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Trial record 7 of 236 for:    levetiracetam

Efficacy of Intravenous Levetiracetam in Neonatal Seizures (NEOLEV2)

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ClinicalTrials.gov Identifier: NCT01720667
Recruitment Status : Completed
First Posted : November 2, 2012
Results First Posted : August 21, 2019
Last Update Posted : August 21, 2019
Sponsor:
Collaborators:
University of California, San Diego
Rady Children's Hospital, San Diego
Auckland City Hospital
Sharp Mary Birch Hospital for Women & Newborns
UCSF Benioff Children’s Hospital Oakland
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
Richard H. Haas, University of California, San Diego

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Neonatal Seizures
Interventions Drug: Intravenous levetiracetam
Drug: Intravenous phenobarbital
Enrollment 280
Recruitment Details  
Pre-assignment Details 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.
Arm/Group Title Intravenous Levetiracetam Intravenous Phenobarbital
Hide Arm/Group Description 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 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.
Period Title: Overall Study
Started 64 42
Recieved Second Infusion of Same Drug 50 20
Recieved Alternate Intervention 45 10
Received 2nd Infusion of Alternate Drug 27 6
Modified ITT 53 30
Completed 60 41
Not Completed 4 1
Reason Not Completed
Adverse Event             1             1
Withdrawal by Subject             3             0
Arm/Group Title Intravenous Levetiracetam Intravenous Phenobarbital Total
Hide Arm/Group Description

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 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 of all reporting groups
Overall Number of Baseline Participants 64 42 106
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants 42 participants 106 participants
<=18 years
64
 100.0%
42
 100.0%
106
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants 42 participants 106 participants
Female
33
  51.6%
18
  42.9%
51
  48.1%
Male
31
  48.4%
24
  57.1%
55
  51.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants 42 participants 106 participants
Hispanic or Latino
18
  28.1%
10
  23.8%
28
  26.4%
Not Hispanic or Latino
39
  60.9%
25
  59.5%
64
  60.4%
Unknown or Not Reported
7
  10.9%
7
  16.7%
14
  13.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants 42 participants 106 participants
American Indian or Alaska Native
1
   1.6%
0
   0.0%
1
   0.9%
Asian
2
   3.1%
3
   7.1%
5
   4.7%
Native Hawaiian or Other Pacific Islander
7
  10.9%
2
   4.8%
9
   8.5%
Black or African American
4
   6.3%
1
   2.4%
5
   4.7%
White
34
  53.1%
25
  59.5%
59
  55.7%
More than one race
3
   4.7%
1
   2.4%
4
   3.8%
Unknown or Not Reported
13
  20.3%
10
  23.8%
23
  21.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 64 participants 42 participants 106 participants
United States 45 30 53
New Zealand 19 12 28
1.Primary Outcome
Title Neonates With Seizure Cessation When Given Levetiracetam (40-60 mg/kg) as First Line Therapy Compared to Phenobarbital (20-40mg/kg)
Hide Description

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.

Time Frame 24 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Treated participants with available primary outcome measure- EEG to 24 hours confirming seizure cessation.
Arm/Group Title Intravenous Levetiracetam Intravenous Phenobarbital
Hide Arm/Group Description:
Intravenous levetiracetam 40 - 60 mg/kg loading dose & 10 mg/kg 8 hourly maintenance
Intravenous phenobarbital 20 - 40 mg/kg loading dose & 1.5 mg/kg 8 hourly maintenance.
Overall Number of Participants Analyzed 53 30
Measure Type: Count of Participants
Unit of Measure: Participants
15
  28.3%
24
  80.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Intravenous Levetiracetam, Intravenous Phenobarbital
Comments Comparison of 24 hour seizure termination rates using a Fisher's exact test.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
2.Secondary Outcome
Title Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital at 48 Hours After Treatment
Time Frame 48 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with evaluable data with 48 hours of seizure monitoring
Arm/Group Title Intravenous Levetiracetam Intravenous Phenobarbital
Hide Arm/Group Description:
Intravenous levetiracetam 40 - 60 mg/kg loading dose & 10 mg/kg 8 hourly maintenance
Intravenous phenobarbital 20 - 40 mg/kg loading dose & 1.5 mg/kg 8 hourly maintenance.
Overall Number of Participants Analyzed 47 28
Measure Type: Count of Participants
Unit of Measure: Participants
8
  17.0%
18
  64.3%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Intravenous Levetiracetam, Intravenous Phenobarbital
Comments Comparison of seizure cessation at 48 hours using Fisher's exact test
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
3.Secondary Outcome
Title Number of Neonates With Seizure Termination at 1 Hour After Treatment
Time Frame 1 hour
Hide Outcome Measure Data
Hide Analysis Population Description
Includes 1 participant in each arm who did not have data available for the primary end point at 24 hours
Arm/Group Title Intravenous Levetiracetam Intravenous Phenobarbital
Hide Arm/Group Description:
Intravenous levetiracetam 40 - 60 mg/kg loading dose & 10 mg/kg 8 hourly maintenance
Intravenous phenobarbital 20 - 40 mg/kg loading dose & 1.5 mg/kg 8 hourly maintenance.
Overall Number of Participants Analyzed 53 30
Measure Type: Count of Participants
Unit of Measure: Participants
26
  49.1%
28
  93.3%
4.Secondary Outcome
Title LEV Dose Escalation Component
Hide Description 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.
Time Frame 24 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Babies who received any treatment of either phenobarbital or levetiracetam within the modified intent to treat
Arm/Group Title Intravenous Levetiracetam Intravenous Phenobarbital
Hide Arm/Group Description:
Intravenous levetiracetam 40 mg/kg loading dose & 10 mg/kg 8 hourly maintenance
Intravenous phenobarbital 20 mg/kg loading dose & 1.5 mg/kg 8 hourly maintenance.
Overall Number of Participants Analyzed 53 30
Measure Type: Count of Participants
Unit of Measure: Participants
4
   7.5%
3
  10.0%
5.Secondary Outcome
Title 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
Hide Description [Not Specified]
Time Frame 24 hours
Hide Outcome Measure Data
Hide Analysis Population Description
HIE participants with hypothermia treatment
Arm/Group Title Intravenous Levetiracetam Intravenous Phenobarbital
Hide Arm/Group Description:
Intravenous levetiracetam 40 - 60 mg/kg loading dose & 10 mg/kg 8 hourly maintenance
Intravenous phenobarbital 20 - 40 mg/kg loading dose & 1.5 mg/kg 8 hourly maintenance.
Overall Number of Participants Analyzed 17 10
Measure Type: Count of Participants
Unit of Measure: Participants
6
  35.3%
9
  90.0%
6.Other Pre-specified Outcome
Title Pharmacokinetic Data
Hide Description To 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.
Time Frame 48 hours
Outcome Measure Data Not Reported
7.Other Pre-specified Outcome
Title Feasibility of Continuous Internet EEG Monitoring
Hide Description Feasibility of centralized remote access to continuous video EEG monitoring in the NICU via the internet
Time Frame Subject study duration
Outcome Measure Data Not Reported
8.Other Pre-specified Outcome
Title Evaluation of the Accuracy of Neonatal Seizure Detection Algorithm
Hide Description A 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.
Time Frame 48 Hours
Outcome Measure Data Not Reported
9.Other Pre-specified Outcome
Title Gather Safety Information on IV Levetiracetam
Hide Description

