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

• 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: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Sherwood Brown, University of Texas Southwestern Medical Center

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Healthy
• Interventions: Drug: Phenytoin (brand name Dilantin); Drug: Hydrocortisone; Drug: Placebo
• Enrollment: 17

Participant Flow

Recruitment Details	Enrollment began 3/11/2008 and was completed 4/23/2009. Subjects were recruited through flyers posted at UTSW medical clinics.
Pre-assignment Details	Subjects were enrolled and randomized to one out of 4 treatments. The study design is a 4-phase crossover study, meaning all subjects received all four treatments during the course of the study. Subjects washed out of each medication cycle for 21 days before beginning the next treatment cycle. Total number of subjects enrolled is 17.

Arm/Group Title	PH + PL Then PL + H Then PL + H Then PL + PL	PH + H Then PH + PL Then PL + H Then PL + PL	PL + PL Then PH + PL Then PH + H Then PL + H	PL + H Then PL + PL Then PH + PL Then PH + H	PL + H Then PH + PL Then PL + PL Then PH + H	PL + H Then PL + PL Then PH + H Then PH + PL	PL + H Then PH +H Then PH + PL Then PL + PL	PL + H Then PH + H Then PL + PL Then PH + PL	PL + H Then PH + PL Then PH + H Then PL + PL	PH + H Then PL + H Then PL + PL Then PH + PL	PH + H Then PL + H Then PH + PL Then PL + PL	PH + H Then PH + PL Then PL + PL Then PL + H	PH + H Then PL + PL Then PH + PL Then PL + H	PH + H Then PL + PL Then PL + H Then PH + PL	PH + PL Then PL + PL Then PH + H Then PL + H	PH + PL Then PL + PL Then PL + H Then PH + H	PH + PL Then PH + H Then PL + PL Then PL + H	PH + PL Then PH + H Then PL + H Then PL + PL	PL + PL Then PH + PL Then PL + H Then PH + H	PL + PL Then PH + H Then PH + PL Then PL + H	PL + PL Then PL + H Then PH + PL Then PH + H	PL + PL Then PL + H Then PH + H Then PH + PL	PL + PL Then PH + H Then PL + H Then PH + PL	PH + PL Then PL + H Then PL + PL Then PH + H
Arm/Group Description	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400 mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets followed by hydrocortisone (160 mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400 mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone 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 imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours (20mg) and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin (400mg/day) followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400 mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.
Period Title: Overall Study
Started	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	1	0	1	0	1	0	1	1	1
Treatment #2	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	0	0	1	0	1	0	1	1	1
Treatment #3	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	0	0	1	0	1	0	1	1	1
Treatment #4	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	0	0	1	0	1	0	1	0	0
Completed	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	0	0	1	0	1	0	1	0	0
Not Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1	1
Reason Not Completed
Withdrawal by Subject	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Adverse Event	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0

Baseline Characteristics

Arm/Group Title		Total Study Population
Arm/Group Description		Seventeen healthy controls, in a one-hour imaging session, received a structural MRI, 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 received placebo + placebo, phenytoin + placebo, hydrocortisone + placebo, or hydrocortisone + phenytoin in a random fashion. Thus, each participant received 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 was assessed.
Overall Number of Baseline Participants		17
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	17 participants
	<=18 years	2 11.8%
	Between 18 and 65 years	15 88.2%
	>=65 years	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	17 participants
		27.1 (9.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	17 participants
	Female	9 52.9%
	Male	8 47.1%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	17 participants
		17

Outcome Measures

1. Primary Outcome

Title	Difference in RAVLT Total T-Score Between Treatments
Description	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.
Time Frame	At end of each treatment condition (on average 21 days between treatments)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenytoin&Hydrocortisone	Placebo&Placebo	Phenytoin&Placebo	Placebo&Hydrocortisone
Arm/Group Description:	Examining all participants for the condition in which they took both phenytoin and hydrocortisone.	Examining all participants for the condition in which they took placebo for both administrations.	Examining all participants for the condition in which they took phenytoin and placebo.	Examining all participants for the condition in which they took placebo and hydrocortisone.
Overall Number of Participants Analyzed	15	16	16	15
Mean (Standard Error); Unit of Measure: T-score
	57.76 (0.51)	56.11 (0.67)	53.08 (0.45)	42.76 (2.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, Placebo&Hydrocortisone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.01
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, Placebo&Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.12
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo&Placebo, Phenytoin&Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.15
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Placebo, Placebo&Hydrocortisone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.10
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

2. Secondary Outcome

Title	Hippocampal Activation Differences Between Treatment Conditions
Description	[Not Specified]
Time Frame	At the end of each treatment condition

