A randomized, double-blind, placebo-controlled trial of pleconaril for the treatment of neonates with enterovirus sepsis

Mark J. Abzug, Marian G. Michaels, Ellen Wald, Richard F. Jacobs, José R. Romero, Pablo J. Sánchez, Gregory Wilson, Paul Krogstad, Gregory A. Storch, Robert Lawrence, Mark Shelton, April Palmer, Joan Robinson, Penelope Dennehy, Sunil K. Sood, Gretchen Cloud, Penelope Jester, Edward P. Acosta, Richard Whitley, David KimberlinNational Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group

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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.

Original languageEnglish (US)
Article numberpiv015
Pages (from-to)53-62
Number of pages10
JournalJournal of the Pediatric Infectious Diseases Society
Volume5
Issue number1
DOIs
StatePublished - Oct 31 2015

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Keywords

  • Enterovirus
  • Hepatitis
  • Neonatal
  • Pleconaril
  • Sepsi

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Abzug, M. J., Michaels, M. G., Wald, E., Jacobs, R. F., Romero, J. R., Sánchez, P. J., Wilson, G., Krogstad, P., Storch, G. A., Lawrence, R., Shelton, M., Palmer, A., Robinson, J., Dennehy, P., Sood, S. K., Cloud, G., Jester, P., Acosta, E. P., Whitley, R., ... National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (2015). A randomized, double-blind, placebo-controlled trial of pleconaril for the treatment of neonates with enterovirus sepsis. Journal of the Pediatric Infectious Diseases Society, 5(1), 53-62. [piv015]. https://doi.org/10.1093/jpids/piv015