Safety, Pk and Anti-inflammatory Effects of CC10 Protein in Premature Infants With Respiratory Distress Syndrome (RDS)

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 was 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 respiratory morbidity (CRM; 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 CRM in these infants.

Official Title
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Safety and Tolerability of Recombinant Human Clara Cell 10kDa Protein (rhCC10) Delivered Intratracheally 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: recombinant human CC10 (rhCC10)
* Drug: recombinant human CC10 (rhCC10)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newborn infants were considered for the study if the following criteria were met: Age < 24 hours; Birthweight between 700 and 1,300 grams; Gestational age greater than or equal to 24 weeks; 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 100 mg/kg (Survanta; Ross Laboratories); Written informed consent from the infant's parent or legal guardian prior to enrollment of the patient and agrees to all study-related procedures and evaluations, including those required after hospital discharge. Exclusion Criteria: • Major congenital abnormalities (chromosomal, genetic, cardiac, pulmonary, or renal);

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br> | Drug: placebo<br>* Half normal saline solution; single dose delivered intratracheally (IT). Treatment was delivered within four hours after surfactant treatment. Dose was delivered IT in two (2) equal aliquots via a premeasured feeding tube placed in the distal third of the endotracheal tube with the patient in the right and then left lateral decubitus position and 30 degrees of Trendelenburg.<br>|
| Experimental: High dose rhCC10<br>5 mg/kg study drug (rhCC10) | Drug: recombinant human CC10 (rhCC10)<br>* 5 mg/kg rhCC10, single dose delivered intratracheally (IT). Treatment was delivered within four hours after surfactant treatment. Dose was delivered IT in two (2) equal aliquots via a premeasured feeding tube placed in the distal third of the endotracheal tube with the patient in the right and then left lateral decubitus position and 30 degrees of Trendelenburg.<br>* Other names: Clara cell 10 kDa protein;|
| Experimental: Low Dose rhCC10<br>1.5 mg/kg study drug (rhCC10) | Drug: recombinant human CC10 (rhCC10)<br>* 1.5 mg/kg rhCC10, single dose delivered intratracheally (IT). Treatment was delivered within four hours after surfactant treatment. Dose was delivered IT in two (2) equal aliquots via a premeasured feeding tube placed in the distal third of the endotracheal tube with the patient in the right and then left lateral decubitus position and 30 degrees of Trendelenburg<br>* Other names: Clara cell 10 kDa protein;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and type of adverse events | All adverse events were monitored according to the NCI Common Toxicity Criteria. In addition, adverse events specific to, or likely to occur in, premature infants were also monitored, including apnea/bradycardia, sepsis (culture-confirmed), patent ductus arteriosus, retinopathy of prematurity, intraventricular hemorrhage, periventricular leukomalacia, and necrotizing enterocolitis (NEC). | Adverse events were monitored through 36 wks post-menstrual age (PMA) or hospital discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of pulmonary inflammatory markers | Total cell and neutophil counts were performed on TAF fluids. In addition, a panel of cytokines were measured in TAF from patients at times 0, 1, and 2 days | Days 0-7 | 
| Total number of days on mechanical ventilation |  | Through 36 wks postmenstrual age or discharge | 
| Hospitalization at 36 weeks PMA |  | Through 36 wks postmenstrual age or discharge | 
| Chronic Respiratory Morbidity | Physical exams and Bayley neurological exams were performed at 12 months PMA. Data pertaining to respiratory outcomes were collected at 6 and 12 months PMA. | 6 & 12 months postmenstrual age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CC10, BPD, Bronchopulmonary dysplasia, premature infants, neonates, pulmonary inflammation, lung function, RDS