A Randomized-Controlled Trial of Inhaled Hypertonic Saline (7%) to Evaluate the Lung Clearance Index

A Randomized-Controlled Trial of Inhaled Hypertonic Saline (7%) to Evaluate the Lung Clearance Index as a Short-term Pharmacodynamic Biomarker in Patients With Cystic Fibrosis.

The Lung Clearance Index (LCI) is a non invasive measure of lung function that is more sensitive than FEV1. It can be used to measure lung function in children younger than 6 years of age. Therefore, it has a future role in assessing novel therapeutics in the Cystic Fibrosis (CF) population. As such, determining if it can be used as a short term pharmacodynamic biomarker is paramount.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Hypertonic Saline 7%; Drug: Isotonic Saline 0.9% (Placebo)

Detailed Description

Inhaled Hypertonic saline (7%) is a treatment intervention for Cystic Fibrosis patients and has previously been shown to improve lung function and decrease the number of pulmonary exacerbations. The Cystic Fibrosis Transmembrane Regulator Gene (CFTR) protein is essential for maintaining fluid and electrolyte homeostasis in the lung and CFTR defects cause depletion of the periciliary liquid layer which results in impaired mucociliary clearance. Inhaled hypertonic saline (7%) acts as an osmotic agent in the lungs; it repletes the airway surface liquid (ASL) and improves mucociliary clearance.

In addition, we have recently demonstrated that the Lung Clearance Index (LCI) is also a responsive outcome measure. In an intervention study in which patients were treated with hypertonic saline inhalation twice daily for 28 days, LCI but not FEV1 significantly improved in 17 pediatric Cystic Fibrosis (CF) patients with mild lung disease. In this study, LCI was more sensitive to a change in response to treatment than spirometry in a small number of patients. However, it still remains unknown if the LCI will be able to detect a treatment effect on a shorter time scale after an intervention. Its use as a short-term pharmacodynamic biomarker in CF patients remains unknown. The ability of the LCI to detect treatment effects within hours after an intervention would be invaluable to the development of new therapeutic interventions for CF patients.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • St. Michaels Hospital
    • Toronto, Ontario, Canada, M5V1X8
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 14 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of CF as defined by two or more clinical features of CF and a documented sweat chloride > 60 mEq/L by quantitative pilocarpine iontophoresis test or a genotype showing two well characterized disease causing mutations
• Informed consent and verbal assent (as appropriate) provided by the subject's parent or legal guardian and the subject
• At least six years of age at enrolment
• Able to perform reproducible spirometry meeting American Thoracic Society standards
• Pre-bronchodilator FEV1 % predicted > or equal to 40 % predicted
• Ability to perform a reproducible LCI maneuver at screening

Exclusion Criteria:

• Known respiratory culture positive for Burkholderia cepacia
• Previous lung transplantation
• Use of intravenous antibiotics within 14 days of screening
• Use of oral antibiotics including prophylactic antibiotics (e.g., augmentin, tetracycline, cloxacillin, cephalosporins, septra, bactrim) within 14 days of screening
• Initiation of a new maintenance (e.g high dose ibuprofen, Pulmozyme®, aerosolized antibiotics) within 14 days of screening
• Use of systemic corticosteroids within 14 days of screening
• Investigational drug use within 30 days of screening
• Use of hypertonic saline (7%) < 4 weeks before screening or outside of the study protocol
• Participation in any therapeutic clinical study <4 weeks or, 5 half-lives, whichever is longer, before screening
• Smoking < 3 months before screening
• Presence of a condition or abnormality that in the opinion of the site investigator would compromise the safety of the subject or the quality of the data

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hypertonic Saline; The treatment intervention is 1 inhalation of 7% hypertonic saline (4ml)	Drug: Hypertonic Saline 7%; PARI Hyper-Sal™ Sodium Chloride Solution - 7%
Placebo Comparator: Isotonic Saline; The placebo intervention is 1 inhalation of 0.9% isotonic saline	Drug: Isotonic Saline 0.9% (Placebo)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lung Clearance Index	The change in the Lung Clearance Index as measured by nitrogen washout between baseline and 24 hours after each inhalation of Hypertonic Saline (7%) and Isotonic Saline (0.9%)	Baseline to 24 hrs post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary Function Testing	Forced Expiratory Volume in one second (FEV1) % predicted, Forced Expiratory Vital Capacity (FVC) % predicted and Forced Expiratory Flow rate (FEF) 25-75 % predicted will be measured using spirometry.	Baseline, 1,2,4 and 24hrs post-dose
Lung Clearance Index measured using Mass Spectroscopy	The multiple breath washout will be performed in the classical method using a mass spectroscopy (MS): each test consists of two phases: a wash-in phase and washout phase using an inert dry gas mixture containing 4% Sulfur hexafluoride (SF6), 4% He, 21% oxygen and balance nitrogen.	Baseline, 1,2,4 and 24 hrs post dose
Lung Clearance Index measured using Nitrogen Washout	The change in the Lung Clearance Index as measured by nitrogen washout between baseline and 1,2 and 4 hours after each inhalation of Hypertonic Saline (7%) and Isotonic Saline (0.9%)	Baseline, 1,2, 4hrs post dose

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Investigators: Principal Investigator: Reshma Amin, MD, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: October 22, 2014
• First Submitted That Met QC Criteria: October 24, 2014
• First Posted (Estimate): October 28, 2014

Study Record Updates

• Last Update Posted (Estimate): May 22, 2015
• Last Update Submitted That Met QC Criteria: May 20, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: pediatric; Hypertonic Saline; lung clearance index; Multiple Breath Washout
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: 1000024909