German Trial of Acyclovir and Corticosteroids in Herpes-simplex-virus-encephalitis (HSVE); a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial.

Title of the study:GACHE: GERMAN TRIAL OF ACYCLOVIR AND CORTICOSTEROIDS IN
HERPES-SIMPLEX-VIRUS-ENCEPHALITIS. A multicenter, multinational, randomized,
double-blind, placebo-controlled German, Austrian and Dutch trial.

Background: The treatment of HSVE remains one of the major unsolved problems in
Neurology. The current gold standard in therapy is acyclovir, a drug that
inhibits viral replication, but despite antiviral treatment mortality remains
up to 15%. Even after early antiviral treatment, less than 20% of patients are
able to go back to work and the majority of patients suffer from severe
disability. Raschilas et al. reported in 2002 a series of 85 patients in which
20% remained severely disabled, 28% moderately disabled, and only 14% of
patients had a good recovery according to the Glasgow Outcome Scale (GOS).
McGrath et al. described in a series of 34 patients a mortality of 12%, and 40%
of the surviving patients presented an outcome ranging from moderate disability
and severe disability to vegetative state. This is a discouraging,
unsatisfactory situation for treating physicians, the disabled patients and
their families, and constitutes an enormous burden to the public health
services. This has been an urgent topic during the last decade despite the
availability of antiviral treatment with acyclovir. Apart from direct
virus-mediated tissue damage, secondary mechanisms have proven to play a
significant role in the pathogenesis of HSVE (Sköldenberg et al. 2006,
Meyding-Lamadé et al 2002, Martinez-Torres et al. 2004, and Sellner et al.
2005). In experimental animal models of HSVE the adjuvant therapy with
corticosteroids given together with the antiviral therapy has proven to be more
effective than antiviral therapy alone in reducing the extent of structural
abnormalities in brain tissue observed with MRI (Meyding-Lamadé et al. 2003).
Corticosteroids are considered to be useful for the treatment of HSVE when they
are administered together with the antiviral medication (Sköldenberg et al.
2006; Kamei et al. 2005). A recent retrospective analysis has reported a
favorable outcome of patients with HSVE receiving adjuvant therapy with
corticosteroids (Kamei et al. 2005). Adjuvant corticosteroids are also used for
the treatment of patients with HSVE relapse (Sköldenberg et al. 2006). Kamei et
al. (2005) have carried out a non-randomised retrospective study of 45 patients
with HSVE. A poor outcome was evident with older age, lower GCS score at
initiation of aciclovir, and no administration of corticosteroid. Older age,
lower GCS at admission and no administration of corticosteroids were
significant independent predictors of outcome. The adjuvant use of
corticosteroids has been recommended and used by experts from neurocritical
care units in Europe and Japan for the treatment of herpes-encephalitis. So far
however, this important question whether or not the adjuvant treatment with
corticosteroids proves to be superior as compared to the standard antiviral
treatment for HSVE, has not been addressed in a randomized trial. In our
opinion, it is of utmost importance to address this question in a prospective,
controlled clinical trial.
Summary: The information obtained from experimental animal research and from
recent retrospective clinical observations, indicates that a substantial
benefit in
outcome can be expected in patients with HSVE who are treated with adjuvant
dexamethasone. But currently there is no available evidence to support the
routine
use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter
trial is
the only useful instrument to address this question.

GACHE aims to evaluate the effect on morbidity and mortality of early adjuvant
corticosteroids (dexamethasone) in the treatment of adult patients with HSVE.
The major motivation for this trial is the extremely unsatisfactory outcome of
patients despite effective antiviral treatment with the actual golden standard
acyclovir.

The study design of GACHE is that of a multicenter, randomized, double-blind,
placebocontrolled, parallel group clinical trial in adult patients with HSVE.
The statistical design is that of a group sequential design with a maximum of
three stages, rejection boundaries according to (O*Brien and Fleming, 1979) and
a potential sample size adjustment for the last stage (Müller, 2001).

Study medication (dexamethasone / placebo): Patients will be randomly assigned
to receive study medication as soon as the diagnosis of HSVE is confirmed with
PCR. The study medication is administered intravenously: Dexamethasone at a
dosage of 40 mg every 24 hours for four days, or placebo that is identical in
appearance to the active drug.

Day 0 (after randomization): Physical and neurological examinations.
Day 0 or as soon as possible after positive HSV PCR, at the latest 48 hours
after initiation of study medication (Dexamethasone/placebo): MRI-scan.
Day 7 to 10 after randomization: Physical and neurological examination.
At discharge, at the latest Day 30 after randomization: Physical and
neurological
examination, mRS, GOS, Barthel Index.
6 months after randomization: Physical and neurological examination,
neuropsychological testing, mRS, GOS, Barthel-Index, cranial MRI
12 months after randomization: Physical and neurological examination, mRS, GOS,
Barthel-Index. All examinations are part of the routine treatment of the
patients. There will be no further investigation of blood samples or CT/MRI
scans that are part of the study.