Efficacy of Intravenous Levetiracetam in Neonatal Seizures (NEOLEV2)

• 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: Richard H. Haas
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Intravenous Levetiracetam	Intravenous Phenobarbital	Total
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
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

Outcome Measures

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)
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

Outcome Measure Data

Analysis Population Description

Treated participants with available primary outcome measure- EEG to 24 hours confirming seizure cessation.

Arm/Group Title	Intravenous Levetiracetam	Intravenous Phenobarbital
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%

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
Description	A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures.
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Participants with evaluable data with 48 hours of seizure monitoring

Arm/Group Title	Intravenous Levetiracetam	Intravenous Phenobarbital
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%

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
Description	A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures.
Time Frame	1 hour

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
Description	[Not Specified]
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

HIE participants with hypothermia treatment

Arm/Group Title	Intravenous Levetiracetam	Intravenous Phenobarbital
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
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
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
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
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
Description	Analysis of missing data impact on the outcome measures
Time Frame	48 hours

Outcome Measure Data Not Reported

Adverse Events

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
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%)
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
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.

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Dr. Richard Haas
• Organization: University of California San Diego, School of Medicine
• Phone: (858) 822-6700
• EMail: rhaas@ucsd.edu

Publications of Results:

Sharpe C, Davis SL, Reiner GE, Lee LI, Gold JJ, Nespeca M, Wang SG, Joe P, Kuperman R, Gardner M, Honold J, Lane B, Knodel E, Rowe D, Battin MR, Bridge R, Goodmar J, Castro B, Rasmussen M, Arnell K, Harbert M, Haas R. Assessing the Feasibility of Providing a Real-Time Response to Seizures Detected With Continuous Long-Term Neonatal Electroencephalography Monitoring. J Clin Neurophysiol. 2019 Jan;36(1):9-13. doi: 10.1097/WNP.0000000000000525.

Other Publications:

Sharpe CM, Capparelli EV, Mower A, Farrell MJ, Soldin SJ, Haas RH. A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life. Pediatr Res. 2012 Jul;72(1):43-9. doi: 10.1038/pr.2012.51. Epub 2012 Apr 11.

• Responsible Party: Richard H. Haas, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT01720667
• 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