Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis (INFU/PARA)
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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. |
- Mortality [ Time Frame: On day 7 from the institution of treatment ] [ Designated as safety issue: Yes ]All patients should stay in hospital ≥7 days.
- 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 |
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:
- Trauma, or relevant underlying illness such as intracranial shunt, previous neurological abnormality (cerebral palsy, Down's syndrome, meningitis)
- Previous hearing impairment (if known)
- Immunosuppression, except HIV infection
- More than one parenteral dose of a pretreatment antimicrobial. Children with oral antimicrobials are included, this information being marked in the FOLLOW-UP sheet.
- Active tuberculosis (if tuberculotic meningitis is diagnosed during trial, it will be included in intention-to-treat (ITT) analysis)
- Known hepatic disease.
Contacts and Locations| Contact: Irmeli R Roine, MD, PhD | +56-2-6768707 | irmeli.roine@gmail.com |
| Contact: Tuula I Pelkonen, MD, PhD | +358-50-4140758 | tuula.pelkonen@hotmail.com |
| 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 | |
| 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 4, 2012 |
| Health Authority: | Finland: Data Protection Board |
Keywords provided by Helsinki University:
|
Bacterial meningitis infusion bolus paracetamol |
Additional relevant MeSH terms:
|
Meningitis Meningitis, Pneumococcal Meningitis, Bacterial Central Nervous System Infections Central Nervous System Diseases Nervous System Diseases Central Nervous System Bacterial Infections Bacterial Infections Pneumococcal 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 May 23, 2013