Cognitive Deficits
Conditions
Keywords
Healthy volunteers, Topiramate, Neurocognition, Drug-induced cognitive deficits
Brief summary
Cognitive impairment is a widely reported side effect of many commonly used drugs. Even a mild, untoward effect on an essential function such a linguistic behavior, a directly observable product of complex cognitive processes, is disruptive to daily life. Nevertheless, the mechanisms underlying a drug's impact on cognition are poorly understood. This lack of understanding impedes the ability to predict both the effects of drugs in development and the degree to which an individual is vulnerable to the cognitive impact of a particular agent. Topiramate (TPM, an antiepileptic drug) is, with increasing frequency, being prescribed for a range of conditions including migraine prophylaxis, obesity and pain. It is a prime example of a drug that causes speech and language problems severe enough in some patients to result in discontinuation of therapy. For reasons not well understood, TPM has a poorer cognitive profile than many of the older antiepileptic drugs. The investigators' rational for this study is that it will offer insight into the mechanisms underlying drug-induced cognitive deficits.
Detailed description
The investigators' long-term goal is to enhance clinical strategies and inform drug development in order to maximize the benefits of individual drug therapy while minimizing adverse cognitive/language-related side effects. The investigators' objective in this application is to elucidate the relationship among drug exposure as measured by plasma drug levels, its neurophysiological effects, and consequent effects on the cognitive processes observable in everyday language use. Using topiramate (TPM) as a prototype, the investigators will apply the tools of clinical pharmacology, computational linguistics, neuroscience, and engineering to the design and execution of randomized, double blind, crossover studies using three (3) doses of TPM, one (1) dose of a comparator drug (lorazepam-LZP) and a placebo. In order to isolate the cognitive effects of TPM from those possibly arising from an underlying medical condition, subjects will be healthy adults. The investigators will capitalize on an innovative system for automated language and speech analysis (SALSA) developed in our laboratory, to quantify the effects of TPM administration on effective language use, a crucial component of normal day-to-day functioning.
Interventions
DRUGLorazepam
Lorazepam: 2mg, po, 1x
OTHERPlacebo
Non-active placebo, po, 1x
DRUGTopiramate 100mg
Topiramate: 100 mg, po, 1x
DRUGTopiramate 150mg
Topiramate: 150 mg, po, 1x
DRUGTopiramate 200mg
Topiramate: 200 mg, po, 1x
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy men and women * Ages 18-50 * Women are post-menopausal or using approved birth control methods * To control for brain lateralization of language functions, subjects need to have a dominant right hand.
Exclusion criteria
* Presence of clinically significant cardiovascular, endocrine, hematopoietic, hepatic, renal, neurologic, and/or psychiatric disease including suicidality * Vision or hearing impairments * Current or a history of drug or alcohol abuse * living outside of the Twin Cities Metropolitan area. * The use of concomitant medications known to affect Topiramate (TPM), Lorazepam (LZP), or the use of any concomitant medications that may alter cognitive function * Prior adverse reaction or prior hypersensitivity to TPM, LZP or related compounds * A positive pregnancy test (administered to all women before enrollment, and prior to each study session). * Subjects who have received any investigational drug within the previous 30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in COWA Unique Word Count | Session 1 to Session 5 | Study has 3 arms (100mg, 150mg, or 200mg topiramate) and 3 periods per arm (topiramate, 2mg lorazepam, or placebo). Topiramate (TPM), Lorazepam (LZP), or Placebo (PLA) was given to the participant at the beginning of Sessions 2, 3, and 4 (crossover design). No drug was given at Sessions 1 and 5. The baseline value was defined as the average of the values at Session 1 and Session 5. The change from baseline for Topiramate is the value at 2.5 hours post-dose at the Topiramate visit minus the value at baseline, divided by the value at baseline; similarly for Lorazepam and Placebo. |
| Change From Baseline in Spontaneous Narrative Raw Word Count | Session 1 to Session 5 | Study has 3 arms (100mg, 150mg, or 200mg topiramate) and 3 periods per arm (topiramate, 2mg lorazepam, or placebo). Topiramate (TPM), Lorazepam (LZP), or Placebo (PLA) was given to the participant at the beginning of Sessions 2, 3, and 4 (crossover design). No drug was given at Sessions 1 and 5. The baseline value was defined as the average of the values at Session 1 and Session 5. The change from baseline for Topiramate is the value at 2.5 hours post-dose at the Topiramate visit minus the value at baseline, divided by the value at baseline; similarly for Lorazepam and Placebo. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Topiramate 100mg Randomized to Topiramate; 100mg; lorazepam 2mg or placebo; Each subject in this arm received each treatment in random order with a two-week washout between treatments
Topiramate: Topiramate: 100 mg, 150 mg or 200 mg, po, 1x | 14 |
| Topiramate 150mg Randomized to Topiramate; 150mg; lorazepam 2mg or placebo; Each subject in this arm received each treatment in random order with a two-week washout between treatments
Lorazepam: Lorazepam: 2mg, po, 1x | 15 |
| Topiramate 200mg Randomized to Topiramate; 200 mg; lorazepam 2mg or placebo; Each subject in this arm received each treatment in random order with a two-week washout between treatments
Placebo | 17 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| First Intervention | Adverse Event | 1 | 1 | 1 |
| First Intervention | Protocol Violation | 0 | 1 | 1 |
| First Intervention | Study ending | 0 | 1 | 0 |
| Second Intervention | Adverse Event | 0 | 0 | 1 |
| Second Intervention | Study ending | 1 | 0 | 0 |
| Second Intervention | Withdrawal by Subject | 0 | 0 | 1 |
| Third Intervention | Protocol Violation | 1 | 0 | 0 |
| Third Intervention | Withdrawal by Subject | 2 | 2 | 0 |
Baseline characteristics
| Characteristic | Topiramate 150mg | Topiramate 200mg | Total | Topiramate 100mg |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 17 Participants | 46 Participants | 14 Participants |
| Age, Continuous | 38.54 Years STANDARD_DEVIATION 10.21 | 26.41 Years STANDARD_DEVIATION 8.42 | 28.52 Years STANDARD_DEVIATION 9.99 | 31.9 Years STANDARD_DEVIATION 11.48 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 12 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 9 Participants | 25 Participants | 8 Participants |
| Region of Enrollment United States | 15 participants | 17 participants | 46 participants | 14 participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 24 Participants | 8 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 22 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 | 0 / 17 | 0 / 46 | 0 / 46 |
| other Total, other adverse events | 0 / 14 | 0 / 15 | 1 / 17 | 0 / 46 | 0 / 46 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 | 0 / 17 | 0 / 46 | 0 / 46 |
Outcome results
Primary
Change From Baseline in COWA Unique Word Count
Study has 3 arms (100mg, 150mg, or 200mg topiramate) and 3 periods per arm (topiramate, 2mg lorazepam, or placebo). Topiramate (TPM), Lorazepam (LZP), or Placebo (PLA) was given to the participant at the beginning of Sessions 2, 3, and 4 (crossover design). No drug was given at Sessions 1 and 5. The baseline value was defined as the average of the values at Session 1 and Session 5. The change from baseline for Topiramate is the value at 2.5 hours post-dose at the Topiramate visit minus the value at baseline, divided by the value at baseline; similarly for Lorazepam and Placebo.
