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Effects of Tolcapone on Frontotemporal Dementia

This study is currently recruiting participants.
Verified October 2011 by Columbia University
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Columbia University
ClinicalTrials.gov Identifier:
NCT00604591
First received: January 19, 2008
Last updated: October 18, 2011
Last verified: October 2011
History of Changes
  Purpose

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 Intervention Phase
Frontotemporal Lobar Degeneration
 Drug: Tolcapone
 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Investigation of the Dopamine System in Frontotemporal Dementia

Resource links provided by NLM:

MedlinePlus related topics: Dementia
U.S. FDA Resources

Further study details as provided by Columbia University:

Primary Outcome Measures:
  • Reaction time on the most difficult N-back condition that the patients can successfully perform. [ Time Frame: To complete over the next 3 years. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • A difference in the normalized BOLD signal intensity between subjects on placebo vs. tolcapone. [ Time Frame: To complete over the next 3 years. ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: January 2008
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Tolcapone
    200 mg by mouth three times a day
    Other Name: Tasmar
Detailed Description:

Objective:

  1. To test the clinical and cognitive effects on frontotemporal dementia (FTD) patients of a medication that increases the amount of the neurotransmitter dopamine in the brain. In autopsy, cerebrospinal fluid, and imaging studies, patients with frontotemporal dementia demonstrate deficiencies in the dopamine neurotransmitter system. This medication acts by inhibiting an enzyme, catechol O-methyl-transferase (COMT) that degrades dopamine. The proposed project will also use fMRI to determine the effects of COMT inhibition on prefrontal cortex and temporal lobe efficiency at rest and while the patients read words that describe animal functions and social attributes and perform a working memory task.
  2. Determine the effect of COMT genotype on symptom presentation and disease course in FTD patients. The COMT gene has a common polymorphism that affects its function.

Study population: 30 patients with FTD will participate in the medication trial. These patients will be included with a larger group of FTD patients (for a total of approximately 100 patients) for the analyses of the effect of COMT genotype on symptom presentation and progression.

Research Design: A 24-day double-blind, placebo-controlled crossover trial and an analysis of COMT genotype on symptom presentation and progression.

Outcome measures:

  1. A comparison of measures of behavioral and cognitive symptoms, and fMRI blood oxygenation level-dependent (BOLD) activation in the prefrontal cortex and temporal lobe, when the patients are taking a COMT inhibitor versus when they are taking a placebo.
  2. A comparison between COMT genotypes of the ratio of verbal fluency to overall score on the RBANS cognitive battery and loss in points on the Mattis DRS-2 divided by symptom duration.
  Eligibility

Ages Eligible for Study:   40 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Diagnosis of FTD.
  • Age 40 to 85. The majority of FTD patients are between the ages of 45-65.
  • Assigned durable power of attorney. To allow us to perform research on cognitively impaired subjects ethically.
  • Caregiver willing and able to accept the responsibilities involved in the study.
  • MDRS2 score less than 132. This is to ensure that the patients have measurable cognitive deficits to attempt to improve in the medication trial.

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. This is because of the association between tolcapone and hepatotoxicity. This includes hepatitis, with the exception of a past hepatitis A infection from which the subject has completely recovered.
  • Current alcohol abuse. This is because of the association between tolcapone and hepatotoxicity.
  • Active substance abuse.
  • Elevated liver function tests. This is because of the association between tolcapone and hepatotoxicity.
  • Patient is taking tolcapone or any other COMT inhibitor, benserazide, alpha-methyldopa, dobutamine, apomorphine, isoproterenol, an MAO-I, or clozapine. This is because these medications can have interactions with tolcapone that could result in adverse effects for the patient.
  • Symptomatic cardiovascular disease (i.e., angina, TIAs, syncope). This is to help ensure that patients are medically stable during the study.
  • Uncontrolled hyper- or hypotension. This is to help ensure that patients are medically stable during the proposed project.
  • Any other contraindication to tolcapone.
  • Any medication that significantly affects the dopamine system, including stimulants and antipsychotic medications. This is because these medications could interfere with the testing of our research hypothesis. We will accept patients washed out of these medications. The washout period will be at least two weeks, but may be longer depending on the medication. If a patient cannot tolerate the washout, they will not participate in the study.
  • Pregnant women. Women of childbearing potential will be screened by history for the possibility of pregnancy and undergo a urine pregnancy test on the first day of the study.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00604591

Contacts
Contact: Edward D Huey, MD (212) 305-1134 edh2126@columbia.edu

Locations
United States, New York
Columbia University Medical Center, 622 West 168th Street Recruiting
New York, New York, United States, 10032
Contact: Edward D Huey, MD     212-305-1134     edh2126@columbia.edu    
Sponsors and Collaborators
Columbia University
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Edward Huey, MD Columbia University
  More Information

Publications:

Responsible Party: Columbia University
ClinicalTrials.gov Identifier: NCT00604591     History of Changes
Other Study ID Numbers: AAAF4151, 5R00NS060766-03
Study First Received: January 19, 2008
Last Updated: October 18, 2011
Health Authority: United States: Federal Government

Keywords provided by Columbia University:
Dementia Treatment
Frontotemporal Dementia
Dopamine

Additional relevant MeSH terms:
Dementia
Frontotemporal Dementia
Aphasia, Primary Progressive
Pick Disease of the Brain
Frontotemporal Lobar Degeneration
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
TDP-43 Proteinopathies
Neurodegenerative Diseases
Proteostasis Deficiencies
Metabolic Diseases
Aphasia
 Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms
Tolcapone
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 16, 2013