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Phenytoin as a Neuroprotective Agent Against Corticosteroid-induced Functional Imaging Changes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00591006
Recruitment Status : Completed
First Posted : January 11, 2008
Results First Posted : August 19, 2015
Last Update Posted : August 19, 2015
Sponsor:
Information provided by (Responsible Party):
Sherwood Brown, University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE December 27, 2007
First Posted Date  ICMJE January 11, 2008
Results First Submitted Date  ICMJE July 8, 2013
Results First Posted Date  ICMJE August 19, 2015
Last Update Posted Date August 19, 2015
Study Start Date  ICMJE January 2008
Actual Primary Completion Date July 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 12, 2015)
Difference in RAVLT Total T-Score Between Treatments [ Time Frame: At end of each treatment condition (on average 21 days between treatments) ]
The Rey Auditory Verbal Learning Test (RAVLT) evaluates a wide diversity of functions, including short-term auditory-verbal memory, and retention of information. Test raw scores are converted to T-scores. T-scores have a mean of 30 ± 10 where higher scores are indicative of better verbal memory. Total T-score differences following study treatment interventions are reported.
Original Primary Outcome Measures  ICMJE
 (submitted: January 10, 2008)
Scored Memory and Mood Assessments specified; fMRI Neuroimaging data obtained through Novelty Detection Tasks; Structural MRI and MRS measuring Hippocampal volume and activation [ Time Frame: 3 days after introduction to Phenytoin/Hydrocortisone or Placebo ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2015)
  • Hippocampal Activation Differences Between Treatment Conditions [ Time Frame: At the end of each treatment condition ]
  • Para-Hippocampal Activation Differences Between Treatment Conditions [ Time Frame: At the end of each treatment condition ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phenytoin as a Neuroprotective Agent Against Corticosteroid-induced Functional Imaging Changes
Official Title  ICMJE Phenytoin as a Neuroprotective Agent Against Corticosteroid-induced Functional Imaging Changes
Brief Summary

The purpose of this research is to determine if patients who receive phenytoin (also commonly known as Dilantin) before taking corticosteroids will show less memory impairment and hypomanic symptoms (feelings of agitation, overexcitement or hyperactivity) than those receiving placebo (an inactive substance). This research also seeks to determine if patients taking phenytoin before corticosteroids show more activity in the area of the brain involved with memory than those receiving placebo.

This research is being done because increased levels of cortisol (the body's natural corticosteroid) in the body are frequently associated with forgetfulness, and interventions that may prevent or reverse this effect are of great importance.

Detailed Description

Introduction and aims: Stress and corticosteroid exposure are associated with changes in the human and animal hippocampus. In animals, phenytoin prevents dendritic changes in the hippocampus secondary to corticosterone. We propose to use functional magnetic resonance imaging (fMRI) to explore the effects of 3-days of exposure to placebo, hydrocortisone, phenytoin and hydrocortisone plus phenytoin on hippocampal activation. If phenytoin attenuates the effects of hydrocortisone, we will use this model system to explore other potential neuroprotective agents

CONCISE SUMMARY OF PROJECT: Sixteen healthy participants will, in a one-hour imaging session, receive a structural magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and fMRI scan four separate times with a 21 day washout between each study drug exposure in a crossover design. Prior to each scan each participant will receive placebo + placebo, phenytoin + placebo, hydrocortisone + placebo, or hydrocortisone + phenytoin in a random fashion. Thus, each participant will receive each of the four possible study drug combinations in a random order with an extended drug washout between each exposure. Hippocampal activation, volume and biochemistry, as well as mood and memory will be assessed. The figure in Appendix I illustrates the study design.

All participants will complete a University of Texas (UT) Southwestern (UTSW) Institutional Review Board (IRB) approved informed consent process and give written consent to participate prior to study entry.

At the first screening visit, demographic information and a complete medical and psychiatric history will be obtained. The Structured Clinical Interview for DSM-IV (SCID) (First et al 1995) will be used to rule out exclusionary psychiatric illnesses. Mood will be assessed with the Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), and Activation (ACT) subscale of the ISS. Cognition will be assessed with the Rey Auditory Verbal Learning Test (RAVLT) (declarative memory-hippocampus), Digit Span Backwards, and two computer tests — the Sternberg Memory Task (SMT, declarative memory-hippocampus) (Sternberg 1969), and Running Memory Continuous Performance Task (RMCPT, working memory-prefrontal cortex) (Baddeley 1986). Alternative versions of the tests will be used throughout the study to minimize any learning effects. For subjects who successfully pass the screening, fMRI sessions will be scheduled, and they will be asked to return 4 days prior to their first scan. If subjects feel uncomfortable answering any questions on the questionnaires during their screening visit, they can refuse to do so, and they will be removed from the study. If any psychological disorders are diagnosed at this stage (e.g., mood disorders such as depression), subjects will be removed from the study and referred either to Parkland hospital or to a private psychiatrist based on their insurance coverage for further evaluations and treatment. If at a later stage any abnormalities are uncovered through imaging, subjects will be notified immediately. Subjects will be provided with a referral to either Parkland Hospital or a different facility based on their insurance coverage. With the subject's consent, we will also notify their primary physician. Pregnancy tests will be obtained for females at baseline and prior to the start of each new medication cycle to ensure that no pregnant women are participating in the study (5 times total during the study).

