Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks’ Gestational Age: A Randomized Clinical Trial

Dale L Phelps; Kristi L Watterberg; Tracy L Nolen; Carol A Cole; C Michael Cotten; William Oh; Brenda B Poindexter; Kristin M Zaterka-Baxter; Abhik Das; Conra Backstrom Lacy; Ann Marie Scorsone; Michele C Walsh; Edward F Bell; Kathleen A Kennedy; Kurt Schibler; Gregory M Sokol; Matthew M Laughon; Satyanarayana Lakshminrusimha; William E Truog; Meena Garg; Waldemar A Carlo; Abbot R Laptook; Krisa P Van Meurs; David P Carlton; Amanda Graf; Sara B DeMauro; Luc P Brion; Seetha Shankaran; Faruk H Orge; Richard J Olson; Helen Mintz-Hittner; Michael B Yang; Kathryn M Haider; David K Wallace; Mina Chung; Denise Hug; Irena Tsui; Martin S Cogen; John P Donahue; Michael Gaynon; Amy K Hutchinson; Don L Bremer; Graham Quinn; Yu-Guang He; William R Lucas, Jr; Timothy W Winter; Stephen D Kicklighter; Kartik Kumar; Patricia R Chess; Tarah T Colaizy; Anna Marie Hibbs; Namasivayam Ambalavanan; Heidi M Harmon; Elisabeth C McGowan; Rosemary D Higgins

doi:10.1001/jama.2018.14996

. 2018 Oct 23;320(16):1649–1658. doi: 10.1001/jama.2018.14996

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks’ Gestational Age

A Randomized Clinical Trial

Dale L Phelps ^1,^✉, Kristi L Watterberg ², Tracy L Nolen ³, Carol A Cole ¹, C Michael Cotten ⁴, William Oh ⁵, Brenda B Poindexter ^6,⁷, Kristin M Zaterka-Baxter ³, Abhik Das ⁸, Conra Backstrom Lacy ², Ann Marie Scorsone ¹, Michele C Walsh ⁹, Edward F Bell ¹⁰, Kathleen A Kennedy ¹¹, Kurt Schibler ⁶, Gregory M Sokol ⁷, Matthew M Laughon ¹², Satyanarayana Lakshminrusimha ¹³, William E Truog ¹⁴, Meena Garg ¹⁵, Waldemar A Carlo ¹⁶, Abbot R Laptook ⁵, Krisa P Van Meurs ¹⁷, David P Carlton ¹⁸, Amanda Graf ¹⁹, Sara B DeMauro ²⁰, Luc P Brion ²¹, Seetha Shankaran ²², Faruk H Orge ²³, Richard J Olson ²⁴, Helen Mintz-Hittner ²⁵, Michael B Yang ²⁶, Kathryn M Haider ²⁷, David K Wallace ²⁸, Mina Chung ²⁹, Denise Hug ³⁰, Irena Tsui ³¹, Martin S Cogen ³², John P Donahue ³³, Michael Gaynon ³⁴, Amy K Hutchinson ³⁵, Don L Bremer ³⁶, Graham Quinn ³⁷, Yu-Guang He ³⁸, William R Lucas Jr ³⁹, Timothy W Winter ⁴⁰, Stephen D Kicklighter ⁴¹, Kartik Kumar ¹¹, Patricia R Chess ¹, Tarah T Colaizy ¹⁰, Anna Marie Hibbs ⁹, Namasivayam Ambalavanan ¹⁶, Heidi M Harmon ⁷, Elisabeth C McGowan ⁵, Rosemary D Higgins ⁴², for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

¹School of Medicine and Dentistry, University of Rochester, Rochester, New York

²Health Sciences Center, University of New Mexico, Albuquerque

³Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina

⁴Department of Pediatrics, Duke University, Durham, North Carolina

⁵Department of Pediatrics, Women & Infants’ Hospital, Brown University, Providence, Rhode Island

⁶Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio

⁷Department of Pediatrics, School of Medicine, Indiana University, Indianapolis

⁸Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland

⁹Department of Pediatrics, Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, Ohio

¹⁰Department of Pediatrics, University of Iowa, Iowa City

¹¹Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center, Houston

¹²Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of North Carolina, Chapel Hill

¹³Department of Pediatrics, State University of New York, Buffalo

¹⁴Department of Pediatrics, Children’s Mercy Hospital and University of Missouri School of Medicine, Kansas City

¹⁵Department of Pediatrics, University of California, Los Angeles

¹⁶Division of Neonatology, University of Alabama at Birmingham

¹⁷Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California

¹⁸Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia

¹⁹Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio

²⁰Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia

²¹Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas

²²Department of Pediatrics, Wayne State University, Detroit, Michigan

²³Department of Ophthalmology, Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, Ohio

²⁴Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City

²⁵Department of Ophthalmology and Visual Science, McGovern Medical School, University of Texas Health Science Center, Houston

²⁶Department of Ophthalmology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio

²⁷Department of Ophthalmology, School of Medicine, Indiana University, Indianapolis

²⁸Department of Pediatrics, Duke University, Durham, North Carolina

²⁹Department of Ophthalmology, School of Medicine and Dentistry, University of Rochester, Rochester, New York

³⁰Department of Ophthalmology, Children’s Mercy Hospital and University of Missouri School of Medicine, Kansas City

³¹Department of Ophthalmology, University of California, Los Angeles

³²Department of Ophthalmology, University of Alabama at Birmingham

³³Alpert Medical School, Women & Infants’ Hospital, Brown University, Providence, Rhode Island

³⁴Department of Ophthalmology, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children’s Hospital, Palo Alto, California

³⁵Department of Ophthalmology, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia

³⁶Department of Ophthalmology, Nationwide Children’s Hospital, Columbus, Ohio

³⁷Department of Ophthalmology, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia

³⁸Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas

³⁹Department of Ophthalmology, Wayne State University, Detroit, Michigan

⁴⁰Division of Ophthalmology, Department of Surgery, Health Sciences Center, University of New Mexico, Albuquerque

⁴¹Department of Pediatrics, Division of Neonatology, WakeMed Health and Hospitals, Raleigh, North Carolina

⁴²Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

^✉

Corresponding Author: Dale L. Phelps, MD, Division of Neonatology, 601 Elmwood Ave, Box 651, Rochester, NY 14642 (dale_phelps@urmc.rochester.edu).

Group Information: The members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network appear at the end of the article.

Accepted for Publication: September 24, 2018.

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.

Concept and design: Phelps, Watterberg, Nolen, Cole, Cotten, Oh, Poindexter, Zaterka-Baxter, Kennedy, Truog, Carlo, Brion, Quinn, Kicklighter, Chess, Ambalavanan, Higgins.

