Herpes Simplex 2, Meningitis, Viral
Conditions
Keywords
meningitis, HSV-2, Herpes simplex 2, viral meningitis, aseptic meningitis, acyclovir, valacyclovir, aciclovir, valaciclovir
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
Interventions
DRUGAcyclovir 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.
DRUGPlacebo
Placebo either in IV formulation or as tablets identical to valacyclovir tablets.
Sponsors
Jacob Bodilsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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).
Intervention model description
Investigator initiated, double-blind, 2-arm (1:1 allocation), international, multicentre, parallel group, randomised, placebo controlled, superiority trial.
Eligibility
Sex/Gender
ALL
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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. |
| 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. |
Contacts
Primary ContactJacob Bodilsen, MD
Backup ContactHenrik Nielsen, Professor
Outcome results
None listed