Characterizing and Predicting Drug Effects on Cognition

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT01889602
• Collaborator: (none)
• Enrollment: 60
• Location: 1
• Arms: 3
• Duration (Months): 37
• Patients Per Site Per Month: 1.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cognitive Deficits	Drug: Lorazepam; Other: Placebo; Drug: Topiramate 100mg; Drug: Topiramate 150mg; Drug: Topiramate 200mg	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Characterizing and Predicting Drug Effects on Cognition
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Topiramate 100mg 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.	Drug: Lorazepam; Lorazepam: 2mg, po, 1x; Other Names: Ativan ; Other: Placebo; Non-active placebo, po, 1x; Drug: Topiramate 100mg; Topiramate: 100 mg, po, 1x; Other Names: Topamax
Experimental: Topiramate 150mg 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.	Drug: Lorazepam; Lorazepam: 2mg, po, 1x; Other Names: Ativan ; Other: Placebo; Non-active placebo, po, 1x; Drug: Topiramate 150mg; Topiramate: 150 mg, po, 1x; Other Names: Topamax
Experimental: Topiramate 200mg 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.	Drug: Lorazepam; Lorazepam: 2mg, po, 1x; Other Names: Ativan ; Other: Placebo; Non-active placebo, po, 1x; Drug: Topiramate 200mg; Topiramate: 200 mg, po, 1x; Other Names: Topamax

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota	Minneapolis	Minnesota	United States	55414

Sponsors and Collaborators

• University of Minnesota

Investigators

• Principal Investigator: Susan E. Marino, PhD, Assistant Professor

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 15, 2015

More Information

Publications

None provided.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT01889602
• Other Study ID Numbers: CPDEC
• First Posted: Jun 28, 2013
• Last Update Posted: Dec 17, 2019
• Last Verified: Dec 1, 2019

• Keywords provided by University of Minnesota: Healthy volunteers; Topiramate; Neurocognition; Drug-induced cognitive deficits
• Additional relevant MeSH terms: Cognition Disorders; Cognitive Dysfunction; Topiramate; Lorazepam

Study Results

Participant Flow

Arm/Group Title	Topiramate 100mg	Topiramate 150mg	Topiramate 200mg
Arm/Group Description	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	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	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
Period Title: First Intervention
STARTED	20	20	20
COMPLETED	19	17	18
NOT COMPLETED	1	3	2
Period Title: First Intervention
STARTED	19	17	18
COMPLETED	19	17	18
NOT COMPLETED	0	0	0
Period Title: First Intervention
STARTED	19	17	18
COMPLETED	18	17	16
NOT COMPLETED	1	0	2
Period Title: First Intervention
STARTED	18	17	16
COMPLETED	18	17	16
NOT COMPLETED	0	0	0
Period Title: First Intervention
STARTED	18	17	16
COMPLETED	15	15	16
NOT COMPLETED	3	2	0
Period Title: First Intervention
STARTED	15	15	16
COMPLETED	15	15	16
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Topiramate 100mg	Topiramate 150mg	Topiramate 200mg	Total
Arm/Group Description	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	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	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	Total of all reporting groups
Overall Participants	14	15	17	46
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	15 100%	17 100%	46 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (Years) [Median (Standard Deviation) ]
Median (Standard Deviation) [Years]	31.9 (11.48)	38.54 (10.21)	26.41 (8.42)	28.52 (9.99)
Sex: Female, Male (Count of Participants)
Female	8 57.1%	8 53.3%	8 47.1%	24 52.2%
Male	6 42.9%	7 46.7%	9 52.9%	22 47.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	2 13.3%	0 0%	2 4.3%
Asian	0 0%	0 0%	3 17.6%	3 6.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	5 35.7%	4 26.7%	3 17.6%	12 26.1%
White	8 57.1%	8 53.3%	9 52.9%	25 54.3%
More than one race	1 7.1%	1 6.7%	2 11.8%	4 8.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%	15 100%	17 100%	46 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in COWA Unique Word Count
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm: Topiramate 100mg, Period: Topiramate	Arm:Topiramate 150mg, Period: Topiramate	Arm: Topiramate 200mg, Period: Topiramate	Arm: Topiramate 100mg, Period: Lorazepam	Arm: Topiramate 150mg, Period: Lorazepam	Arm: Topiramate 200mg, Period: Lorazepam	Arm: Topiramate 100mg, Period: Placebo	Arm: Topiramate 150mg, Period: Placebo	Arm: Topiramate 200mg, Period: Placebo
Arm/Group Description	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 topiramate period. Topiramate: 100 mg po, 1x	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	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	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	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	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	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	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	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
Measure Participants	14	15	17	14	15	17	14	15	17
Mean (Standard Deviation) [Word Count]	-0.407725385 (0.110593408)	-0.425898667 (0.186240451)	-0.412534118 (0.154640084)	-0.108298333 (0.240452491)	0.131452143 (0.263967943)	-0.095221176 (0.228163172)	-0.011651538 (0.152526619)	0.077431333 (0.176020802)	0.047164706 (0.166162762)

2. Primary Outcome

Title	Change From Baseline in Spontaneous Narrative Raw Word Count
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm: Topiramate 100mg, Period: Topiramate	Arm:Topiramate 150mg, Period: Topiramate	Arm: Topiramate 200mg, Period: Topiramate	Arm: Topiramate 100mg, Period: Lorazepam	Arm: Topiramate 150mg, Period: Lorazepam	Arm: Topiramate 200mg, Period: Lorazepam	Arm: Topiramate 100mg, Period: Placebo	Arm: Topiramate 150mg, Period: Placebo	Arm: Topiramate 200mg, Period: Placebo
Arm/Group Description	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 topiramate period. Topiramate: 100 mg po, 1x	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	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	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	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	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	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	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	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
Measure Participants	14	15	17	14	15	17	14	15	17
Mean (Standard Deviation) [Word Count]	-0.01596 (0.360237984)	-0.131732 (0.192165204)	-0.323135625 (0.297067179)	0.109636 (0.236323153)	0.016635385 (0.283748379)	-0.128177333 (0.281246222)	0.117455385 (0.360519103)	-0.01098 (0.272331286)	0.011456471 (0.225720885)

Adverse Events

Time Frame	30 days following the last administration of study drug.
Adverse Event Reporting Description	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.
Arm/Group Title	Topiramate 100mg		Topiramate 150mg		Topiramate 200mg		Lorazepam 2mg		Placebo
Arm/Group Description	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		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		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		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		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
All Cause Mortality
	Topiramate 100mg		Topiramate 150mg		Topiramate 200mg		Lorazepam 2mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/15 (0%)		0/17 (0%)		0/46 (0%)		0/46 (0%)
Serious Adverse Events
	Topiramate 100mg		Topiramate 150mg		Topiramate 200mg		Lorazepam 2mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/15 (0%)		0/17 (0%)		0/46 (0%)		0/46 (0%)
Other (Not Including Serious) Adverse Events
	Topiramate 100mg		Topiramate 150mg		Topiramate 200mg		Lorazepam 2mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/15 (0%)		1/17 (5.9%)		0/46 (0%)		0/46 (0%)
Eye disorders
Eye Twitching	0/14 (0%)	0	0/15 (0%)	0	1/17 (5.9%)	1	0/46 (0%)	0	0/46 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.