Acquisition, analysis, or interpretation of data: Phelps, Watterberg, Nolen, Cotten, Oh, Poindexter, Zaterka-Baxter, Das, Backstrom Lacy, Scorsone, Walsh, Bell, Schibler, Sokol, Laughon, Lakshminrusimha, Truog, Garg, Carlo, Laptook, Van Meurs, Carlton, Graf, DeMauro, Brion, Shankaran, Orge, Mintz-Hittner, Yang, Haider, Wallace, Chung, Hug, Tsui, Cogen, Donahue, Gaynon, Hutchinson, He, Lucas, Winter, Kumar, Chess, Colaizy, Hibbs, Ambalavanan, Harmon, McGowan, Higgins.

Drafting of the manuscript: Phelps, Watterberg, Nolen, Oh, Backstrom Lacy, Scorsone, Carlton, Brion, Chess, Ambalavanan.

Critical revision of the manuscript for important intellectual content: Phelps, Watterberg, Nolen, Cole, Cotten, Oh, Poindexter, Zaterka-Baxter, Das, Scorsone, Walsh, Bell, Kennedy, Schibler, Sokol, Laughon, Lakshminrusimha, Truog, Garg, Carlo, Laptook, Van Meurs, Carlton, Graf, DeMauro, Brion, Shankaran, Orge, Mintz-Hittner, Yang, Haider, Wallace, Chung, Hug, Tsui, Cogen, Donahue, Gaynon, Hutchinson, Quinn, He, Lucas, Winter, Kicklighter, Kumar, Chess, Colaizy, Hibbs, Ambalavanan, Harmon, McGowan, Higgins.

Statistical analysis: Nolen, Oh, Das, Scorsone, Brion, Chung.

Obtained funding: Phelps, Poindexter, Walsh, Bell, Carlo, Carlton, Shankaran, He.

Administrative, technical, or material support: Phelps, Zaterka-Baxter, Backstrom Lacy, Scorsone, Bell, Kennedy, Sokol, Laughon, Lakshminrusimha, Truog, Garg, Carlo, Carlton, Graf, Brion, Yang, Chung, Hug, Donahue, Lucas, Chess, Hibbs, Higgins.

Supervision: Phelps, Cotten, Poindexter, Das, Scorsone, Kennedy, Schibler, Sokol, Lakshminrusimha, Truog, Carlo, Van Meurs, Carlton, Brion, Shankaran, Yang, Kicklighter, Chess, Higgins.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Laughon reported receiving grant support from the National Institutes of Health and the US Food and Drug Administration; and personal fees from United Therapeutics. Dr Carlo reported serving as a board director and owning stock in Mednax. Dr Wallace reported the possibililty of receiving future royalties from FocusROP. Dr Chung reported receiving personal fees from Wave Life Sciences, Santeen, and Spark Therapeutics; and grant support from Lowry Medical Research Institute and the National Institutes of Health. No other disclosures were reported.

Funding/Support: Funded by grants U10 HD36790, UG1 HD27904, UG1 HD21364, UG1 HD68284, UG1 HD27853, UG1 HD40492, UG1 HD27851, UG1 HD27856, UG1 HD87229, UG1 HD68278, UG1 HD27880, UG1 HD34216, UG1 HD68270, UG1 HD53109, UG1 HD53089, UG1 HD68244, UG1 HD68263, UG1 HD40689, and UG1 HD21385 from the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Eye Institute and by grants UL1 TR41, UL1 TR42, UL1 TR77, UL1 TR93, UL1 TR442, UL1 TR454, and UL1 TR1117 from the National Center for Advancing Translational Sciences. Abbott Nutrition Division (Abbott Laboratories) provided the myo-inositol.

Role of the Funder/Sponsor: The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development hold the investigational new drug application and staff had input into the design and conduct of the study; but no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication; however, the program scientist assisted with protocol development, study execution, and agreed to submit the findings for publication. Abbott Nutrition Division had no role in the design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication; however, staff provided onsite monitoring to assist in quality assurance of the data collection. Data were collected at participating sites of the Neonatal Research Network and were transmitted to RTI International (the data coordinating center for the network), which stored, managed, and analyzed the data for this study.

