Condition category
Infections and Infestations
Date applied
22/08/2005
Date assigned
04/10/2005
Last edited
19/10/2011
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Prof Heikki Peltola

ORCID ID

Contact details

POB 281
Hospital for Children and Adolescents
Helsinki
00290
Finland
heikki.peltola@hus.fi

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

1

Study information

Scientific title

Acronym

BOL/INFLU-PARA/PLA

Study hypothesis

1. Can the prognosis of childhood Bacterial Meningitis (BM) be improved by instituting beeta-lactam such as cefotaxime with a slow infusion, instead of giving traditionally large doses intermittently from the early beginning?
2. Can the prognosis be further improved by large doses of paracetamol?
3. To which extent is the prognosis of BM affected by the host response and Cerebrospinal Fluid (CSF) genome count and serotype, paying special attention to Streptococcus pneumoniae?

Please note that as of 22nd January 2008 an update has been performed on this trial record. Any changes to the trial record can be found under the date 22/01/2008 in the specific section.

Ethics approval

Added as of 22/01/2008:
Approval of the protocol: June 2005
Approval of the amended protocol: 21 December 2007

The data Safety and Monitoring Board is formed by Dr Heinz-J. Schmitt, Professor of Pediatric Infectious Diseases at Johannes Gutenberg University, Mainz, and two clinical statisticians, Dr R¨¹diger von Kries, Professor of Pediatrics and Chief of the Department of Pediatric and Adolescent Epidemiology, Ludwig Maximilian University, Munich, and Dr Jean Baptiste du Prel, Johannes Gutenberg University, Mainz. The Board's responsibility is to follow-up the study from the ethical and scientific points of view, and it has an access to the treatment codes at any time. If an indisputable significance between groups is met before the study ends, the team interrupts the trial for ethical reasons.

After the first 50 - 100 enrolled patients, the Board will check the accuracy of the study. Thereafter, the situation is checked every six months.

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Childhood bacterial meningitis

Intervention

All children will receive cefotaxime 250 mg/kg/day for seven days, except salmonella meningitis for which antimicrobial treatment should last for 14 days or more. Regardless of etiology, the children are randomised in a double-blind fashion in two groups for the first 24 hours: 50% receive cefotaxime in two 12-hour infusions, the other 50% getting cefotaxime in four boluses.

Added as of 22/01/2008:
In addition to the intervention of cefotaxime bolus versus cefotaxime infusions:
During the first 48 hours, 50% of the patients are randomised to receive high dose paracetamol (first dose 30 mg/kg, then 20 mg/kg every six hours for 42 hours) and the other 50% an oral placebo.

Thus the four treatment alternatives are:
1. Cefotaxime boluses + oral high dose paracetamol
2. Cefotaxime boluses + oral placebo
3. Cefotaxime infusions + oral high dose paracetamol
4. Cefotaxime infusions + oral placebo

Analysis plan:
Analysis by intention to treat will include all children in whom bacterial meningitis was suggested and a study medication was instituted. The patients in whom meningitis was confirmed (greater than or equal to 1 diagnostic criterium fulfilled) will be analysed per protocol.

Chi square test is used to test potential differences in the primary endpoints comparing the groups of infusion versus bolus dosing, and those receiving versus not receiving paracetamol. The secondary endpoints are examined similarly.

Intervention type

Drug

Phase

Not Specified

Drug names

Cefotaxime, paracetamol

Primary outcome measures

Current primary endpoints as of 22/01/2008:
1. Death (measuring the exact time from institution of antimicrobial) OR severe neurological sequelae (blindness, quadriplegia, hydrocephalus requiring a shunt, or severe psychomotor retardation) at discharge
2. Profound hearing loss (more than 80 dB in both ears) at discharge

Previous primary endpoints:
1. Death (measuring the exact time from institution of antimicrobial)
2. Severe neurological sequelae (blindness, quadriplegia, hydrocephalus requiring a shunt, or severe psychomotor retardation)
3. Profound hearing loss (more than 80 dB in both ears), as found at discharge from hospital and dismal outcome denotes death, severe neurological sequelae and/or profound hearing loss.