Safety 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.

Time Frame 5 days
Outcome Measure Data Not Reported
10.Post-Hoc Outcome
Title Imputation Sensitivity Analysis
Hide Description Analysis of missing data impact on the outcome measures
Time Frame 48 hours
Outcome Measure Data Not Reported
Time Frame Up to 5 days after treatment
Adverse Event Reporting Description Data not collected separately for each intervention
 
Arm/Group Title Intravenous Phenobarbital Intravenous Levetiracetam
Hide Arm/Group Description 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 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.
All-Cause Mortality
Intravenous Phenobarbital Intravenous Levetiracetam
Affected / at Risk (%) Affected / at Risk (%)
Total   1/42 (2.38%)      2/64 (3.13%)    
Show Serious Adverse Events Hide Serious Adverse Events
Intravenous Phenobarbital Intravenous Levetiracetam
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/42 (11.90%)      1/64 (1.56%)    
Cardiac disorders     
Heart Rate Abnormality   0/42 (0.00%)  0/64 (0.00%) 
Gastrointestinal disorders     
Poor Feeding   0/42 (0.00%)  0/64 (0.00%) 
General disorders     
New Medications   0/42 (0.00%)  0/64 (0.00%) 
Infections and infestations     
Infection   0/42 (0.00%)  0/64 (0.00%) 
Nervous system disorders     
Sedation   0/42 (0.00%)  0/64 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory Abnormality  [1]  1/42 (2.38%)  0/64 (0.00%) 
Vascular disorders     
Hypotension  [2]  4/42 (9.52%)  1/64 (1.56%) 
Indicates events were collected by systematic assessment
[1]
Grade 4 respiratory distress thought probably or possibly due to study medication
[2]
Grade 4 hypotension thought probably or possibly due to study medications
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Intravenous Phenobarbital Intravenous Levetiracetam
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   13/42 (30.95%)      12/64 (18.75%)    
Cardiac disorders     
Heart Rate Abnormailty  [1]  1/42 (2.38%)  3/64 (4.69%) 
Vasopressor Requirement  [2]  13/42 (30.95%)  13 10/64 (15.63%)  10
Gastrointestinal disorders     
Poor Feeding  [3]  7/42 (16.67%)  6/64 (9.38%) 
General disorders     
New Medical Problem  [4]  6/42 (14.29%)  5/64 (7.81%) 
New Medications   7/42 (16.67%)  3/64 (4.69%) 
Infections and infestations     
Infection  [5]  3/42 (7.14%)  2/64 (3.13%) 
Nervous system disorders     
Sedation  [6]  8/42 (19.05%)  7/64 (10.94%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory Abnormality  [7]  12/42 (28.57%)  8/64 (12.50%) 
Vascular disorders     
Hypotension  [8]  7/42 (16.67%)  3/64 (4.69%) 
Indicates events were collected by systematic assessment
[1]
Specific finding of heart rate abnormality on a day on which an adverse event was reported
[2]
Hypotension requiring vasopressor support on at least one day
[3]
Specific finding of poor feeding on a day on which adverse event was documented
[4]
New Medical Problem reported on a day where an adverse event is documented
[5]
Specific finding of infection on a day on which adverse event was documented
[6]
Specific finding of sedation on a day on which an adverse event was documented
[7]
Specific finding of respiratory abnormality documented on a day on which an adverse event was documented
[8]
Specific finding of hypotension on a day on which an adverse event was indicated.
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. Richard Haas
Organization: University of California San Diego, School of Medicine
Phone: (858) 822-6700
EMail: rhaas@ucsd.edu
Layout table for additonal information
Responsible Party: Richard H. Haas, University of California, San Diego
ClinicalTrials.gov Identifier: NCT01720667     History of Changes
Other Study ID Numbers: NoGA - R01 FD004147-01A1 Haas
1R01FD004147-01A1 ( U.S. FDA Grant/Contract )
First Submitted: October 22, 2012
First Posted: November 2, 2012
Results First Submitted: July 3, 2019
Results First Posted: August 21, 2019
Last Update Posted: August 21, 2019