A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis

• Published in: Journal of the Pediatric Infectious Diseases Society Vol. 5; no. 1; pp. 53 - 62
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.03.2016
• Series: Editor's choice
• Subjects: Antiviral Agents - blood; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Antiviral Agents - urine; Double-Blind Method; Enterovirus - drug effects; Enterovirus - genetics; Enterovirus - isolation & purification; Enterovirus Infections - blood; Enterovirus Infections - complications; Enterovirus Infections - drug therapy; Enterovirus Infections - urine; Female; Humans; Infant; Infant, Newborn; Male; Neonatal Sepsis - blood; Neonatal Sepsis - drug therapy; Neonatal Sepsis - urine; Neonatal Sepsis - virology; Original and Commentaries; Oropharynx - virology; Oxadiazoles - blood; Oxadiazoles - pharmacokinetics; Oxadiazoles - therapeutic use; Oxadiazoles - urine; Oxazoles; Rectum - virology; neonatal; pleconaril; enterovirus; hepatitis; sepsis
• ISSN: 2048-7193; 2048-7207; 2048-7207
• DOI: 10.1093/jpids/piv015

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.