Efficacy of Recombinant Human Clara Cell 10 Protein (rhCC10) Administered to Premature Neonates With Respiratory Distress Syndrome

Recombinant human CC10 protein (rhCC10) is a novel therapeutic agent used to prevent the
development of chronic respiratory morbidity (CRM; repeated respiratory infections, asthma,
re-hospitalizations) in preterm infants. Native CC10 is a natural anti-inflammatory and
immunomodulatory factor produced by Clara Cells in the lung and is the most abundant protein
in respiratory mucosa. Animal data demonstrate that a single intratracheal dose of rhCC10
administered shortly after birth reduces lung inflammation (important biomarkers linked to
lung injury in preterm infants), promotes normal lung development, preserves lung
architecture, improves pulmonary function, suppresses the response to endotoxin and enhances
resistance to pulmonary infections. In preterm infants who die or develop lung inflammation
and subsequent bronchopulmonary dysplasia (BPD), both the concentration and activity of CC10
are significantly reduced indicating that CC10 is essential for preventing lung injury and
promoting normal lung development. In a small phase I study, rhCC10 significantly decreased
several indices of pulmonary inflammation in the lungs of premature infants who were at risk
of developing BPD and associated CRM. The drug appeared to be safe, well-tolerated, and
reduce risk of re-hospitalization due to respiratory illness for 9-10 months after a single
intratracheal dose at the time of birth (0/11 rhCC10-treated infants vs. 3/6
placebo-treated). This supports the protective role of rhCC10 against damage from hyperoxia,
mechanical ventilation, inflammation, and infection in the immature lung. A more normal
airway epithelium will produce significantly more endogenous CC10, with both factors
contributing to enhanced resistance to infections, less asthma, and improved long-term
respiratory outcome. We propose to conduct a Phase 2 clinical trial to evaluate rhCC10 in
extremely premature infants (<29 weeks gestation) for the prevention of BPD and CRM. This
will be a randomized, double-blind, placebo-controlled dose escalation study in 88 premature
infants. A single intratracheal dose of study drug (rhCC10 or placebo) will be administered
to preterm infants receiving surfactant and mechanical ventilation for treatment of RDS.
Infants will be followed to evaluate safety, pharmacokinetics, and short and long term
efficacy of this approach. Safety will be evaluated through serious adverse event (SAE) and
adverse event monitoring and by Bayley neurodevelopmental assessments at 18 months corrected
gestational age (CGA). Efficacy measurements will include the primary combined endpoint of
alive without evidence of CRM through 12 months CGA (defined by parental diaries and
pulmonary questionnaires) comparing rhCC10 treated to placebo controls. The availability of a
therapy which prevents lung injury, promotes lung development, and prevents serious
respiratory infections and asthma in high risk preterm infants would be a highly significant
advancement in care.

Inclusion Criteria:

- Age less than or equal to 24 hours;

- Birth weight 600 - 1250 grams;

- Gestational age 24-29 weeks (not less than 24 weeks); at birth based on best estimate
using obstetrical sonography (first or second trimester), solid dating criteria, or
Ballard examination;

- Birth weight appropriate for gestational age;

- 5 minute Apgar score >5;

- Diagnosis of neonatal RDS based on clinical and radiographic criteria;

- Requiring intubation and mechanical ventilation for treatment of RDS;

- Received at least one dose of surfactant (prophylaxis or rescue); and

- Written informed consent is obtained from at least one of the infant's parents or
legal guardians (see section 6.2) prior to enrollment of the subject. The parent(s) or
legal guardian(s) must agree to all study-related procedures and evaluations.

Exclusion Criteria:

- 5 minute Apgar score of ≤ 5;

- Major congenital anomaly (chromosomal, renal, cardiac, hepatic, neurologic, or
pulmonary malformations; minor anomalies such as cleft lip/palate are permitted);

- Evidence of severe neonatal depression (as defined by cord blood acid-base balance
(pH) ≤ 7.00 and/or an Apgar score of < 4 at 10 minutes);

- Evidence of congenital infection;

- Requires a major surgical procedure prior to administration of Study drug

- Enrollment in any other study involving administration of another investigational
drug;

- Any condition which could preclude receiving study drug or performing any
study-related procedures;

- Use of postnatal corticosteroids prior to administration of r-hCC10, except as
specified in the protocol;

- Use of inhaled nitric oxide prior to administration of r-hCC10;

- Mother is known to be seropositive for HIV (per maternal medical records);

- Parent or guardian is unable or unwilling to complete the study diary;

- Parent or guardian is unable to bring the infant back to the study center for
follow-up evaluations.