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

NCT ID: NCT01941745

Last Updated: 2019-09-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 88 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2017-08-25

Brief 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.

Conditions

Respiratory Distress Syndrome in Premature Infant; Bronchopulmonary Dysplasia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

half normal saline

Single dose of half normal saline at 2 ml/kg given intratracheally times one dose

Group Type: PLACEBO_COMPARATOR

Half normal saline

Intervention Type: DRUG

2 ml/kg

Low Dose rhCC10

1.5 mg/kg study drug (rhCC10)in 2 ml/kg given intratracheally times one dose

Group Type: EXPERIMENTAL

Low Dose rhCC10

Intervention Type: DRUG

1.5 mg/kg study drug (rhCC10)

High dose rhCC10

5 mg/kg of rhCC10 given in 2 ml/kg and administered intratracheally times one dose

Group Type: EXPERIMENTAL

High dose rhCC10

Intervention Type: DRUG

5 mg/kg in 2 ml/kg

Interventions

Half normal saline

2 ml/kg

Intervention Type: DRUG

Low Dose rhCC10

1.5 mg/kg study drug (rhCC10)

Intervention Type: DRUG

High dose rhCC10

5 mg/kg in 2 ml/kg

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 24 Weeks
• Maximum Eligible Age: 29 Weeks
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: collaborator

Therabron Therapeutics, Inc.

INDUSTRY

Sponsor Role: collaborator

Baystate Medical Center

OTHER

Sponsor Role: collaborator

Poznan University of Medical Sciences

OTHER

Sponsor Role: collaborator

SP ZOZ Szpital Uniwersytecki w Krakowie Oddizat Neonatologii

UNKNOWN

Sponsor Role: collaborator

Instytut Centrum Zdrowia Matki Polki Klinika Neonatologii

UNKNOWN

Sponsor Role: collaborator

Tufts Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jonathan Davis, MD

Role: PRINCIPAL_INVESTIGATOR

Tufts Medical Center

Richard Parad, MD/MPH

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Tufts Medical Center

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Baystate Medical Center

Springfield, Massachusetts, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

Grant #3899

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

rhCC10 Study 2013

Identifier Type: -

Identifier Source: org_study_id