Saline Hypertonic in Preschoolers + CT

Several observational studies have shown that cystic fibrosis (CF) patients less than or
equal to 6 years of age have clinically silent airway damage. There is growing interest in
early initiation of therapies to prevent or delay the progression of this lung disease in CF.
In SHIP-CT, the investigators will evaluate treatment effects of HS relative to IS on
measures of structural lung disease obtained from chest CT using a novel scoring system
sensitive to early lung changes, the Perth-Rotterdam Annotated Grid Morphometric Analysis
method for CF (PRAGMA-CF), that quantifies the volume percentage of diseased airways (%Dis),
bronchiectasis (%Bx), and trapped air (%TA). As a secondary evaluation of structural airway
damage, the investigators will use an image analysis system to measure airway dimensions
relative to adjacent arteries (AA-system). Longitudinal changes in CT measures will also be
compared to changes in lung function measured by the lung clearance index (LCI) obtained by
N2 Multiple Breath Washout (MBW) and to clinical outcomes.

The primary hypothesis is that HS will reduce structural lung disease as assessed by the
PRAGMA-CF computed tomography score relative to IS during the 48-week treatment period among
preschool children with CF.

SHIP-CT is a parallel study to SHIP001 (ClinicalTrials.gov Identifier NCT02378467). The
primary hypothesis of SHIP001, which runs in North America, is that compared to IS, HS will
improve the LCI, a measure of ventilation heterogeneity, during the 48-week treatment period
among preschool children with CF. The SHIP-CT study (SHIP002) will use a nearly identical
study design as the SHIP001 study, with similar eligibility criteria and treatment arms, to
determine whether HS reduces structural lung disease as measured by chest computed tomography
(CT), in addition to stabilizing or improving functional outcomes as measured by LCI.

This is a multicenter, randomized, double-blind, controlled, parallel group trial assessing
structural lung disease in children with CF ages 3 to 5 at enrollment. Participants will be
randomized 1:1 to receive 7% hypertonic saline (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. Parents or the legal
guardian will be contacted at Weeks 1, 4 and 8 to document changes in health status, adverse
events, concomitant medications/treatments, and encourage study treatment compliance. Parents
or the legal guardian will also be contacted approximately every 6 weeks between visit 3, 4,
5, and 6 to address individual issues or concerns related to study treatment or study
participation, and to document changes in health status, medications and treatments.

Total duration of participant participation will be up to 53 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:

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

1. A documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis
(QPIT)

2. A documented genotype with two disease-causing mutations in the CFTR gene

2. Informed consent by parent or legal guardian

3. Age ≥ 36 months and ≤72 months at screening visit

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

5. Ability to cooperate with chest CT at the enrollment visit as determined by the lung
function technician

Exclusion Criteria:

1. Chest CT within 8 months prior to the Screening visit

2. Acute intercurrent respiratory infection, defined as an increase in cough, wheezing,
or respiratory rate with onset within 3 weeks preceding screening or enrollment visit

3. Acute wheezing at screening or enrollment visit

4. Oxygen saturation < 95% (<90% in centers located above 4000 feet elevation) at
screening or enrollment visit

5. Other major organ dysfunction, excluding pancreatic dysfunction

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

7. Investigational drug use within 30 days prior to screening or enrollment visit

8. Treatment with inhaled HS at any concentration within 30 days prior to screening or
enrollment visit

9. Initiation (i.e. new prescription) of any inhaled hydrating agent such as mannitol or
mucolytic agents such as dornase alpha within 30 days prior to the screening or
enrollment visit

10. Chronic lung disease not related to CF

11. Inability to tolerate first dose of study treatment at the enrollment visit