Trial Outcomes & Findings for Efficacy of Intravenous Levetiracetam in Neonatal Seizures (NCT NCT01720667)
NCT ID: NCT01720667
Last Updated: 2019-08-21
Results Overview
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. Seizure cessation from 15 minutes after completion of infusion for 24 hours as assessed by continuous EEG reviewed by neurophysiologists.
Recruitment status
COMPLETED
Study phase
PHASE1/PHASE2
Target enrollment
280 participants
Primary outcome timeframe
24 hours
Results posted on
2019-08-21
Participant Flow
280 were enrolled to EEG monitoring and of these 106 were randomized to treatment as neonatal seizures were thought to have occurred. 174 excluded as they did not have electrographic seizures; from 6 participants only verbal not written consent obtained.
Participant milestones
| Measure |
Intravenous Levetiracetam
Intravenous levetiracetam 40 - 60 mg/kg loading dose. If electrographic seizures persisted or recurred 15 minutes following completion of the infusion, subjects received a further 20 mg/kg LEV infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes following completion of the second infusion, the subject was then treated with PHB 20 mg/kg. Another dose of 20 mg/kg PHB given if seizures persist. Unresponsive subjects exit the study. All subjects received maintenance LEV 10 mg/kg/dose given IV q8 hours continued for five days.
|
Intravenous Phenobarbital
Intravenous phenobarbital 20 mg/kg loading dose. If electrographic seizures persisted or recurred 15 minutes following completion of the infusion, subjects received a further 20 mg/kg PHB infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes following completion of the second infusion, the subject was then treated with LEV 40 mg/kg first. Another dose of 20 mg/kg PHB given if seizures persist. Unresponsive subjects exit the study. All subjects received maintenance 1.5 mg/kg PHB mg/kg/dose given IV q8 hours continued for five days.
|
|---|---|---|
|
Overall Study
STARTED
|
64
|
42
|
|
Overall Study
Recieved Second Infusion of Same Drug
|
50
|
20
|
|
Overall Study
Recieved Alternate Intervention
|
45
|
10
|
|
Overall Study
Received 2nd Infusion of Alternate Drug
|
27
|
6
|
|
Overall Study
Modified ITT
|
53
|
30
|
|
Overall Study
COMPLETED
|
60
|
41
|
|
Overall Study
NOT COMPLETED
|
4
|
1
|
Reasons for withdrawal
| Measure |
Intravenous Levetiracetam
Intravenous levetiracetam 40 - 60 mg/kg loading dose. If electrographic seizures persisted or recurred 15 minutes following completion of the infusion, subjects received a further 20 mg/kg LEV infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes following completion of the second infusion, the subject was then treated with PHB 20 mg/kg. Another dose of 20 mg/kg PHB given if seizures persist. Unresponsive subjects exit the study. All subjects received maintenance LEV 10 mg/kg/dose given IV q8 hours continued for five days.
|
Intravenous Phenobarbital
Intravenous phenobarbital 20 mg/kg loading dose. If electrographic seizures persisted or recurred 15 minutes following completion of the infusion, subjects received a further 20 mg/kg PHB infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes following completion of the second infusion, the subject was then treated with LEV 40 mg/kg first. Another dose of 20 mg/kg PHB given if seizures persist. Unresponsive subjects exit the study. All subjects received maintenance 1.5 mg/kg PHB mg/kg/dose given IV q8 hours continued for five days.
|
|---|---|---|
|
Overall Study
Adverse Event
|
1
|
1
|
|
Overall Study
Withdrawal by Subject
|
3
|
0
|
Baseline Characteristics
Efficacy of Intravenous Levetiracetam in Neonatal Seizures
Baseline characteristics by cohort
| Measure |
Intravenous Levetiracetam
n=64 Participants
Intravenous levetiracetam 40 to 60 mg/kg loading dose. 10 mg/kg 8 hourly maintenance
Intravenous levetiracetam: Intravenous load of levetiracetam (40 to 60 mg/kg) following identification of EEG confirmed neonatal seizure.
