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Aciclovir Versus Placebo for HSV-2 Meningitis (AMEN)

Primary Purpose

Herpes Simplex 2, Meningitis, Viral

Status

Not yet recruiting

Phase

Phase 4

Locations

Study Type

Interventional

Intervention

Acyclovir 50 MG/ML

Placebo

About this trial

This is an interventional treatment trial for Herpes Simplex 2 focused on measuring meningitis, HSV-2, Herpes simplex 2, viral meningitis, aseptic meningitis, acyclovir, valacyclovir, aciclovir, valaciclovir

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Active arm

Placebo

Arm Description

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).

Randomisation to 7 days of IV and/or oral placebo.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Secondary endpoint 2 Extended Glasgow outcome scale score

Extended Glasgow outcome scale score. Range 1 to 8 with higher scores indicating better outcome.

Secondary endpoint 3 All-cause mortality

All-cause mortality

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.

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.

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.

Secondary outcome 7 neurological deficit

Any new neurological deficit reported by patient or observed during clinical examination

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.

Secondary outcome 9 complications

Peripheral venous line associated complications (i.e. catheter-associated infection, thrombosis, or haemorrhage).

Secondary outcome 10Severe adverse events

Severe adverse events, i.e. incident treatment-emergent serious adverse events.

Full Information

NCT ID

NCT05452928

First Posted

July 1, 2022

Last Updated

January 30, 2023

Sponsor

Jacob Bodilsen

1. Study Identification

Unique Protocol Identification Number

NCT05452928

Brief Title

Aciclovir Versus Placebo for HSV-2 Meningitis

Acronym

AMEN

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Not yet recruiting

Study Start Date

January 1, 2024 (Anticipated)

Primary Completion Date

June 1, 2027 (Anticipated)

Study Completion Date

June 1, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Jacob Bodilsen

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Herpes Simplex 2, Meningitis, Viral

Keywords

meningitis, HSV-2, Herpes simplex 2, viral meningitis, aseptic meningitis, acyclovir, valacyclovir, aciclovir, valaciclovir

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

Investigator initiated, double-blind, 2-arm (1:1 allocation), international, multicentre, parallel group, randomised, placebo controlled, superiority trial.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

We will use a centralised internet-based computer-generated randomisation schedule prepared and overseen by an experienced statistician. Patients will be randomised in a 1:1 ratio in permuted blocks of two to six and stratified by country, sex, and adjunctive dexamethasone treatment (yes/no).

Allocation

Randomized

Enrollment

150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Active arm

Arm Type

Active Comparator

Arm Description

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).

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Randomisation to 7 days of IV and/or oral placebo.

Intervention Type

Drug

Intervention Name(s)

Acyclovir 50 MG/ML

Other Intervention Name(s)

Valacyclovir

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo either in IV formulation or as tablets identical to valacyclovir tablets.

Primary Outcome Measure Information:

Title

Primary endpoint (proportion with a Total Morbidity Score)

Description

Time Frame

7 days since randomisation

Secondary Outcome Measure Information:

Title

Secondary endpoint 1 (Proportion of patients with ≤50% reduction of Total Morbidity Score)

Description

Proportion of patients with ≤50% reduction of Total Morbidity Score since randomisation. Please see characterization of score under primary endpoint.

Time Frame

7 days since randomisation

Title

Secondary endpoint 2 Extended Glasgow outcome scale score

Description

Extended Glasgow outcome scale score. Range 1 to 8 with higher scores indicating better outcome.

Time Frame