One day prior to each study drug course, mood will be assessed with HRSD, YMRS, and ACT subscale of Internal State Scale, and cognition will be assessed with the Sternberg Memory Task.

Three days prior to imaging, participants will take two capsules containing phenytoin tablets (100 mg) or identical placebo by mouth at 0900 hours and 2100 hours (400 mg/day) for a total of three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Beginning two days prior to the imaging (the day after initiating the phenytoin or placebo), participants will begin taking 4 tablets containing hydrocortisone (20 mg) or placebo also at 0900 hours and 2100 hours (160 mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The doses were selected to achieve a low therapeutic blood level of phenytoin and stress level of cortisol. Newcomer et al. (1999) used this dose of hydrocortisone in healthy controls. The imaging will be performed at approximately 1300 hours.

Imaging will be performed after each three day exposure to study medications. Mood assessments and the SMT will be conducted at baseline and prior to and after each course of study medication (day medication course begins and on the day of the neuroimaging). The SMT has a large number of equivalent versions and thus can be administered numerous times. By administering prior to each exposure to study drug we can determine whether or not memory will, as expected, have returned to baseline after each washout period. Other cognitive testing including the RAVLT, Digits Backwards, and RMCPT will be performed after each course of study medication. Cognitive testing is not performed prior to receiving the study medication to avoid multiple testing over a short period of time which is unnecessary given the baseline and placebo data which can be used for comparison.

Monitoring study drug levels: Blood will be drawn at baseline (approximately 1400 hours) to assess cortisol levels. Blood will be drawn after each scan (approximately 1400 hours) to assess cortisol and phenytoin levels and to ensure adherence to the medications. We anticipate an increase in cortisol levels following administration of cortisol compared to baseline in subjects taking cortisol, and that therapeutic levels of phenytoin for seizures (10 to 20 mg/l) will be achieved.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: Phenytoin (brand name Dilantin)
    Three days prior to imaging, participants will take two capsules containing phenytoin tablets (100 mg) by mouth at 0900 hours and 2100 hours (400 mg/day) for a total of three days with the last dose at 0900 hours on the day of the imaging (7 doses total).
    Other Names:
    • 5,5-Diphenylhydantoin
    • Fenitoin
    • Antisacer
    • Difenin
    • Dihydan
    • Dilantin
    • Diphenylhydantoin
    • Epamin
    • Hydantol
    • Sodium Diphenylhydantoinate
  • Drug: Hydrocortisone
    Beginning two days prior to the imaging (the day after initiating the phenytoin or placebo), participants will begin taking 4 tablets containing hydrocortisone (20 mg) or placebo also at 0900 hours and 2100 hours (160 mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The doses were selected to achieve a low therapeutic blood level of phenytoin and stress level of cortisol. Newcomer et al. (1999) used this dose of hydrocortisone in healthy controls. The imaging will be performed at approximately 1300 hours.
    Other Names:
    • Cortef
    • Corticosteroids
  • Drug: Placebo
    Participants take two capsules of placebo 100 mg at 0900 hours and 2100 hours for a total of 3 days with the last dose at 0900 hours on the day of imaging (7 doses total). Beginning two days prior to the imaging (the day after initiating placebo), participants will being taking 4 tablets containing placebo (20 mg) also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total).
    Other Name: Sugar pill
Study Arms  ICMJE Experimental: Four Treatments Per Participant
This study has one arm due to a crossover design. All 17 subjects received 4 treatments: placebo then placebo, phenytoin then placebo, placebo then hydrocortisone, and phenytoin then hydrocortisone. Each treatment was randomly assigned and had a unique sequence out of 24 possible sequences.
Interventions:
  • Drug: Phenytoin (brand name Dilantin)
  • Drug: Hydrocortisone
  • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 29, 2012)
17
Original Estimated Enrollment  ICMJE
 (submitted: January 10, 2008)
16
Actual Study Completion Date  ICMJE July 2009
Actual Primary Completion Date July 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 18-50 years
  • Men or women
  • Vision corrected to at least 20-40
  • No tobacco use
  • Education of ≥12 years (No GED)

Exclusion Criteria:

  • History of major psychiatric illness defined as major depressive disorder, bipolar disorder, post traumatic stress disorder, panic disorder, schizoaffective disorder, schizophrenia or eating disorders
  • History of drug or alcohol abuse or dependence
  • History of neurological disorders including seizures, brain surgery, multiple sclerosis, Parkinson's disease
  • Taking central nervous system (CNS) acting medications (e.g. antidepressants, hypnotics)
  • History of allergic reaction or medical contraindication to phenytoin or hydrocortisone therapy
  • Metal implants, claustrophobia or other contraindications to MRI
  • Significant medical conditions (e.g. myocardial infarction, diabetes)
  • Pregnant or nursing women
  • Prisoners
  • History of mental retardation, special education classes, dementia or other severe cognitive disorders
  • Baseline Hamilton Rating Scale for Depression Score > 7
  • History of a suicide attempt
  • History of systemic corticosteroid use or current inhaled corticosteroid use
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00591006
Other Study ID Numbers  ICMJE 1R21MH078182( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sherwood Brown, University of Texas Southwestern Medical Center
Study Sponsor  ICMJE University of Texas Southwestern Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sherwood Brown, M.D.,Ph.D. UT Southwestern Medical Center of Dallas
PRS Account University of Texas Southwestern Medical Center
Verification Date August 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP