Antiepileptic Drugs and Vascular Risk Markers

• Sponsor: Thomas Jefferson University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00774306
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 52
• Arms: 4
• Duration (Months): 38

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if certain seizure medications raise levels of cholesterol and other blood components which could increase the risk of heart attacks and strokes.

Condition or Disease	Intervention/Treatment	Phase
Subarachnoid Hemorrhage	Drug: phenytoin; Drug: valproate; Drug: levetiracetam	N/A

Detailed Description

There is some evidence that certain seizure medicines may raise levels of cholesterol and other blood components which could increase the risk of heart attacks and strokes, however, more research is needed. Individuals with acute subarachnoid hemorrhage traditionally are treated with seizure medicines, but it is not clear which one is best, or if any such medication is necessary at all.

This study is intended to find out if certain seizure medications raise levels of cholesterol and other blood components which could lead to an increased risk of heart attacks and strokes.

In this study, 200 people with acute subarachnoid hemorrhage will be randomized to treatment with one of three different seizure medicines-phenytoin, valproate, or levetiracetam-or to receive no seizure medication at all. In each participant, cholesterol and other blood markers that relate to heart attack and stroke risk will be measured shortly after hospital admission and again 8 weeks later. At the 8-week point most participants will have their seizure medication discontinued, and the same blood tests will be repeated.

Information from this study could lead to changes in how seizure medications are prescribed both in the subarachnoid hemorrhage population and in other people who are prone to seizures.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effects of Antiepileptic Drugs on Serum Lipids and Inflammation in Patients With Subarachnoid Hemorrhage
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Participants randomized to Group 1 will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses.	Drug: phenytoin; Phenytoin is a anti-seizure medication. Participants will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses.; Other Names: Dilantin, Cerebyx (a phenytoin pro-drug)
Active Comparator: 2 Participants randomized to Group 2 will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses or in a once-daily extended release formulation.	Drug: valproate; Valproate is an anti-seizure medication. Participants will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses.; Other Names: Depakote, Depacon
Active Comparator: 3 Participants randomized to Group 3 will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses.	Drug: levetiracetam; Levetiracetam is an anti-seizure medication. Participants will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses.; Other Names: Keppra
No Intervention: 4 Participants randomized to Group 4 will receive no drug intervention.

Outcome Measures

Primary Outcome Measures

1. Change in Serum Cholesterol, Non-HDL Cholesterol, HDL Cholesterol, Lipoprotein(a), and C-reactive Protein From Baseline to Second Draw and Third Draw in Each of the 4 Study Arms [8 weeks, 16 weeks]

Secondary Outcome Measures

1. Incidence of Acute Seizures, Incidence of Late Seizures, Overall Neurologic Function (as Measured by Modified Rankin Scale Scores) [8 weeks, 16 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Acute subarachnoid hemorrhage, Hunt-Hess Grades I-IV

• Within 48 hours of admission

Exclusion Criteria:

• Grade V subarachnoid hemorrhage

• Being treated with a lipid-lowering agent

• Contraindication to phenytoin, valproate, or levetiracetam (e.g. history of allergy to one of these agents)

• Contraindication to receiving no antiepileptic drug treatment (e.g. history of pre-existing epilepsy, seizure activity on admission EEG)

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Thomas Jefferson University
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Scott Mintzer, MD, Assistant Professor of Neurology, Jefferson Comprehensive Epilepsy Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT00774306
• Other Study ID Numbers: K23NS058669; 1K23NS058669
• First Posted: Oct 17, 2008
• Last Update Posted: Dec 18, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Thomas Jefferson University: vascular risk; lipid fractions; lipoprotein(a); C-reactive protein; subarachnoid hemorrhage; antiepileptic drug; randomized; seizure; cholesterol
• Additional relevant MeSH terms: Subarachnoid Hemorrhage; Hemorrhage; Phenytoin; Levetiracetam; Valproic Acid

Study Results

Participant Flow

Arm/Group Title	Phenytoin	Valproate	Levetiracetam	No Anticonvulsant
Arm/Group Description	Participants randomized to Group 1 will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses. phenytoin: Phenytoin is a anti-seizure medication. Participants will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses. They will be maintained on it throughout the study period. Daily dose will be adjusted to maintain levels in the standard therapeutic range of 10-20 mg/dL. Upon discharge, they will remain on the drug in oral form until follow-up with the principal investigator 6 weeks later. x x	Participants randomized to Group 2 will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses or in a once-daily extended release formulation. valproate: Valproate is an anti-seizure medication. Participants will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses.	Participants randomized to Group 3 will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses. levetiracetam: Levetiracetam is an anti-seizure medication. Participants will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses.	Participants randomized to Group 4 will receive no drug intervention.
Period Title: Overall Study
STARTED	24	5	16	7
COMPLETED	6	3	8	2
NOT COMPLETED	18	2	8	5

