Program Schedule

80
A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates with Enterovirus Sepsis

Session: Oral Abstract Session: Defining and Reducing the Impact of Pediatric Infections
Thursday, October 9, 2014: 9:15 AM
Room: The Pennsylvania Convention Center: 111-AB

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

Mark Abzug, MD1, Marian Michaels, MD2, Ellen Wald, MD3, Richard Jacobs, MD4, Jose R. Romero, MD5, Pablo J. Sanchez, MD, FIDSA6, Gregory Wilson, MD7, Paul Krogstad, MD8, Gregory Storch, MD, FIDSA9, Robert Lawrence, MD10, Mark Shelton, MD11, April Palmer, MD12, Joan Robinson, MD13, Penelope H. Dennehy, MD, FIDSA14, Sunil Sood, MD15, Gretchen Cloud, MS16, Penelope Jester, MSN BSN16, Edward Acosta, PharmD17, Richard Whitley, MD, FIDSA18, David W. Kimberlin, MD, FIDSA19 and National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, (1)University of Colorado School of Medicine, Aurora, CO, (2)Pediatric Infectious Diseases, Children's Hospital of Pittsburgh, Pittsburgh, PA, (3)University of Wisconsin Children's Hospital, Madison, WI, (4)Univ. of Arkansas for Med. Sc., Little Rock, AR, (5)University of Arkansas for Medical Sciences, Little Rock, AR, (6)Pediatrics, Nationwide Children's Hospital - The Ohio State University, Columbus, OH, (7)Vanderbilt, Nashville, TN, (8)Pediatrics, Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, (9)St. Louis Children's Hospital, St. Louis, MO, (10)University of Florida, Gainesville, FL, (11)Infectious Diseases, Cook Children's Medical Center, Fort Worth, TX, (12)Pediatrics, University of Mississippi Medical Center, Jackson, MS, (13)University of Alberta, Edmonton, AB, Canada, (14)Pediatrics, The Alpert Medical School of Brown University, Providence, RI, (15)North Shore LIJ Health System, Manhasset, NY, (16)University of Alabama at Birmingham, Birmingham, AL, (17)University of Alabama Birmingham, Birmingham, AL, (18)Pediatrics, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, (19)Pediatrics, University of Alabama At Birmingham, Birmingham, AL

Disclosures:

M. Abzug, None

M. Michaels, None

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

Findings in the abstracts are embargoed until 12:01 a.m. EDT, Oct. 8th with the exception of research findings presented at the IDWeek press conferences.

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