A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates with Enterovirus Sepsis
Background: Neonatal enterovirus (EV) infections have high morbidity & mortality. Antiviral therapy is not currently available. Pleconaril is an oral capsid binder with activity against EVs.
Methods: Neonates with suspected EV sepsis (hepatitis, coagulopathy, or myocarditis) were randomized 2:1 to receive oral pleconaril or placebo x 7 days. Specimens (oropharynx, rectum, urine, serum) for viral culture & polymerase chain reaction (PCR), pharmacokinetic analysis, & safety evaluations were obtained over 14 days & clinical assessments were performed over 24 months.
Results: 61 subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed EV-infected by culture or PCR (31 treatment, 12 placebo). Baseline characteristics were similar between EV-infected groups; median (range) age at illness onset was 4.5 (1-15) & 5.0 (1-10) days, respectively. Low culture yields precluded demonstrating a difference in the primary endpoint, day 5 oropharyngeal culture positivity (25% positive on Day 1 & 0% on Day 5 in the treatment group v. 30% on Day 1 & 0% on Day 5 in the placebo group). However, subjects in the treatment group became culture-negative from all anatomic sites combined faster than subjects in the placebo group (Fig 1; median 4.0 v. 7.0 days, p = 0.08) & fewer subjects in the treatment group remained PCR-positive from the oropharynx when last sampled (83% positive on Day 1 & 23% positive at a median of 14 days in the treatment group v. 100% positive on Day 1 & 58% positive at a median of 14 days in the placebo group, p = 0.02). By intent to treat, 10/43 (23%) of all subjects in the treatment group & 8/18 (44%) in the placebo group died (Fig 2; p = 0.02 for 2 month survival difference). Among EV-confirmed subjects, 7/31 (23%) in the treatment group died v. 5/12 (42%) in the placebo group (Fig 3; p = 0.26). Pleconaril concentrations exceeded the IC90 after the first treatment day, but 41% of subjects did not achieve this target during the 1st treatment day. 1 subject in the treatment group & 3 in the placebo group had treatment-related adverse events.
Conclusion: Shorter times to culture & PCR negativity & suggestion of greater survival among pleconaril recipients support potential efficacy & warrant further evaluation.
SEQ Figure \* ARABIC 1. Culture positive
SEQ Figure \* ARABIC 2. Survival, all subjects
SEQ Figure \* ARABIC 3. Survival, EV-confirmed
E. Wald, None
R. Jacobs, None
J. R. Romero, None
P. J. Sanchez, None
G. Wilson, None
P. Krogstad, None
G. Storch, None
R. Lawrence, None
M. Shelton, None
A. Palmer, None
J. Robinson, None
P. H. Dennehy, None
S. Sood, None
G. Cloud, None
P. Jester, None
E. Acosta, None
R. Whitley, None
D. W. Kimberlin, None
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