CASG 106: A Double-Blind, Placebo-Controlled, Virologic Efficacy Trial of Pleconaril in the Treatment of Neonates with Enteroviral Sepsis Syndrome (DMID Protocol Number 99-018)
Neonates <15 days of age (birth weight >1500 g, gestational age >32 wks) with suspected neonatal enteroviral sepsis will qualify for enrollment. Infants must have evidence of severe hepatic involvement, myocardial involvement, and/or consumptive coagulopathy syndrome and have had onset of symptoms <10 days before administration of study drug. Infants will be randomized to receive either study drug at 5mg/kg/dose through a feeding tube three times a day for seven days (21 doses) or placebo (2:1 drug to placebo assignment). Infants will have throat, rectal, conjunctival, urine and serum specimens obtained on day 1 (before the first dose of study drug) for viral culture and PCR (detects enteroviral nucleic acid –RNA). If cerebrospinal fluid is available, viral culture and PCR will be performed; performance of a lumbar puncture is not required for study entry. Sites for viral culture and PCR, on subsequent days 2, 3, 4, 5, 7, 10, and 14 include throat, rectum, urine, and serum. The volume of serum for culture and PCR is 0.5 cc/sample.
The first dosing cohort will receive the study drug at 5 mg/kg/dose PO q8 hrs. for seven days (21 doses). Infants will have complete pharmacokinetic profiles (0.6 ml of whole blood/sample; 2, 4, 8 hrs. after first dose; 0, 2, 4 hrs. after second dose on day 3, 0, 1, 2, 4 hrs. after dose 21) until pharmacokinetic analysis is completed for six patients with hepatic involvement who have received active drug.
Pharmacokinetic data will be reviewed by the Data and Safety Monitoring Board (DSMB) of the NIAID Collaborative Antiviral Study Group (CASG). Results will be compared with data on Pleconaril pharmacokinetics in 16 neonates with and without hepatic disease who were previously in studies conducted by the National Institute of Child Health and Human Development Pediatric Pharmacology Research Units. Determination will then be made as to whether to change the dose (amount and/or frequency) in subsequently enrolled infants. Abbreviated pharmacokinetic profiles (before dose 12; 2 and 4 hrs. after dose 12) will be performed on subsequent infants. If the patient requires ECMO (Extracorporeal Membrane Oxygenation), complete pharmacokinetic profile will be obtained around the third to fifth dose after ECMO is started. ECMO is a special procedure that allows sick or injured lungs the opportunity to rest and get better. Safety labs will be obtained on days 1, 3, 5, 7, 10, and 14, and consist of complete blood cell count, electrolytes, BUN, creatinine, ALT, total and direct bilirubin, total protein, albumin, cholesterol, glucose, and calcium. A careful medical history and physical examination will be performed at entry, and daily physical examinations will be performed during the study drug administration. Data on hospital course and total hospital charges will be obtained. Infants will be followed at two months of age, and then every six months up to 24 months of age. An estimate of developmental status will be determined. Liver function tests and/or CBC will be obtained if these were initially abnormal.
While the infant is hospitalized, a small amount of blood (½ teaspoon) will be drawn from the baby’s mother (if given consent to do so). This will be a one time blood draw. This blood will help to determine the amount of antibodies (cells that fight the disease) against the enterovirus in the mother’s blood.
Infants (birth weight >1500 grams; gestational age >32 weeks) who are <15 days of age at time of onset of symptoms of probable enteroviral sepsis syndrome will be enrolled if onset of symptoms will be <10 days before the initiation of study drug. They must have one or more of the following conditions: SGPT > 3 X the upper limit of normal; 2) platelet count <100,000 and prothrombin time >1.5 times normal and fibrin split products >35 mg%; 3) cardiac shortening <25% or cardiac ejection fraction <50%, as measured by echocardiography. Infants of both sexes and all races/ethnicities are eligible for enrollment. Both English and Spanish speaking subjects may be enrolled. Infants may receive broad-spectrum antibiotics and acyclovir concomitantly with study drug. Confirmation of enteroviral disease is not required for enrollment into this trial. If a non-enteroviral diagnosis is confirmed after enrollment, study drug will be discontinued immediately.