Effect of Hypertonic Saline on Mucus Clearance in Children Ages 5-12 With Cystic Fibrosis

Cystic Fibrosis Clinical Trial

Official title:

Sustained Impact of Hypertonic Saline on Mucociliary Clearance in Young Children With Cystic Fibrosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01031706
• Other study ID #: 09-1258
• Secondary ID: 1P50HL084934
• Status: Completed
• Phase: N/A
• First received: December 11, 2009
• Last updated: May 29, 2014
• Start date: September 2009
• Est. completion date: July 2012

Study information

• Verified date: March 2014
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Previous work demonstrated that inhaled hypertonic saline (HS) reduces exacerbation frequency and improves lung function in adults with cystic fibrosis (CF). It is unclear, however, whether HS will benefit young patients suffering from CF. The investigators propose to further support the concept that HS can benefit children with mild CF lung disease by performing a relatively short, placebo controlled study of HS in 5-12 year olds, using lung function and mucociliary clearance as key outcome measures.

Description:

Our current understanding of the pathogenesis of CF lung disease stems from data that demonstrate the presence of airway surface liquid (ASL) dehydration in CF. ASL dehydration in CF is caused by defective chloride secretion through the cystic fibrosis transmembrane regulator (CFTR) and increased sodium reabsorption through the epithelial sodium channel (ENaC). ASL dehydration, in turn, interferes with the mucociliary clearance apparatus, causing a breach in a critical line of lung host defense. A number of novel therapeutics are now being developed to address this basic defect of disease, including the use of inhaled hypertonic saline.

Previous work demonstrated that inhaled hypertonic saline (HS) reduces exacerbation frequency and improves lung function in patients with clinically apparent lung disease. A number of issues revolving around the use of HS in CF remain unresolved. First, the typical patients enrolled in previous studies were adults (mean age = 26 yrs) with established lung disease (mean FEV1=78%). Despite our hypothesis that HS should positively affect MCC in preserved/normal airways, a common view of HS is that it benefits CF patients by inducing cough and transiently promoting the clearance of thick CF secretions. It has been questioned, therefore, whether HS will benefit patients who are younger and have mild (or undetectable) lung disease and potentially normal (though unmeasured) rates of MCC. Second, it is unclear whether the substantial beneficial effects of HS in CF were achieved because of a long (>4 hours) duration of action or in spite of an extremely short (~45 minutes) duration of action (the traditional view based upon experiments in normal epithelia). This issue is important, as it relates to the development and dosing of hydrator therapies that may have different pharmacodynamic profiles. Certainly, if twice daily dosing of a short acting compound is sufficient to provide significant clinical benefit, it would reduce the challenge of drug discovery for CF and ease the treatment burden imposed upon patients. The study of HS in CF provides us an opportunity to address this issue.

The hypothesis being tested is that HS will rehydrate CF airway secretions, producing a sustained acceleration in MCC in young children with CF, regardless of whether a measurable mucus clearance defect exists at this relatively early stage of disease. We predict a substantial acceleration of MCC will reduce the exacerbation rate in young children with CF. In addition, with the growing number of treatment modalities that are prescribed to patients with CF, adherence to complex and time consuming medical regimens becomes increasingly problematic and important. We therefore, wish to test an improved drug delivery platform for HS- the eFlow (Pari Pharma) vibrating mesh nebulizer, which has the potential to reduce treatment times, improve compliance, and increase treatment efficacy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: July 2012
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 5 Years to 12 Years

Eligibility

Inclusion Criteria:

• Gender: Females or Males. If the subject is female and of childbearing potential (first menses has occurred), she must have a documented negative pregnancy test at screening and prior to each mucociliary clearance study. Those of childbearing potential must be abstinent or using an acceptable method of birth control (i.e. an Intrauterine Contraceptive Device with a failure rate of <1%, hormonal contraceptives or a barrier method).

• Age: 5-12 years, inclusive

• Diagnosis: Cystic fibrosis documented by a compatible clinical presentation and sweat chloride > 60 mEq/l or 2 disease causing CFTR mutations.

• Severity of the Disease: Suitable patients will have mild lung disease, as defined by:

• Pulmonary Function: Each patient must have an FEV1 of greater than or equal to 60% of predicted at the screening visit.

• Hemoglobin saturation: Patients must have an oxygen saturation of >92% on room air as determined by pulse oximetry at the screening visit.

• Informed consent - The patient and a parent or legally authorized guardian must agree to the subject's participation in the study by signing and dating the informed consent/assent forms after the nature of the study has been fully explained and all questions have been satisfactorily answered.

Exclusion Criteria:

• Unstable or asthmatic lung disease: As defined by a change in medical regimen during the preceding 2 weeks; an FEV1 15% below recent (within 6 months) clinical measurements. Patients with a history of co-existent asthma, as manifested by wheezing and significant bronchoreactivity (>15% increase in FEV1 with bronchodilator), will also be excluded.

• Other medication usage: Patients unable or unwilling to be withdrawn from hypertonic saline therapy for two weeks prior to Visit 1 (baseline MCC visit). Patients using Pulmozyme will be permitted to participate in this trial. Patients on chronic, cycling antibiotics will be required to have completed at least 2 full cycles of the prescribed antibiotic prior to enrollment and should not cycle on or off this therapy during the treatment period of the study.

• Spirometry Performance: Those subjects who are unable to perform acceptable, reproducible spirometry will be excluded from this study.

• Drug allergy: A history of allergy or intolerance to any of the study medications, including albuterol or hypertonic saline.

• Have received an investigational drug or therapy during the preceding 30 days.

• Have had radiation exposure within the past year that would cause them to exceed Federal Regulations by participating in this study.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• Hypertonic Saline
inhaled HS (6% NaCl, 4mL) three times a day for 28 days
• Placebo
4 ml 0.12% NaCl inhaled three times a day x 28 days

Locations

Country	Name	City	State
United States	University of North Carolina	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (7)

Bennett WD, Olivier KN, Zeman KL, Hohneker KW, Boucher RC, Knowles MR. Effect of uridine 5'-triphosphate plus amiloride on mucociliary clearance in adult cystic fibrosis. Am J Respir Crit Care Med. 1996 Jun;153(6 Pt 1):1796-801. — View Citation

Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006 Jan 19;354(3):241-50. — View Citation

Elkins MR, Bye PT. Inhaled hypertonic saline as a therapy for cystic fibrosis. Curr Opin Pulm Med. 2006 Nov;12(6):445-52. Review. — View Citation

Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova EG, Xuan W, Bye PT; National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006 Jan 19;354(3):229-40. — View Citation

Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy JT, Davis CW, Boucher RC. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell. 1998 Dec 23;95(7):1005-15. — View Citation

Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life for children with cystic fibrosis. J Pediatr Psychol. 2003 Dec;28(8):535-45. — View Citation

Tarran R. Regulation of airway surface liquid volume and mucus transport by active ion transport. Proc Am Thorac Soc. 2004;1(1):42-6. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Mucociliary Clearance Rate	Average radio tracer clearance through 90 minutes (MCC90) is primary index of mucociliary clearance at each study.; Primary study outcome: is absolute change in MCC90 between baseline and at end of treatment (where MCC measured 8-12 hours after final dose of study drug) - reflects sustained impact on MCC	Baseline versus after completion of 4 week treatment period	No
Secondary	FEV1 (Spirometry) Change	Absolute change in % predicted FEV1 between baseline and after 4 weeks of treatment calculated	Baseline and after 4 weeks of treatment	Yes