Group Information: The following investigators, in addition to those listed as authors, participated in this study: Richard A. Polin, MD, steering committee chair (Division of Neonatology, College of Physicians and Surgeons, Columbia University); Martin Keszler, MD, Angelita M. Hensman, MS, RNC-NIC, Michael R. Muller, PharmD, Elisa Vieira, RN, BSN, and Jennifer A. Keller, RN, BSN (Alpert Medical School, Women & Infants’ Hospital, Brown University); Nancy S. Newman, BA, RN, Bonnie S. Siner, RN, Michael Banchy, RPH, Jeffrey L. Blumer, MD, Eileen K. Stork, MD, and Arlene Zadell, RN (Case Western Reserve University, Rainbow Babies & Children’s Hospital); Eugenia K. Pallotto, MD, MSCE, Howard W. Kilbride, MD, Prabhu S. Parimi, MD, Cheri Gauldin, RN, BSN, CCRC, Lisa Gaetano, MSN, RN, Anne M. Holmes, RN, MSN, MBA-HCM, CCRC, and Allison Knutson, BSN, RNC-NIC (Children’s Mercy Hospital, University of Missouri School of Medicine, Kansas City); Suhas G. Kallapur, MD, Cathy Grisby, BSN, CCRC, Barbara Alexander, RN, Estelle E. Fischer, MHSA, MBA, Lenora Jackson, CRC, Kristin Kirker, CRC, Holly L. Mincey, MS, RN, BSN, Michael E. Gray, MD, and Patricia Cobb, MS (Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical Center, and Good Samaritan Hospital); Ronald N. Goldberg, MD, Kimberley A. Fisher, PhD, FNP-BC, IBCLC, Joanne Finkle, RN, JD, Mary Miller-Bell, PharmD, RPh, Gregory A. Westby, BSPharm, RPh, Chi Dang-Hornik, PharmD, BCPS, Sharon Fridovich Freeman, MD, Sasapin Grace Prakalapakorn, MD, MPH, Matthew M. Laughon, MD, MPH, Carl L. Bose, MD, Janice Bernhardt, MS, RN, Cindy Clark, RN, Diane D. Warner, MD, MPH, Sofia Aliaga, MD, MPH, Kristin Allyne, BSN, RN, Linda Manor, RPh, Jan Niklas Ulrich, MD, Kevin Gertsch, MD, Ginger Rhodes-Ryan, ARNP, MSN, NNP-BC, Jerry Magolan, MD, and Jeffery Board, MD (Duke University School of Medicine, University Hospital, University of North Carolina, Duke Regional Hospital, and WakeMed Health and Hospitals); Barbara J. Stoll, MD, Ellen C. Hale, RN, BS, CCRC, Yvonne Loggins, RN, and Colleen Mackie, BS, RT (Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown); Stephanie Wilson Archer, MA (Eunice Kennedy Shriver National Institute of Child Health and Human Development); Edward A. Liechty, MD, Dianne E. Herron, RN, CCRC, Annette Head, RPh, and Elizabeth Hynes, RNC-NIC (Indiana University, Riley Hospital for Children and Methodist Hospital at Indiana University Health); Jon E. Tyson, MD, MPH, Amir M. Khan, MD, Julie Arldt-McAlister, MSN, APRN, Shanti Brown, RCPhT, Farida El-Ali, RPH, Carmen Garcia, RN, BSN, Karen Martin, RN, Georgia E. McDavid, RN, Hatice Ozsoy, PhD, RPh, Emily K. Stephens, RN, BSN, Vu Ta, PharmD, Christine Wong, PharmD, and Sharon L. Wright, MT (ASCP) (McGovern Medical School, University of Texas Health Science Center, Houston, and Children’s Memorial Hermann Hospital); Pablo J. Sánchez, MD, Leif D. Nelin, MD, Sudarshan R. Jadcherla, MD, Patricia Luzader, RN, Christine A. Fortney, PhD, RN, Gail E. Besner, Nehal A. Parikh, MD, David L. Rogers, MD, Richard P. Golden, MD, and Catherine Olson Jordan, MD (Nationwide Children’s Hospital and Ohio State University Wexner Medical Center); Dennis Wallace, PhD, Marie G. Gantz, PhD, Jeanette O’Donnell Auman, BS, Margaret M. Crawford, BS, CCRP, Jenna Gabrio, BS, CCRP, Carolyn M. Petrie Huitema, MS, CCRP, James W. Pickett II, BS, and Annie M. VonLehmden, BS (RTI International); David K. Stevenson, MD, M. Bethany Ball, BS, CCRC, Steven Chinn, PharmD, and Melinda S. Proud, RCP (Stanford University and Lucile Packard Children’s Hospital); Monica V. Collins, RN, BSN, M Ed, Shirley S. Cosby, RN, BSN, Rebecca J. Quinn, PharmD, Brenda Reed Denson, PharmD, and Ann Marie Arciniegas-Bernal, MD (University of Alabama at Birmingham Health System and Children’s Hospital of Alabama); Uday Devaskar, MD, Teresa Chanlaw, MPH, and Rachel Geller, RN, BSN (University of California, Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center); Jane E. Brumbaugh, MD, Karen J. Johnson, RN, BSN, Jacky R. Walker, RN, Claire A. Lindauer, RN, Kristine M. Johnson, BSPharm, RPh, Angela Merriss, BA, CPhT, Joanna L. Nohr, PharmD, BCPS, Susannah Q. Longmuir, MD, Arlene V. Drack, MD, Scott A. Larson, MD, Kevin R. Gertsch, MD, and Vikki P. Bell (University of Iowa); Robin K. Ohls, MD, Conra Backstrom Lacy, RN, Mary Ruffaner Hanson, RN, BSN, Sandra Sundquist Beauman, MSN, RNC, Carol H, Hartenberger, MPH, RN, Nancy A. Morgan, RPh, MBA, and Susan J. Kunkel, PharmD (University of New Mexico Health Sciences Center); Mikko K. Hallman, MD (University of Oulu, and Oulu University Hospital, Oulu, Finland); Barbara Schmidt, MD, MSc, Haresh Kirpalani, MB, MSc, Soraya Abbasi, MD, Aasma S. Chaudhary, BS, RRT, Toni Mancini, RN, BSN, CCRC, Monte D. Mills, MD, Stefanie L. Davidson, MD, Gil Binenbaum, MD, MSCE, William V. Anninger, MD, Kenneth Rockwell Jr, PharmD, MS, Mina Ricciardelli, PharmD, and Sze Man Yau, RPh (University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children's Hospital of Philadelphia); Carl D’Angio, MD, Ronnie Guillet, MD, PhD, Gary D. Markowitz, MD, Stephen A. Bean, PharmD, Melissa F. Carmen, MD, Carol A. Cole, RPh, Ann Marie Turner, PharmD, Anne Marie Reynolds, MD, MPH, Stephanie Guilford, BS, Michael G. Sacilowski, MAT, Holly I. M. Wadkins, MA, Rosemary Jensen, Ashley Williams, MS Ed, Kristin Johnson, BS, PharmD, BCPS, Rajeev S. Ramchandran, MD, Matthew S. Pihlblad, MD, Steven Awner, MD, and Kristin Johnson, BS, PharmD, BCPS (University of Rochester Medical Center, Golisano Children's Hospital, and the University of Buffalo Women's and Children's Hospital of Buffalo); Myra H. Wyckoff, MD, Diana M. Vasil, RNC-NIC, Christine Cha, PharmD, Juana Cisneros, RN, Maria M. De Leon, BSN, RN, Frances Eubanks, BSN, RN, Lynda Godowic, PharmD, RPh, Laura Grau, RN, Helen C. Lira, PharmD, Azadeh Mozaffari, PharmD, RPh, Lara Pavageau, MD, and Reshma Wright, RPh (University of Texas Southwestern Medical Center, Parkland Health and Hospital System, and Children’s Medical Center Dallas); and Athina Pappas, MD, Beena G. Sood, MD, MS, Rebecca Bara, RN, BSN, Kirsten Childs, RN, BSN, Mary E. Johnson, RN, BSN, Mirjana Lulic-Botica, RPh, and Bogdan Panaitescu, MD (Wayne State University, Hutzel Women’s Hospital and Children’s Hospital of Michigan).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We are indebted to the medical and nursing colleagues and the infants and their parents who agreed to take part in this study. We thank the following members of the data and safety monitoring committee who received compensation: Christine A. Gleason, MD, chair (University of Washington); Marilee C. Allen, MD (Johns Hopkins University School of Medicine); Robert J. Boyle, MD (University of Virginia Health System); Traci Clemons, PhD (EMMES Corporation); Mary E. D’Alton, MD (Columbia Ob/Gyn Midtown); Ralph E. Kauffman, MD (University of Missouri, Kansas City, Medical Research Department at Children’s Mercy Hospital); Menachem Miodovnik, MD (Washington Hospital Center); T. Michael O’Shea, MD, MPH (Wake Forest University School of Medicine); Lois Smith, MD (Harvard University Children’s Hospital); and Steven J. Weiner, MS (George Washington University). We also thank the following members of the data and safety monitoring committee who were not compensated: Abhik Das, PhD, ex officio (RTI International); Donald Everett, MA, ex officio (National Eye Institute); and Marian Willinger, PhD, ex officio (Eunice Kennedy Shriver National Institute of Child Health and Human Development). We also acknowledge the BOOST study ROP credentialing site, which allowed Neonatal Research Network ophthalmologists to use its online system to certify their ROP training.

^✉

Corresponding author.

PMCID: PMC6233812 PMID: 30357297

Key Points

Question

Does administration of myo-inositol to premature infants for up to 10 weeks reduce the incidence of type 1 retinopathy of prematurity?

Findings

In this randomized clinical trial that included 638 premature infants younger than 28 weeks’ gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 retinopathy of prematurity or death compared with placebo (29% vs 21%, respectively).

Meaning

These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

Abstract

Importance

Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety.

