Phenytoin and Driving Safety: A Randomized, Controlled Cross-Over Study

Sponsor
University of Iowa (Other)
Overall Status
Completed
CT.gov ID
NCT00581893
Collaborator
(none)
20
1
2
40
0.5

Study Details

Study Description

Brief Summary

Automobile driving is a crucial aspect of everyday life, yet vehicular crashes represent a serious public health problem. Patients with epilepsy are at elevated risk for automobile crashes, causing great personal suffering and financial costs to society. Most collisions involving epileptic drivers are not seizure related but may instead result from cognitive effects upon driving performance of epilepsy and antiepileptic drugs (AEDs). Several million American drivers take AEDs for treatment of medical conditions besides epilepsy and may also be at risk for cognitive impairments that can reduce driving performance. Empirical evidence of the effects of AEDs on driving performance would enable development of driving guidelines that could lower the risk of injurious motor vehicle collisions; however, this evidence is currently lacking. The broad goal of our project is to determine the specific effects of the most commonly utilized AED, phenytoin, by assessing driving performance and cognitive abilities in neurologically normal volunteers taking phenytoin in a randomized, double-blind, placebo-controlled, crossover study. Our proposed experiments will assess: (1) cognitive functions using standardized neuropsychological tests (of attention, perception, memory, and executive functions), (2) driving performance during phenytoin and placebo administration, and (3) the effects of phenytoin-related cognitive performance upon driving performance. To measure driving performance, we will use a state-of-the-art fixed-base interactive driving simulator that allows us to observe driver errors in an environment that is challenging yet safe for the driver and tester, under conditions of optimal stimulus and response control. The results of this study of 30 drivers treated with phenytoin and placebo will increase the understanding of the role of AED-related cognitive impairment on driving safety errors. A better understanding of the impact of AEDs upon driving performance is necessary to rationally develop interventions that could help prevent crashes by drivers treated with AEDs.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

Patients with epilepsy are at elevated risk for automobile crashes, causing great personal suffering and financial costs to society. Most collisions involving epileptic drivers are not seizure related but may instead result from cognitive effects upon driving performance of epilepsy and antiepileptic drugs (AEDs). Several million American drivers take AEDs for treatment of medical conditions besides epilepsy and may also be at risk for cognitive impairments that can reduce driving performance. Empirical evidence of the effects of AEDs on driving performance would enable development of driving guidelines that could lower the risk of injurious motor vehicle collisions; however, this evidence is currently lacking.

The broad goal of the current project is to determine the specific effects of AEDs on cognitive function and driving performance. To address this goal we will assess driving performance and cognitive abilities in neurologically normal volunteers taking phenytoin (Dilantin), the most commonly prescribed AED. Effects of phenytoin on driving performance and cognition will be addressed in a randomized, double-blind, placebo-controlled, crossover study. Driver cognition will be assessed using a battery of neuropsychological tests. Driving performance will be objectively assessed in all participants on standardized tasks enacted in a state-of-the-art driving simulator. Our 3 Specific Aims are:

Aim 1: To assess the effects of phenytoin on cognitive abilities that are crucial to the driving task, including perception, attention, memory, and executive function.

Hypothesis 1: A driver's cognitive abilities will decline during steady-state phenytoin administration compared to placebo. Drivers with higher blood levels of phenytoin will show greater decline.

Aim 2: To assess effects of phenytoin on driving performance and safety errors in a state-of-the-art driving simulator.

Hypothesis 2: Driving performance will decline and driver safety errors will increase during phenytoin administration compared to placebo. Drivers with higher blood levels of phenytoin will show greater impairments of driving.

Aim 3: To assess the effects of phenytoin-related cognitive impairments upon driving performance in a state-of-the-art driving simulator.

Hypothesis 3. Impairments of cognitive function affecting perception, attention, memory, executive function, and arousal will increase the likelihood of driver errors that may lead to a crash.

Our hypotheses would be supported if the drivers taking phenytoin, as opposed to placebo, demonstrate worse cognitive performance on neuropsychological tests, and more safety errors and crashes in the simulator. The hypotheses would also be supported if drivers with higher phenytoin levels show greater impairments of cognition and driving. Once the effects of phenytoin on driving performance are demonstrated in this project, we will have evidence to support more comprehensive research addressing specific dosing and serum levels and acute versus chronic administration.

There is currently no evidence concerning the effects of phenytoin on driving performance. Accurate driving performance data on patients receiving phenytoin would allow determination of fair and accurate criteria for making recommendations to drive or not to drive affecting millions of patients taking AEDS for epilepsy and other conditions. These data could also help reduce the risk of car crashes due to medication side effects.

Study Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Other
Official Title:
Phenytoin and Driving Safety: A Randomized, Controlled Cross-Over Study
Study Start Date :
Aug 1, 2005
Actual Primary Completion Date :
Dec 1, 2008
Actual Study Completion Date :
Dec 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Experimental: 1

Phenytoin administration

Drug: Phenytoin
Phenytoin will be dosed to a target dose of 5 mg/kg qhs for one month
Other Names:
  • Dilantin
  • Placebo Comparator: 2

    Placebo

    Drug: Placebo oral capsule
    Placebo

    Outcome Measures

    Primary Outcome Measures

    1. Number of Subjects Who Had a Driving Simulator Crash Event [1 month]

      Number of subjects who had a crash event during the driving simulator test.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    25 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    • Anticipating a 10-15% drop-out rate, we will induct 30 neurologically normal subjects (age 18 (21) -60) to obtain 25 evaluable subjects who are legally licensed to drive in their state of residence and have been actively driving under appropriate legal guidelines for at least 5 years (to minimize performance variations of novice drivers).

