the investigators observed that single doses of 10% followed by 15% xylitol was well tolerated by subjects with cystic fibrosis who were stable.

In this study, the investigators plan to study the safety and efficacy of 2 weeks of inhaled xylitol compared to 2 weeks of hypertonic saline in a randomized crossover design in stable subjects with cystic fibrosis

Conditions

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Cystic Fibrosis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Aerosolized Hypertonic xyltiol

Aerosolized xylitol (5 ml) twice daily for 14 days

Group Type EXPERIMENTAL

Xylitol

Intervention Type DRUG

Aerosolized 15% xylitol, 5 ml twice a day for 2 weeks

Hypertonic saline

Intervention Type DRUG

4 ml of 7 % saline aerosolized twice a day for 2 weeks

Hypertonic saline

Aerosolized 7% hypertonic saline (4 ml) twice daily for 14 days

Group Type ACTIVE_COMPARATOR

Xylitol

Intervention Type DRUG

Aerosolized 15% xylitol, 5 ml twice a day for 2 weeks

Hypertonic saline

Intervention Type DRUG

4 ml of 7 % saline aerosolized twice a day for 2 weeks

Interventions

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Xylitol

Aerosolized 15% xylitol, 5 ml twice a day for 2 weeks

Intervention Type DRUG

Hypertonic saline

4 ml of 7 % saline aerosolized twice a day for 2 weeks

Intervention Type DRUG

Other Intervention Names

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Xylo-pentane-1, 2, 3, 4, 5-pentol 7% NaCl

Eligibility Criteria

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Inclusion Criteria

* Documented diagnosis of CF (medical record evidence of 2 identified CFTR(Cystic fibrosis transmembrane conductance regulator) mutations or a positive sweat chloride test or nasal voltage difference, and 1 or more clinical findings of CF)
* Age 16 or greater
* FEV1\>30% predicted
* Oxygen saturation \> or equal too 90% on room air
* Clinically stable, without evidence of pulmona4ry exacerbation for at least 2 weeks prior to screening (defined as use of oral or intravenous antibiotics for cystic fibrosis exacerbation)
* Use of effective contraception in women
* Ability to provide written informed consent and assent
* Successful completion of the trial doses of study drugs

Exclusion Criteria

* Pregnancy
* Hemoptysis more than 100 mL within the last 30 days
* Change in chronic medication within the last 30 days
* History of elevated serum creatinine (\> than or equal to 2 mg/dl) within 30 days or at screening
* History of lung and other solid organ transplantation
* Wait-listed for lung or other solid organ transplant
* Known intolerance to inhaled hypertonic saline
Minimum Eligible Age

16 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Ann & Robert H Lurie Children's Hospital of Chicago

OTHER

Sponsor Role collaborator

Northwestern University

OTHER

Sponsor Role collaborator

Joseph Zabner

OTHER

Sponsor Role lead

Responsible Party

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Joseph Zabner

Professor

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Joseph Zabner, MD

Role: PRINCIPAL_INVESTIGATOR

University of Iowa

Lakshmi Durairaj, MD

Role: STUDY_DIRECTOR

University of Iowa

Locations

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Northwestern University

Chicago, Illinois, United States

Site Status

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Site Status

Countries

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United States

References

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Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005 May 12;352(19):1992-2001. doi: 10.1056/NEJMra043184. No abstract available.

Reference Type BACKGROUND
PMID: 15888700 (View on PubMed)

Zabner J, Smith JJ, Karp PH, Widdicombe JH, Welsh MJ. Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro. Mol Cell. 1998 Sep;2(3):397-403. doi: 10.1016/s1097-2765(00)80284-1.

Reference Type BACKGROUND
PMID: 9774978 (View on PubMed)

Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zasloff M, Wilson JM. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell. 1997 Feb 21;88(4):553-60. doi: 10.1016/s0092-8674(00)81895-4.

Reference Type BACKGROUND
PMID: 9038346 (View on PubMed)

Bals R, Wang X, Wu Z, Freeman T, Bafna V, Zasloff M, Wilson JM. Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J Clin Invest. 1998 Sep 1;102(5):874-80. doi: 10.1172/JCI2410.

Reference Type BACKGROUND
PMID: 9727055 (View on PubMed)

Travis SM, Conway BA, Zabner J, Smith JJ, Anderson NN, Singh PK, Greenberg EP, Welsh MJ. Activity of abundant antimicrobials of the human airway. Am J Respir Cell Mol Biol. 1999 May;20(5):872-9. doi: 10.1165/ajrcmb.20.5.3572.

Reference Type BACKGROUND
PMID: 10226057 (View on PubMed)

Makinen KK, Bennett CA, Hujoel PP, Isokangas PJ, Isotupa KP, Pape HR Jr, Makinen PL. Xylitol chewing gums and caries rates: a 40-month cohort study. J Dent Res. 1995 Dec;74(12):1904-13. doi: 10.1177/00220345950740121501.

Reference Type BACKGROUND
PMID: 8600188 (View on PubMed)

Soderling E, Makinen KK, Chen CY, Pape HR Jr, Loesche W, Makinen PL. Effect of sorbitol, xylitol, and xylitol/sorbitol chewing gums on dental plaque. Caries Res. 1989;23(5):378-84. doi: 10.1159/000261212.

Reference Type BACKGROUND
PMID: 2766327 (View on PubMed)

Makinen KK. Long-term tolerance of healthy human subjects to high amounts of xylitol and fructose: general and biochemical findings. Int Z Vitam Ernahrungsforsch Beih. 1976;15:92-104.

Reference Type BACKGROUND
PMID: 783060 (View on PubMed)

Uhari M, Kontiokari T, Koskela M, Niemela M. Xylitol chewing gum in prevention of acute otitis media: double blind randomised trial. BMJ. 1996 Nov 9;313(7066):1180-4. doi: 10.1136/bmj.313.7066.1180.

Reference Type BACKGROUND
PMID: 8916749 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15377394 (View on PubMed)

Singh PK, Jia HP, Wiles K, Hesselberth J, Liu L, Conway BA, Greenberg EP, Valore EV, Welsh MJ, Ganz T, Tack BF, McCray PB Jr. Production of beta-defensins by human airway epithelia. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14961-6. doi: 10.1073/pnas.95.25.14961.

Reference Type BACKGROUND
PMID: 9843998 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11027360 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16781897 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16483382 (View on PubMed)

Marks JH, Hare KL, Saunders RA, Homnick DN. Pulmonary function and sputum production in patients with cystic fibrosis: a pilot study comparing the PercussiveTech HF device and standard chest physiotherapy. Chest. 2004 Apr;125(4):1507-11. doi: 10.1378/chest.125.4.1507.

Reference Type BACKGROUND
PMID: 15078765 (View on PubMed)

Other Identifiers

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201209728

Identifier Type: -

Identifier Source: org_study_id

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