Table 1 Trial synopsis

Indication

Herpes-simplex-virus-encephalitis

Trial locations

Departments of Neurology of academic medical centers in Germany, Austria and the Netherlands.

Design

Multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with herpes-encephalitis. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaption in the last stage.

Objectives

The purpose of this study is to assess the efficacy and safety of adjuvant dexamethasone in the treatment of adult patients with herpes-encephalitis.

Eligibility criteria – inclusion

Proven herpes-encephalitis (positive HSV-DNA-PCR); age 18–85; focal neurological signs not longer than 5 days prior to admission, informed consent, women of childbearing potential: negative pregnancy testing in urine.

Eligibility criteria – exclusion

History of hypersensitivity to corticosteroids, systemic corticosteroid treatment within the last 6 months or at present time, two fixed dilated pupils, pre-event score mRS >2 or Barthel Index<95, pregnancy, breast feeding women, recent history of active tuberculosis or systemic fungal infection, recent head trauma/neurosurgery/peptic ulcer disease, life expectancy < 3 years, other serious illness that confound treatment assessment, simultaneous participation in another clinical trial, previous participation in another clinical trial in the last 30 days, previous participation in this clinical trial, women of childbearing potential who are not using a highly effective birth control method, acute viral infections other than HSVE (herpes zoster, poliomyelitis, chickenpox), Hepatitis B surface Antigen (HBsAg)-positive chronic active hepatitis, approximately eight weeks before to two weeks after prophylactic vaccination, lymphadenitis following Bacille Calmette Guérin (BCG) vaccination.

Treatment

Experimental Group: 10 mg/kg BW acyclovir (i.v., 1 hour infusion) every 8 hours for 14 days (Dosage adaptation in case of decreased creatinine clearance) + dexamethasone 40 mg intravenously every 24 hours for 4 days

Control Group: 10 mg/kg BW acyclovir (i.v., 1 hour infusion) every 8 hours for 14 days (Dosage adaptation in case of decreased creatinine clearance) + Placebo every 24 hours for 4 days

Endpoints

Primary Endpoint: Binary functional outcome after 6 months measured by the modified Rankin scale (mRS), a seven-point-scale 0 – 6. A mRS-score of 3 to 6 will be seen as an unfavourable outcome.

Secondary endpoints: Mortality after 6 and 12 months, functional outcome after 6 months measured by Glasgow outcome scale (GOS) and quality of life (EuroQol 5D), functional outcome after 12 months (mRS, GOS) and quality of life (EuroQol 5D), neuropsychological testing after 6 months, cranial MRI findings after 6 months, Seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months.

Examinations/Follow-up

Day 0, 7, at discharge (at the latest at day 30), 6 months and 12 months after randomization.

Sample size

372 patients, potential sample size extension after the second interim analysis up to a maximum of 450 patients

Trial duration:

9 years: 2 years and 6 months preparation, 5 years and 6 months recruitment, 1 year follow-up.

Steering committee

Prof. Dr. Uta Meyding-Lamadé; Department of Neurology, Krankenhaus Nordwest, Frankfurt am Main

Prof. Dr. W. Hacke, Director, Department of Neurology, University of Heidelberg

Prof. Dr. N. Victor, Director, Institute of Medical Biometry and Informatics, University of Heidelberg