|
Intravenous Phenobarbital
n=42 Participants
Intravenous phenobarbital 20 to 40 mg/kg load. 1.5 mg/kg 8 hourly maintenance
Intravenous phenobarbital: Intravenous load of phenobarbital (20 to 40 mg/kg) following EEG confirmation of seizure activity load.
|
Total
n=106 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Categorical
<=18 years
|
64 Participants
n=93 Participants
|
42 Participants
n=4 Participants
|
106 Participants
n=27 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
0 Participants
n=93 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=27 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=93 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=27 Participants
|
|
Sex: Female, Male
Female
|
33 Participants
n=93 Participants
|
18 Participants
n=4 Participants
|
51 Participants
n=27 Participants
|
|
Sex: Female, Male
Male
|
31 Participants
n=93 Participants
|
24 Participants
n=4 Participants
|
55 Participants
n=27 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
18 Participants
n=93 Participants
|
10 Participants
n=4 Participants
|
28 Participants
n=27 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
39 Participants
n=93 Participants
|
25 Participants
n=4 Participants
|
64 Participants
n=27 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
7 Participants
n=93 Participants
|
7 Participants
n=4 Participants
|
14 Participants
n=27 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
1 Participants
n=93 Participants
|
0 Participants
n=4 Participants
|
1 Participants
n=27 Participants
|
|
Race (NIH/OMB)
Asian
|
2 Participants
n=93 Participants
|
3 Participants
n=4 Participants
|
5 Participants
n=27 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
7 Participants
n=93 Participants
|
2 Participants
n=4 Participants
|
9 Participants
n=27 Participants
|
|
Race (NIH/OMB)
Black or African American
|
4 Participants
n=93 Participants
|
1 Participants
n=4 Participants
|
5 Participants
n=27 Participants
|
|
Race (NIH/OMB)
White
|
34 Participants
n=93 Participants
|
25 Participants
n=4 Participants
|
59 Participants
n=27 Participants
|
|
Race (NIH/OMB)
More than one race
|
3 Participants
n=93 Participants
|
1 Participants
n=4 Participants
|
4 Participants
n=27 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
13 Participants
n=93 Participants
|
10 Participants
n=4 Participants
|
23 Participants
n=27 Participants
|
|
Region of Enrollment
United States
|
45 participants
n=93 Participants
|
30 participants
n=4 Participants
|
53 participants
n=27 Participants
|
|
Region of Enrollment
New Zealand
|
19 participants
n=93 Participants
|
12 participants
n=4 Participants
|
28 participants
n=27 Participants
|
PRIMARY outcome
Timeframe: 24 hoursPopulation: Treated participants with available primary outcome measure- EEG to 24 hours confirming seizure cessation.
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. Seizure cessation from 15 minutes after completion of infusion for 24 hours as assessed by continuous EEG reviewed by neurophysiologists.
Outcome measures
| Measure |
Intravenous Levetiracetam
n=53 Participants
Intravenous levetiracetam 40 - 60 mg/kg loading dose \& 10 mg/kg 8 hourly maintenance
|
Intravenous Phenobarbital
n=30 Participants
Intravenous phenobarbital 20 - 40 mg/kg loading dose \& 1.5 mg/kg 8 hourly maintenance.
|
|---|---|---|
|
Neonates With Seizure Cessation When Given Levetiracetam (40-60 mg/kg) as First Line Therapy Compared to Phenobarbital (20-40mg/kg)
|
15 Participants
|
24 Participants
|
SECONDARY outcome
Timeframe: 48 hoursPopulation: Participants with evaluable data with 48 hours of seizure monitoring
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures.
Outcome measures
| Measure |
Intravenous Levetiracetam
n=47 Participants
Intravenous levetiracetam 40 - 60 mg/kg loading dose \& 10 mg/kg 8 hourly maintenance
|
Intravenous Phenobarbital
n=28 Participants
Intravenous phenobarbital 20 - 40 mg/kg loading dose \& 1.5 mg/kg 8 hourly maintenance.
|
|---|---|---|
|
Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital at 48 Hours After Treatment
|
8 Participants
|
18 Participants
|
SECONDARY outcome
Timeframe: 1 hourPopulation: Includes 1 participant in each arm who did not have data available for the primary end point at 24 hours
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures.
