Use of Autologous Cord Blood Mononuclear Cells Infusion for the Prevention of Bronchopulmonary Dysplasia in Extremely Preterm Neonates: A Study Protocol for a Placebo-Controlled Randomized Multicenter Trial [NCT03053076]

Zhuxiao Ren, Xu Fang, Qi Zhang, Y G Mai, X Y Tang, Q Q Wang, C H Lai, W H Mo, Y H Dai, Q Meng, Jing Wu, Z Z Ao, H Q Jiang, Yong Yang, L H Qu, C B Deng, Wei Wei, Yongsheng Li, Q I Wang, Jie Yang, Zhuxiao Ren, Xu Fang, Qi Zhang, Y G Mai, X Y Tang, Q Q Wang, C H Lai, W H Mo, Y H Dai, Q Meng, Jing Wu, Z Z Ao, H Q Jiang, Yong Yang, L H Qu, C B Deng, Wei Wei, Yongsheng Li, Q I Wang, Jie Yang

Abstract

Background: Despite the rapid advance of neonatal care, bronchopulmonary dysplasia (BPD) remains a significant burden for the preterm population, and there is a lack of effective intervention. Stem cell depletion because of preterm birth is regarded as one of the underlying pathological mechanisms for the arrest of alveolar and vascular development. Preclinical and small-sample clinical studies have proven the efficacy and safety of stem cells in treating and preventing lung injury. However, there are currently no randomized clinical trials (RCTs) investigating the use of autologous cord blood mononuclear cells (ACBMNC) for the prevention of BPD in premature infants. The purpose of this study is to investigate the effects of infusion of ACBMNC for the prevention of BPD in preterm neonates <28 weeks. Methods: In this prospective, randomized controlled double-blind multi-center clinical trial, 200 preterm neonates <28 weeks gestation will be randomly assigned to receive intravenous ACBMNC infusion (5 × 107 cells/kg) or placebo (normal saline) within 24 h after birth in a 1:1 ratio using a central randomization system. The primary outcome will be survival without BPD at 36 weeks of postmenstrual age or at discharge, whichever comes first. The secondary outcomes will include the mortality rate, other common preterm complication rates, respiratory support duration, length, and cost of hospitalization, and long-term outcomes after a 2-year follow-up. Conclusion: This will be the first randomized, controlled, blinded trial to evaluate the efficacy of ACBMNC infusion as a prevention therapy for BPD. The results of this trial will provide valuable clinical evidence for recommendations on the management of BPD in extremely preterm infants. Clinical Trial Registration: ClinicalTrials.gov, NCT03053076, registered 02/14/2017, retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0006WN4&selectaction=Edit&uid=U0002PLA&ts=2&cx=9y23d4 (Additional File 2).

Keywords: autologous; bronchopulmonary dysplasia; cord blood cells; extremely preterm infants; prevention.

Copyright © 2020 Ren, Zhang, Fang, Mai, Tang, Wang, Lai, Mo, Dai, Meng, Wu, Ao, Jiang, Yang, Qu, Deng, Wei, Li and Yang.

Figures

Figure 1
Figure 1
Flow diagram.

References

    1. Lancet Neonatal Survival Steering Team. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: when? Where? Why? Lancet. (2005) 365:891–900. 10.1016/S0140-6736(05)71048-5
    1. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al. . Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA. (2015) 314:1039–51. 10.1001/jama.2015.10244
    1. Niver D. Bronchopulmonary dysplasia: structural challenges and stem cell treatment potential. Adv Neonatal Care. (2014) 14:E1–11. 10.1097/ANC.0000000000000050
    1. Pérez Tarazona S, Solano Galán P, Bartoll Alguacil E, Alfonso Diego J. Bronchopulmonary dysplasia as a risk factor for asthma in school children and adolescents: a systematic review. Allergol Immunopathol. (2018) 46:87–9. 10.1016/j.aller.2017.02.004
    1. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. ., Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. (2010) 126:443–56.
    1. Ronkainen E, Perhomaa M, Mattila L, Hallman M, Dunder T. Structural pulmonary abnormalities still evident in schoolchildren with new bronchopulmonary dysplasia. Neonatology. (2018) 113:122–30. 10.1159/000481356
    1. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med. (2007) 357:1946–55. 10.1056/NEJMra067279
    1. Walter J, Ware LB, Matthay MA. Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis. Lancet Respir Med. (2014) 2:1016–26. 10.1016/S2213-2600(14)70217-6
    1. Ren Z, Yang J. Autologous cord blood cells infusion in preterm neonates safely reduces respiratory support duration and potentially preterm complications. Stem Cells Trans Med. (2019). 10.1002/sctm.19-0106
    1. Yang J, Ren Z, Zhang C, Rao Y, Zhong J, Wang Z, et al. . Safety of autologous cord blood cells for preterms: a descriptive study. Stem Cells Int. (2018) 2018:5268057. 10.1155/2018/5268057
    1. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. (2013) 122:491–8. 10.1182/blood-2013-02-453175
    1. Mezey E, Nemeth K. Mesenchymal stem cells and infectious diseases: smarter than drugs. Immunol Lett. (2015) 168:208–14. 10.1016/j.imlet.2015.05.020
    1. Möbius MA, Thébaud B. Bronchopulmonary dysplasia: where have all the stem cells gone?: origin and (potential) function of resident lung stem cells. Chest. (2017) 152:1043–52. 10.1016/j.chest.2017.04.173
    1. van Haaften T, Byrne R, Bonnet S, Rochefort GY, Akabutu J, Bouchentouf M, et al. . Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med. (2009) 180:1131–42. 10.1164/rccm.200902-0179OC
    1. De Paepe ME, Mao Q, Ghanta S, Hovanesian V, Padbury JF. Alveolar epithelial cell therapy with human cord blood-derived hematopoietic progenitor cells. Am J Pathol. (2011) 178:1329–39. 10.1016/j.ajpath.2010.11.062
    1. Chang YS, Ahn SY, Yoo HS, Sung SI, Choi SJ, Oh WI, et al. . Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr. (2014) 164:966–72.e6. 10.1016/j.jpeds.2013.12.011
    1. Cotten CM, Murtha AP, Goldberg RN, Grotegut CA, Smith PB, Goldstein RF, et al. . Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr. (2014) 164:973–9.e1. 10.1016/j.jpeds.2013.11.036
    1. Kotowski M, Litwinska Z, Klos P, Pius-Sadowska E, Zagrodnik-Ulan E, Ustianowski P, et al. Autologus cord blood transfusion in preterm infants-Could its humoral effect be the key to control prematurity-related complications? A preliminary study. J Physiol Pharmacol. (2017) 68:921–7.
    1. Rudnicki J, Kawa MP, Kotowski M, Michalczyk B, Ustianowski P, Czajka R, et al. . Clinical evaluation of the safety and feasibility of whole autologous cord blood transplant as a source of stem and progenitor cells for extremely premature neonates: preliminary report. Exp Clin Transplant. (2015) 13:563–72.
    1. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. . Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. (2005) 116:1353. 10.1542/peds.2005-0249
    1. Borghesi A, Cova C, Gazzolo1 D, Stronati M. Stem cell therapy for neonatal diseases associated with preterm birth. J Clin Neonatol. (2013) 2:1–7. 10.4103/2249-4847.109230
    1. Carnall D. National Health and Family Planning Commission of the People's Republic of China: Umbilical Cord Blood and Stem Cell Bank Management Regulation. Available online at: (Chinese: ).
    1. Gomella T, Cummingham M, Fabien E. Neonatology. 6th ed New York, NY: Lange; (2009).
    1. Baker CD, Balasubramaniam V, Mourani PM, Sontag MK, Black CP, Ryan SL, et al. . Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia. Eur Respir J. (2012) 40:1516–22. 10.1183/09031936.00017312
    1. Efstathiou N, Soubasi V, Koliakos G, Kyriazis G, Zafeiriou DI, Slavakis A, et al. . Mobilization of circulating progenitor cells following brain injury in premature neonates could be indicative of an endogenous repair process. A pilot study. Hippokratia. (2015) 19:141–7.
    1. Kourembanas S. Stem cell-based therapy for newborn lung and brain injury: feasible, safe, and the next therapeutic breakthrough? J Pediatr. (2014) 164:954–6. 10.1016/j.jpeds.2014.01.064
    1. O'Reilly M, Thébaud B. Stem cells for the prevention of neonatal lung disease. Neonatology. (2015) 107:360–4. 10.1159/000381135
    1. Bagher L, Esfahani EN, Amini P, Nikbin B, Alimoghaddam K, Amiri S, et al. Stem cell therapy in treatment of different diseases. Acta Medica Iranica. (2012) 50:79–96.
    1. Ho MS, Mei SH, Stewart DJ. The immunomodulatory and therapeutic effects of mesenchymal stromal cells for acute lung injury and sepsis. J Cell Physiol. (2015) 230:2606–17. 10.1002/jcp.25028
    1. Sun JM, Song AW, Case LE, Mikati MA, Gustafson KE, Simmons R, et al. . Effect of autologous cord blood infusion on motor function and brain connectivity in young children with cerebral palsy: a randomized, placebo-controlled trial. Stem Cells Transl Med. (2017) 6:2071–8. 10.1002/sctm.17-0102
    1. Park WS, Ahn SY, Sung SI, Ahn JY, Chang YS. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr Res. (2017) 83:214–222. 10.1038/pr.2017.249
    1. Lee JW, Fang X, Krasnodembskaya A, Howard JP, Matthay MA. Concise review: mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. Stem Cells. (2011) 29:913–9. 10.1002/stem.643
    1. Marshall H. First stem cell treatment for BPD in preterm infants. Lancet Respir Med. (2014) 2:181. 10.1016/S2213-2600(14)70007-4
    1. Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. . Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. (2019) 7:154–62.
    1. Solves P, López M, Mirabet V, Blanquer A, Roig R, Perales A. Characteristics of umbilical cord blood units collected from preterm deliveries. Gynecol Obstet Invest. (2009) 68:181–5. 10.1159/000232382
    1. Girdlestone J. Mesenchymal stromal cells with enhanced therapeutic properties. Immunotherapy. (2016) 8:1405–16. 10.2217/imt-2016-0098
    1. Surate Solaligue DE, Rodríguez-Castillo JA, Ahlbrecht K, Morty RE. Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. (2017) 313:L1101–53. 10.1152/ajplung.00343.2017
    1. Ota C, Baarsma HA, Wagner DE, Hilgendorff A, Königshoff M. Linking bronchopulmonary dysplasia to adult chronic lung diseases: role of WNT signaling. Mol Cell Pediatr. (2016) 3:34. 10.1186/s40348-016-0062-6
    1. Simones AA, Beisang DJ, Panoskaltsis-Mortari A, Roberts KD. Mesenchymal stem cells in the pathogenesis and treatment of bronchopulmonary dysplasia: a clinical review. Pediatr Res. (2017). 10.1038/pr.2017.237
    1. Ren ZX, Zheng XE, Yang HM, Zhang Qi, Liu XH, Zhang XL, et al. . Human umbilical cord mesenchymal stem cells inhibit bacterial growth and alleviate antibiotic resistance in neonatal imipenem-resistant pseudomonas aeruginosa infection. Innate Immunity. (2019). 10.1177/1753425919883932

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit