Infant Study of Inhaled Saline in Cystic Fibrosis

A growing body of evidence supports the importance of intervention in Cystic Fibrosis (CF)
lung disease during infancy and early childhood, in order to potentially delay or prevent
irreversible lung disease. Yet, aside from antimicrobial therapies, the CF community has no
clinical trial evidence base with which to guide pulmonary therapies in children <6 years of
age. Hypertonic Saline (HS) is the most attractive chronic maintenance therapy to investigate
in these young 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.

This study is a randomized, parallel group, controlled trial to assess the efficacy and
safety of 7% HS inhaled twice daily for 48 weeks among young children with CF 4 to < 60
months of age at enrollment. The primary hypothesis is that, compared to isotonic saline
(IS), HS will decrease the number of protocol-defined pulmonary exacerbations during the 48
week treatment period. The results of the proposed trial may for the first time provide
evidence for early initiation of HS, which, by improving mucociliary clearance, may delay or
hinder the cycle of infection and inflammation responsible for progressive airway damage in
CF lung disease.

Inclusion Criteria:

- Diagnosis of CF by newborn screening or at least one clinical feature of CF, AND
either: (a) A documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine
iontophoresis or (b) A genotype with two identifiable CF-causing mutations

- Informed consent by parent or legal guardian

- Age 4 months to < 60 months at Enrollment visit. If participating in Infant Pulmonary
Function testing (selected sites), age 4 months to < 16 months at Enrollment visit.

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

Exclusion Criteria:

- Acute intercurrent respiratory infection, defined as an increase in cough, wheezing,
or respiratory rate with onset in 1 week preceding Enrollment visit

- Acute wheezing at Enrollment visit (prior to HS test dose), or at Infant PFT visit
(prior to infant pulmonary function testing), as applicable

- Oxygen saturation < 95% (< 90% in centers located above 4000 feet elevation) at
Enrollment visit (prior to HS test dose) or at Infant PFT visit (prior to infant
pulmonary function testing), as applicable

- Other major organ dysfunction, excluding pancreatic dysfunction

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

- Investigational drug use within 30 days prior to Enrollment visit, or within 30 days
prior to Infant PFT visit as applicable

- Treatment with inhaled hypertonic saline at any concentration within 30 days of
Enrollment visit, or within 30 days prior to Infant PFT visit as applicable

- Chronic lung disease not related to CF

- Intolerance of test dose of HS at Enrollment visit

- A sibling that has been randomized and is still enrolled in ISIS002

Additional Exclusion Criteria for Participation in Infant Pulmonary Function Testing:

- History of adverse reaction to sedation

- Clinically significant upper airway obstruction as determined by the Site Investigator
(e.g. severe laryngomalacia, markedly enlarged tonsils, significant snoring, diagnosed
obstructive sleep apnea)

- Severe gastroesophageal reflux, defined as persistent frequent emesis despite
anti-reflux therapy

- Acute intercurrent respiratory infection, defined as an increase in cough, wheezing,
or respiratory rate with onset in 2 weeks preceding visit