Objective

To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks’ gestational age.

Design, Setting, and Participants

Randomized clinical trial included 638 infants younger than 28 weeks’ gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group.

Interventions

A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks.

Main Outcomes and Measures

Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP.

Results

Among 638 infants (mean, 26 weeks’ gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks’ postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%).

Conclusions and Relevance

Among premature infants younger than 28 weeks’ gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

This randomized clinical trial compares the effects of myo-inositol vs placebo on type 1 retinopathy of prematurity (ROP) among infants younger than 28 weeks’ gestational age.

Introduction

Retinopathy of prematurity (ROP) is a common morbidity among premature infants and a leading cause of childhood blindness worldwide.^1,2 Investigations conducted from 1986 through 1992 of myo-inositol use as a surfactant component found that infants with respiratory distress syndrome who were treated with inositol had improved survival, lower rates of pneumothorax or intraventricular hemorrhage, and reduced rates of ROP.^3,4,5,6,7

Furthermore, in 2000-2001, researchers comparing (1) human milk feedings (normally high in inositol) vs formulas that did not contain inositol and (2) inositol-supplemented formula vs non–inositol-supplemented formula found higher rates of ROP in the infants fed non–inositol-supplemented formula.^8,9 Use of antenatal steroids and exogenous surfactant has since reduced respiratory morbidity from respiratory distress syndrome; however, ROP remains a serious sequela among survivors of extremely preterm birth.^10,11 A 2012 Cochrane meta-analysis concluded that myo-inositol reduced preterm death, severe intraventricular hemorrhage, and ROP, which warranted the undertaking of a large multicenter randomized clinical trial.¹²

Retinal vessels first begin to vascularize the developing retina, growing in from the hyaloid artery at about 16 weeks’ gestational age. The retinal vessels generally reach the ora serrata (full vascularization) at 36 to 45 weeks’ postmenstrual age (PMA; defined as the sum of gestational age at birth plus No. of weeks postnatal), but this process is more prolonged if ROP develops.^10,13 The stresses of preterm birth, most notably sustained high Pao₂ levels that suppress the proangiogenic factors supporting growth, result in retinal ischemia as the retina becomes more metabolically active. As ischemia increases, excessive neovascularization follows. If mild, neovascularization may resolve spontaneously or it may progress to an uncontrolled level, leading to retinal detachment.^10,13 Retinopathy of prematurity has been classified by various prognostic grades or types to assist ophthalmologists in selecting the best time to surgically intervene to prevent retinal detachments.¹⁰ Type 1 ROP meets the criteria for surgical intervention determined by serial retinal examinations. The purpose of this trial was to test the safety and efficacy of myo-inositol among infants younger than 28 weeks’ gestational age to reduce the rates of type 1 ROP.

Methods

This double-blind placebo-controlled randomized clinical trial was approved by the US Food and Drug Administration, and reviewed and approved by the institutional review boards at each recruiting institution and the Neonatal Research Network data coordinating center prior to enrollment. Infants were enrolled once written informed consent was obtained from a parent or guardian prior to 72 hours of age. The trial was conducted by the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Neonatal Research Network. The trial protocol appears in Supplement 1 and the statistical analysis plan appears in Supplement 2.

Population

Infants born before 28 0/7 weeks of gestation, surviving for at least 12 hours, and admitted to 1 of the 18 Neonatal Research Network centers before 72 hours’ postnatal age were screened for eligibility (Figure). The centers included major universities throughout the United States.

Figure. — ^aOne ineligible infant (aged <12 hours) was randomized in error; however, this infant continued in the study.

^bBecause these infants received only less than 2 of 100 possible doses, they remained in the placebo group for the safety analyses.

^cAfter 20 months of study enrollment, the study was suspended because of a manufacturing issue. All study drug dosing was suspended at this time and was not restarted.

Exclusion criteria included any major congenital anomaly, any eye anomaly, or any moribund condition. Because type 1 ROP is known to vary among individuals from different racial/ethnic backgrounds, the mother’s self-reported race/ethnicity (selected from defined categories provided by the National Institutes of Health) was collected from electronic medical records.^1,11

Randomization and Masking

Computer-generated and centrally administered randomization used a permuted block design with block sizes of 2 and 4. Participants were stratified within center and by subgroups of gestational age (<26 0/7 vs 26 0/7 to 27 6/7 weeks of gestation) and randomized in a 1:1 ratio. Infants from multiple births were randomized individually. With the exception of pharmacists, who prepared the daily unit doses of myo-inositol or placebo according to randomization assignment, all other clinical and research personnel and families were blind to group assignment.

Intervention

The active drug was an isotonic, sterile, pyrogen- and preservative-free aqueous solution of 5% myo-inositol (50 mg/mL) at neutral pH and was provided by Abbott Laboratories. After conducting pharmacokinetic and safety studies of myo-inositol in extremely preterm infants, a dose of 40 mg/kg every 12 hours was selected to achieve serum concentrations similar to those previously reported.^14,15 A therapeutic duration of up to 10 weeks was chosen to sustain serum myo-inositol levels similar to those found in utero throughout the period of normal retinal vascular development and because of the reported benefits in the treatment of ROP and survival.¹²

The placebo was a solution of 5% glucose for intravenous infusion from pharmacy stock. Both solutions were clear, colorless, nonviscous, and slightly sweet if tasted. Doses were initially given intravenously, changed to enteral when the infant was receiving enteral feedings of 120 mL/kg/d, or changed sooner if intravenous fluids were discontinued. Treatment continued for up to 10 weeks, until hospital discharge, or until 34 weeks’ PMA.¹⁶ No changes to the protocol occurred during the trial.

Primary Outcome

The unfavorable primary outcome was type 1 ROP, which was defined as meeting the criteria for ophthalmological intervention to prevent retinal detachment, a more severe ROP type than ROP type 1 (eg, aggressive posterior ROP or rush disease), or death before the ROP outcome could be determined.¹⁰ The favorable primary outcome was survival with only milder ROP or no ROP. Infants were followed up as outpatients to determine the primary outcome up to a maximum of 55 weeks’ PMA.

The severity of ROP was determined with serial eye examinations by ophthalmologists highly experienced with ROP beginning at 31 weeks’ PMA.^17,18 The lead ophthalmologist at each trial center had extensive experience in identifying and managing ROP, was certified in the diagnosis of ROP via the International Classification of Retinopathy of Prematurity, and ensured consistency among that center’s examiners.^18,19 If an infant developed type 1 ROP in either eye, a second examination by an independent examiner or fundus photographs were required to confirm or document the findings prior to the surgical intervention.

For infants who missed follow-up visits, all available clinical ROP data were reviewed through an independent process to determine the ROP outcome of (1) most likely never had type 1 ROP or (2) most likely developed type 1 ROP. This adjudication was performed under the supervision of the data coordinating center.

