Long Term Treatment of Herpes Simplex Encephalitis (HSE) With Valacyclovir

Herpes simplex encephalitis (HSE) remains the most common cause of sporadic fatal
encephalitis in the world. This study is a phase III, double-blind, placebo controlled study
of long term therapy with valacyclovir as a treatment of herpes encephalitis. The primary
objective of this study is to assess the impact of valacyclovir (VACV) therapy (following
standard intravenous acyclovir therapy) on neuropsychological impairment at one year post
therapy, based on the cumulative scores of the Mattis Dementia Rating Scale (MDRS). The
secondary objectives of the study are to: assess the effect of therapy on neuropsychological
impairment at various time points; assess the effect of therapy on quality of life, based on
the SF-36 Quality of Life Assessment; measure the effect of therapy on herpes simplex virus
(HSV) deoxyribonucleic acid (DNA) in the cerebral spinal fluid (CSF); and assess the safety
and tolerability of long term VACV therapy in patients with HSE. The tertiary objective of
the study is to determine the frequency of symptomatic relapse/recurrence of HSE. Study
participants will include 120 males and females, 12 years of age and older, diagnosed with
HSE; laboratory confirmed CSF positive for HSV DNA by polymerase chain reaction (PCR).
Consenting study participants will be randomized (1:1) to either valacyclovir (active drug),
500 mg tablets, four tablets three times daily for 90 days or placebo (identical to active
drug in appearance), 500 mg tablets, four tablets three times daily for 90 days. The primary
endpoints of the study are to assess the impact of valacyclovir therapy [following standard
intravenous acyclovir (ACV) therapy] on neuropsychological impairment at one year post
therapy and survival with no or mild neuropsychological impairment at 12 months after
initiation of study medication, as measured by the MDRS. The secondary endpoints include:
survival with no or mild neuropsychological impairment at 90 days and at 6, 12 and 24 months,
as measured by the MDRS, the Mini-Mental Status Examination (MMSE), and the Glasgow Coma
Scale; effect of study medication on quality of life measurements; effect of antiviral
therapy on HSV DNA in CSF (measured quantitatively by PCR at Day 0 and Day 90); and safety
and tolerance of VACV administered at a dose of 2.0 grams given orally three times a day for
90 days. Each study participant will participate for approximately 24 months.

Inclusion Criteria:

- Informed consent and/or assent must be obtained from the patient or legal guardian.

- Patients with encephalopathy consistent with herpes simplex encephalitis (HSE) whose
cerebral spinal fluid (or brain biopsy sample) is positive for herpes simplex virus
(HSV) deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR).

- Patients who are receiving and will have completed intravenous (IV) acyclovir (ACV)
therapy for a minimum duration of 14 days to a maximum of 21 days and a minimum dose
of 30 mg/kg/day to a maximum of 60 mg/kg/day, or equivalent dose as adjusted for renal
dysfunction.

- Patient is expected to be available for follow-up visits of study drug administration
and through the 24 month study visit.

- Patients who are 12 years of age or older.

- Patients who weigh greater than or equal to 45.5kg (100 pounds).

- All female patients with childbearing potential must have a negative pregnancy test
within 72 hours prior to initiation of study drug. If the pregnancy test is positive,
the patient is ineligible for the study.

- Women must be post-menopausal, surgically sterile or willing to use adequate
contraception (barrier method with spermicide, intrauterine device (IUD), oral
contraceptives, implant or other licensed hormone method) from time of study
enrollment through 1 month after the last dose of study treatment.

- Men must be surgically sterile or willing to use contraception (barrier method with
spermicide) from time of study enrollment through 1 month after the last dose of study
treatment.

Exclusion Criteria:

- Patients with herpes simplex virus (HSV) meningitis only, without evidence of HSV
encephalitis.

- Patients with an anticipated life expectancy < 90 days.

- Patients with creatinine clearance of less than or equal to 50ml/min./1.73 m^2.

- Pregnant or breastfeeding females.

- Patients who have received any anti-herpesvirus medication (e.g. ganciclovir) other
than intravenous acyclovir (ACV) for acute therapy of the current episode of herpes
simplex encephalitis (HSE).

- Patients who are unable to swallow oral medications at the time of study drug
randomization (Day 0).

- Patients who are > 3 days beyond completion of treatment course with intravenous (IV)
ACV.

- Patients who are expected to receive long-term (> 30 days/year) therapy with antiviral
medications active against HSV [e.g. ACV, valacyclovir (VACV), famciclovir].