Clinical Research Article | Published:

The role of recombinant human CC10 in the prevention of chronic pulmonary insufficiency of prematurity



Preterm neonates can develop chronic pulmonary insufficiency of prematurity (CPIP) later in infancy. Recombinant human CC10 protein (rhCC10) is an anti-inflammatory agent that could potentially prevent CPIP.


The safety and efficacy of a single intratracheal dose of rhCC10 in reducing CPIP at 12 months corrected gestational age (CGA) was evaluated in a Phase II double-blind, randomized, placebo-controlled, multisite clinical trial. Eighty-eight neonates were randomized: 22 to placebo and 22 to 1.5 mg/kg rhCC10 in the first cohort and 21 to placebo and 23 to 5 mg/kg rhCC10 in the second cohort. Neonates were followed to 12 months CGA.


With CPIP defined as signs/symptoms, medical visits, hospital readmissions, and use of medications for respiratory complications at 12 months CGA, no significant differences were observed between rhCC10 or placebo groups. Only 5% of neonates had no evidence of CPIP at 12 months CGA.


A single dose of rhCC10 was not effective in reducing CPIP at 12 CGA. Since most neonates had evidence of CPIP using these exploratory endpoints, it is essential to develop more robust outcome measures for clinical trials of respiratory medications in high-risk premature neonates.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Davis, J. M. & Rosenfeld, W. in Neonatology, 7th edn (eds Avery, G. B., Fletcher, M. A., & MacDonald M.) (JB Lippincott Co, Philadelphia, PA, 2014).

  2. 2.

    Shinwell, E. S. et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch. Dis. Child Fetal Neonatal Ed. 83, F177–F181 (2000).

  3. 3.

    Watterberg, K. L. et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 114, 1649–1657 (2004).

  4. 4.

    Steinhorn, R. et al. Bronchopulmonary dysplasia and chronic pulmonary insufficiency of prematurity: developing optimal endpoints for drug development. J. Pediatr. 191, 15–21 (2017).

  5. 5.

    Parad, R. B. et al. Prediction of respiratory outcome in extremely low gestational age infants. Neonatology 107, 241–248 (2015).

  6. 6.

    Bernard, A. et al. Clara cell protein in human amniotic fluid: a potential marker of fetal lung growth. Pediatr. Res. 36, 771–775 (1994).

  7. 7.

    Ramsay, P. L. et al. Clara cell secretory protein oxidation and expression in premature infants who develop bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 164, 155–161 (2001).

  8. 8.

    Shashikant, B. N. et al. Dose response to rhCC10-augmented surfactant therapy in a lamb model of infant respiratory distress syndrome: physiological, inflammatory, and kinetic profiles. J. Appl. Physiol. 99, 2204–2211 (2005).

  9. 9.

    Wolfson, M. R. et al. Recombinant human Clara cell secretory protein treatment increases lung mRNA expression of surfactant proteins and vascular endothelial growth factor in a premature lamb model of respiratory distress syndrome. Am. J. Perinatol. 25, 637–645 (2008).

  10. 10.

    Levine, C. R. et al. Safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human clara cell protein in premature infants with respiratory distress syndrome. Pediatr. Res. 58, 15–21 (2005).

  11. 11.

    Chandra, S. et al. Safety and efficacy of intratracheal recombinant human clara cell protein in a newborn piglet model of acute lung injury. Pediatr. Res. 54, 509–515 (2003).

  12. 12.

    Stevens, T. P. et al. Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (SUPPORT). J. Pediatr. 165, 240–249 (2014).

  13. 13.

    Mantile, G. et al. Human Clara cell 10-kDa protein is the counterpart of rabbit uteroglobin. J. Biol. Chem. 268, 20343–20351 (1993).

  14. 14.

    Draper, E. S. et al. Variability in very preterm stillbirth and in-hospital mortality across Europe. Pediatrics 139, e20161990 (2017).

  15. 15.

    Morrow, L. A. et al. Antenatal determinants of bronchopulmonary dysplasia and late respiratory disease in preterm infants. Am. J. Respir. Crit. Care Med. 136, 364–374 (2017).

  16. 16.

    Rava, M., Lidwien, A. M. & Smit, R. N. Gene–environment interactions in the study of asthma in the postgenomewide association studies era. Cur Opin. Allergy Clin. Immunol. 15, 70–78 (2015).

  17. 17.

    Greenough, A. Long term respiratory outcomes of extreme prematurity (<32 weeks). Semin. Fetal Neonatal Med. 17, 73–76 (2012).

  18. 18.

    Lefkowitz, W. & Rosenberrg, S. H. Bronchopulmonary dysplasia: pathway from disease to long-term outcome. J. Perinatol. 28, 837–840 (2008).

  19. 19.

    Poindexter, B. B. et al. Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program. Ann. Am. Thorac. Soc. 12, 1822–1830 (2015).

  20. 20.

    Keller, R. L. et al. Bronchopulmonary dysplasia and perinatal characteristics predict 1-year respiratory outcomes in newborns born at extremely low gestational age: a prospective cohort study. J. Pediatr. 187, 89–97 (2017).

  21. 21.

    Isayama, T. et al. Revisiting the definition of bronchopulmonary dysplasia: effect of changing panoply of respiratory support for preterm neonates. JAMA Pediatr. 171, 271–279 (2017).

  22. 22.

    Davis, J. M. et al. Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics 111, 469–476 (2003).

Download references


The authors wish to thank: (1) the members of the Data Safety Monitoring Committee, including Dr. Tamsin Knox (Chair), Dr. Steven Abman, Dr. John Kinsella, Dr. Martin Keszler, and Dr. Farzad Noubary; (2) Dr. Helen Christou and Dr. Sarbattama Sen for aid in subject recruitment; and (3) Dr. Morgan Newsome and Elyse Shenberger for technical assistance. This study was funded by an Orphan Product Grant (#FD-R-003899-01) to J.M.D. (Tufts Medical Center) from the Office of Orphan Product Development of the US Food and Drug Administration and the Clinical and Translational Science Award (UL1TR001064) from the National Center for Advancing Translational Science.

Author information

Competing interests

The authors declare no competing interests.

Correspondence to Jonathan M. Davis.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1