The adjudicators, who were blind to trial group assignment and who did not review the data for any infant from the center at which he or she was employed, were ophthalmologists with extensive ROP experience. The adjudication process was performed to reduce missing data bias because incomplete follow-up is more common among participants with mild or no ROP than among those who develop type 1 ROP. A pocket guide was provided as a tool to assist research personnel with the recording of the ROP outcomes and for the scheduling of follow-up examinations (eFigure 1 in Supplement 3).

Secondary Outcomes

The preplanned secondary efficacy outcomes were occurrence of any type of ROP; self-resolving type 2 ROP or greater; and all-cause mortality up to 55 weeks’ PMA. All-cause mortality also is reported through the earliest of the following events: hospital transfer, hospital discharge, or 120 days of age.

Clinical diagnoses of bronchopulmonary dysplasia, bronchopulmonary dysplasia or death reported as caused by bronchopulmonary dysplasia, and severe intraventricular hemorrhage through hospital discharge, hospital transfer, death, or 120 days of age were secondary efficacy and safety outcomes and were recorded using uniform definitions established for the Neonatal Research Network protocols.²⁰

Safety Outcomes

Additional clinical diagnoses were recorded as safety outcomes through hospital discharge, hospital transfer, death, or 120 days of age using Neonatal Research Network protocol definitions. For each death, the site principal investigator reviewed the infant’s course and verified the primary and contributing causes of death, taking into account discussion with the clinical team, autopsy results (if an autopsy was performed), and the results of any internal mortality review. Multiple causes of death could be listed per infant.

Adverse events were prospectively monitored and recorded according to organ system, severity, and possible relatedness to the trial drug. All adverse events (ie, any untoward medical occurrence in a patient temporally associated with the use of a drug in humans) either considered related to the drug or not related and occurring prior to 7 days after the end of dosing were collected with the exception of mild and expected events.

Prespecified Exploratory Outcomes

The components of the primary outcome (type 1 ROP and death before determination of ROP outcome) were prespecified exploratory outcomes along with weight, length, and head circumference measured through 7 days after the end of dosing. Cystic areas in the cerebral parenchyma were recorded through 28 days. Follow-up evaluations were scheduled for 22 to 26 months’ corrected age and are not reported herein.

Statistical Analyses

Based on an occurrence rate for the primary outcome of 30% in a large study,²¹ the estimated total enrollment was 1672 (836 per group) to achieve 90% power to detect an absolute reduction of 7% or greater in type 1 ROP or death prior to the determination of an ROP outcome (assuming a 2-tailed α level of .05 using a Mantel-Haenszel test).²² Inflating the sample size for an estimated lost to follow-up rate of 3% to 5%, and a single interim analysis for 1000 enrollees with final outcomes, the projected sample size was 1760. The analyses for all other secondary and safety outcomes were exploratory and not intended to be formal tests of hypotheses; therefore, no adjustments were made for multiplicity.

For the primary and secondary outcomes, the analyses were performed on an intention-to-treat basis and included adjudicated ROP outcomes according to the prespecified statistical analysis plan (Supplement 2). Individuals for whom adjudicated ROP outcomes could not be obtained were treated as missing completely at random and were excluded from the primary analysis. Poisson regression was used to estimate adjusted relative risks (RRs) and a generalized linear model with a binomial distribution and identity link was used to estimate the adjusted absolute risk differences (and associated 95% CIs) for myo-inositol vs placebo for the primary outcome and for all binary secondary outcomes.^22,23,24 The analyses were adjusted for center when possible and gestational age strata. For the primary outcome, gestational age strata × sex interaction terms were explored to determine if the treatment effect differed by gestational age or sex. For continuous secondary outcomes, analysis of covariance models that controlled for strata defined by gestational age and center were used. Growth was assessed using repeated measure models that controlled for site and gestational age strata.

Causes of death (including due to infectious organisms) were summarized. Infectious organisms were explored post hoc in an attempt to understand the observed increase in mortality in the myo-inositol group that led to early trial termination. The post hoc analyses by drug lot used the same modeling approaches but compared lot groups instead of treatment groups.

All statistical analyses were performed using 2-sided tests with SAS software version 9.4 (SAS Institute Inc). A P value of less than .05 was considered statistically significant. No adjustments of the P value threshold were planned to account for the interim safety reviews of the trial data conducted by the data and safety monitoring committee.

Trial Termination

The trial protocol specified that the Neonatal Research Network data and safety monitoring committee would monitor safety and the overall trial performance at a preplanned frequency when approximately 25%, 50%, and 75% of the enrolled participants had completed trial therapy. The first preplanned safety review was scheduled to occur after 19 months of enrollment. At 18 months, trial enrollment and treatment were suspended because of a manufacturing issue.

Particulate matter was identified in lot 3 of the trial drug before it was released for use. Because of this, the stored quality control vials from lot 2 (then currently in use) were subjected to an additional examination. This examination revealed particulate matter had developed in 17 of the approximately 900 vials examined (1.9%). Quality control vials from lot 1 (no longer in use) had passed all scheduled inspections. The particulate matter was later identified as glass lamellae and is discussed below with the associated analyses.

Due to the timing of the trial suspension, a review of the safety data by lot was added to the first preplanned safety review of the accumulating data by the data and safety monitoring committee. The data and safety monitoring committee recommended the continued suspension of the trial while the remaining data were collected and a final recommendation was made approximately 4 months later that the trial be stopped early based on a statistically significant increase in all-cause deaths through 55 weeks’ PMA in the myo-inositol group, which was unrelated to the manufacturing issue.

The review of the lot data did not show any evidence of harm to neonates exposed to lot 2 of the trial drug compared with those exposed to lot 1. No further drug was given and full data collection was continued as planned for up to 55 weeks’ PMA.¹⁶

Results

Participants

From April 17, 2014, through September 4, 2015, 1398 infants were screened, 1323 met the eligibility criteria, and 638 (48% of 1323 eligible infants) were randomized. The final date of follow-up was February 12, 2016, and 589 infants (92%) had a study outcome. The major reason for not enrolling in the trial was lack of informed consent (601). Six randomized participants received no doses (4 in the myo-inositol group and 2 in the placebo group) because of death or trial withdrawal prior to the first dose.

Of the 317 infants randomized to receive myo-inositol, 313 received the trial drug. Forty-two did not complete treatment due to the suspension of the trial (34 of those received ≥10 days of dosing) and 297 reached a primary outcome.

In the placebo group, 319 of the 321 participants received the assigned treatment, 36 did not complete treatment due to trial suspension (32 with ≥10 days of dosing) and 297 reached a primary outcome. Participants who did not receive the full course of treatment were included in the analyses.

The baseline characteristics of infants in the myo-inositol group and in the placebo group were similar (Table 1). The mean gestational age was 26 weeks, the mean birthweight was 780 g, and 53% of enrollees were younger than 26 weeks’ gestational age.

Table 1. Baseline Characteristics of Infants.

