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

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.

Keywords: enterovirus; hepatitis; neonatal; pleconaril; sepsis.

Figure 1.

Time to culture negativity for all anatomic sites (oropharynx, rectum, urine, and serum) combined among the 19 subjects in the treatment group and 7 in the placebo group who were culture positive from any site. A subject was considered culture negative on a given study day only when culture assays from all sampled sites on that day were negative.

Figure 2.

Survival over 2 months among all enrolled subjects (A) and among enterovirus-confirmed subjects (B).

Figure 3.

Survival over 2 months among enterovirus-confirmed subjects according to treatment group and receipt of intravenous immune globulin (IVIG).

Figure 4.

Pleconaril concentration as a function of formulation (A) and time (B). In (A), the X denotes the median simulated steady-state maximum concentration (C_max,ss) for each formulation. In (B), subjects dosed with the 2 formulations are combined. The solid line represents simulated median concentration–time data and dashed lines are the 5^th and 95^th percentile confidence intervals.