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

NCT00591006 | Completed Phase 3 Results

• 1 other identifier: 1R21MH078182
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

Phenytoin; Dilantin; Corticosteroid; Neuroprotection; Mania; Cognition; Mood; Memory; Hydrocortisone; Healthy Controls; MRI; hippocampal activation

Outcome Measures

Primary Outcomes (1)

• Difference in RAVLT Total T-Score 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.

  At end of each treatment condition (on average 21 days between treatments)

Secondary Outcomes (2)

• Hippocampal Activation Differences Between Treatment Conditions

  At the end of each treatment condition

• Para-Hippocampal Activation Differences Between Treatment Conditions

  At the end of each treatment condition

Study Arms (1)

Four Treatments Per Participant

EXPERIMENTAL

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.

Drug: Phenytoin (brand name Dilantin); Drug: Hydrocortisone; Drug: Placebo

Interventions

Phenytoin (brand name Dilantin) DRUG

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).

Also known as: 5,5-Diphenylhydantoin, Fenitoin, Antisacer, Difenin, Dihydan, Dilantin, Diphenylhydantoin, Epamin, Hydantol, Sodium Diphenylhydantoinate

Four Treatments Per Participant

Hydrocortisone DRUG

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.

Also known as: Cortef, Corticosteroids

Four Treatments Per Participant

Placebo DRUG

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).

Also known as: Sugar pill

Four Treatments Per Participant

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead

Study Sites (1)

UT Southwestern Medical Center of Dallas/Parkland Memorial Hospital

Dallas, Texas, 75390-8849, United States

Location

MeSH Terms

Conditions

Mania

Interventions

Phenytoin; Hydrocortisone; Adrenal Cortex Hormones; Sugars

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Hydantoins; Imidazolidines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Carbohydrates

Limitations and Caveats

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

Results Point of Contact

• Title: E. Sherwood Brown
• Organization: The University of Texas Southwestern Medical Center

sherwood.brown@utsouthwestern.edu

214 645 6950

Study Officials

• Sherwood Brown, M.D.,Ph.D.

  UT Southwestern Medical Center of Dallas

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 27, 2007
• First Posted: January 11, 2008
• Study Start: January 1, 2008
• Primary Completion: July 1, 2009
• Study Completion: July 1, 2009
• Last Updated: August 19, 2015
• Results First Posted: August 19, 2015

Record last verified: 2015-08

Locations

US (1)