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Research Letter |

Short-term Outcomes of Infants Enrolled in Randomized Clinical Trials vs Those Eligible but Not Enrolled FREE

Elizabeth E. Foglia, MD1; Tracy L. Nolen, DrPH2; Sara B. DeMauro, MD, MSCE1; Abhik Das, PhD3; Edward F. Bell, MD4; Barbara J. Stoll, MD5; Barbara Schmidt, MD, MSc1 ; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
[+] Author Affiliations
1Department of Pediatrics, University of Pennsylvania, Philadelphia
2Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina
3Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland
4Department of Pediatrics, University of Iowa, Iowa City
5Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
JAMA. 2015;313(23):2377-2379. doi:10.1001/jama.2015.5734.
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Published online

It is unknown whether participation in a neonatal randomized clinical trial (RCT) is independently associated with differences in outcomes. Our objective was to compare in-hospital outcomes between extremely premature infants enrolled in RCTs and those who were eligible but not enrolled in RCTs conducted by the National Institute of Child Health and Human Development Neonatal Research Network (NRN).

A retrospective analysis of infants at NRN sites between January 1, 1999, and December 31, 2012, was performed. Included infants were eligible for NRN RCTs and had outcomes recorded in the NRN very low-birth-weight registry (Generic Database [GDB]). We excluded cluster randomized trials, trials of investigational therapies (to ensure that enrolled and nonenrolled infants were likely to be treated similarly), and infants eligible for the Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (a similar analysis was previously published).1

We identified all eligible infants using trial screening logs. The exposure was enrollment in at least 1 RCT. Nonexposed infants were eligible for at least 1 RCT but not enrolled in any trial. The primary outcome was a composite of (1) death; (2) bronchopulmonary dysplasia (supplemental oxygen at 36 weeks postmenstrual age); (3) severe brain injury (intraventricular hemorrhage with ventricular enlargement, intraparenchymal hemorrhage, or cystic periventricular leukomalacia); or (4) severe retinopathy of prematurity (≥stage 3 or treatment in either eye).

Secondary outcomes included individual components of the primary outcome, culture-proven late-onset sepsis, and necrotizing enterocolitis (≥stage 2). Outcomes were assessed at 120 days of life, hospital discharge or transfer, or death (whichever came first).

Using SAS version 9.3 (SAS Institute Inc), we explored the association between trial enrollment and outcomes using logistic regression with and without control for prespecified baseline covariates. All tests were 2-sided with P < .05 indicating statistical significance. Local institutional review boards approved all RCTs and the GDB. Written informed consent was obtained for enrollment in all RCTs. Informed or waiver of consent was obtained for the GDB, as determined by local review boards.

Six RCTs met the inclusion criteria. These investigated phototherapy, glutamine, nitric oxide, umbilical cord clamping, delivery room continuous positive airway pressure, and vitamin E. Of 5389 eligible infants, 3795 were enrolled in at least 1 RCT and 1594 were not enrolled in any RCT. Enrolled infants were more likely to be white and Hispanic and less likely to be outborn or to receive cardiopulmonary resuscitation at birth (Table 1).

Table Graphic Jump LocationTable 1.  Maternal and Infant Characteristics of Enrolled Infants in Randomized Controlled Trials and Those Eligible But Not Enrolled

The primary outcome did not differ significantly between groups (68% in enrolled group vs 69% in eligible but not enrolled group; adjusted odds ratio, 1.08 [95% CI, 0.93-1.26]; P = .29). There were no differences in the secondary outcomes in the adjusted analysis (Table 2). Furthermore, the primary outcome did not differ between groups when analyzed by individual trial.

Table Graphic Jump LocationTable 2.  Primary and Secondary Outcomes by Enrollment Status and Primary Outcome by Individual Trial

Only a few studies with divergent findings have examined whether trial participation is associated with differences in outcomes in preterm newborns.13 The present study did not find differences in mortality or neonatal morbidity between trial participants and nonparticipants. Similarly, meta-analyses of studies of adults and older children have demonstrated no significant differences in outcomes between trial participants and nonparticipants who were treated similarly outside trials.4,5

Extremely preterm infants who were eligible for RCTs were simultaneously enrolled in the GDB, providing a unique opportunity to assess the association between trial participation and outcomes. We included all trial participants in the enrolled group rather than just control infants because some RCTs were comparative effectiveness trials without a control group.

We did not directly compare outcomes of infants who received a specific intervention inside and outside of RCTs because exposures to some interventions, such as nitric oxide, were not consistently recorded in the GDB. One limitation is that maternal education and insurance status were not recorded consistently.

In a cohort of more than 5000 extremely preterm infants, important in-hospital outcomes were neither better nor worse in infants enrolled in RCTs compared with eligible but nonenrolled infants. These findings may reassure those who have concerns about performing RCTs in this vulnerable population.

