AMEN: Aciclovir Versus Placebo for HSV-2 Meningitis

Sponsor

Jacob Bodilsen (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05452928

Collaborator

(none)

150

Enrollment

Arms

Anticipated Duration (Months)

Study Details

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

Condition or Disease	Intervention/Treatment	Phase
Herpes Simplex 2 Meningitis, Viral	Drug: Acyclovir 50 MG/ML Drug: Placebo	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes 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).

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2022

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

Jun 1, 2028

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Primary endpoint (proportion with a Total Morbidity Score) [7 days since randomisation]
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) [7 days since randomisation]
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 [7 days, 3 months, and 12 months since randomisation]
Extended Glasgow outcome scale score. Range 1 to 8 with higher scores indicating better outcome.
Secondary endpoint 3 All-cause mortality [7 days, 3 months, and 12 months since randomisation]
All-cause mortality
Secondary endpoint 4 EQ-5D-5L [7 days, 3 months, and 12 months since randomisation]
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 [7 days, 3 months, and 12 months since randomisation]
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) [7 days, 3 months, and 12 months since randomisation]
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 [7 days, 3 months, and 12 months since randomisation]
Any new neurological deficit reported by patient or observed during clinical examination
Secondary outcome 8 Completion of assigned treatment [7 days since randomisation]
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 [7 days since randomisation]
Peripheral venous line associated complications (i.e. catheter-associated infection, thrombosis, or haemorrhage).
Secondary outcome 10Severe adverse events [7 days since randomisation]
Severe adverse events, i.e. incident treatment-emergent serious adverse events.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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