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenytoin&Hydrocortisone	PBO&PBO	Phenytoin&PBO	PBO&Hydrocortisone
Arm/Group Description:	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). Beginning two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone (20 mg) 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 imaging will be performed at 1300 hours.	Participants will take two capsules containing 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 placebo), participants will begin taking 4 tablets of 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 imaging will be performed at 1300 hours.	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). Beginning two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing 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 imaging will be performed at 1300 hours.	Participants will take two capsules containing 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 placebo), participants will begin taking 4 tablets containing hydrocortisone (20 mg) 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 imaging will be performed at 1300 hours.
Overall Number of Participants Analyzed	13	15	15	14
Mean (Standard Deviation); Unit of Measure: percentage of BOLD activation
	1.035 (0.180)	1.288 (.06)	1.135 (0.161)	1.121 (0.144)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, PBO&Hydrocortisone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.08
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, PBO&PBO
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.01
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	PBO&PBO, Phenytoin&PBO
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.01
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	PBO&PBO, PBO&Hydrocortisone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.02
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

3. Secondary Outcome

Title	Para-Hippocampal Activation Differences Between Treatment Conditions
Description	[Not Specified]
Time Frame	At the end of each treatment condition

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenytoin&Hydrocortisone	PBO&PBO	Phenytoin&PBO	PBO&Hydrocortisone
Arm/Group Description:	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). Beginning two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone (20 mg) 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 imaging will be performed at 1300 hours.	Participants will take two capsules containing placebo by mouth at 0900 hours and 2100 hours 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 placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours.	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). Beginning two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours.	Participants will take two capsules containing placebo by mouth at 0900 hours and 2100 hours 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 placebo), participants will begin taking 4 tablets containing hydrocortisone (20 mg) 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 imaging will be performed at 1300 hours.
Overall Number of Participants Analyzed	13	15	15	14
Mean (Standard Deviation); Unit of Measure: percentage of BOLD activation
	1.293 (0.264)	1.604 (0.315)	1.464 (0.246)	1.401 (0.202)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, PBO&Hydrocortisone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.08
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, PBO&PBO
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.01
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	PBO&PBO, Phenytoin&PBO
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.11
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	PBO&PBO, PBO&Hydrocortisone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.06
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Adverse Events

Time Frame	Throughout entirety of trial
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Phenytoin, Then Hydrocortisone		Phenytoin, Then Placebo		Placebo, Then Hydrocortisone		Placebo, Then Placebo
Arm/Group Description	Placebo, Placebo Phenytoin, Dilantin : 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 imaging will be performed at 1300 hours.		Phenytoin, Placebo Phenytoin, Dilantin : 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 imaging will be performed at 1300 hours.		Hydrocortisone, Placebo Phenytoin, Dilantin : 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 imaging will be performed at 1300 hours.		Hydrocortisone, Phenytoin Phenytoin, Dilantin : 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 imaging will be performed at 1300 hours.
All-Cause Mortality
	Phenytoin, Then Hydrocortisone		Phenytoin, Then Placebo		Placebo, Then Hydrocortisone		Placebo, Then Placebo
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--		--/--
Serious Adverse Events
	Phenytoin, Then Hydrocortisone		Phenytoin, Then Placebo		Placebo, Then Hydrocortisone		Placebo, Then Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/16 (6.25%)		0/16 (0.00%)		1/14 (7.14%)		0/15 (0.00%)
General disorders
MRI anxiety * [1]	0/16 (0.00%)	0	0/16 (0.00%)	0	1/14 (7.14%)	1	0/15 (0.00%)	0
Nervous system disorders
Pre-existing condition discovered during MRI * [2]	1/16 (6.25%)	1	0/16 (0.00%)	0	0/14 (0.00%)	0	0/15 (0.00%)	0
* Indicates events were collected by non-systematic assessment; [1] Physical symptoms manifesting from stress of MRI scan during scan (e.g. difficulty breathing, sweating, tremors, disorientation, etc.); [2] Mega cisterna magna discovered at initial MRI. Determined to be benign.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Phenytoin, Then Hydrocortisone		Phenytoin, Then Placebo		Placebo, Then Hydrocortisone		Placebo, Then Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0.00%)		0/16 (0.00%)		0/14 (0.00%)		0/15 (0.00%)

Limitations and Caveats

The sample size in this pilot study was modest; The duration of exposure to hydrocortisone was subacute;

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: E. Sherwood Brown
• Organization: The University of Texas Southwestern Medical Center
• Phone: 214 645 6950
• EMail: sherwood.brown@utsouthwestern.edu

• Responsible Party: Sherwood Brown, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT00591006
• Other Study ID Numbers: 1R21MH078182 ( U.S. NIH Grant/Contract )
• First Submitted: December 27, 2007
• First Posted: January 11, 2008
• Results First Submitted: July 8, 2013
• Results First Posted: August 19, 2015
• Last Update Posted: August 19, 2015