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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Helsinki University
Sponsor:
Collaborator:
Foundation for Paediatric Research, Finland
Information provided by (Responsible Party):
Heikki Peltola, Helsinki University
ClinicalTrials.gov Identifier:
NCT01540838
First received: February 23, 2012
Last updated: September 3, 2013
Last verified: September 2013
  Purpose

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 Intervention Phase
Bacterial Meningitis
Drug: Infusion with paracetamol
Drug: Bolus without paracetamol
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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.

Resource links provided by NLM:


Further study details as provided by Helsinki University:

Primary Outcome Measures:
  • Mortality [ Time Frame: On day 7 from the institution of treatment ] [ Designated as safety issue: Yes ]
    All patients should stay in hospital ≥7 days.


Secondary Outcome Measures:
  • Mortality [ Time Frame: On days 14, 21, and 28 from the institution of treatment. ] [ Designated as safety issue: Yes ]
  • Status on the modified Glasgow Outcome Scale [ Time Frame: Examined on days 7, 14, 21, and 28 since institution of treatment ] [ Designated as safety issue: Yes ]
    Scores from 5 to 1

  • Death or any sequelae [ Time Frame: Examined on days 7, 14, 21, and 28 since institution of treatment ] [ Designated as safety issue: Yes ]
    Defined as any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree, or any hearing impairment. Hearing is deemed impaired if the better ear fails to detect a threshold of 40 dB. The cut-off levels for moderate and severe hearing impairment are 60 dB and 80 dB, respectively.

  • A change in hearing threshold compared to the first test result [ Time Frame: Examined on days 7, 14, 21, and 28 since instituion of treatment ] [ Designated as safety issue: Yes ]
    Hearing thresholds are determined by an independent observer on the bases of the BERA register, for each ear separately.

  • Death or severe neurological sequelae [ Time Frame: Examined on days 7, 14, 21 and 28 since institution of treatment ] [ Designated as safety issue: Yes ]
    Severe neurological sequelae are defined as blindness, tetraplegia/paresia, hydrocephalus requiering a shunt and severe prychomotor retardation

  • Deafness [ Time Frame: Examined on days 7, 14, 21 and 28 since initiation of treatment ] [ Designated as safety issue: Yes ]
    Defined as a hearing threshold >80dBs in the better ear.


Estimated Enrollment: 400
Study Start Date: February 2012
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   2 Months to 15 Years
Genders Eligible for Study:   Both
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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01540838

Contacts
Contact: Irmeli R Roine, MD, PhD +56-2-26762228 irmeli.roine@gmail.com
Contact: Tuula I Pelkonen, MD, PhD +358-50-4140758 tuula.pelkonen@hotmail.com

Locations
Angola
Hospital Pediatrico David Bernardino Recruiting
Luanda, Angola
Contact: Manuel Leite Cruzeiro, MD    +244-912-511017    mcruzeirol@gmail.com   
Principal Investigator: Manuel Leite Cruzeiro, MD         
Sponsors and Collaborators
Helsinki University
Foundation for Paediatric Research, Finland
Investigators
Study Director: Heikki O Peltola, MD, PhD Childrens Hospital of Helsinki University Central Hospital
  More Information

Publications:
Responsible Party: Heikki Peltola, Profesor, Helsinki University
ClinicalTrials.gov Identifier: NCT01540838     History of Changes
Other Study ID Numbers: INFU/PARA-BOLU/PLACE
Study First Received: February 23, 2012
Last Updated: September 3, 2013
Health Authority: Finland: Data Protection Board

Keywords provided by Helsinki University:
Bacterial meningitis
infusion
bolus
paracetamol

Additional relevant MeSH terms:
Pneumococcal Infections
Meningitis
Meningitis, Pneumococcal
Meningitis, Bacterial
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Bacterial Infections
Bacterial Infections
Streptococcal Infections
Gram-Positive Bacterial Infections
Acetaminophen
Antipyretics
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 20, 2014