Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants

K L Watterberg¹, E Fernandez¹, M C Walsh², W E Truog³, B J Stoll⁴, G M Sokol⁵, K A Kennedy⁶, M V Fraga⁷, S S Beauman¹, B Carper⁸, A Das⁹, A F Duncan⁶, W F Buss¹⁰, C Gauldin³, C B Lacy¹, P J Sanchez¹¹, S Chawla¹², S Lakshminrusimha¹³, C M Cotten¹⁴, K P Van Meurs¹⁵, B B Poindexter¹⁶, E F Bell¹⁷, W A Carlo¹⁸, U Devaskar¹⁹, M H Wyckoff²⁰, R D Higgins²¹

Affiliations

¹ Department of Pediatrics/Neonatology, Children's Hospital of New Mexico, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
² Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, OH, USA.
³ Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA.
⁴ Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA.
⁵ Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁷ Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA, USA.
⁸ Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, NC, USA.
⁹ Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, MD, USA.
¹⁰ Department of Pharmacy, Indiana University Health, Indianapolis, IN, USA.
¹¹ Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
¹² Department of Pediatrics, Wayne State University, Detroit, MI, USA.
¹³ Department of Pediatrics, University of Buffalo Women's and Children's Hospital of Buffalo, Buffalo, NY, USA.
¹⁴ Department of Pediatrics, Duke University, Durham, NC, USA.
¹⁵ Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
¹⁶ Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁷ Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
¹⁸ Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁹ Department of Pediatrics, University of California, Los Angeles, CA, USA.
²⁰ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²¹ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

PMID: 28880260
PMCID: PMC5688018
DOI: 10.1038/jp.2017.131

Randomized Controlled Trial

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants

K L Watterberg et al. J Perinatol. 2017 Nov.

. 2017 Nov;37(11):1220-1223.

doi: 10.1038/jp.2017.131. Epub 2017 Sep 7.

Authors

Affiliations

¹ Department of Pediatrics/Neonatology, Children's Hospital of New Mexico, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
² Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, OH, USA.
³ Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA.
⁴ Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA.
⁵ Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁷ Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA, USA.
⁸ Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, NC, USA.
⁹ Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, MD, USA.
¹⁰ Department of Pharmacy, Indiana University Health, Indianapolis, IN, USA.
¹¹ Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
¹² Department of Pediatrics, Wayne State University, Detroit, MI, USA.
¹³ Department of Pediatrics, University of Buffalo Women's and Children's Hospital of Buffalo, Buffalo, NY, USA.
¹⁴ Department of Pediatrics, Duke University, Durham, NC, USA.
¹⁵ Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
¹⁶ Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁷ Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
¹⁸ Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁹ Department of Pediatrics, University of California, Los Angeles, CA, USA.
²⁰ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²¹ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

PMID: 28880260
PMCID: PMC5688018
DOI: 10.1038/jp.2017.131

Abstract

Objective: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.

Study design: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.

Results: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.

Conclusion: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

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Conflict of interest statement

Conflict of interest:

No authors report conflicts of interest for this study

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References

1. Fernandez E, Watterberg KL, Faix RG, Yoder BA, Walsh MC, Lacy CB, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants. Am J Perinatol. 2015;32(11):1024–30. - PMC - PubMed
1. Fernandez E, Watterberg KL, Faix RG, Yoder BA, Walsh MC, Lacy CB, et al. Incidence, management, and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants. Am J Perinatol. 2014;31(11):947–56. - PMC - PubMed
1. Kamath BD, Fashaw L, Kinsella JP. Adrenal insufficiency in newborns with congenital diaphragmatic hernia. J Pediatr. 156(3):495–7. e1. - PMC - PubMed
1. Soliman AT, Taman KH, Rizk MM, Nasr IS, Alrimawy H, Hamido MS. Circulating adrenocorticotropic hormone (ACTH) and cortisol concentrations in normal, appropriate-for-gestational-age newborns versus those with sepsis and respiratory distress: Cortisol response to low-dose and standard-dose ACTH tests. Metabolism. 2004;53(2):209–14. - PubMed
1. Fernandez EF, Montman R, Watterberg KL. ACTH and cortisol response to critical illness in term and late preterm newborns. J Perinatol. 2008;28(12):797–802. - PMC - PubMed

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Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants

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Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants

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Conflict of interest statement

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