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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Topiramate 100mg | Experimental | Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 100mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments. |
|
| Topiramate 150mg | Experimental | Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 150mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments. |
|
| Topiramate 200mg | Experimental | Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 200mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lorazepam | Drug | Lorazepam: 2mg, po, 1x |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Session 1 to Session 5 |
| 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. | Session 1 to Session 5 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Susan E. Marino, PhD | Assistant Professor | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Minnesota | Minneapolis | Minnesota | 55414 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32297992 | Derived | Callisto SP, Illamola SM, Birnbaum AK, Barkley CM, Bathena SPR, Leppik IE, Marino SE. Severity of Topiramate-Related Working Memory Impairment Is Modulated by Plasma Concentration and Working Memory Capacity. J Clin Pharmacol. 2020 Sep;60(9):1166-1176. doi: 10.1002/jcph.1611. Epub 2020 Apr 16. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| FG002 | 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 |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
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| First Washout Period of at Least 2 Weeks |
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| Second Intervention |
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| Second Washout Period of at Least 2 Week |
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| Third Intervention |
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| Third Washout Period of at Least 2 Weeks |
|
To address reviewer comments about inconsistencies between participate flow and baseline population: Baseline analysis population is only subjects who completed the trial. The participant flow section is divided into time periods. The baseline characteristics are divided by intervention. The two sections will not correspond.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Topiramate 150mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | Word Count | Session 1 to Session 5 |
|
30 days following the last administration of study drug.
Study is a 3x3 latin square design with 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). Sessions 1 and 5 are washouts.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Eye Twitching | Eye disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Susan Marino | University of Minnesota | 612-624-2964 | marin007@umn.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 15, 2015 | Dec 4, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| ID | Term |
|---|---|
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D008140 | Lorazepam |
| D000077236 | Topiramate |
| ID | Term |
|---|---|
| D001570 | Benzodiazepinones |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
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| Placebo | Other | Non-active placebo, po, 1x |
|
| Topiramate 100mg | Drug | Topiramate: 100 mg, po, 1x |
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| Topiramate 150mg | Drug | Topiramate: 150 mg, po, 1x |
|
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| Topiramate 200mg | Drug | Topiramate: 200 mg, po, 1x |
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| Study ending |
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| NOT COMPLETED |
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| NOT COMPLETED |
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| NOT COMPLETED |
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| NOT COMPLETED |
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| NOT COMPLETED |
|
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 |
| BG002 | 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 |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Standard Deviation | Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Arm:Topiramate 150mg, Period: Topiramate | 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. This is the topiramate period. Topiramate: 150 mg po, 1x |
| OG002 | Arm: Topiramate 200mg, Period: Topiramate | Randomized to Topiramate; 200mg; lorazepam 2mg or placebo; Each subject in this arm received each treatment in random order with a two-week washout between treatments. This is the topiramate period. Topiramate: 200 mg po, 1x |
| OG003 | Arm: Topiramate 100mg, Period: Lorazepam | 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. This is the lorazepam period. Lorazepam: 2 mg po, 1x |
| OG004 | Arm: Topiramate 150mg, Period: Lorazepam | 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. This is the lorazepam period. Lorazepam: 2 mg po, 1x |
| OG005 | Arm: Topiramate 200mg, Period: Lorazepam | Randomized to Topiramate; 200mg; lorazepam 2mg or placebo; Each subject in this arm received each treatment in random order with a two-week washout between treatments. This is the lorazepam period. Lorazepam: 2 mg po, 1x |
| OG006 | Arm: Topiramate 100mg, Period: Placebo | 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. This is the placebo period. Placebo: po, 1x |
| OG007 | Arm: Topiramate 150mg, Period: Placebo | 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. This is the placebo period. Placebo: po, 1x |
| OG008 | Arm: Topiramate 200mg, Period: Placebo | Randomized to Topiramate; 200mg; lorazepam 2mg or placebo; Each subject in this arm received each treatment in random order with a two-week washout between treatments. This is the placebo period. Placebo: po, 1x |
|
|
| 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. | Posted | Mean | Standard Deviation | Word Count | Session 1 to Session 5 |
|
|
|
| 0 |
| 14 |
| 0 |
| 14 |
| 0 |
| 14 |
| EG001 | 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 | 0 | 15 | 0 | 15 | 0 | 15 |
| EG002 | 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 | 0 | 17 | 0 | 17 | 1 | 17 |
| EG003 | Lorazepam 2mg | Randomized to Topiramate; 100, 150, or 200 mg; lorazepam 2mg; Each subject in this arm received each treatment in random order with a two-week washout between treatments | 0 | 46 | 0 | 46 | 0 | 46 |
| EG004 | Placebo | Randomized to Topiramate; 100, 150, or 200 mg; placebo; Each subject in this arm received each treatment in random order with a two-week washout between treatments | 0 | 46 | 0 | 46 | 0 | 46 |
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| D000072471 |
| Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D005632 | Fructose |
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| D002241 | Carbohydrates |
| D007661 | Ketoses |