Slow initial beeta-lactam infusion, and high-dose paracetamol to improve the prognosis of childhood bacterial meningitis, especially of pneumococcal meningitis
| ISRCTN | ISRCTN62824827 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN62824827 |
| Secondary identifying numbers | 1 |
- Submission date
- 22/08/2005
- Registration date
- 04/10/2005
- Last edited
- 19/10/2011
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Not provided at time of registration
Contact information
Prof Heikki Peltola
Scientific
Scientific
POB 281
Hospital for Children and Adolescents
Helsinki
00290
Finland
| heikki.peltola@hus.fi |
Study information
| Study design | Randomised controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Scientific title | |
| Study acronym | BOL/INFLU-PARA/PLA |
| Study objectives | 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(s) | 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. |
| Health condition(s) or problem(s) studied | 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 |
| Pharmaceutical study type(s) | |
| Phase | Not Specified |
| Drug / device / biological / vaccine name(s) | Cefotaxime, paracetamol |
| Primary outcome measure | 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 study start date | 27/06/2005 |
| Completion date | 30/12/2008 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 2 Months |
| Sex | Both |
| Target number of participants | 750 (No. of patients enrolled 05/10/07: 600) |
| Key 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) |
| Key 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. |
| Date of first enrolment | 27/06/2005 |
| Date of final enrolment | 30/12/2008 |
Locations
Countries of recruitment
- Angola
- Finland
Study participating centre
POB 281
Helsinki
00290
Finland
00290
Finland
Sponsor information
Luanda Hospital (Angola)
Hospital/treatment centre
Hospital/treatment centre
Hospital Pediatrico
Universidade Agostinho Neto
Faculdade de Medicina
Departamento de Pediatria
Luanda
C.P. 3067
Angola
| Phone | +88 244 924 181 555 |
|---|---|
| lbernandino@netangola.com |
Funders
Funder type
Research organisation
The Pediatric Research Foundation (Finland)
No information available
Sigrid Juselius Foundation (Finland)
No information available
Helsinki University Central Hospital Research (Finland)
No information available
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/08/2011 | Yes | No |
