Bacterial Meningitis
Conditions
Keywords
Bacterial meningitis, infusion, bolus, paracetamol
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.
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.
Interventions
DRUGInfusion 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.
DRUGBolus 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.
Sponsors
Foundation for Paediatric Research, Finland
University of Helsinki
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Months to 15 Years
Healthy volunteers
No
Inclusion 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:
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Day 7 Mortality | 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
| Measure | Time frame | Description |
|---|---|---|
| Status on the Modified Glasgow Outcome Scale | 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. |
| Death or Any Neurological Sequelae on Day 7 | 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. |
| A Change in Hearing Threshold Compared to the First Test Result | 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. |
| All Deaths During Hospital Stay | 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. |
| Number of Participants With Deafness | 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. |
| Death or Any Neurological Sequelae at Discharge From Hospital. | 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. |
| Death or Severe Neurological Sequelae at Discharge | 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 |
| Death or Severe Neurological Sequelae on Day 7 | 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 |
Countries
Angola
Participant flow
Recruitment details
1128 patients were assessed for eligibility at the Hospital´s Emergency Service from Jan 2012 to Jan 2017. 753 were excluded and 375 enrolled and randomized.
Participants by arm
| Arm | Count |
|---|---|
| Infusion With Paracetamol Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen)
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. | 188 |
| Bolus With Placebo Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol
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. | 187 |
| Total | 375 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Additional antibiotic treatment | 1 | 2 |
| Overall Study | Died before treatment initiation | 1 | 1 |
| Overall Study | Not BM. Other treatment | 3 | 1 |
| Overall Study | Open nasogastric tube | 9 | 7 |
| Overall Study | Treatment doses missing | 8 | 12 |
Baseline characteristics
| Characteristic | Infusion With Paracetamol | Total | Bolus With Placebo |
|---|---|---|---|
| Age, Continuous | 43.6 months STANDARD_DEVIATION 42 | 44.6 months STANDARD_DEVIATION 42.9 | 45.7 months STANDARD_DEVIATION 43.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 188 Participants | 375 Participants | 187 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 179 Participants | 357 Participants | 178 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 18 Participants | 9 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Angola | 188 Participants | 375 Participants | 187 Participants |
| Sex: Female, Male Female | 87 Participants | 158 Participants | 71 Participants |
| Sex: Female, Male Male | 101 Participants | 217 Participants | 116 Participants |
| Weight-for-age, Z-score | -1.179 Z-score STANDARD_DEVIATION 1.376 | -1.209 Z-score STANDARD_DEVIATION 1.4 | -1.239 Z-score STANDARD_DEVIATION 1.426 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 72 / 188 | 76 / 187 |
| other Total, other adverse events | 0 / 188 | 0 / 187 |
| serious Total, serious adverse events | 0 / 188 | 0 / 187 |
Outcome results
Primary
Day 7 Mortality
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.
Time frame: On day 7 from the institution of treatment
Population: All participants who received at least one dose of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infusion With Paracetamol | Day 7 Mortality | 61 Participants |
| Bolus With Placebo | Day 7 Mortality | 64 Participants |
Secondary
A Change in Hearing Threshold Compared to the First Test Result
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.
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.
Population: We were finally able to perform post-treatment audiological examinations in solely 37 participants, and 10 of these lacked primary audiological examinations. Thus, this outcome is reported for 27 participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infusion With Paracetamol | A Change in Hearing Threshold Compared to the First Test Result | 0 dB |
| Bolus With Placebo | A Change in Hearing Threshold Compared to the First Test Result | 0 dB |
Secondary
All Deaths During Hospital Stay
All patients who had received at least one dose of treatment and died during the 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.
Population: All patients who had received at least one dose of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infusion With Paracetamol | All Deaths During Hospital Stay | 71 Participants |
| Bolus With Placebo | All Deaths During Hospital Stay | 75 Participants |
Secondary
Death or Any Neurological Sequelae at Discharge From Hospital.
Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.
Time frame: Examined at discharge from hospital. The longest hospital stay was 84 days.
Population: All patients who hade received at least one dose of treatment, and of whom information on any neurological sequelae was available at discharge from hospital.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infusion With Paracetamol | Death or Any Neurological Sequelae at Discharge From Hospital. | 104 Participants |
| Bolus With Placebo | Death or Any Neurological Sequelae at Discharge From Hospital. | 89 Participants |
Secondary
Death or Any Neurological Sequelae on Day 7
Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.
Time frame: Examined on day 7 since institution of treatment.
Population: All patients who had received at least one dose of treatment, and from whom the information on any neurological sequelae was available on day 7.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infusion With Paracetamol | Death or Any Neurological Sequelae on Day 7 | 96 Participants |
| Bolus With Placebo | Death or Any Neurological Sequelae on Day 7 | 86 Participants |
Secondary
Death or Severe Neurological Sequelae at Discharge
Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation
Time frame: Examined at discharge from hospital. The longest hospital stay was 84 days.
Population: All patients who received at least one dose of treatment, and of whom information on severe neurological sequelae was available at discharge from hospital.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infusion With Paracetamol | Death or Severe Neurological Sequelae at Discharge | 90 Participants |
| Bolus With Placebo | Death or Severe Neurological Sequelae at Discharge | 85 Participants |
Secondary
Death or Severe Neurological Sequelae on Day 7
Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation
Time frame: Examined on day 7 since institution of treatment
Population: All patients who received at least one dose of treatment, and of whom information on severe neurological sequelae was available on day 7.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infusion With Paracetamol | Death or Severe Neurological Sequelae on Day 7 | 80 Participants |
| Bolus With Placebo | Death or Severe Neurological Sequelae on Day 7 | 75 Participants |
Secondary
Number of Participants With Deafness
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.
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.
Population: We were finally able to perform post-treatment audiological examinations in solely 37 participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infusion With Paracetamol | Number of Participants With Deafness | 3 Participants |
| Bolus With Placebo | Number of Participants With Deafness | 1 Participants |
Secondary
Status on the Modified Glasgow Outcome Scale
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.
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.
Population: We were finally able to perform post-treatment audiological examinations in solely 37 participants, of whom one lacked information on the neurological outcome. Thus, the Glasgow Outcome Scale score could be estimated for 36 participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infusion With Paracetamol | Status on the Modified Glasgow Outcome Scale | 5 score on a scale |
| Bolus With Placebo | Status on the Modified Glasgow Outcome Scale | 5 score on a scale |