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Trial record 5 of 23 for:    "Bacterial Meningitis" | "Anti-Bacterial Agents"

Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis (INFU/PARA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01540838
Recruitment Status : Completed
First Posted : February 29, 2012
Results First Posted : September 24, 2019
Last Update Posted : September 24, 2019
Sponsor:
Collaborator:
Foundation for Paediatric Research, Finland
Information provided by (Responsible Party):
Heikki Peltola, MD, PhD, Helsinki University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Bacterial Meningitis
Interventions Drug: Infusion with paracetamol
Drug: Bolus without paracetamol
Enrollment 375
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.

Pre-assignment Details  
Arm/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description

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.

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.

Period Title: Overall Study
Started 188 187
Completed 166 164
Not Completed 22 23
Reason Not Completed
Open nasogastric tube             9             7
Treatment doses missing             8             12
Additional antibiotic treatment             1             2
Died before treatment initiation             1             1
Not BM. Other treatment             3             1
Arm/Group Title Infusion With Paracetamol Bolus With Placebo Total
Hide Arm/Group Description

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.

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.

Total of all reporting groups
Overall Number of Baseline Participants 188 187 375
Hide Baseline Analysis Population Description
ITT population
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 187 participants 187 participants 374 participants
43.6  (42.0) 45.7  (43.8) 44.6  (42.9)
[1]
Measure Analysis Population Description: The exact age of one patient was unknown.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 188 participants 187 participants 375 participants
Female
87
  46.3%
71
  38.0%
158
  42.1%
Male
101
  53.7%
116
  62.0%
217
  57.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 188 participants 187 participants 375 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
188
 100.0%
187
 100.0%
375
 100.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 188 participants 187 participants 375 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
179
  95.2%
178
  95.2%
357
  95.2%
White
0
   0.0%
0
   0.0%
0
   0.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
9
   4.8%
9
   4.8%
18
   4.8%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Angola Number Analyzed 188 participants 187 participants 375 participants
188
 100.0%
187
 100.0%
375
 100.0%
Weight-for-age, Z-score   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Z-score
Number Analyzed 187 participants 186 participants 373 participants
-1.179  (1.376) -1.239  (1.426) -1.209  (1.400)
[1]
Measure Description: 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.
[2]
Measure Analysis Population Description: Information on the exact age in months was missing from one patient, and the information on the exact weight was missing from one patient.
1.Primary Outcome
Title Day 7 Mortality
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of treatment.
Arm/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 187 186
Measure Type: Count of Participants
Unit of Measure: Participants
61
  32.6%
64
  34.4%
2.Secondary Outcome
Title All Deaths During Hospital Stay
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All patients who had received at least one dose of treatment.
Arm/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 187 186
Measure Type: Count of Participants
Unit of Measure: Participants
71
  38.0%
75
  40.3%
3.Secondary Outcome
Title Status on the Modified Glasgow Outcome Scale
Hide Description

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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 19 17
Median (Inter-Quartile Range)
Unit of Measure: score on a scale
5
(3 to 5)
5
(5 to 5)
4.Secondary Outcome
Title Death or Any Neurological Sequelae on Day 7
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 166 168
Measure Type: Count of Participants
Unit of Measure: Participants
96
  57.8%
86
  51.2%
5.Secondary Outcome
Title A Change in Hearing Threshold Compared to the First Test Result
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 13 14
Median (Inter-Quartile Range)
Unit of Measure: dB
0
(-20 to 0)
0
(0 to 0)
6.Secondary Outcome
Title Death or Severe Neurological Sequelae on Day 7
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients who received at least one dose of treatment, and of whom information on severe neurological sequelae was available on day 7.
Arm/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 172 173
Measure Type: Count of Participants
Unit of Measure: Participants
80
  46.5%
75
  43.4%
7.Secondary Outcome
Title Number of Participants With Deafness
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
We were finally able to perform post-treatment audiological examinations in solely 37 participants.
Arm/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 20 17
Measure Type: Count of Participants
Unit of Measure: Participants
3
  15.0%
1
   5.9%
8.Secondary Outcome
Title Death or Any Neurological Sequelae at Discharge From Hospital.
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 181 179
Measure Type: Count of Participants
Unit of Measure: Participants
104
  57.5%
89
  49.7%
9.Secondary Outcome
Title Death or Severe Neurological Sequelae at Discharge
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 186 183
Measure Type: Count of Participants
Unit of Measure: Participants
90
  48.4%
85
  46.4%
Time Frame During the patient´s hospital stay of at least 7 days until discharge. The longest hospital stay was 84 days.
Adverse Event Reporting Description

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.

 
Arm/Group Title Infusion With Paracetamol Bolus With Placebo
Hide Arm/Group Description

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.

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.

All-Cause Mortality
Infusion With Paracetamol Bolus With Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   72/188 (38.30%)      76/187 (40.64%)    
Show Serious Adverse Events Hide Serious Adverse Events
Infusion With Paracetamol Bolus With Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/188 (0.00%)      0/187 (0.00%)    
Nervous system disorders     
Any adverse events   0/188 (0.00%)  0 0/187 (0.00%)  0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Infusion With Paracetamol Bolus With Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/188 (0.00%)      0/187 (0.00%)    
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Okko Savonius, PhD candidate
Organization: University of Helsinki, Children´s Hospital, Helsinki University Hospital
Phone: +358456731185
EMail: okko.savonius@helsinki.fi
Layout table for additonal information
Responsible Party: Heikki Peltola, MD, PhD, Helsinki University
ClinicalTrials.gov Identifier: NCT01540838     History of Changes
Other Study ID Numbers: INFU/PARA-BOLU/PLACE
First Submitted: February 23, 2012
First Posted: February 29, 2012
Results First Submitted: February 21, 2019
Results First Posted: September 24, 2019
Last Update Posted: September 24, 2019