Phase III Randomized Study of Oral Acyclovir in Infants With Herpes Simplex Virus Infection Involving the Central Nervous System

PROTOCOL OUTLINE: This is a randomized, double blind, placebo controlled, multicenter study.
Patients are stratified according to disease (CNS disease with or without cutaneous
involvement vs disseminated disease with CNS involvement).

All patients receive acyclovir IV every 8 hours on days 1-21. On day 19, patients undergo a
lumbar puncture and must have a negative CSF PCR to be randomized. If patients have a
positive CSF PCR on day 19, they continue to receive acyclovir IV every 8 hours. Treatment
continues every 7 days with a repeat CSF PCR on the fifth day until a negative CSF PCR
result is achieved. Patients are then randomized to one of two treatment arms.

Arm I: Patients receive oral acyclovir three times a day for 6 months. Arm II: Patients
receive placebo. In case of cutaneous recurrence during the first 12 months of the study,
patients receive open label oral acyclovir (if CSF PCR is negative) or acyclovir IV (if CSF
PCR is positive) for 5 days. Patients may or may not continue on study drug following this
treatment.

Patients are followed at 6, 12, 24, 36, 48, and 60 months of age.

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

- Infants diagnosed with herpes simplex virus infection involving the central nervous
system with or without evidence of viral dissemination to other organs (i.e., skin,
liver, or lungs) HSV-1 or HSV-2 isolated from cutaneous lesions from any site (skin,
oropharynx, cerebrospinal fluid (CSF), urine, etc.) OR Must have positive CSF
polymerase chain reaction (PCR) if no cutaneous skin lesions are present and viral
cultures are negative No infection limited to skin, eyes, or mouth Evidence of CNS
involvement includes one or more of the following: Abnormal CSF indices for term
infants (WBC greater than 22/mm3 and protein greater than 115 mg/dL) Abnormal CSF
indices for preterm infants (WBC greater than 25/mm3 and protein greater than 220
mg/dL) Abnormal neuroimaging study (CT with contrast, MRI with gadolinium, or head
ultrasound) Disseminated disease is defined as one or more of the following: SGPT at
least 2.5 times upper limit of normal Pneumonia/pneumonitis Necrotizing enterocolitis
Disseminated intravascular coagulopathy

- Birth weight at least 800 grams

--Prior/Concurrent Therapy--

- No concurrent nursing from a mother who is receiving acyclovir, valacyclovir, or
famciclovir for longer than 120 hours or 5 days

--Patient Characteristics--

- Renal: Creatinine no greater than 1.5 mg/dL

- Cardiovascular: No prior grade 3 or 4 intraventricular hemorrhage

- Other: No infants known to be born to HIV positive women