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

Brief Title

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

Official Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional

Primary Outcome

Survival Without Evidence of Chronic Pulmonary Insufficiency of Prematurity (CPIP) at 12 Months Corrected Gestational Age (CGA)

Secondary Outcome

 Long Term Efficacy - Survival Without Evidence of Chronic Pulmonary Insufficiency of Prematurity (CPIP) at 6 Months Corrected Gestational Age (CGA)

Condition

Respiratory Distress Syndrome in Premature Infant

Intervention

Half normal saline

Study Arms / Comparison Groups

 half normal saline

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

88

Start Date

October 2013

Completion Date

August 25, 2017

Primary Completion Date

August 25, 2017

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.
      

Gender

All

Ages

24 Weeks - 29 Weeks

Accepts Healthy Volunteers

No

Contacts

Jonathan Davis, MD, , 

Location Countries

United States

Location Countries

United States

NCT ID

NCT01941745

Organization ID

rhCC10 Study 2013

Secondary IDs

Grant #3899

Responsible Party

Sponsor

Study Sponsor

Tufts Medical Center

Collaborators

 Brigham and Women's Hospital

Study Sponsor

Jonathan Davis, MD, Principal Investigator, Tufts Medical Center

Verification Date

August 2019