Outcome measures
| Measure |
Intravenous Levetiracetam
n=53 Participants
Intravenous levetiracetam 40 - 60 mg/kg loading dose \& 10 mg/kg 8 hourly maintenance
|
Intravenous Phenobarbital
n=30 Participants
Intravenous phenobarbital 20 - 40 mg/kg loading dose \& 1.5 mg/kg 8 hourly maintenance.
|
|---|---|---|
|
Number of Neonates With Seizure Termination at 1 Hour After Treatment
|
26 Participants
|
28 Participants
|
SECONDARY outcome
Timeframe: 24 hoursPopulation: Babies who received any treatment of either phenobarbital or levetiracetam within the modified intent to treat
Number of babies with seizure control at levetiracetam (60 mg/Kg load) who had not responded to 40 mg/kg load and number of babies with seizure control at 40 mg/kg who had not responded to 20 mg/kg.
Outcome measures
| Measure |
Intravenous Levetiracetam
n=53 Participants
Intravenous levetiracetam 40 - 60 mg/kg loading dose \& 10 mg/kg 8 hourly maintenance
|
Intravenous Phenobarbital
n=30 Participants
Intravenous phenobarbital 20 - 40 mg/kg loading dose \& 1.5 mg/kg 8 hourly maintenance.
|
|---|---|---|
|
LEV Dose Escalation Component
|
4 Participants
|
3 Participants
|
SECONDARY outcome
Timeframe: 24 hoursPopulation: HIE participants with hypothermia treatment
Outcome measures
| Measure |
Intravenous Levetiracetam
n=17 Participants
Intravenous levetiracetam 40 - 60 mg/kg loading dose \& 10 mg/kg 8 hourly maintenance
|
Intravenous Phenobarbital
n=10 Participants
Intravenous phenobarbital 20 - 40 mg/kg loading dose \& 1.5 mg/kg 8 hourly maintenance.
|
|---|---|---|
|
Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital Within the Hypoxic Ischemic Encephalopathy (HIE) Population and Treated With Hypothermia
|
6 Participants
|
9 Participants
|
OTHER_PRE_SPECIFIED outcome
Timeframe: 48 hoursTo obtain additional pharmacokinetic data "Area under the plasma concentration versus time curve (AUC) and Peak Plasma Concentration (Cmax)" of intravenous levetiracetam to confirm findings from our previous pharmacokinetic study.
Outcome measures
Outcome data not reported
OTHER_PRE_SPECIFIED outcome
Timeframe: Subject study durationFeasibility of centralized remote access to continuous video EEG monitoring in the NICU via the internet
Outcome measures
Outcome data not reported
OTHER_PRE_SPECIFIED outcome
Timeframe: 48 HoursA novel neonatal seizure detection algorithm will be compared to the gold standard of two encephalographers reading 48 hours of neonatal video EEG in the measurement of seizure burden.
Outcome measures
Outcome data not reported
OTHER_PRE_SPECIFIED outcome
Timeframe: 5 daysSafety information to be collected includes daily recording of any adverse events during the 5 day treatment protocol. Complete Blood Count and Comprehensive Chemistry panels after 48 hours of treatment collected.
