Effects of Tolcapone on Frontotemporal Dementia
Information source: Columbia University
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Frontotemporal Lobar Degeneration
Intervention: Tolcapone (Drug)
Phase: Phase 2
Sponsored by: Columbia University
Official(s) and/or principal investigator(s):
Edward Huey, MD, Principal Investigator, Affiliation: Columbia University
Edward D Huey, MD, Phone: (212) 305-1134, Email: firstname.lastname@example.org
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.
Official title: Investigation of the Dopamine System in Frontotemporal Dementia
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Primary outcome: Reaction time on the most difficult N-back condition that the patients can successfully perform.
Secondary outcome: A difference in the normalized BOLD signal intensity between subjects on placebo vs. tolcapone.
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
Research Design: A 24-day double-blind, placebo-controlled crossover trial and an analysis
of COMT genotype on symptom presentation and progression.
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
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
Minimum age: 40 Years.
Maximum age: 85 Years.
- 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.
- 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
- Active substance abuse.
- Elevated liver function tests. This is because of the association between tolcapone
- 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
Locations and Contacts
Edward D Huey, MD, Phone: (212) 305-1134, Email: email@example.com
Columbia University Medical Center, 622 West 168th Street, New York, New York 10032, United States; Recruiting
Edward D Huey, MD, Phone: 212-305-1134, Email: firstname.lastname@example.org
Adler CH, Singer C, O'Brien C, Hauser RA, Lew MF, Marek KL, Dorflinger E, Pedder S, Deptula D, Yoo K. Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III. Arch Neurol. 1998 Aug;55(8):1089-95.
Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, Alce G, Iudicello JE, Akbar N, Egan MF, Goldberg TE, Weinberger DR. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007 May;32(5):1011-20. Epub 2006 Oct 25.
Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006 Aug 24;442(7105):916-9. Epub 2006 Jul 16.
Starting date: January 2008
Last updated: October 18, 2011