Because severe neurological sequelae and death may form a continuum, their combination is taken as a composite endpoint. Various patient characteristics are taken into account as covariates, those being essentially the age, etiology (pneumococcus, Hib, meningococcus, other agents, and unidentified etiology), blood hemoglobin level, potential HIV- and/or malaria-infection, and the presenting status. This is graded by Glasgow Coma Scale (adjusted for age), the Blantyre Coma Scale, and the Herson-Todd Score. Also blood hemoglobin concentration will be related to the outcome, which is assessed with the modified Glasgow Outcome Scale.

Secondary outcome measures

Current secondary endpoints as of 22/01/2008:
1. Death or any audiological or any neurological sequelae: any neurological sequelae are, in addition to severe neurological sequelae : hemiparesis, monoparesis moderate psychomotor retardation, or ataxia. Psychomotor retardation is graded by (according to the Denver-II developmental screening test). Hearing is deemed impaired if a threshold of 40 dB remains unrecognized by the better ear, the cut-off levels for moderate and severe hearing impairment being 60 dB and 80 dB, respectively
2. Glasgow Outcome Scale
3. Potential differences in the indices of inflammation such as serum C-reactive protein (CRP) will also be examined

Previous secondary endpoints:
The secondary endpoints comprise any audiological or neurological sequelae (according to
the Denver-II developmental screening test). Hearing is deemed impaired if a threshold of 40 dB is not recognized by the better ear. The cut-off levels for moderate and severe hearing impairment are 60 dB and 80 dB, respectively. Potential differences in the indices of inflammation such as serum C-Reactive Protein (CRP) will also be examined.

Overall trial start date

27/06/2005

Overall trial end date

30/12/2008

Reason abandoned

Eligibility

Participant inclusion criteria

[Added as of 22/01/2008: All children aged at least 2 months with suspected or confirmed bacterial meningitis.]

Diagnosis:
BM is defined as a case with:
1. Positive CSF culture, or
2. Symptoms and signs compatible with bacterial meningitis, and positive blood culture, or
3. Symptoms and signs compatible with bacterial meningitis, and at least two of the following criteria:
3.1. CSF pleocytosis more than or equal to 100 cells/mm^3
3.2. A positive Gram-stain result
3.3. Positive latex agglutination test
3.4. Serum C-Reactive Protein (CRP) more than or equal to 40 mg/l, or
4. Symptoms and signs compatible with bacterial meningitis, and positive CSF antigen detection by Polymerase Chain Reaction (PCR)

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

750 (No. of patients enrolled 05/10/07: 600)

Participant exclusion criteria

The exclusion criteria comprise the age less than two months, trauma, or relevant underlying illness such as intracranial shunt, previous neurological disease (cerebral palsy, Down's syndrome, meningitis), previous hearing impairment if known, and immunosuppression, except Human Immunodeficiency Virus (HIV) infection.

Recruitment start date

27/06/2005

Recruitment end date

30/12/2008

Locations

Countries of recruitment

Angola

Trial participating centre

POB 281
Helsinki
00290
Finland

Sponsor information

Organisation

Luanda Hospital (Angola)

Sponsor details

Hospital Pediatrico
Universidade Agostinho Neto
Faculdade de Medicina
Departamento de Pediatria
Luanda
C.P. 3067
Angola
+88 244 924 181 555
lbernandino@netangola.com

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Research organisation

Funder name

The Pediatric Research Foundation (Finland)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Sigrid Juselius Foundation (Finland)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Helsinki University Central Hospital Research (Finland)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2011 results in http://www.ncbi.nlm.nih.gov/pubmed/21550313

Publication citations

  1. Results

    Pelkonen T, Roine I, Cruzeiro ML, Pitkäranta A, Kataja M, Peltola H, Slow initial β-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial., Lancet Infect Dis, 2011, 11, 8, 613-621, doi: 10.1016/S1473-3099(11)70055-X.

Additional files

Editorial Notes