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 Kimberlin & 1 others National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group

Research output: Contribution to journalArticle

31 Citations (Scopus)

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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Enterovirus
Sepsis
Placebos
Therapeutics
Oropharynx
pleconaril
Polymerase Chain Reaction
Myocarditis
Rectum
Hepatitis
Antiviral Agents
Pharmacokinetics
Urine
Safety
Mortality

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., ... 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

A randomized, double-blind, placebo-controlled trial of pleconaril for the treatment of neonates with enterovirus sepsis. / Abzug, Mark J.; Michaels, Marian G.; Wald, Ellen; Jacobs, Richard F.; Romero, José R.; Sánchez, Pablo J.; Wilson, Gregory; Krogstad, Paul; Storch, Gregory A.; Lawrence, Robert; Shelton, Mark; Palmer, April; Robinson, Joan; Dennehy, Penelope; Sood, Sunil K.; Cloud, Gretchen; Jester, Penelope; Acosta, Edward P.; Whitley, Richard; Kimberlin, David; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

In: Journal of the Pediatric Infectious Diseases Society, Vol. 5, No. 1, piv015, 31.10.2015, p. 53-62.

Research output: Contribution to journalArticle

Abzug, MJ, Michaels, MG, Wald, E, Jacobs, RF, Romero, JR, Sánchez, PJ, Wilson, G, Krogstad, P, Storch, GA, Lawrence, R, Shelton, M, Palmer, A, Robinson, J, Dennehy, P, Sood, SK, Cloud, G, Jester, P, Acosta, EP, Whitley, R, Kimberlin, D & 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, vol. 5, no. 1, piv015, pp. 53-62. https://doi.org/10.1093/jpids/piv015
Abzug, Mark J. ; Michaels, Marian G. ; Wald, Ellen ; Jacobs, Richard F. ; Romero, José R. ; Sánchez, Pablo J. ; Wilson, Gregory ; Krogstad, Paul ; Storch, Gregory A. ; Lawrence, Robert ; Shelton, Mark ; Palmer, April ; Robinson, Joan ; Dennehy, Penelope ; Sood, Sunil K. ; Cloud, Gretchen ; Jester, Penelope ; Acosta, Edward P. ; Whitley, Richard ; Kimberlin, David ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. / A randomized, double-blind, placebo-controlled trial of pleconaril for the treatment of neonates with enterovirus sepsis. In: Journal of the Pediatric Infectious Diseases Society. 2015 ; Vol. 5, No. 1. pp. 53-62.
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AU - Abzug, Mark J.

AU - Michaels, Marian G.

AU - Wald, Ellen

AU - Jacobs, Richard F.

AU - Romero, José R.

AU - Sánchez, Pablo J.

AU - Wilson, Gregory

AU - Krogstad, Paul

AU - Storch, Gregory A.

AU - Lawrence, Robert

AU - Shelton, Mark

AU - Palmer, April

AU - Robinson, Joan

AU - Dennehy, Penelope

AU - Sood, Sunil K.

AU - Cloud, Gretchen

AU - Jester, Penelope

AU - Acosta, Edward P.

AU - Whitley, Richard

AU - Kimberlin, David

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N2 - 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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