Mark J Abzug1, Marian G Michaels2, Ellen Wald3, Richard F Jacobs4, José R Romero5, Pablo J Sánchez6, Gregory Wilson7, Paul Krogstad8, Gregory A Storch9, Robert Lawrence10, Mark Shelton11, April Palmer12, Joan Robinson13, Penelope Dennehy14, Sunil K Sood15, Gretchen Cloud16, Penelope Jester16, Edward P Acosta16, Richard Whitley16, David Kimberlin16. 1. Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora. 2. Children's Hospital, Pittsburgh of University of Pittsburgh Medical Center. 3. University of Wisconsin, Milwaukee. 4. University of Arkansas for Medical Sciences, Little Rock. 5. University of Nebraska School of Medicine, Omaha, and University of Arkansas for Medical Sciences, Little Rock. 6. University of Texas Southwestern, Dallas, and Nationwide Children's Hospital-The Ohio State University, Columbus. 7. Vanderbilt University, Nashville, Tennessee. 8. University of California, Los Angeles. 9. Washington University, St. Louis, Missouri. 10. University of Florida, Gainesville. 11. Cooks Children Hospital, Ft. Worth, Texas. 12. University of Mississippi Medical Center, Jackson. 13. University of Alberta, Canada. 14. Hasbro Children's Hospital, Providence, Rhode Island. 15. North Shore LIJ Health System, New York. 16. University of Alabama at Birmingham.
Abstract
BACKGROUND: Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available. METHODS:Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed. RESULTS:Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events. CONCLUSIONS:Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation.
RCT Entities:
BACKGROUND:Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available. METHODS: Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed. RESULTS: Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events. CONCLUSIONS: Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation.
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