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

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ClinicalTrials.gov Identifier: NCT01540838
Recruitment Status : Completed
First Posted : February 29, 2012
Results First Posted : September 24, 2019
Last Update Posted : September 24, 2019
Sponsor:
Collaborator:
Foundation for Paediatric Research, Finland
Information provided by (Responsible Party):
Heikki Peltola, MD, PhD, Helsinki University

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.


Condition or disease Intervention/treatment Phase
Bacterial Meningitis Drug: Infusion with paracetamol Drug: Bolus without paracetamol Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 375 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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.
Actual Study Start Date : February 2012
Actual Primary Completion Date : February 2017
Actual Study Completion Date : February 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Meningitis

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 Name: 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 Name: Paracetamol=acetaminophen




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.


  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Months to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01540838


Locations
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Angola
Hospital Pediatrico David Bernardino
Luanda, Angola
Sponsors and Collaborators
Helsinki University
Foundation for Paediatric Research, Finland
Investigators
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Study Director: Heikki O Peltola, MD, PhD Childrens Hospital of Helsinki University Central Hospital
  Study Documents (Full-Text)

Documents provided by Heikki Peltola, MD, PhD, Helsinki University:

Publications:
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Responsible Party: Heikki Peltola, MD, PhD, Profesor, Helsinki University
ClinicalTrials.gov Identifier: NCT01540838     History of Changes
Other Study ID Numbers: INFU/PARA-BOLU/PLACE
First Posted: February 29, 2012    Key Record Dates
Results First Posted: September 24, 2019
Last Update Posted: September 24, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: We are working on an agreement to share data with all the participants,
Keywords provided by Heikki Peltola, MD, PhD, Helsinki University:
Bacterial meningitis
infusion
bolus
paracetamol
Additional relevant MeSH terms:
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Meningitis, Bacterial
Cefoxitin
Meningitis
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Bacterial Infections
Bacterial Infections
Central Nervous System Infections
Acetaminophen
Lactams
Cefotaxime
beta-Lactams
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Anti-Bacterial Agents
Anti-Infective Agents