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

September 22, 2019 updated by: Heikki Peltola, MD, PhD, University of Helsinki

Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis, Especially of Pneumococcal Meningitis, in Angola.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

375

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Angola
      • Luanda, Angola
        • Hospital Pediátrico David Bernardino

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 months to 15 years (CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Infusion with paracetamol
Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen)
Drug: 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.
Other Names:
  • paracetamol=acetaminophen
ACTIVE_COMPARATOR: Bolus with placebo
Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol
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.
Other Names:
  • Paracetamol=acetaminophen

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Day 7 Mortality
Time Frame: On day 7 from the institution of treatment
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.
On day 7 from the institution of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All Deaths During 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.
All patients who had received at least one dose of treatment and died during the hospital stay.
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.
Status on the Modified Glasgow Outcome Scale
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.

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.
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.
Death or Any Neurological Sequelae on Day 7
Time Frame: Examined on day 7 since institution of treatment.
Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.
Examined on day 7 since institution of treatment.
A Change in Hearing Threshold Compared to the First Test Result
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.
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.
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.
Death or Severe Neurological Sequelae on Day 7
Time Frame: Examined on day 7 since institution of treatment
Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation
Examined on day 7 since institution of treatment
Number of Participants With Deafness
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.
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.
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.
Death or Any Neurological Sequelae at Discharge From Hospital.
Time Frame: Examined at discharge from hospital. The longest hospital stay was 84 days.
Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.
Examined at discharge from hospital. The longest hospital stay was 84 days.
Death or Severe Neurological Sequelae at Discharge
Time Frame: Examined at discharge from hospital. The longest hospital stay was 84 days.
Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation
Examined at discharge from hospital. The longest hospital stay was 84 days.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Helsinki

Collaborators

Foundation for Paediatric Research, Finland

Investigators

  • Study Director: Heikki O Peltola, MD, PhD, Childrens Hospital of Helsinki University Central Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

February 1, 2012

Primary Completion (ACTUAL)

February 1, 2017

Study Completion (ACTUAL)

February 1, 2017

Study Registration Dates

First Submitted

February 23, 2012

First Submitted That Met QC Criteria

February 28, 2012

First Posted (ESTIMATE)

February 29, 2012

Study Record Updates

Last Update Posted (ACTUAL)

September 24, 2019

Last Update Submitted That Met QC Criteria

September 22, 2019

Last Verified

September 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • INFU/PARA-BOLU/PLACE

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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