Trial Outcomes & Findings for Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis (NCT NCT01540838)

NCT ID: NCT01540838

Last Updated: 2019-09-24

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 375 participants
• Primary outcome timeframe: On day 7 from the institution of treatment
• Results posted on: 2019-09-24

Participant Flow

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.

Participant milestones

Measure	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.	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.
Overall Study STARTED	188	187
Overall Study COMPLETED	166	164
Overall Study NOT COMPLETED	22	23

Reasons for withdrawal

Measure	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.	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.
Overall Study Open nasogastric tube	9	7
Overall Study Treatment doses missing	8	12
Overall Study Additional antibiotic treatment	1	2
Overall Study Died before treatment initiation	1	1
Overall Study Not BM. Other treatment	3	1

Baseline Characteristics

The exact age of one patient was unknown.

Baseline characteristics by cohort

Measure	Infusion With Paracetamol n=188 Participants 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.	Bolus With Placebo n=187 Participants 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 n=375 Participants Total of all reporting groups
Age, Continuous	43.6 months STANDARD_DEVIATION 42.0 • n=187 Participants • The exact age of one patient was unknown.	45.7 months STANDARD_DEVIATION 43.8 • n=187 Participants • The exact age of one patient was unknown.	44.6 months STANDARD_DEVIATION 42.9 • n=374 Participants • The exact age of one patient was unknown.
Sex: Female, Male Female	87 Participants n=188 Participants	71 Participants n=187 Participants	158 Participants n=375 Participants
Sex: Female, Male Male	101 Participants n=188 Participants	116 Participants n=187 Participants	217 Participants n=375 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=188 Participants	0 Participants n=187 Participants	0 Participants n=375 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants n=188 Participants	0 Participants n=187 Participants	0 Participants n=375 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	188 Participants n=188 Participants	187 Participants n=187 Participants	375 Participants n=375 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=188 Participants	0 Participants n=187 Participants	0 Participants n=375 Participants
Race (NIH/OMB) Asian	0 Participants n=188 Participants	0 Participants n=187 Participants	0 Participants n=375 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=188 Participants	0 Participants n=187 Participants	0 Participants n=375 Participants
Race (NIH/OMB) Black or African American	179 Participants n=188 Participants	178 Participants n=187 Participants	357 Participants n=375 Participants
Race (NIH/OMB) White	0 Participants n=188 Participants	0 Participants n=187 Participants	0 Participants n=375 Participants
Race (NIH/OMB) More than one race	0 Participants n=188 Participants	0 Participants n=187 Participants	0 Participants n=375 Participants
Race (NIH/OMB) Unknown or Not Reported	9 Participants n=188 Participants	9 Participants n=187 Participants	18 Participants n=375 Participants
Region of Enrollment Angola	188 Participants n=188 Participants	187 Participants n=187 Participants	375 Participants n=375 Participants
Weight-for-age, Z-score	-1.179 Z-score STANDARD_DEVIATION 1.376 • n=187 Participants • Information on the exact age in months was missing from one patient, and the information on the exact weight was missing from one patient.	-1.239 Z-score STANDARD_DEVIATION 1.426 • n=186 Participants • Information on the exact age in months was missing from one patient, and the information on the exact weight was missing from one patient.	-1.209 Z-score STANDARD_DEVIATION 1.400 • n=373 Participants • Information on the exact age in months was missing from one patient, and the information on the exact weight was missing from one patient.

PRIMARY outcome

Timeframe: On day 7 from the institution of treatment

Population: All participants who received at least one dose 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.

Outcome measures

Measure	Infusion With Paracetamol n=187 Participants 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.	Bolus With Placebo n=186 Participants 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.
Day 7 Mortality	61 Participants	64 Participants

SECONDARY outcome

Timeframe: 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.

All patients who had received at least one dose of treatment and died during the hospital stay.

Outcome measures

Measure	Infusion With Paracetamol n=187 Participants 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.	Bolus With Placebo n=186 Participants 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 Deaths During Hospital Stay	71 Participants	75 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Infusion With Paracetamol n=19 Participants 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.	Bolus With Placebo n=17 Participants 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.
Status on the Modified Glasgow Outcome Scale	5 score on a scale Interval 3.0 to 5.0	5 score on a scale Interval 5.0 to 5.0

SECONDARY outcome

Timeframe: 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.

Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.

Outcome measures

Measure	Infusion With Paracetamol n=166 Participants 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.	Bolus With Placebo n=168 Participants 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.
Death or Any Neurological Sequelae on Day 7	96 Participants	86 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Infusion With Paracetamol n=13 Participants 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.	Bolus With Placebo n=14 Participants 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.
A Change in Hearing Threshold Compared to the First Test Result	0 dB Interval -20.0 to 0.0	0 dB Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: 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.

Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation

Outcome measures

Measure	Infusion With Paracetamol n=172 Participants 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.	Bolus With Placebo n=173 Participants 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.
Death or Severe Neurological Sequelae on Day 7	80 Participants	75 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Infusion With Paracetamol n=20 Participants 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.	Bolus With Placebo n=17 Participants 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.
Number of Participants With Deafness	3 Participants	1 Participants

SECONDARY outcome

Timeframe: 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.

Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.

Outcome measures

Measure	Infusion With Paracetamol n=181 Participants 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.	Bolus With Placebo n=179 Participants 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.
Death or Any Neurological Sequelae at Discharge From Hospital.	104 Participants	89 Participants

SECONDARY outcome

Timeframe: 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.

Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation

Outcome measures

Measure	Infusion With Paracetamol n=186 Participants 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.	Bolus With Placebo n=183 Participants 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.
Death or Severe Neurological Sequelae at Discharge	90 Participants	85 Participants

Adverse Events

Infusion With Paracetamol

Serious events: 0 serious events

Other events: 0 other events

Deaths: 72 deaths

Bolus With Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 76 deaths

Serious adverse events

Measure	Infusion With Paracetamol n=188 participants at risk 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.	Bolus With Placebo n=187 participants at risk 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.
Nervous system disorders Any adverse events	0.00% 0/188 • 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.	0.00% 0/187 • 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.

Other adverse events

Adverse event data not reported

Additional Information

Dr. Okko Savonius, PhD candidate

University of Helsinki, Children´s Hospital, Helsinki University Hospital

Phone: +358456731185

Email: okko.savonius@helsinki.fi

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place