Section Editor: Jody W. Zylke, MD, Deputy Editor.

Corresponding Author: Elizabeth E. Foglia, MD, Division of Neonatology, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104 (foglia@email.chop.edu).

Author Contributions: Drs Nolen and Das had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Foglia, Nolen, DeMauro, Das, Schmidt.

Acquisition, analysis, or interpretation of data: Foglia, Nolen, DeMauro, Bell, Stoll, Schmidt.

Drafting of the manuscript: Foglia, Nolen.

Critical revision of the manuscript for important intellectual content: Foglia, DeMauro, Das, Bell, Stoll, Schmidt.

Statistical analysis: Nolen, Das.

Obtained funding: Bell, Stoll.

Administrative, technical, or material support: Stoll.

Study supervision: Stoll, Schmidt.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network’s Generic Database Study via cooperative agreements.

Role of the Funder/Sponsor: The National Institutes of Health and the NICHD had no role in the design and conduct of the study; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Independent Statistical Analysis: Data collected at participating sites of the NICHD Neonatal Research Network were transmitted to RTI International, the data coordinating center for the network, which performed the storage, management, analysis, and interpretation of the data.

Group Information: Members of the NICHD Neonatal Research Network who contributed to this article: Rosemary D. Higgins, MD (NICHD, Bethesda, Maryland), Brenda B. Poindexter, MD, MS (Department of Pediatrics, Indiana University School of Medicine, Indianapolis), Seetha Shankaran, MD (Department of Pediatrics, Wayne State University, Detroit, Michigan), and Krisa P. Van Meurs, MD (Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California).

Disclaimer: This article represents the views of the authors and does not necessarily represent the views of the NICHD.

Additional Information: The entire list of the members of the NICHD Neonatal Research Network appears in Shankaran et al.6

Rich  W, Finer  NN, Gantz  MG,  et al; SUPPORT and Generic Database Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Enrollment of extremely low birth weight infants in a clinical research study may not be representative. Pediatrics. 2012;129(3):480-484.
PubMed   |  Link to Article
Schmidt  B, Gillie  P, Caco  C, Roberts  J, Roberts  R.  Do sick newborn infants benefit from participation in a randomized clinical trial? J Pediatr. 1999;134(2):151-155.
PubMed   |  Link to Article
Rüegger  CM, Kraus  A, Koller  B,  et al.  Randomized controlled trials in very preterm infants: does inclusion in the study result in any long-term benefit? Neonatology. 2014;106(2):114-119.
PubMed   |  Link to Article
Vist  GE, Bryant  D, Somerville  L, Birminghem  T, Oxman  AD.  Outcomes of patients who participate in randomized controlled trials compared to similar patients receiving similar interventions who do not participate. Cochrane Database Syst Rev. 2008;(3):MR000009.
PubMed
Fernandes  N, Bryant  D, Griffith  L,  et al.  Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis. CMAJ. 2014;186(16):E596-E609.
PubMed   |  Link to Article
Shankaran  S, Laptook  AR, Pappas  A,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014;312(24):2629-2639.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Maternal and Infant Characteristics of Enrolled Infants in Randomized Controlled Trials and Those Eligible But Not Enrolled
Table Graphic Jump LocationTable 2.  Primary and Secondary Outcomes by Enrollment Status and Primary Outcome by Individual Trial

References

Rich  W, Finer  NN, Gantz  MG,  et al; SUPPORT and Generic Database Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Enrollment of extremely low birth weight infants in a clinical research study may not be representative. Pediatrics. 2012;129(3):480-484.
PubMed   |  Link to Article
Schmidt  B, Gillie  P, Caco  C, Roberts  J, Roberts  R.  Do sick newborn infants benefit from participation in a randomized clinical trial? J Pediatr. 1999;134(2):151-155.
PubMed   |  Link to Article
Rüegger  CM, Kraus  A, Koller  B,  et al.  Randomized controlled trials in very preterm infants: does inclusion in the study result in any long-term benefit? Neonatology. 2014;106(2):114-119.
PubMed   |  Link to Article
Vist  GE, Bryant  D, Somerville  L, Birminghem  T, Oxman  AD.  Outcomes of patients who participate in randomized controlled trials compared to similar patients receiving similar interventions who do not participate. Cochrane Database Syst Rev. 2008;(3):MR000009.
PubMed
Fernandes  N, Bryant  D, Griffith  L,  et al.  Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis. CMAJ. 2014;186(16):E596-E609.
PubMed   |  Link to Article
Shankaran  S, Laptook  AR, Pappas  A,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014;312(24):2629-2639.
PubMed   |  Link to Article
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