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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Respiratory Distress Syndrome in Premature Infant, Bronchopulmonary Dysplasia

Intervention / Treatment
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* Drug: Half normal saline
* Drug: Low Dose rhCC10
* Drug: High dose rhCC10


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 24 Weeks
Maximum Age: 29 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: half normal saline<br>Single dose of half normal saline at 2 ml/kg given intratracheally times one dose | Drug: Half normal saline<br>* 2 ml/kg<br>|
| Experimental: Low Dose rhCC10<br>1.5 mg/kg study drug (rhCC10)in 2 ml/kg given intratracheally times one dose | Drug: Low Dose rhCC10<br>* 1.5 mg/kg study drug (rhCC10)<br>|
| Experimental: High dose rhCC10<br>5 mg/kg of rhCC10 given in 2 ml/kg and administered intratracheally times one dose | Drug: High dose rhCC10<br>* 5 mg/kg in 2 ml/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Without Evidence of Chronic Pulmonary Insufficiency of Prematurity (CPIP) at 12 Months Corrected Gestational Age (CGA) | Number of events of survived participants without one or more of the CPIP components defined below: Medical/ER visits (CPIP-DV): At least one non-routine medical visit for respiratory causes. Respiratory re-hospitalizations (CPIP-RH): One or more re-hospitalizations for respiratory causes. Respiratory Symptoms (CPIP-SS): Evidence of respiratory symptoms (e.g. coughing and wheezing) or use of respiratory medications by parental diaries or pulmonary questionnaires. Respiratory Medications (CPIP-RM): Administration of respiratory medications (including oxygen). CPIP is defined as the presence of one or more parent-reported outcomes at 12 months CGA, validated by Respiratory diaries (presence of wheezing, coughing, and/or respiratory medication use ≥2 days per week for 3 consecutive weeks), and Pulmonary questionnaires (decrease in respiratory illness requiring medications, unscheduled medical visits and/or ER or hospital admissions). | 12 Months Corrected Gestational Age (*no imputation for missing data) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long Term Efficacy - Survival Without Evidence of Chronic Pulmonary Insufficiency of Prematurity (CPIP) at 6 Months Corrected Gestational Age (CGA) | Number of events of survived participants, graded as not having 1, 2, 3, or 4 of the CPIP components defined below: Medical/ER visits (CPIP-DV): ≥1 non-routine medical visit(s) for respiratory causes. Respiratory re-hospitalizations (CPIP-RH): ≥1 re-hospitalization(s) for respiratory causes Respiratory Symptoms (CPIP-SS): Parent-reported evidence of respiratory symptoms (e.g. coughing and wheezing) or use of respiratory medications Respiratory Medications (CPIP-RM): Administration of respiratory medications (including oxygen) A participant graded without 4 CPIP components is considered in better health than a participant graded without 1 CPIP component. CPIP components were parent-validated via respiratory diaries (wheezing, coughing, and/or respiratory medication use ≥2 days/wk for 3 consecutive wks), and pulmonary questionnaires (decrease in respiratory illness requiring medications, unscheduled medical visits and/or ER or hospital admissions). | 6 months Corrected Gestational Age | 
| Safety and Efficacy - Number of Participants With Adverse Events | The safety of the study drug was assessed by accounting the number of participants with Adverse Events (AEs) in the treatment and placebo groups. | Adverse events are monitored through 36 wks post-menstrual age (PMA) | 
| Short Term Efficacy - Number of Neonates With Oxygen Requirement at 36 Weeks Post Menstrual Age | Short term efficacy evaluations involve number of neonates with oxygen requirement at 36 weeks post menstrual age. | 36 weeks post-menstrual age |