Effects of Tolcapone on Frontotemporal Dementia

Sponsor

Columbia University (Other)

Overall Status

Completed

CT.gov ID

NCT00604591

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

Enrollment

Location

Arms

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will test the effects of a medication called tolcapone on cognitive, behavioral, and language problems seen in patients with frontotemporal dementia (FTD). Tolcapone increases the amount of dopamine, a brain chemical that may be lowered in FTD. The study will see if tolcapone can improve thinking, behavior, and language in people with FTD and will look at the effects of the drug on brain activity.

Patients with FTD who are between 40 and 85 years of age may be eligible for this study.

Participants will be seen as outpatients at the Columbia University Medical Center approximately one a week for 4 weeks. They take tolcapone or a placebo (a look-alike pill with no active ingredient) during study week 1. During study week 3, those who took placebo during week 1 now take tolcapone for 1 week and those who took tolcapone now take placebo. In addition, patients undergo the following tests and procedures:

Neurological tests to evaluate attention, problem-solving and memory. These tests are repeated several times during the course of the study.
Test to look for a gene that affects the amount of dopamine in the brain, using blood samples collected in a previous study.
Blood draws four times during the study.
Functional MRI (fMRI) to learn about changes in brain regions that are involved in performing tasks. For fMRI, the patient lies on a table that can slide in and out of the scanner, a narrow metal cylinder surrounded by a magnetic field. The procedure takes about 60 minutes and is performed four times over the course of the . FMRI involves taking pictures of the brain during MRI while the subject performs a task so that changes in the brain that occur during these tasks can be studied.

Condition or Disease	Intervention/Treatment	Phase
Frontotemporal Lobar Degeneration	Drug: Tolcapone Drug: Placebo	Phase 2

Detailed Description

FTD is a significant cause of disability and death with an estimated prevalence of 15 cases per 100,000 persons in the 45- to 64-year-old age range. Despite the magnitude of this problem, there is currently a relative lack of understanding of the causes of, and treatments for, FTD, possibly because criteria for its diagnosis have only recently been developed. As an outcome of the proposed investigations, the investigators expect to determine the effects of cortical dopamine augmentation in FTD, evaluate the effect of dopamine augmentation on processing efficiency with fMRI, and explore the effects of a genetic polymorphism on symptom presentation and disease course. The research proposed in this protocol is significant because it could provide a new class of treatments for FTD, identify the fMRI findings associated with symptom improvement, and determine the contribution of a genetic polymorphism to symptom presentation and disease course.

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Investigation of the Dopamine System in Frontotemporal Dementia

Study Start Date :

Jul 1, 2011

Actual Primary Completion Date :

Oct 1, 2014

Actual Study Completion Date :

Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo then Tolcapone Participants take placebo during study week 1 and then tolcapone during week 3. On Day 1, 100 mg of tolcapone/placebo will be taken at three specific times: once in the morning, once in the afternoon, once at night. Then, from Days 2-6, 200 mg of tolcapone/placebo will be taken three times a day: once in the morning, once in the afternoon, once at night. On Day 7, 200 mg of tolcapone/placebo will be taken only in the morning and afternoon. On Day 8, 200 mg of tolcapone/placebo will be taken only in the morning. After the last dose on Day 8 is taken, the wash-out period begins and lasts through Day 14.	Drug: Tolcapone 200 mg by mouth three times a day Other Names: Tasmar Drug: Placebo 200 mg by mouth three times a day Other Names: Sugar pill
Experimental: Tolcapone then Placebo Participants take tolcapone during study week 1 and then placebo during week 3. On Day 1, 100 mg of tolcapone/placebo will be taken at three specific times: once in the morning, once in the afternoon, once at night. Then, from Days 2-6, 200 mg of tolcapone/placebo will be taken three times a day: once in the morning, once in the afternoon, once at night. On Day 7, 200 mg of tolcapone/placebo will be taken only in the morning and afternoon. On Day 8, 200 mg of tolcapone/placebo will be taken only in the morning. After the last dose on Day 8 is taken, the wash-out period begins and lasts through Day 14.	Drug: Tolcapone 200 mg by mouth three times a day Other Names: Tasmar Drug: Placebo 200 mg by mouth three times a day Other Names: Sugar pill

Arm

Intervention/Treatment

Placebo Comparator: Placebo then Tolcapone

Participants take placebo during study week 1 and then tolcapone during week 3. On Day 1, 100 mg of tolcapone/placebo will be taken at three specific times: once in the morning, once in the afternoon, once at night. Then, from Days 2-6, 200 mg of tolcapone/placebo will be taken three times a day: once in the morning, once in the afternoon, once at night. On Day 7, 200 mg of tolcapone/placebo will be taken only in the morning and afternoon. On Day 8, 200 mg of tolcapone/placebo will be taken only in the morning. After the last dose on Day 8 is taken, the wash-out period begins and lasts through Day 14.

Drug: Tolcapone

200 mg by mouth three times a day

Other Names:

Tasmar

Drug: Placebo

200 mg by mouth three times a day

Other Names:

Sugar pill

Experimental: Tolcapone then Placebo

Participants take tolcapone during study week 1 and then placebo during week 3. On Day 1, 100 mg of tolcapone/placebo will be taken at three specific times: once in the morning, once in the afternoon, once at night. Then, from Days 2-6, 200 mg of tolcapone/placebo will be taken three times a day: once in the morning, once in the afternoon, once at night. On Day 7, 200 mg of tolcapone/placebo will be taken only in the morning and afternoon. On Day 8, 200 mg of tolcapone/placebo will be taken only in the morning. After the last dose on Day 8 is taken, the wash-out period begins and lasts through Day 14.

Drug: Tolcapone

200 mg by mouth three times a day

Other Names:

Tasmar

Drug: Placebo

200 mg by mouth three times a day

Other Names:

Sugar pill

Outcome Measures

Primary Outcome Measures

Reaction time on the most difficult N-back condition that the patients can successfully perform. [To complete over the next 3 years.]

Secondary Outcome Measures

A difference in the normalized BOLD signal intensity between subjects on placebo vs. tolcapone. [To complete over the next 3 years.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of frontotemporal dementia (FTD)
Age 40 to 85
Assigned durable power of attorney
Caregiver willing and able to accept the responsibilities involved in the study
Mattis Dementia Rating Scale-2 (MDRS2) score less than 132

Exclusion Criteria:

The diagnosis of any other type of dementia besides FTD including Alzheimer's disease, Lewy body dementia, vascular dementia, dementia associated with Parkinson's disease, corticobasal syndrome, and progressive supranuclear palsy.
Known allergy or serious adverse reaction to tolcapone
Active liver disease
Current alcohol abuse
Active substance abuse
Elevated liver function tests
Patient is taking tolcapone or any other catechol-O-methyltransferase (COMT) inhibitor, benserazide, alpha-methyldopa, dobutamine, apomorphine, isoproterenol, an monoamine oxidase inhibitor (MAO-I), or clozapine
Symptomatic cardiovascular disease (e.g., angina, transient ischemic attack (TIA) , syncope)
Uncontrolled hyper- or hypotension
Any other contraindication to tolcapone
Any medication that significantly affects the dopamine system, including stimulants and antipsychotic medications
Pregnant women