Time frame: Session 1 to Session 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm: Topiramate 100mg, Period: Topiramate | Change From Baseline in COWA Unique Word Count | -0.407725385 Word Count | Standard Deviation 0.110593408 |
| Arm:Topiramate 150mg, Period: Topiramate | Change From Baseline in COWA Unique Word Count | -0.425898667 Word Count | Standard Deviation 0.186240451 |
| Arm: Topiramate 200mg, Period: Topiramate | Change From Baseline in COWA Unique Word Count | -0.412534118 Word Count | Standard Deviation 0.154640084 |
| Arm: Topiramate 100mg, Period: Lorazepam | Change From Baseline in COWA Unique Word Count | -0.108298333 Word Count | Standard Deviation 0.240452491 |
| Arm: Topiramate 150mg, Period: Lorazepam | Change From Baseline in COWA Unique Word Count | 0.131452143 Word Count | Standard Deviation 0.263967943 |
| Arm: Topiramate 200mg, Period: Lorazepam | Change From Baseline in COWA Unique Word Count | -0.095221176 Word Count | Standard Deviation 0.228163172 |
| Arm: Topiramate 100mg, Period: Placebo | Change From Baseline in COWA Unique Word Count | -0.011651538 Word Count | Standard Deviation 0.152526619 |
| Arm: Topiramate 150mg, Period: Placebo | Change From Baseline in COWA Unique Word Count | 0.077431333 Word Count | Standard Deviation 0.176020802 |
| Arm: Topiramate 200mg, Period: Placebo | Change From Baseline in COWA Unique Word Count | 0.047164706 Word Count | Standard Deviation 0.166162762 |
Primary
Change From Baseline in Spontaneous Narrative Raw Word Count
Study has 3 arms (100mg, 150mg, or 200mg topiramate) and 3 periods per arm (topiramate, 2mg lorazepam, or placebo). Topiramate (TPM), Lorazepam (LZP), or Placebo (PLA) was given to the participant at the beginning of Sessions 2, 3, and 4 (crossover design). No drug was given at Sessions 1 and 5. The baseline value was defined as the average of the values at Session 1 and Session 5. The change from baseline for Topiramate is the value at 2.5 hours post-dose at the Topiramate visit minus the value at baseline, divided by the value at baseline; similarly for Lorazepam and Placebo.
Time frame: Session 1 to Session 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm: Topiramate 100mg, Period: Topiramate | Change From Baseline in Spontaneous Narrative Raw Word Count | -0.01596 Word Count | Standard Deviation 0.360237984 |
| Arm:Topiramate 150mg, Period: Topiramate | Change From Baseline in Spontaneous Narrative Raw Word Count | -0.131732 Word Count | Standard Deviation 0.192165204 |
| Arm: Topiramate 200mg, Period: Topiramate | Change From Baseline in Spontaneous Narrative Raw Word Count | -0.323135625 Word Count | Standard Deviation 0.297067179 |
| Arm: Topiramate 100mg, Period: Lorazepam | Change From Baseline in Spontaneous Narrative Raw Word Count | 0.109636 Word Count | Standard Deviation 0.236323153 |
| Arm: Topiramate 150mg, Period: Lorazepam | Change From Baseline in Spontaneous Narrative Raw Word Count | 0.016635385 Word Count | Standard Deviation 0.283748379 |
| Arm: Topiramate 200mg, Period: Lorazepam | Change From Baseline in Spontaneous Narrative Raw Word Count | -0.128177333 Word Count | Standard Deviation 0.281246222 |
| Arm: Topiramate 100mg, Period: Placebo | Change From Baseline in Spontaneous Narrative Raw Word Count | 0.117455385 Word Count | Standard Deviation 0.360519103 |
| Arm: Topiramate 150mg, Period: Placebo | Change From Baseline in Spontaneous Narrative Raw Word Count | -0.01098 Word Count | Standard Deviation 0.272331286 |
| Arm: Topiramate 200mg, Period: Placebo | Change From Baseline in Spontaneous Narrative Raw Word Count | 0.011456471 Word Count | Standard Deviation 0.225720885 |