Efficacy of Recombinant Human Clara Cell 10 Protein (rhCC10) Administered to Premature Neonates With Respiratory Distress Syndrome
Condition: Respiratory Distress Syndrome in Premature Infant; Bronchopulmonary Dysplasia
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia; Premature Birth; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Bronchopulmonary Dysplasia (BPD) is a multi-factorial disease process that is the end result
      of an immature, surfactant deficient lung that has been exposed to hyperoxia, mechanical
      ventilation and infection. These conditions initiate an inflammatory response characterized
      by elevated inflammatory cell infiltrates and proinflammatory cytokines that lead to the
      development of significant acute and chronic lung injury.

      The study drug, rhCC10, is a recombinant version of natural human CC10 protein. Native CC10
      is produced primarily by non-ciliated respiratory epithelial cells, called Clara cells and is
      the most abundant protein in the mucosal fluids in normal healthy lungs.

      The purpose of this study is to evaluate the pharmacokinetics, safety, tolerability and
      anti-inflammatory effects of a single intratracheal (IT) dose of rhCC10 to intubated
      premature infants receiving positive pressure ventilation for treatment of respiratory
      distress syndrome (RDS) to prevent long term respiratory complications referred to as
      bronchopulmonary dysplasia, and, more recently, as Chronic Pulmonary Insufficiency of
      Prematurity (CPIP; asthma, cough, wheezing, multiple respiratory infections).

      CC10 regulates inflammatory responses and protects the structural integrity of pulmonary
      tissue while preserving pulmonary mechanical function during various insults (eg. viral
      infection, bacterial endotoxin, ozone, allergens, hyperoxia). Together these properties
      suggest that administration of rhCC10 may help to facilitate development of normal airway
      epithelia and prevent the inflammation that leads to CPIP in these infants.

      This study is funded by the FDA Office of Orphan Product Development (OOPD).
    

Detailed description: 
      Recombinant human CC10 protein (rhCC10) is a novel therapeutic agent used to prevent the
      development of chronic respiratory morbidity (CPIP; 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 CPIP. 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 CPIP. 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 CPIP 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.
    

Intervention name(s): Half normal saline; Low Dose rhCC10; High dose rhCC10
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 2 ml/kg; 1.5 mg/kg study drug (rhCC10); 5 mg/kg in 2 ml/kg
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment