Aciclovir Versus Placebo for HSV-2 Meningitis

Study Overview
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Brief Summary
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To determine whether active treatment with (val)acyclovir is superior for treatment of viral meningitis compared with placebo assessed by numbers meeting a primary, objective endpoint at 7 days after randomisation

Official Title
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Aciclovir for HSV-2 Meningitis: A Double-blind Randomised Controlled Trial (AMEN)

Conditions
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Herpes Simplex 2, Meningitis, Viral

Intervention / Treatment
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* Drug: Acyclovir 50 MG/ML
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥18 years of age admitted on suspicion of viral meningitis defined as: A clinical presentation consistent with viral meningitis (e.g. headache, nuchal rigidity, photophobia, or fever) AND Cerebrospinal fluid (CSF) pleocytosis (>4 leukocytes x 106/L) AND HSV-2 positive by PCR of the CSF Glasgow Coma Scale score of 15 AND Ability to absorb oral medications Exclusion Criteria: Patients fulfilling any of the following criteria will be excluded: Encephalitis as defined by the International Encephalitis Consortium if diagnosed during standard care (see Glossary)20 Transverse myelitis as defined by the Transverse Myelitis Consortium Working Group if diagnosed during standard care (see Glossary)21 Severe immuno-compromise defined as an ongoing need for biological- or chemotherapy (e.g. natalizumab), prednisolone >20 mg/day for ≥14 days, uncontrolled HIV/AIDS (see glossary), haematological malignancies, and organ transplant recipients14,18,22 Moderate to severe concomitant genital herpes requiring systemic aciclovir Pregnancy (proven by positive urine or plasma human chorionic gonadotropin test in fertile women) Hepatic impairment (aspartate aminotransferase or alanine aminotransferase levels >5 times the upper limit of normal) Impaired renal function (estimated glomerular filtration rate <25 mL/min) Intolerance to (val)aciclovir Probenecid treatment Systemic antiviral therapy with an antiherpetic effect for >24 hours Previous enrolment into this trial
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Investigator initiated, double-blind, 2-arm (1:1 allocation), international, multicentre, parallel group, randomised, placebo controlled, superiority trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active arm<br>Randomisation to 7 days of active treatment with IV aciclovir 10 mg/kg q8h and possibility for oral step-down therapy with valaciclovir 1g q8h, or placebo (IV q8h and/or oral q8h). | Drug: Acyclovir 50 MG/ML<br>* Patients are randomised to active treatment with IV acyclovir with the possibility of step-down to valacyclovir. If the treating physician prefers, initial IV treatment can be omitted and the patient can be treated with valacyclovir throughout the study period.<br>* Other names: Valacyclovir;|
| Placebo Comparator: Placebo<br>Randomisation to 7 days of IV and/or oral placebo. | Drug: Placebo<br>* Placebo either in IV formulation or as tablets identical to valacyclovir tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary endpoint (proportion with a Total Morbidity Score) | The proportion with a Total Morbidity Score (TMS) >6 is considered treatment failure. The score is a sum of scores for headache (range 0 to 6), nuchal rigidity (range 0 to 4), photophobia (range 0 to 4), myalgia (range 0 to 4), fever (range 0 to 4), nausea (range 0 to 4). The score thus ranges from 0 to 21 with higher scores indicating more severe symptoms. | 7 days since randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary endpoint 1 (Proportion of patients with ≤50% reduction of Total Morbidity Score) | Proportion of patients with ≤50% reduction of Total Morbidity Score since randomisation. Please see characterization of score under primary endpoint. | 7 days since randomisation | 
| Secondary endpoint 2 Extended Glasgow outcome scale score | Extended Glasgow outcome scale score. Range 1 to 8 with higher scores indicating better outcome. | 7 days, 3 months, and 12 months since randomisation | 
| Secondary endpoint 3 All-cause mortality | All-cause mortality | 7 days, 3 months, and 12 months since randomisation | 
| Secondary endpoint 4 EQ-5D-5L | EQ-5D-5L. Comprises 5 questions with an ordinal scale from 1 to 5 with higher scores indicating more morbidity. Finally, a visual analog score is filled ranging from 0 to 100 with higher scores indicating better health. | 7 days, 3 months, and 12 months since randomisation | 
| Secondary endpoint 5 Mental Fatigue Scale | Mental Fatigue Scale. Comprises 14 questions with scores from 0 to 3 with higher values suggesting more morbidity. A combined score >10.5 usually suggests mental fatigue problems. | 7 days, 3 months, and 12 months since randomisation | 
| Secondary endpoint 6 (SF-36) | Short Form Health Survey 36 (SF-36). Scores eight different domains from 0 to 100 with higher values indicating no disability. | 7 days, 3 months, and 12 months since randomisation | 
| Secondary outcome 7 neurological deficit | Any new neurological deficit reported by patient or observed during clinical examination | 7 days, 3 months, and 12 months since randomisation | 
| Secondary outcome 8 Completion of assigned treatment | Completion of assigned treatment (active or placebo) assessed by administered intravenous or oral treatment as signed off by nurses in hospitalized patients and pill counts for patients discharged with oral study drug. | 7 days since randomisation | 
| Secondary outcome 9 complications | Peripheral venous line associated complications (i.e. catheter-associated infection, thrombosis, or haemorrhage). | 7 days since randomisation | 
| Secondary outcome 10Severe adverse events | Severe adverse events, i.e. incident treatment-emergent serious adverse events. | 7 days since randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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meningitis, Herpes simplex 2, viral meningitis, aseptic meningitis, acyclovir, valacyclovir, aciclovir, valaciclovir, HSV-2