Outcome measures
Outcome data not reported
POST_HOC outcome
Timeframe: 48 hoursAnalysis of missing data impact on the outcome measures
Outcome measures
Outcome data not reported
Adverse Events
Intravenous Phenobarbital
Serious events: 5 serious events
Other events: 13 other events
Deaths: 1 deaths
Intravenous Levetiracetam
Serious events: 1 serious events
Other events: 12 other events
Deaths: 2 deaths
Serious adverse events
| Measure |
Intravenous Phenobarbital
n=42 participants at risk
Intravenous phenobarbital 20 mg/kg loading dose. If electrographic seizures persisted or recurred 15 minutes following completion of the infusion, subjects received a further 20 mg/kg PHB infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes following completion of the second infusion, the subject was then treated with LEV 40 mg/kg first. Another dose of 20 mg/kg PHB given if seizures persist. Unresponsive subjects exit the study. All subjects received maintenance 1.5 mg/kg PHB mg/kg/dose given IV q8 hours continued for five days.
|
Intravenous Levetiracetam
n=64 participants at risk
Intravenous levetiracetam 40 - 60 mg/kg loading dose. If electrographic seizures persisted or recurred 15 minutes following completion of the infusion, subjects received a further 20 mg/kg LEV infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes following completion of the second infusion, the subject was then treated with PHB 20 mg/kg. Another dose of 20 mg/kg PHB given if seizures persist. Unresponsive subjects exit the study. All subjects received maintenance LEV 10 mg/kg/dose given IV q8 hours continued for five days.
|
|---|---|---|
|
Vascular disorders
Hypotension
|
9.5%
4/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
1.6%
1/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory Abnormality
|
2.4%
1/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
0.00%
0/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Cardiac disorders
Heart Rate Abnormality
|
0.00%
0/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
0.00%
0/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Nervous system disorders
Sedation
|
0.00%
0/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
0.00%
0/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Gastrointestinal disorders
Poor Feeding
|
0.00%
0/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
0.00%
0/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Infections and infestations
Infection
|
0.00%
0/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
0.00%
0/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
General disorders
New Medications
|
0.00%
0/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
0.00%
0/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
Other adverse events
| Measure |
Intravenous Phenobarbital
n=42 participants at risk
Intravenous phenobarbital 20 mg/kg loading dose. If electrographic seizures persisted or recurred 15 minutes following completion of the infusion, subjects received a further 20 mg/kg PHB infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes following completion of the second infusion, the subject was then treated with LEV 40 mg/kg first. Another dose of 20 mg/kg PHB given if seizures persist. Unresponsive subjects exit the study. All subjects received maintenance 1.5 mg/kg PHB mg/kg/dose given IV q8 hours continued for five days.
|
Intravenous Levetiracetam
n=64 participants at risk
Intravenous levetiracetam 40 - 60 mg/kg loading dose. If electrographic seizures persisted or recurred 15 minutes following completion of the infusion, subjects received a further 20 mg/kg LEV infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes following completion of the second infusion, the subject was then treated with PHB 20 mg/kg. Another dose of 20 mg/kg PHB given if seizures persist. Unresponsive subjects exit the study. All subjects received maintenance LEV 10 mg/kg/dose given IV q8 hours continued for five days.
|
|---|---|---|
|
Vascular disorders
Hypotension
|
16.7%
7/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
4.7%
3/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Cardiac disorders
Heart Rate Abnormailty
|
2.4%
1/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
4.7%
3/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory Abnormality
|
28.6%
12/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
12.5%
8/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Nervous system disorders
Sedation
|
19.0%
8/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
10.9%
7/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Gastrointestinal disorders
Poor Feeding
|
16.7%
7/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
9.4%
6/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Infections and infestations
Infection
|
7.1%
3/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
3.1%
2/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
General disorders
New Medical Problem
|
14.3%
6/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
7.8%
5/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
General disorders
New Medications
|
16.7%
7/42 • Up to 5 days after treatment
Data not collected separately for each intervention
|
4.7%
3/64 • Up to 5 days after treatment
Data not collected separately for each intervention
|
|
Cardiac disorders
Vasopressor Requirement
|
31.0%
13/42 • Number of events 13 • Up to 5 days after treatment
Data not collected separately for each intervention
|
15.6%
10/64 • Number of events 10 • Up to 5 days after treatment
Data not collected separately for each intervention
|
Additional Information
Dr. Richard Haas
University of California San Diego, School of Medicine
Phone: (858) 822-6700
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place