Durability of Hypertonic Saline for Enhancing Mucociliary Clearance in Cystic Fibrosis

July 17, 2012 updated by: Scott Donaldson, University of North Carolina, Chapel Hill
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

16

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27516
        • University of North Carolina at Chapel Hill

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Hypertonic Saline - 1 hour
sodium chloride (7%); mucociliary clearance measured 1 hour post dose
Drug: sodium chloride (7%)
4mL nebulized 7% sodium chloride
Other Names:
  • Hyper-Sal
  • Hypertonic saline (7%)
Experimental: Hypertonic Saline - 4 hours
sodium chloride (7%); mucociliary clearance measured four hours post-dose.
Drug: sodium chloride (7%)
4mL nebulized 7% sodium chloride
Other Names:
  • Hyper-Sal
  • Hypertonic saline (7%)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Duration of action of hypertonic saline as determined by measurements of mucociliary clearance/cough clearance 4 hours post dose.
1-4 hours post-dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of North Carolina, Chapel Hill

Collaborators

Johns Hopkins University
Novartis Pharmaceuticals

Investigators

  • Principal Investigator: William Bennett, PhD, University of North Carolina, Chapel Hill

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2009

Primary Completion (Actual)

May 1, 2010

Study Completion (Actual)

May 1, 2010

Study Registration Dates

First Submitted

March 19, 2010

First Submitted That Met QC Criteria

March 25, 2010

First Posted (Estimate)

March 29, 2010

Study Record Updates

Last Update Posted (Estimate)

August 21, 2012

Last Update Submitted That Met QC Criteria

July 17, 2012

Last Verified

August 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 09-0670

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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