Characteristic^a	Myo-inositol (n = 317)^b	Placebo (n = 321)^b
Gestational age
Mean (SD), wk	25.6 (1.4)	25.7 (1.3)
<26 0/7 wk, No. (%)	169 (53)	170 (53)
Birth weight, mean (SD), g	776 (195)	785 (198)
Male sex, No. (%)	158 (50)	163 (51)
Racial/ethnic group, No. (%)^c
Non-Hispanic white	133 (44)	132 (43)
Non-Hispanic black	119 (39)	113 (37)
Asian	11 (4)	6 (2)
Hispanic or Latino	38 (13)	45 (15)
Received antenatal steroids, No. (%)	281 (89)	283 (88)
Apgar score at 5 min, median (IQR)^d	7 (5-8)	6 (4-8)
Early-onset sepsis (<72 h), No. (%)	7 (2)	9 (3)
Age at initiation of drug therapy, mean (SD), d	2.8 (0.8)	2.8 (0.8)

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Abbreviation: IQR, interquartile range.

^{^a}

These characteristics were chosen because they are believed to have an effect on neonatal morbidity and mortality outcomes in this extremely preterm population.

^{^b}

Includes all infants who were randomized and not the 313 in the myo-inositol group and the 320 in the placebo group who were included in the primary outcome analysis.

^{^c}

Self-reported by the family and selected from categories defined by the National Institutes of Health. There were missing data for 13 infants in the myo-inositol group and for 14 in the placebo group.

^{^d}

Summarizes the condition of the newborn after birth. Neonates are given a score of 0, 1, or 2 (best) for 5 items: color, tone, breathing, heart rate, and grimace resulting in a score from 0 to 10. There were missing data for 4 infants in the myo-inositol group and for 5 in the placebo group.

Primary Outcome

Adjudication of the ROP outcome was required for 39 infants (16 in the myo-inositol group and 23 in the placebo group). Death or type 1 ROP occurred more often in the myo-inositol group compared with the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0% to 13%]; adjusted RR, 1.41 [95% CI, 1.08 to 1.83], P = .01; Table 2). For the prespecified exploratory analyses of the components of the primary outcome, death before determination of ROP occurred in 16% of the myo-inositol group vs 10% of the placebo group (adjusted risk difference, 4% [95% CI, −1% to 9%]; adjusted RR, 1.53 [95% CI, 1.03 to 2.25], P = .03).

Table 2. Primary Outcome and Exploratory Analysis^a.

	No./Total No. (%)		Adjusted Risk Difference (95% CI), %^b	Adjusted RR (95% CI)^c	P Value^d
	Myo-inositol	Placebo	Adjusted Risk Difference (95% CI), %^b	Adjusted RR (95% CI)^c	P Value^d
Primary Outcome
Type 1 ROP or death before determination of ROP outcome using the adjudicated ROP outcome^e^,^f	91/313 (29)	66/320 (21)	7 (0 to 13)	1.41 (1.08 to 1.83)	.01
Prespecified Exploratory Analysis^g
Type 1 ROP^e	37/247 (15)	28/264 (11)	2 (−3 to 8)	1.43 (0.91 to 2.24)	.12
Death before determination of ROP outcome	50/317 (16)	33/321 (10)	4 (−1 to 9)	1.53 (1.03 to 2.25)	.03
Type 1 ROP including adjudicated ROP outcome^f	41/263 (16)	33/287 (11)	3 (−3 to 8)	1.38 (0.91 to 2.10)	.13

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Abbreviations: ROP, retinopathy of prematurity; RR, relative risk.

^{^a}

Outcomes collected up to 55 weeks’ postmenstrual age.

^{^b}

A generalized linear model with a binomial distribution and identity link was used. The analyses were adjusted for center when possible and gestational age strata.

^{^c}

Poisson regression was used. The analyses were adjusted for center when possible and gestational age strata.

^{^d}

Tested based on a score test using the robust variance estimator of the treatment effect in the Poisson regression model.

^{^e}

Type 1 ROP defined as the level of severity meeting criteria for surgical intervention.¹⁰

^{^f}

The ROP outcome was assigned by adjudication for 16 infants in the myo-inositol group and 23 in the placebo group when the final ROP outcome was not available.

^{^g}

Included components of the primary outcome.

The rates for type 1 ROP only were not significantly different with or without the adjudicated ROP outcome. Using the adjudicated ROP outcome, 16% in the myo-inositol group and 11% in the placebo group developed type 1 ROP (adjusted risk difference, 3% [95% CI, −3% to 8%]; adjusted RR, 1.38 [95% CI, 0.91 to 2.10], P = .13). The overall treatment × sex interaction and treatment × gestational age strata interaction were not significant (P = .20 and P = .51, respectively).

Secondary Outcomes

The between-group differences for presence of any ROP outcome and the type 2 ROP or greater outcome were not significantly different. All-cause mortality up to 55 weeks’ PMA was 18% in the myo-inositol group and 11% in the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted RR, 1.66 [95% CI, 1.14-2.43], P = .007; Table 3). The between-group differences for bronchopulmonary dysplasia and severe intraventricular hemorrhage were not significantly different (Table 3).

Table 3. Secondary Outcomes, Adverse Events, and Exploratory Outcomes.

