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| Name | Class |
|---|---|
| Foundation for Paediatric Research, Finland | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Infusion with paracetamol | Experimental | Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) |
|
| Bolus with placebo | Active Comparator | Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Infusion with paracetamol | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | On day 7 from the institution of treatment |
| Measure | Description | Time Frame |
|---|---|---|
| All Deaths During Hospital Stay | All patients who had received at least one dose of treatment and died during the 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. |
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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: Exclusion criteria
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Heikki O Peltola, MD, PhD | Childrens Hospital of Helsinki University Central Hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Pediatrico David Bernardino | Luanda | Angola |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21550313 | Background | Pelkonen T, Roine I, Cruzeiro ML, Pitkaranta A, Kataja M, Peltola H. Slow initial beta-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial. Lancet Infect Dis. 2011 Aug;11(8):613-21. doi: 10.1016/S1473-3099(11)70055-X. Epub 2011 May 5. | |
| 35288394 | Derived |
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We are working on an agreement to share data with all the participants,
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
ITT population
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | The exact age of one patient was unknown. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | All participants who received at least one dose of treatment. | Posted | Count of Participants | Participants | On day 7 from the institution of treatment |
|
During the patient´s hospital stay of at least 7 days until discharge. The longest hospital stay was 84 days.
No specific events or findings, a part from the follow up-data detailed in the protocol, were considered as potential adverse events to be registered because both death, serious sequelae, and/or prolonged hospital stay, given as examples of severe adverse events, are part of the possible course of childhood bacterial meningitis, as such.
Deaths and other follow-up data were assessed by attending physician.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Any adverse events | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Okko Savonius, PhD candidate | University of Helsinki, Children´s Hospital, Helsinki University Hospital | +358456731185 | okko.savonius@helsinki.fi |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 21, 2012 | Aug 19, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D016920 | Meningitis, Bacterial |
| ID | Term |
|---|---|
| D020806 | Central Nervous System Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
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|
|
| Bolus without paracetamol | Drug | 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. |
|
|
| 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. |
| 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. |
| 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. | Examined on day 7 since institution of treatment. |
| 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. | 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. |
| 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 | Examined on day 7 since institution of treatment |
| 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. | 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. |
| 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. | Examined at discharge from hospital. The longest hospital stay was 84 days. |
| 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 | Examined at discharge from hospital. The longest hospital stay was 84 days. |
| Pelkonen T, Roine I, Kallio M, Jahnukainen K, Peltola H. Prevalence and significance of anaemia in childhood bacterial meningitis: a secondary analysis of prospectively collected data from clinical trials in Finland, Latin America and Angola. BMJ Open. 2022 Mar 14;12(3):e057285. doi: 10.1136/bmjopen-2021-057285. |
| 32246138 | Derived | Savonius O, Rugemalira E, Roine I, Cruzeiro ML, Peltola H, Pelkonen T. Extended Continuous beta-Lactam Infusion With Oral Acetaminophen in Childhood Bacterial Meningitis: A Randomized, Double-blind Clinical Trial. Clin Infect Dis. 2021 May 18;72(10):1738-1744. doi: 10.1093/cid/ciaa341. |
| Additional antibiotic treatment |
|
| Died before treatment initiation |
|
| Not BM. Other treatment |
|
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| months |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Weight-for-age, Z-score | The Weight-for-age Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of a reference population. Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population. These data were calculated using the World Health Organisation (WHO) reference data. | Information on the exact age in months was missing from one patient, and the information on the exact weight was missing from one patient. | Mean | Standard Deviation | Z-score |
|
| 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. |
|
|
| Secondary | All Deaths During Hospital Stay | All patients who had received at least one dose of treatment and died during the hospital stay. | All patients who had received at least one dose of treatment. | Posted | Count of Participants | Participants | 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. |
|
|
|
| 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. | 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. | Posted | Median | Inter-Quartile Range | score on a 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. |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | Examined on day 7 since institution of treatment. |
|
|
|
| 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. | 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. | Posted | Median | Inter-Quartile Range | dB | 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. |
|
|
|
| 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 | All patients who received at least one dose of treatment, and of whom information on severe neurological sequelae was available on day 7. | Posted | Count of Participants | Participants | Examined on day 7 since institution of treatment |
|
|
|
| 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. | We were finally able to perform post-treatment audiological examinations in solely 37 participants. | Posted | Count of Participants | Participants | 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. |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | Examined at discharge from hospital. The longest hospital stay was 84 days. |
|
|
|
| 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 | All patients who received at least one dose of treatment, and of whom information on severe neurological sequelae was available at discharge from hospital. | Posted | Count of Participants | Participants | Examined at discharge from hospital. The longest hospital stay was 84 days. |
|
|
|
| 72 |
| 188 |
| 0 |
| 188 |
| 0 |
| 188 |
| EG001 | 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. | 76 | 187 | 0 | 187 | 0 | 187 |
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| D002494 | Central Nervous System Infections |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008581 | Meningitis |
| D000090862 | Neuroinflammatory Diseases |
| Aniline Compounds |
| D000588 | Amines |
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|