Saline Hypertonic in Preschoolers

A growing body of evidence supports the importance of intervention in cystic fibrosis (CF)
lung disease during early childhood, in order to potentially delay or prevent irreversible
lung damage. Yet, aside from antimicrobial therapies, the CF community has no clinical trial
evidence base with which to guide chronic pulmonary therapies in preschool children.
Hypertonic saline (HS) is the most attractive chronic maintenance therapy to investigate in
preschool children because it addresses defective mucociliary clearance, an early step in the
cascade of events leading to CF lung disease that is expected to be abnormal prior to the
onset of airway infection and inflammation.

Based on several studies, HS appears to be safe in children less than 6 years of age, but its
effectiveness has been difficult to measure. In a previous study (ISIS), children less than 6
years old receiving HS had the same number of lung infections as children receiving a control
treatment. However, the investigators think that children this young need a more sensitive
test, such as lung function testing, to see if HS works in preventing lung damage. Multiple
Breath Washout (MBW) is a relatively easy lung function test to perform with preschool
children. It calculates a measurement called the Lung Clearance Index (LCI), a sensitive
measure of airway inhomogeneity. In a sub-study of the ISIS study in 25 children, LCI
improved in children that inhaled HS twice daily for 48 weeks.

This is a multicenter, randomized, double-blind, controlled, parallel group trial assessing
LCI in children with CF ages 3 to 5 at enrollment. Participants will be randomized 1:1 to
receive 7% HS (treatment arm) vs. 0.9 % isotonic saline (control arm) administered twice
daily via jet nebulizer for 48 weeks. Study visits will occur at Screening, Enrollment, and
at Weeks 12, 24, 36 and 48. Contact with a parent or legal guardian to assess adherence and
interim medical history will occur at 1, 4 and 8 weeks after enrollment and then quarterly
between subsequent study visits. Except for the screening visit, study visits will occur on a
quarterly basis.

Total duration of participation will be up to 52 weeks. As enrollment will occur over
approximately 18 months, total duration of the study is expected to be up to 30 months (18
months enrollment plus 12 months for the last participants to complete study participation).

Inclusion Criteria:

- Diagnosis of CF as evidenced by one or more clinical feature consistent with the CF
phenotype or positive CF newborn screen AND one or more of the following criteria:

- A documented sweat chloride ≥ 60 milliequivalents of solute per litre (mEq/L) by
quantitative pilocarpine iontophoresis (QPIT)

- A documented genotype with two disease-causing mutations in the Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) gene

- Informed consent by parent or legal guardian

- Age ≥ 36 months and ≤72 months at Screening visit

- Ability to comply with medication use, study visits and study procedures as judged by
the site investigator

- Ability to perform technically acceptable MBW measurements at the screening and
enrollment visits

Exclusion Criteria:

- Acute intercurrent respiratory infection, defined as an increase in cough, wheezing,
or respiratory rate with onset within 3 weeks preceding Screening or Enrollment visit

- Acute wheezing at Screening or Enrollment visit

- Oxygen saturation < 95% (<90% in centers located above 4000 feet elevation) at
Screening or Enrollment visit

- Physical findings that would compromise the safety of the participant or the quality
of the study data as determined by site investigator

- Investigational drug use within 30 days prior to Screening or Enrollment visit

- Treatment with inhaled hypertonic saline at any concentration within 30 days prior to
Screening or Enrollment visit

- Chronic lung disease not related to CF

- Inability to tolerate first dose of study treatment at the Enrollment visit