	No./Total No. (%)		Adjusted Risk Difference (95% CI), %^a	Adjusted RR (95% CI)^b	P Value^c
	Myo-inositol	Placebo	Adjusted Risk Difference (95% CI), %^a	Adjusted RR (95% CI)^b	P Value^c
Secondary Outcomes
Any ROP^d	171/267 (64)	183/286 (64)	1 (−7 to 8)	1.02 (0.91 to 1.14)	.75
≥Type 2 ROP^d	125/263 (48)	142/285 (50)	−2 (−10 to 6)	0.98 (0.83 to 1.14)	.76
All-cause mortality^d	56/317 (18)	34/321 (11)	6 (0 to 11)	1.66 (1.14 to 2.43)	.007
All-cause mortality^e	50/317 (16)	33/321 (10)	4 (−1 to 9)	1.53 (1.03 to 2.25)	.03
Bronchopulmonary dysplasia^e^,^f	159/272 (58)	165/288 (57)	3 (−5 to 10)	1.03 (0.91 to 1.16)	.66
Bronchopulmonary dysplasia or death caused by it prior to 37 wk^e	159/272 (58)	165/288 (57)	3 (−5 to 10)	1.03 (0.91 to 1.16)	.66
Severe intraventricular hemorrhage (grade 3 or 4)^e	51/311 (16)	50/317 (16)	−1 (−6 to 4)	1.04 (0.74 to 1.48)	.81
Adverse Events^e
Late-onset sepsis (>72 h of age)	83/317 (26)	64/321 (20)	5 (−1 to 11)	1.31 (0.99 to 1.73)	.06
Suspected or proven necrotizing enterocolitis	29/317 (9)	30/321 (9)	−0 (−5 to 4)	0.98 (0.60 to 1.59)	.93
Surgical necrotizing enterocolitis	14/317 (4)	9/321 (3)	2 (−1 to 4)	1.57 (0.69 to 3.58)	.28
Spontaneous gastrointestinal perforation without necrotizing enterocolitis	19/317 (6)	22/321 (7)	−1 (−4 to 2)	0.87 (0.48 to 1.57)	.65
Time receiving intervention, mean (95% CI), d^g
Ventilation through 28 d	15.3 (14.1 to 16.5)	15.4 (14.2 to 16.6)	−0.07 (−1.62 to 1.47)^h		.93
Oxygen through 28 d	23.6 (22.7 to 24.5)	23.9 (23.0 to 24.8)	−0.26 (−1.42 to 0.90)^h		.66
Parenteral nutrition	29.6 (27.1 to 32.0)	26.2 (23.7 to 28.7)	3.33 (0.14 to 6.53)^h		.04
Pulmonary hemorrhage	27/317 (9)	28/321 (9)	−1 (−5 to 3)	0.97 (0.59 to 1.61)	.92
Patent ductus arteriosus	160/316 (51)	165/321 (51)	−1 (−9 to 7)	0.98 (0.85 to 1.14)	.83
Requiring indomethacin	64/316 (20)	72/321 (22)	−2 (−8 to 4)	0.90 (0.67 to 1.21)	.49
Requiring surgery	40/316 (13)	43/321 (13)	−1 (−6 to 3)	0.94 (0.63 to 1.40)	.76
Seizure treatment ≥2 d	9/317 (3)	7/320 (2)	1 (−2 to 3)	1.29 (0.49 to 3.43)	.60
Negative hearing screening result in either ear at hospital discharge	35/211 (17)	26/215 (12)	5 (−2 to 11)	1.38 (0.86 to 2.20)	.18
Prespecified Exploratory Outcome^e
Cystic areas in the cerebral parenchyma measured through 28 d	12/108 (11)	8/97 (8)	4 (−5 to 12)	1.35 (0.59 to 3.12)	.47

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Abbreviations: ROP, retinopathy of prematurity; RR, relative risk.

^{^a}

A generalized linear model with a binomial distribution and identity link was used. The analyses were adjusted for center when possible and gestational age strata.

^{^b}

Poisson regression was used. The analyses were adjusted for center when possible and gestational age strata.

^{^c}

For binary outcomes, tested based on a score test using the robust variance estimator of the treatment effect in the Poisson regression model. For continuous outcomes, tested based on analysis of covariance model.

^{^d}

Outcomes collected up to 55 weeks’ postmenstrual age.

^{^e}

Outcomes collected through the first event: death, hospital discharge, hospital transfer, or 120 days after birth.

^{^f}

Defined as requiring oxygen at 36 weeks’ postmenstrual age for oxygen saturation greater than 90%.

^{^g}

Analysis of covariance models were used that controlled for strata defined by gestational age and center.

^{^h}

Data expressed as difference in means (95% CI).

Adverse Events

The between-group differences for the majority of the clinical outcomes were not significantly different through hospital discharge, hospital transfer, death, or 120 days of age. However, the between-group difference for mean No. of days receiving parental nutrition was significant and there was a greater number of days reported on average in the myo-inositol group (29.6 vs 26.2 days in placebo group; between-group difference, 3.33 [95% CI, 0.14 to 6.53], P = .04). In both treatment groups, the most common cause of death before reaching the ROP outcome was respiratory distress syndrome (50% for myo-inositol vs 58% for placebo), followed by sepsis (40% vs 39%, respectively), and intracranial hemorrhage (14% vs 27%) (Table 4).

Table 4. Causes of Death Before Reaching Retinopathy of Prematurity (ROP) Outcome.

	No./Total No. (%)^a
	Myo-inositol	Placebo
Death before reaching ROP outcome, No. (%)	50/317 (16)	33/321 (10)
Respiratory distress syndrome	25/50 (50)	19/33 (58)
Sepsis	20/50 (40)	13/33 (39)
Intracranial hemorrhage	7/50 (14)	9/33 (27)
Pulmonary hemorrhage	5/50 (10)	7/33 (21)
Necrotizing enterocolitis	9/50 (18)	5/33 (15)
Spontaneous gastrointestinal perforation	5/50 (10)	5/33 (15)
Immaturity	4/50 (8)	5/33 (15)
Bronchopulmonary dysplasia	6/50 (12)	2/33 (6)
Other infection	6/50 (12)	0
Pulmonary hypoplasia	0	3/33 (9)
Pneumonia	2/50 (4)	0
Congenital malformation	1/50 (2)	1/33 (3)
Multiple organ failure	0	1/33 (3)
Hepatic failure or cirrhosis	0	1/33 (3)
Patent ductus arteriosus	0	1/33 (3)
Any other cause of death	11/50 (22)	7/33 (21)

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^{^a}

There may have been more than 1 primary or contributing cause of death.

The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol and 4% for placebo), spontaneous intestinal perforation without necrotizing enterocolitis (5% vs 6%, respectively), poor perfusion or hypotension (7% vs 4%), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%).

Prespecified Exploratory Outcomes

There were no between-group differences for the prespecified exploratory outcomes of growth (weight gain, head circumference, and length) or the cystic areas in the cerebral parenchyma (Table 3 and eFigure 2 in Supplement 3).

Post hoc Analyses

Post hoc examination of deaths due to late-onset sepsis revealed the suspected causal organisms to be viral in 2% of deaths in the myo-inositol group vs 6% of deaths in the placebo group, gram negative in 8% vs 9% of deaths, respectively, gram positive in 20% vs 12% of deaths, and yeast in 4% vs 3% of deaths. Post hoc analyses of the primary outcome and the clinical outcomes of infants exposed only to lot 1 of myo-inositol compared with those exposed only to lot 2 of myo-inositol (particulates were found in 1.9% of stored lot 2 trial drug vials) showed no evidence of increased risk among infants exposed to lot 2 of myo-inositol (eTables 1 and 2 in Supplement 3).

Discussion

In this trial of supplemental myo-inositol to improve survival without type 1 ROP among extremely preterm infants, myo-inositol did not reduce type 1 ROP rates, and the trial was stopped early for an unexpected significant increase in mortality. The previous beneficial findings of myo-inositol were not observed in the current trial; however, there are several relevant differences between the current and former inositol studies.^3,4,6 Antenatal steroids were not widely used, nor was surfactant available during the earlier trials. The prior studies treated infants for 3 to 10 days with myo-inositol during the acute phase of respiratory distress syndrome, whereas the present trial treated infants for up to 10 weeks to support retinal vascular development.

In the previous trials,^3,4,6 infants were more mature at birth (mean, 27-29 weeks’ gestational age). One explanation could be that a benefit of myo-inositol on the rates of intraventricular hemorrhage, bronchopulmonary dysplasia, and ROP during the earlier studies may have resulted from the predicted beneficial effect of myo-inositol on surfactant function.^3,4,5 Reducing the severity of respiratory distress syndrome could be expected to reduce these morbidities. Thus, a myo-inositol benefit on surfactant function in the current trial may have been outweighed by the beneficial effects of antenatal steroids, exogenous surfactant, and noninvasive ventilatory support in current use.

