Effects of Tolcapone on Frontotemporal Dementia

Investigation of the Dopamine System in Frontotemporal Dementia

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00604591

Enrollment

Registered

2008-01-30

Start date

2008-01-30

Completion date

2016-06-16

Last updated

2024-08-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Frontotemporal Lobar Degeneration

Keywords

Dementia Treatment, Frontotemporal Dementia, Dopamine, Frontotemporal Lobar Degeneration

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.

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.

Interventions

DRUGTolcapone

200 mg by mouth three times a day

DRUGPlacebo

200 mg by mouth three times a day

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

40 Years to 85 Years

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

Design outcomes

Primary

Measure	Time frame	Description
Reaction Time on the N-back Cognitive Test (0-back Condition)	First intervention: Day 8 and Second intervention: Day 21	In the N-back task, subjects are given a response pad with response buttons numbered 1, 2, 3, and 4 at the points of a diamond-shaped box and shown a random series of numbers from 1 to 4 appearing for 500 ms every 1.8 seconds at locations corresponding to the positions of the numbers on the response pad. Instructions presented on the screen above the diamond instruct patients to recall the stimulus seen N numbers previously. In the 0-back condition, the subjects are instructed to press the button with the number on the screen. Three blocks of 40 images will be administered during the working memory task for a total of 120 images.
Reaction Time on the N-back Cognitive Test (1-back Condition)	First intervention: Day 8 and Second intervention: Day 21	In the N-back task, subjects are given a response pad with response buttons numbered 1, 2, 3, and 4 at the points of a diamond-shaped box and shown a random series of numbers from 1 to 4 appearing for 500 ms every 1.8 seconds at locations corresponding to the positions of the numbers on the response pad. Instructions presented on the screen above the diamond instruct patients to recall the stimulus seen N numbers previously. In the 1-back condition, the subjects are instructed to report the number presented one number back from the number displayed on the screen. Three blocks of 40 images will be administered during the working memory task for a total of 120 images.

Secondary

Measure	Time frame	Description
Score on Neuropsychiatric Inventory Questionnaire (NPI-Q)	First intervention: Day 8 and Second intervention: Day 21	The NPI-Q is a retrospective caregiver/informant-based interview that assesses 12 neuropsychiatric symptom domains including delusions, hallucinations, agitation/aggression, depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, night-time behavioral disturbances and appetite/eating disturbances. Each symptom within a domain are rated by the caregiver in terms of severity (1=mild to 3=severe). Total scores are calculated by adding the composite scores to obtain a score ranging from 0 (no symptoms, better outcome) to 36.
Score on the Repeated Battery for the Assessment of Neurological Status (RBANS) for Dementia	First intervention: Day 8 and Second intervention: Day 21	The RBANS is a brief, individually administered test that captures multiple cognitive domains, including attention, language, visuospatial/constructional abilities, immediate memory, and delayed memory. Index scores range from 0 to 20 (better outcome) for each of the 5 domains tested and the composite scores are added to generated a total index score, which ranges from 0 to 100 (better outcome).
Score on the Clinical Global Impressions (CGI) Scale	First intervention: Day 8 and Second intervention: Day 21	The CGI is often used in treatment studies as a proxy for global functioning and is a subjective score assigned by the treating physician that incorporates elements of illness severity, patient distress, patient impairment, and functioning. The CGI is given a numerical ranking each visit after the first, with 6=major worsening, 5=mild worsening, 4=no change, 3=mild improvement, and 2=major improvement. Scores range from a 2 (better outcome) to a 6 (worse outcome).

Countries

United States

Participant flow

Participants by arm

Arm	Count
All Participants Includes all participants who participated in the study since all participants received both tolcapone and placebo in this cross-over designed study. Participants were randomly assigned to start on tolcapone or placebo and then crossed over to received the alternative treatment after a wash-out period.	28
Total	28

Baseline characteristics

Characteristic	All Participants
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	28 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	2 Participants
Race (NIH/OMB) Black or African American	1 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	25 Participants
Reaction Time on the N-back Cognitive Test 0-back accuracy	9141 milliseconds STANDARD_DEVIATION 2225
Reaction Time on the N-back Cognitive Test 1-back accuracy	7863 milliseconds STANDARD_DEVIATION 2323
Sex: Female, Male Female	14 Participants
Sex: Female, Male Male	14 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 28
other Total, other adverse events	6 / 28
serious Total, serious adverse events	0 / 28

Outcome results

Primary

Reaction Time on the N-back Cognitive Test (0-back Condition)

In the N-back task, subjects are given a response pad with response buttons numbered 1, 2, 3, and 4 at the points of a diamond-shaped box and shown a random series of numbers from 1 to 4 appearing for 500 ms every 1.8 seconds at locations corresponding to the positions of the numbers on the response pad. Instructions presented on the screen above the diamond instruct patients to recall the stimulus seen N numbers previously. In the 0-back condition, the subjects are instructed to press the button with the number on the screen. Three blocks of 40 images will be administered during the working memory task for a total of 120 images.