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

Safety and Tolerability of Recombinant Human Clara Cell 10kDa Protein (rhCC10) Delivered Intratracheally to Premature Neonates With Respiratory Distress Syndrome

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.

Study Overview

• Status: Completed
• Conditions: Bronchopulmonary Dysplasia; Respiratory Distress Syndrome in Premature Infant
• Intervention / Treatment: Drug: placebo; Drug: recombinant human CC10 (rhCC10); Drug: recombinant human CC10 (rhCC10)

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Wilmington, Delaware, United States, 19899
      • Christiana HealthCare Systems
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop-University Hospital, SUNY Stony Brook School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 6 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Control	Drug: placebo; 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.
EXPERIMENTAL: High dose rhCC10; 5 mg/kg study drug (rhCC10)	Drug: recombinant human CC10 (rhCC10); 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.; Other Names: rhCC10; CC10; uteroglobin; Clara cell secretory protein; Clara cell 10 kDa protein; Drug: recombinant human CC10 (rhCC10); 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; Other Names: rhCC10; CC10; uteroglobin; Clara cell secretory protein; Clara cell 10 kDa protein
EXPERIMENTAL: Low Dose rhCC10; 1.5 mg/kg study drug (rhCC10)	Drug: recombinant human CC10 (rhCC10); 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.; Other Names: rhCC10; CC10; uteroglobin; Clara cell secretory protein; Clara cell 10 kDa protein; Drug: recombinant human CC10 (rhCC10); 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; Other Names: rhCC10; CC10; uteroglobin; Clara cell secretory protein; Clara cell 10 kDa protein

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Clarassance, Inc.
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Jonathan M Davis, MD, Dept of pediatrics, Winthrop University Hospital, SUNY Stony Brook School of Medicine; Principal Investigator: Ira Gewolb, M.D., University of Maryland Medical Center

Publications and helpful links

General Publications

• Levine CR, Gewolb IH, Allen K, Welch RW, Melby JM, Pollack S, Shaffer T, Pilon AL, Davis JM. The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res. 2005 Jul;58(1):15-21. doi: 10.1203/01.PDR.0000156371.89952.35. Epub 2005 Mar 17.

Study record dates

Study Major Dates

• Study Start: January 1, 2000
• Primary Completion (ACTUAL): June 1, 2002
• Study Completion (ACTUAL): December 1, 2003

Study Registration Dates

• First Submitted: November 14, 2011
• First Submitted That Met QC Criteria: November 16, 2011
• First Posted (ESTIMATE): November 17, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): November 17, 2011
• Last Update Submitted That Met QC Criteria: November 16, 2011
• Last Verified: November 1, 2011

More Information

Terms related to this study

• Keywords: lung function; neonates; BPD; Bronchopulmonary dysplasia; RDS; premature infants; CC10; pulmonary inflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Syndrome; Premature Birth; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia
• Other Study ID Numbers: CC10-2000-001; 9R44HL066965-02 (NIH)