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Durability of Hypertonic Saline for Enhancing Mucociliary Clearance in Cystic Fibrosis

This study has been completed.
Sponsor:
Collaborators:
Johns Hopkins University
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Scott Donaldson, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01094704
First received: March 19, 2010
Last updated: July 17, 2012
Last verified: August 2012

March 19, 2010
July 17, 2012
November 2009
May 2010   (final data collection date for primary outcome measure)
Change in Average Mucociliary Clearance (0-90 Minutes) at 1 and 4 Hrs Post Dose (MCC4hr - MCCbaseline; MCC1hr - MCCbaseline) [ Time Frame: 1-4 hours post-dose ] [ Designated as safety issue: No ]
Duration of action of hypertonic saline as determined by measurements of mucociliary clearance/cough clearance 4 hours post dose.
  • Mucociliary/Cough Clearance [ Time Frame: 4 hours ] [ Designated as safety issue: No ]
    Duration of action of hypertonic saline as determined by measurements of mucociliary clearance/cough clearance four hours post dose.
  • Mucociliary clearance/Cough clearance [ Time Frame: 0 hour ] [ Designated as safety issue: No ]
    Duration of action of hypertonic saline as determined by measurements of mucociliary clearance/cough clearance immediately post dose.
  • Mucociliary/Cough Clearance [ Time Frame: 1 hour ] [ Designated as safety issue: No ]
    Duration of action of hypertonic saline as determined by measurements of mucociliary clearance/cough clearance one hour post dose.
Complete list of historical versions of study NCT01094704 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
Not Provided
 
Durability of Hypertonic Saline for Enhancing Mucociliary Clearance in Cystic Fibrosis
Durability of Hypertonic Saline for Enhancing Mucociliary Clearance in Cystic Fibrosis

Direct measurement of mucociliary and cough clearance (MCC/CC) has been used as a biomarker in cystic fibrosis (CF). Additional knowledge of the performance of this biomarker is needed to inform exploratory clinical trial design in support of programs to develop new inhaled therapies for CF. We hypothesize that MCC/CC measurements can be used to determine the durability of action of agents like hypertonic saline (HS) which increase epithelial lining fluid height.

A reduction in epithelial lining fluid height in cystic fibrosis (CF) as a consequence of decreased function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride channel and related increased activity of the Epithelial sodium (Na) Channel (ENaC) results in impaired mucociliary clearance (MCC), mucus stasis, inflammation, infection, and ultimately progressive bronchiectasis. Inhalation of hypertonic saline (HS), through a direct osmotic effect on the airways, results in an increase in epithelial lining fluid height in vitro and an increase in MCC in vivo as measured following inhalation of a radiotracer with gamma scintigraphy (Sood, et al 2003). MCC as a biomarker is being validated in the clinic, as administration of inhaled hypertonic saline (HS) to cystic fibrosis patients results in short- and medium-term improvements in MCC (Donaldson, et al 2006), while long-term administration of HS is associated with improvements in the registration endpoints of lung function and pulmonary exacerbations (Elkins, et al 2006). Based in large part on these studies, HS has gained acceptance in the CF community, with estimates of up to 50% of patients being treated with this therapy. MCC/CC is thus an excellent choice as a Proof of Concept endpoint for exploratory clinical studies of ENaC modulators. Prior clinical experience with the ENaC blocker amiloride, which improves MCC acutely in healthy volunteers (Sood, et al 2003) but failed to improve lung function in long-term studies in CF (Pons, et al 2000), suggests that durable ENaC modulation will be required for clinical success. It is believed that modulation of ENaC for a period of at least 4 hours will be required to achieve the necessary durability. This durability should also enable twice daily dosing. For comparison we need to know the effectiveness of HS over this same period. Thus, this study is intended to assess 1) the duration of action out to 4 hours for inhaled hypertonic saline (7%) in adult CF patients and 2) the variability of MCC/CC measurements with and without HS treatment. These assessments at UNC will be compared to similar measures at Johns Hopkins University (JHU) for Novartis to determine the feasibility for future multicenter studies using MCC/CC as a primary endpoint.

Interventional
Phase 1
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Cystic Fibrosis
Drug: sodium chloride (7%)
4mL nebulized 7% sodium chloride
Other Names:
  • Hyper-Sal
  • Hypertonic saline (7%)
  • Experimental: Hypertonic Saline - 1 hour
    sodium chloride (7%); mucociliary clearance measured 1 hour post dose
    Intervention: Drug: sodium chloride (7%)
  • Experimental: Hypertonic Saline - 4 hours
    sodium chloride (7%); mucociliary clearance measured four hours post-dose.
    Intervention: Drug: sodium chloride (7%)

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
16
May 2010
May 2010   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Gender: Male or female (non-pregnant, non-lactating)
  • Cystic fibrosis documented by a compatible clinical and radiographic presentation, and sweat chloride > 60 mEq/l or 2 disease causing CFTR mutations.
  • Severity of Disease:

    1. Must have FEV1 of greater than or equal to 50% of predicted at the screening visit.
    2. Must have an oxygen saturation of >92% on room air as determined by pulse oximetry at the screening visit.
  • Patient or legally authorized representative agrees to the patient/individual's participation in the study by signing and dating the informed consent form after the nature of the study has been fully explained and all questions have been satisfactorily answered.

Exclusion Criteria:

  • Unstable 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; or a significant new finding on chest radiograph (pneumothorax, lobar/segmental collapse) not considered a part of the usual, chronic progression of CF lung disease.
  • Patients unable or unwilling to be withdrawn from hypertonic saline therapy, dornase alfa, or N-acetylcysteine 3 days prior to and for the duration of each Baseline and Treatment Period will be excluded.
  • Patients unable to withhold use of long-acting bronchodilators (i.e., Salmeterol, Advair, Formoterol), anti-cholinergics, and vest therapy 12 hours prior to and for the duration of each treatment period.
  • Patients unable to withhold short-acting bronchodilator 6 hours prior to and for the duration of each treatment period except as prescribed by the study protocol.
  • Patients that have received an investigational drug or therapy during the preceding 30 days.
  • Patients that have had radiation exposure within the past year that would cause them to exceed Federal Regulations by participating in this study.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01094704
09-0670
No
Scott Donaldson, University of North Carolina, Chapel Hill
University of North Carolina, Chapel Hill
  • Johns Hopkins University
  • Novartis Pharmaceuticals
Principal Investigator: William Bennett, PhD University of North Carolina, Chapel Hill
University of North Carolina, Chapel Hill
August 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP