Clinical trial NCT01540838: Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis
Official title: Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis, Especially of Pneumococcal Meningitis, in Angola.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Bacterial Meningitis
Keywords: Bacterial meningitis
infusion
bolus
paracetamol
Lead sponsor: University of Helsinki
Sponsor class: OTHER
Collaborators: name: Foundation for Paediatric Research, Finland
First posted: 2012-02-29
Enrollment: 375
Sex: ALL
Minimum age (years): 2
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main purpose of this trial is to test if mortality of childhood bacterial meningitis can be reduced by slow, continuous infusion of cefotaxime initially, instead of the traditional bolus administration four times daily (qid), combined with high-dose paracetamol orally, when both treatments are executed for the first 4 days. The series will be collected at Hospital Pediátrico David Bernardino, Luanda, Angola.

The recruitment of patients begins, the conditions permitting, in early 2012. The criteria for patient participation is a child at the age of 2 months to 15 years who presents with the symptoms and signs suggestive of bacterial meningitis, for whom a lumbar puncture is performed, and the cerebrospinal fluid analysis suggests bacterial meningitis.

Detailed description: The principal objective of the study is to examine if mortality of childhood bacterial meningitis can be reduced by slow continuous infusion of cefotaxime combined with high-dose paracetamol orally for the first 4 days (instead of the traditional qid administration of cefotaxime without concomitant paracetamol). Children qualifying for entry (see criteria below), whose guardian has given informed consent,will be randomized into 2 treatment arms (see details below)and receive the treatments in a double blind fashion (see details below). Primary and secondary outcomes (detailed below) will be evaluated according to predefined criteria and time points (see below).

Results will be analyzed for all patients in ITT datasets and in prespecified subgroups (etiology, nutritional status, etc.) in both crude and adjusted analysis. The efficacy results will be expressed as OR with 95% confidence intervals.

Eligibility criteria: Eligibility criteria:

The study entry is assessed for all children at age 2 months - 15 years who present at these centers with the symptoms and signs suggestive of bacterial meningitis (BM), and to whom lumbar puncture is performed.

Inclusion criteria:

All patients whose cerebrospinal fluid (CSF) turns out to be cloudy, positive by Gram staining or latex agglutination, or shows at least 50 leukocytes per mm3, will be enrolled in the study.

Participants: Exclusion criteria

Exclusion criteria:

1. Trauma, or relevant underlying illness such as intracranial shunt, previous neurological abnormality (cerebral palsy, Down's syndrome, meningitis)
2. Previous hearing impairment (if known)
3. Immunosuppression, except HIV infection
4. More than one parenteral dose of a pretreatment antimicrobial. Children with oral antimicrobials are included, this information being marked in the FOLLOW-UP sheet.
5. Active tuberculosis (if tuberculotic meningitis is diagnosed during trial, it will be included in intention-to-treat (ITT) analysis)
6. Known hepatic disease.

Primary outcomes:
measure: Day 7 Mortality
timeFrame: On day 7 from the institution of treatment
Secondary outcomes:
measure: All Deaths During Hospital Stay
timeFrame: The outcome was assessed each day until the patient was discharged from the hospital. The longest hospital stay was 84 days, while the last death occurred 39 days after treatment initiation.
measure: Status on the Modified Glasgow Outcome Scale
timeFrame: Examined at discharge from hospital, except for hearing evaluations which were performed at earliest seven days since the institution of treatment, during the hospital stay. The longest hospital stay was 84 days.
measure: Death or Any Neurological Sequelae on Day 7
timeFrame: Examined on day 7 since institution of treatment.
measure: A Change in Hearing Threshold Compared to the First Test Result
timeFrame: Hearing thresholds obtained during any of the first three days after hospital admission were compared with hearing thresholds obtained on day seven or later, during the hospital stay. The longest hospital stay was 84 days.
measure: Death or Severe Neurological Sequelae on Day 7
timeFrame: Examined on day 7 since institution of treatment
measure: Number of Participants With Deafness
timeFrame: This outcome includes hearing thresholds determined at earliest seven days after the institution of treatment, during the hospital stay. The longest hospital stay was 84 days.
measure: Death or Any Neurological Sequelae at Discharge From Hospital.
timeFrame: Examined at discharge from hospital. The longest hospital stay was 84 days.
measure: Death or Severe Neurological Sequelae at Discharge
timeFrame: Examined at discharge from hospital. The longest hospital stay was 84 days.
Other outcomes:
Locations:
city: Luanda
country: Angola
facility: Hospital Pediatrico David Bernardino
Study officials:
affiliation: Childrens Hospital of Helsinki University Central Hospital
name: Heikki O Peltola, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Pelkonen T, Roine I, Cruzeiro ML, Pitkaranta A, Kataja M, Peltola H. Slow initial beta-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial. Lancet Infect Dis. 2011 Aug;11(8):613-21. doi: 10.1016/S1473-3099(11)70055-X. Epub 2011 May 5.
citation: Pelkonen T, Roine I, Kallio M, Jahnukainen K, Peltola H. Prevalence and significance of anaemia in childhood bacterial meningitis: a secondary analysis of prospectively collected data from clinical trials in Finland, Latin America and Angola. BMJ Open. 2022 Mar 14;12(3):e057285. doi: 10.1136/bmjopen-2021-057285.
citation: Savonius O, Rugemalira E, Roine I, Cruzeiro ML, Peltola H, Pelkonen T. Extended Continuous beta-Lactam Infusion With Oral Acetaminophen in Childhood Bacterial Meningitis: A Randomized, Double-blind Clinical Trial. Clin Infect Dis. 2021 May 18;72(10):1738-1744. doi: 10.1093/cid/ciaa341.