Aciclovir Versus Placebo for HSV-2 Meningitis (AMEN)

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

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

Study Overview

• Status: Not yet recruiting
• Conditions: Herpes Simplex 2; Meningitis, Viral
• Intervention / Treatment: Drug: Acyclovir 50 MG/ML; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jacob Bodilsen, MD; Phone Number: 004597663920; Email: jacob.bodilsen@rn.dk
• Study Contact Backup: Name: Henrik Nielsen, Professor; Phone Number: 004597663920; Email: henrik.nielsen@rn.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Adults ≥18 years of age admitted on suspicion of viral meningitis defined as:

  1. A clinical presentation consistent with viral meningitis (e.g. headache, nuchal rigidity, photophobia, or fever) AND
  2. Cerebrospinal fluid (CSF) pleocytosis (>4 leukocytes x 106/L) AND
  3. HSV-2 positive by PCR of the CSF
  4. Glasgow Coma Scale score of 15 AND
  5. Ability to absorb oral medications

Exclusion Criteria:

• Patients fulfilling any of the following criteria will be excluded:

  1. Encephalitis as defined by the International Encephalitis Consortium if diagnosed during standard care (see Glossary)20
  2. Transverse myelitis as defined by the Transverse Myelitis Consortium Working Group if diagnosed during standard care (see Glossary)21
  3. 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
  4. Moderate to severe concomitant genital herpes requiring systemic aciclovir
  5. Pregnancy (proven by positive urine or plasma human chorionic gonadotropin test in fertile women)
  6. Hepatic impairment (aspartate aminotransferase or alanine aminotransferase levels >5 times the upper limit of normal)
  7. Impaired renal function (estimated glomerular filtration rate <25 mL/min)
  8. Intolerance to (val)aciclovir
  9. Probenecid treatment
  10. Systemic antiviral therapy with an antiherpetic effect for >24 hours
  11. Previous enrolment into this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active arm; 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; 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.; Other Names: Valacyclovir
Placebo Comparator: Placebo; Randomisation to 7 days of IV and/or oral placebo.	Drug: Placebo; Placebo either in IV formulation or as tablets identical to valacyclovir tablets.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jacob Bodilsen

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: July 1, 2022
• First Submitted That Met QC Criteria: July 11, 2022
• First Posted (Actual): July 12, 2022

Study Record Updates

• Last Update Posted (Estimated): October 1, 2025
• Last Update Submitted That Met QC Criteria: September 30, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: meningitis; valacyclovir; HSV-2; acyclovir; aseptic meningitis; valaciclovir; Herpes simplex 2; viral meningitis; aciclovir
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Virus Diseases; Central Nervous System Viral Diseases; Central Nervous System Infections; Meningitis; Meningitis, Viral; Meningitis, Aseptic; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Guanine; Hypoxanthines; Purinones; Purines; Valacyclovir; Acyclovir
• Other Study ID Numbers: AMEN1; 2020-000033-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be deposited at Mendeley Data (https://data.mendeley.com/).
• IPD Sharing Time Frame: Beginning six months and ending three years after publication, an anonymized dataset can be shared.
• IPD Sharing Access Criteria: Qualified researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No