    • Because this study is intended to determine the potential effects of phenytoin on driving performance, a relatively healthy cohort of patients must be chosen. Chronic medical or psychiatric conditions could cause significant alterations in driving performance independent of those caused by phenytoin, which would complicate interpretation of performance impairments.

    Exclusion Criteria:
    • Subjects who are younger than 18 or older than 60

    • Have history of prior seizures, family history of epilepsy, or prior history of head injury

    • Have a known history of prior drug or alcohol abuse or unwillingness to abstain from drug or alcohol use during the study period

    • Have a past or current active neurological or psychiatric disorder that could impair cognitive or driving performance (i.e. baseline IQ < 90, dementia, mental retardation, stroke, severe head injury, schizophrenia, active clinical depression, progressive brain tumor).

    • Subjects who have a chronic medical condition (i.e. diabetes mellitus, renal insufficiency, congestive heart failure, hepatic dysfunction, hematologic condition, HIV)

    • Taking medications known to affect the central nervous system (i.e. baseline pre-study treatment with antiepileptic drug, anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, narcotics and tranquilizers)

    • Regularly use over-the-counter cough suppressants, antihistamines, or sleep aids; or who ingest over 7 cups of daily coffee or currently smoke cigarettes.

    • Subjects will be excluded if they cannot complete SIREN testing or neuropsychological instruments because of visual or hearing impairment (history or screening discovery of corrected visual acuity of less than 20/50) or other physical disability, or if they have a history of severe motion sickness as an adult-a marker for patients who develop simulator sickness and therefore cannot participate in SIREN testing.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Iowa Hospitals and Clinics Iowa City Iowa United States 52242

    Sponsors and Collaborators

    • University of Iowa

    Investigators

    • Principal Investigator: Erik K St. Louis, M.D., University of Iowa

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Erik St. Louis, Assistant Professor (Clinical), University of Iowa
    ClinicalTrials.gov Identifier:
    NCT00581893
    Other Study ID Numbers:
    • 200512712
    • 5R49CE721682-05
    First Posted:
    Dec 28, 2007
    Last Update Posted:
    Jul 1, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Erik St. Louis, Assistant Professor (Clinical), University of Iowa
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Phenytoin First, Then Placebo Placebo First, Then Phentoin
    Arm/Group Description Subjects first received Phenytoin target dose of 5 mg/kg qhs for one month. After a 14 day washout period, they received the placebo treatment for one month. Subjects first received Placebo for one month. After a 14 day washout period, they received Phenytoin target dose of 5 mg/kg qhs for one month.
    Period Title: First Intervention (1 Month)
    STARTED 10 10
    COMPLETED 10 10
    NOT COMPLETED 0 0
    Period Title: First Intervention (1 Month)
    STARTED 10 10
    COMPLETED 10 10
    NOT COMPLETED 0 0
    Period Title: First Intervention (1 Month)
    STARTED 10 10
    COMPLETED 7 8
    NOT COMPLETED 3 2

    Baseline Characteristics

    Arm/Group Title Cross-over Design
    Arm/Group Description Subjects will be studied on two occasions, in random order. They will randomly be assigned to received either Phenytoin target dose of 5 mg/kg qhs for one month or placebo treatment for one month. After a 14 day washout period, they will receive the opposite treatment from the original.
    Overall Participants 20
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    38.8
    (12.7)
    Sex: Female, Male (Count of Participants)
    Female
    11
    55%
    Male
    9
    45%
    Race and Ethnicity Not Collected (Count of Participants)
    Region of Enrollment (participants) [Number]
    United States
    20
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Subjects Who Had a Driving Simulator Crash Event
    Description Number of subjects who had a crash event during the driving simulator test.
    Time Frame 1 month

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Phenytoin Placebo
    Arm/Group Description Phenytoin target dose of 5 mg/kg Placebo oral capsule
    Measure Participants 20 20
    Count of Participants [Participants]
    2
    10%
    0
    NaN
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phenytoin, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.50
    Comments
    Method McNemar
    Comments

    Adverse Events

    Time Frame Adverse Events were collected from baseline to end of study, approximately 2.5 months, for an overall duration of approximately three years.
    Adverse Event Reporting Description
    Arm/Group Title Phenytoin Placebo
    Arm/Group Description Phenytoin target dose of 5 mg/kg qhs Placebo oral capsule
    All Cause Mortality
    Phenytoin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/20 (0%) 0/20 (0%)
    Serious Adverse Events
    Phenytoin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/20 (0%) 0/20 (0%)
    Other (Not Including Serious) Adverse Events
    Phenytoin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/20 (0%) 0/20 (0%)

    Limitations/Caveats

    The very small sample size of evaluable subjects prevents definitive conclusions on the safety hazards of phenytoin for driving performance.

    More Information

    Certain Agreements

    All Principal Investigators ARE 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 Erik St. Louis
    Organization University of Iowa
    Phone 507-266-7456
    Email StLouis.Erik@mayo.edu
    Responsible Party:
    Erik St. Louis, Assistant Professor (Clinical), University of Iowa
    ClinicalTrials.gov Identifier:
    NCT00581893
    Other Study ID Numbers:
    • 200512712
    • 5R49CE721682-05
    First Posted:
    Dec 28, 2007
    Last Update Posted:
    Jul 1, 2021
    Last Verified:
    Jun 1, 2021