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The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter,
U Meyding-Lamadé1,2, C Jacobi1, F Martinez-Torres1,2
1Department of Neurology, Krankenhaus Nordwest, Frankfurt, Germany.
Insights
This study investigated if dexamethasone improves outcomes for Herpes Simplex Virus Encephalitis (HSVE) patients treated with aciclovir. The trial was stopped early, finding no significant difference between dexamethasone and placebo groups.
Area of Science:
- Neurology
- Infectious Diseases
- Clinical Trials
Background:
- Herpes Simplex Virus Encephalitis (HSVE) has high mortality and disability despite aciclovir treatment.
- Adjuvant dexamethasone shows potential therapeutic benefits in HSVE, but lacks robust clinical trial evidence.
- Current standard treatment for HSVE is aciclovir, which inhibits viral replication.
Purpose of the Study:
- To evaluate the efficacy of adjuvant dexamethasone in addition to standard aciclovir treatment for HSVE.
- To assess the impact of dexamethasone on functional outcomes, mortality, and quality of life in HSVE patients.
- To provide randomized clinical trial evidence regarding corticosteroid use in HSVE.
Main Methods:
- The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) was a randomized, double-blind, placebo-controlled study.
- Adult patients (18-85 years) with proven HSVE received either dexamethasone or placebo alongside aciclovir.
- The primary endpoint was functional outcome at 6 months using the modified Rankin Scale (mRS 0-2 vs. 3-6).
Main Results:
- The GACHE trial was prematurely terminated due to slow patient recruitment, with only 41 patients randomized.
- No significant difference was observed in the primary endpoint (mRS 0-2) between the dexamethasone and placebo groups.
- Secondary endpoints, including mortality and quality of life, also showed no significant differences between the treatment arms.
Conclusions:
- Premature termination of the GACHE trial highlights challenges in conducting randomized trials for rare neurological diseases.
- The use of adjuvant steroids in HSVE remains experimental, with treatment decisions resting with individual physicians.
- The limited sample size prevents definitive conclusions on the efficacy of adjuvant dexamethasone in HSVE.
Introduction:
Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE.
Methods:
The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months.
Results:
The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing).
Conclusion:
GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions.
Trial Registration:
EudraCT-Nr. 2005-003201-81.
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