Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis

NCT ID: NCT01540838

Last Updated: 2019-09-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 375 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-29
• Study Completion Date: 2017-02-28

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.

Conditions

Bacterial Meningitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Infusion with paracetamol

Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen)

Group Type: EXPERIMENTAL

Infusion with paracetamol

Intervention Type: DRUG

The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.

Bolus with placebo

Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol

Group Type: ACTIVE_COMPARATOR

Bolus without paracetamol

Intervention Type: DRUG

The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.

Interventions

Infusion with paracetamol

The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.

Intervention Type: DRUG

Bolus without paracetamol

The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.

Intervention Type: DRUG

Other Intervention Names

paracetamol=acetaminophen; Paracetamol=acetaminophen

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 2 Months
• Maximum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Foundation for Paediatric Research, Finland

OTHER

Sponsor Role: collaborator

University of Helsinki

OTHER

Sponsor Role: lead

Responsible Party

Heikki Peltola, MD, PhD

Profesor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Heikki O Peltola, MD, PhD

Role: STUDY_DIRECTOR

Childrens Hospital of Helsinki University Central Hospital

Locations

Hospital Pediatrico David Bernardino

Luanda, , Angola

Countries

Angola

References

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.

Reference Type: BACKGROUND

PMID: 21550313 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35288394 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32246138 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

INFU/PARA-BOLU/PLACE

Identifier Type: -

Identifier Source: org_study_id