The dose of myo-inositol to produce serum concentrations was similar to those in the previous studies.^5,6,15 However, the combination of longer treatment and the inclusion of infants with younger gestational ages may have resulted in the unexpected increase in mortality through as yet unknown mechanisms. In vitro data have shown that infection of macrophages by some intracellular bacteria is enhanced by their ability to use myo-inositol as an energy source.²⁵

An additional issue for this trial was its suspension when particulates (later identified as glass lamellae) were found in the third lot of drug, which was never used. Glass particulates are a commonly cited reason for drug recalls. Delamination within glass vials is affected by both the glass manufacturing process and the chemical characteristics of the drug, particularly if acidic or caustic.^26,27

The glass lamellae subsequently found in 1.9% of stored vials in lot 2 of the trial drug raised the question whether the observed harmful effect of myo-inositol could have been due to these particles. However, detailed analyses revealed that there were no differences in the outcomes for infants treated with myo-inositol between the 2 lots of the trial drug.

Limitations

This trial was terminated prematurely, thus limiting definitive conclusions. Because the trial did not enroll as many infants as the preplanned sample size, it was underpowered to make conclusions regarding the efficacy of myo-inositol. In addition, the trial was not formally powered to make a conclusive assessment regarding safety.

Conclusions

Supplement 1.

Study protocol

Click here for additional data file.^{(411.7KB, pdf)}

Supplement 2.

Statistical analysis plan

Click here for additional data file.^{(625.3KB, pdf)}

Supplement 3.

eFigure 1. ROP endpoints: myo-inositol to reduce ROP

eFigure 2. Growth charts

eText. Evaluation of drug lot effects

eTable 1. Post-hoc analysis of primary and secondary efficacy outcomes for lot 1 use only vs lot 2 use only: on-treatment population

eTable 2. Post-hoc analysis of secondary efficacy and safety clinical outcomes for lot 1 use only vs lot 2 use only: on-treatment population

Click here for additional data file.^{(160.2KB, pdf)}

Supplement 4.

Data sharing statement

Click here for additional data file.^{(36.9KB, pdf)}

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20.Stoll BJ, Hansen NI, Bell EF, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA. 2015;314(10):1039-1051. doi: 10.1001/jama.2015.10244 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Carlo WA, Finer NN, Walsh MC, et al. ; SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network . Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362(21):1959-1969. doi: 10.1056/NEJMoa0911781 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Greenland S. Model-based estimation of relative risks and other epidemiologic measures in studies of common outcomes and in case-control studies. Am J Epidemiol. 2004;160(4):301-305. doi: 10.1093/aje/kwh221 [DOI] [PubMed] [Google Scholar]
23.McNutt LA, Wu C, Xue X, Hafner JP. Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am J Epidemiol. 2003;157(10):940-943. doi: 10.1093/aje/kwg074 [DOI] [PubMed] [Google Scholar]
24.Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159(7):702-706. doi: 10.1093/aje/kwh090 [DOI] [PubMed] [Google Scholar]
25.Manske C, Schell U, Hilbi H. Metabolism of myo-inositol by Legionella pneumophila promotes infection of amoebae and macrophages. Appl Environ Microbiol. 2016;82(16):5000-5014. doi: 10.1128/AEM.01018-16 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Guadagnino E, Zuccato D. Delamination propensity of pharmaceutical glass containers by accelerated testing with different extraction media. PDA J Pharm Sci Technol. 2012;66(2):116-125. doi: 10.5731/pdajpst.2012.00853 [DOI] [PubMed] [Google Scholar]
27.Zhao J, Lavalley V, Mangiagalli P, Wright JM, Bankston TE. Glass delamination: a comparison of the inner surface performance of vials and pre-filled syringes. AAPS PharmSciTech. 2014;15(6):1398-1409. doi: 10.1208/s12249-014-0167-y [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Study protocol

Click here for additional data file.^{(411.7KB, pdf)}

Supplement 2.

Statistical analysis plan

Click here for additional data file.^{(625.3KB, pdf)}

Supplement 3.

eFigure 1. ROP endpoints: myo-inositol to reduce ROP

eFigure 2. Growth charts

eText. Evaluation of drug lot effects

eTable 1. Post-hoc analysis of primary and secondary efficacy outcomes for lot 1 use only vs lot 2 use only: on-treatment population

eTable 2. Post-hoc analysis of secondary efficacy and safety clinical outcomes for lot 1 use only vs lot 2 use only: on-treatment population

Click here for additional data file.^{(160.2KB, pdf)}

Supplement 4.

Data sharing statement

Click here for additional data file.^{(36.9KB, pdf)}

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PERMALINK

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks’ Gestational Age

Dale L Phelps, MD

Kristi L Watterberg, MD

Tracy L Nolen, DrPH

Carol A Cole, RPh

C Michael Cotten, MD, MHS

William Oh, MD

Brenda B Poindexter, MD, MS

Kristin M Zaterka-Baxter, RN, BSN

Abhik Das, PhD

Conra Backstrom Lacy, RN

Ann Marie Scorsone, MS

Michele C Walsh, MD, MS

Edward F Bell, MD

Kathleen A Kennedy, MD, MPH

Kurt Schibler, MD

Gregory M Sokol, MD

Matthew M Laughon, MD, MPH

Satyanarayana Lakshminrusimha, MD

William E Truog, MD

Meena Garg, MD

Waldemar A Carlo, MD

Abbot R Laptook, MD

Krisa P Van Meurs, MD

David P Carlton, MD

Amanda Graf, MD

Sara B DeMauro, MD, MSCE

Luc P Brion, MD

Seetha Shankaran, MD

Faruk H Orge, MD

Richard J Olson, MD

Helen Mintz-Hittner, MD

Michael B Yang, MD

Kathryn M Haider, MD

David K Wallace, MD, MPH

Mina Chung, MD

Denise Hug, MD

Irena Tsui, MD

Martin S Cogen, MD

John P Donahue, MD, PhD

Michael Gaynon, MD

Amy K Hutchinson, MD

Don L Bremer, MD

Graham Quinn, MD, MSCE

Yu-Guang He, MD

William R Lucas Jr, MD

Timothy W Winter, DO

Stephen D Kicklighter, MD

Kartik Kumar, MD

Patricia R Chess, MD

Tarah T Colaizy, MD, MPH

Anna Marie Hibbs, MD

Namasivayam Ambalavanan, MD

Heidi M Harmon, MD, MS

Elisabeth C McGowan, MD

Rosemary D Higgins, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Population

Figure. Flow of Infants Through Study.

Randomization and Masking

Intervention

Primary Outcome

Secondary Outcomes

Safety Outcomes

Prespecified Exploratory Outcomes

Statistical Analyses

Table 2. Primary Outcome and Exploratory Analysis^a.