Baseline Characteristics

Arm/Group Title	Phenytoin	Valproate	Levetiracetam	No Anticonvulsant	Total
Arm/Group Description	Participants randomized to Group 1 will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses. phenytoin: Phenytoin is a anti-seizure medication. Participants will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses.	Participants randomized to Group 2 will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses or in a once-daily extended release formulation. valproate: Valproate is an anti-seizure medication. Participants will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses.	Participants randomized to Group 3 will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses. levetiracetam: Levetiracetam is an anti-seizure medication. Participants will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses.	Participants randomized to Group 4 will receive no drug intervention.	Total of all reporting groups
Overall Participants	24	5	16	7	52
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	48.5	46	51	49	48
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	22 91.7%	5 100%	14 87.5%	5 71.4%	46 88.5%
>=65 years	2 8.3%	0 0%	2 12.5%	2 28.6%	6 11.5%
Sex: Female, Male (Count of Participants)
Female	14 58.3%	4 80%	10 62.5%	6 85.7%	34 65.4%
Male	10 41.7%	1 20%	6 37.5%	1 14.3%	18 34.6%
Region of Enrollment (participants) [Number]
United States	24 100%	5 100%	16 100%	7 100%	52 100%

Outcome Measures

1. Primary Outcome

Title	Change in Serum Cholesterol, Non-HDL Cholesterol, HDL Cholesterol, Lipoprotein(a), and C-reactive Protein From Baseline to Second Draw and Third Draw in Each of the 4 Study Arms
Time Frame	8 weeks, 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenytoin	Valproate	Levetiracetam	No Anticonvulsant
Arm/Group Description	Participants randomized to Group 1 will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses. phenytoin: Phenytoin is a anti-seizure medication. Participants will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses. They will be maintained on it throughout the study period. x x	Participants randomized to Group 2 will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses or in a once-daily extended release formulation. valproate: Valproate is an anti-seizure medication. Participants will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses.	Participants randomized to Group 3 will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses. levetiracetam: Levetiracetam is an anti-seizure medication. Participants will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses.	Participants randomized to Group 4 will receive no drug intervention.
Measure Participants	0	0	0	0

2. Secondary Outcome

Title	Incidence of Acute Seizures, Incidence of Late Seizures, Overall Neurologic Function (as Measured by Modified Rankin Scale Scores)
Time Frame	8 weeks, 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Phenytoin		Valproate		Levetiracetam		No Anticonvulsant
Arm/Group Description	Participants randomized to Group 1 will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses. phenytoin: Phenytoin is a anti-seizure medication. Participants will receive phenytoin (PHT) at 5 mg/kg/day in 2 divided doses. They will be maintained on it throughout the study period. x x		Participants randomized to Group 2 will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses or in a once-daily extended release formulation. valproate: Valproate is an anti-seizure medication. Participants will receive valproate (VPA) at 15 mg/kg/day in 3 divided doses.		Participants randomized to Group 3 will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses. levetiracetam: Levetiracetam is an anti-seizure medication. Participants will receive levetiracetam (LEV) 1000-1500 mg/day in 2 divided doses.		Participants randomized to Group 4 will receive no drug intervention.
All Cause Mortality
	Phenytoin		Valproate		Levetiracetam		No Anticonvulsant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phenytoin		Valproate		Levetiracetam		No Anticonvulsant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/24 (16.7%)		1/5 (20%)		4/16 (25%)		3/7 (42.9%)
Immune system disorders
drug fever	1/24 (4.2%)		0/5 (0%)		0/16 (0%)		0/7 (0%)
Nervous system disorders
vasospasm	1/24 (4.2%)		1/5 (20%)		2/16 (12.5%)		1/7 (14.3%)
hydrocephalus	1/24 (4.2%)		0/5 (0%)		1/16 (6.3%)		0/7 (0%)
cerebral infarction	0/24 (0%)		0/5 (0%)		0/16 (0%)		1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
pulmonary edema	0/24 (0%)		0/5 (0%)		0/16 (0%)		1/7 (14.3%)
Vascular disorders
deep venous thrombosis	1/24 (4.2%)		0/5 (0%)		1/16 (6.3%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Phenytoin		Valproate		Levetiracetam		No Anticonvulsant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		1/5 (20%)		0/16 (0%)		0/7 (0%)
Infections and infestations
urinary tract infection	0/24 (0%)		1/5 (20%)		0/16 (0%)		0/7 (0%)

Limitations/Caveats

Study terminated due to 1) change in clinical practice; 2) inadequate recruitment and follow-up. Number of pts providing full data was <15% of goal. Because of this, any analysis of data was considered futile, and no analyses were performed.

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.