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Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis (INFU/PARA)

Primary Purpose

Bacterial Meningitis

Status

Completed

Phase

Phase 4

Locations

Angola

Study Type

Interventional

Intervention

Infusion with paracetamol

Bolus without paracetamol

About this trial

This is an interventional treatment trial for Bacterial Meningitis focused on measuring Bacterial meningitis, infusion, bolus, paracetamol

Eligibility Criteria

2 Months - 15 Years (Child)All SexesDoes not accept healthy volunteers

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:

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

Sites / Locations

Hospital Pediatrico David Bernardino

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Infusion with paracetamol

Bolus with placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Day 7 Mortality

All patients who had received at least one dose of treatment and were dead on day 7 from the institution of treatment on day 1.

Secondary Outcome Measures

All Deaths During Hospital Stay

All patients who had received at least one dose of treatment and died during the hospital stay.

Status on the Modified Glasgow Outcome Scale

Scores on the modified Glasgow Outcome Scale which range from a maximum of 5 (best) to a minimum of 1 (worst) points. The Glasgow Outcome Scale categorizes the outcome after brain injury into five categories, based on the level and severeness of disability. As hearing impairment is one of the most common sequelae of bacterial meningitis, an assessment of hearing should be included when estimating the grade of disability. Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately.

Death or Any Neurological Sequelae on Day 7

Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.

A Change in Hearing Threshold Compared to the First Test Result

Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. The better ear's hearing threshold, obtained on admission or shortly thereafter, was compared with the better ear's hearing threshold obtained at earliest after one week of treatment.

Death or Severe Neurological Sequelae on Day 7

Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation

Number of Participants With Deafness

Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. Deafness was defined as a hearing threshold >80 dB in the better ear.

Death or Any Neurological Sequelae at Discharge From Hospital.

Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.

Death or Severe Neurological Sequelae at Discharge

Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation

Full Information

NCT ID

NCT01540838

First Posted

February 23, 2012

Last Updated

September 22, 2019

Sponsor

University of Helsinki

Collaborators

Foundation for Paediatric Research, Finland

1. Study Identification

Unique Protocol Identification Number

NCT01540838

Brief Title

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

Acronym

INFU/PARA

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

2. Study Status

Record Verification Date

September 2019

Overall Recruitment Status

Completed

Study Start Date

February 2012 (Actual)

Primary Completion Date

February 2017 (Actual)

Study Completion Date

February 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Helsinki

Collaborators

Foundation for Paediatric Research, Finland

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

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

Bacterial Meningitis

Keywords

Bacterial meningitis, infusion, bolus, paracetamol

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

375 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Infusion with paracetamol

Arm Type

Experimental

Arm Description

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

Arm Title

Bolus with placebo

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Infusion with paracetamol

Other Intervention Name(s)

paracetamol=acetaminophen

Intervention Description

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

Intervention Name(s)

Bolus without paracetamol

Other Intervention Name(s)

Paracetamol=acetaminophen

Intervention Description

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.

Primary Outcome Measure Information:

Title

Day 7 Mortality

Description

All patients who had received at least one dose of treatment and were dead on day 7 from the institution of treatment on day 1.

Time Frame

On day 7 from the institution of treatment

Secondary Outcome Measure Information:

Title

All Deaths During Hospital Stay

Description

All patients who had received at least one dose of treatment and died during the hospital stay.

Time Frame

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.

Title

Status on the Modified Glasgow Outcome Scale

Description

Time Frame

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.

Title

Death or Any Neurological Sequelae on Day 7

Description

Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.

Time Frame

Examined on day 7 since institution of treatment.

Title

A Change in Hearing Threshold Compared to the First Test Result

Description

Time Frame

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.

Title

Death or Severe Neurological Sequelae on Day 7

Description

Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation

Time Frame

Examined on day 7 since institution of treatment

Title

Number of Participants With Deafness

Description

Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. Deafness was defined as a hearing threshold >80 dB in the better ear.

Time Frame

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.

Title

Death or Any Neurological Sequelae at Discharge From Hospital.

Description

Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.

Time Frame

Examined at discharge from hospital. The longest hospital stay was 84 days.

Title

Death or Severe Neurological Sequelae at Discharge

Description

Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation

Time Frame

Examined at discharge from hospital. The longest hospital stay was 84 days.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Months

Maximum Age & Unit of Time

15 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Heikki O Peltola, MD, PhD

Organizational Affiliation

Childrens Hospital of Helsinki University Central Hospital

Official's Role

Study Director

Facility Information:

Facility Name

Hospital Pediatrico David Bernardino

City

Luanda

Country

Angola

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

We are working on an agreement to share data with all the participants,

Citations:

PubMed Identifier

21550313

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.

Results Reference

background

PubMed Identifier

35288394

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.

Results Reference

derived

PubMed Identifier

32246138

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.

Results Reference

derived

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

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