Clinical trial NCT00604591: Effects of Tolcapone on Frontotemporal Dementia
Official title: Investigation of the Dopamine System in Frontotemporal Dementia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Frontotemporal Lobar Degeneration
Keywords: Dementia Treatment
Frontotemporal Dementia
Dopamine
Frontotemporal Lobar Degeneration
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2008-01-30
Enrollment: 28
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Reaction Time on the N-back Cognitive Test (0-back Condition)
timeFrame: First intervention: Day 8 and Second intervention: Day 21
measure: Reaction Time on the N-back Cognitive Test (1-back Condition)
timeFrame: First intervention: Day 8 and Second intervention: Day 21
Secondary outcomes:
measure: Score on Neuropsychiatric Inventory Questionnaire (NPI-Q)
timeFrame: First intervention: Day 8 and Second intervention: Day 21
measure: Score on the Repeated Battery for the Assessment of Neurological Status (RBANS) for Dementia
timeFrame: First intervention: Day 8 and Second intervention: Day 21
measure: Score on the Clinical Global Impressions (CGI) Scale
timeFrame: First intervention: Day 8 and Second intervention: Day 21
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Edward Huey, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1001/archneur.55.8.1089.
citation: 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. doi: 10.1038/sj.npp.1301227. Epub 2006 Oct 25.
citation: 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. doi: 10.1038/nature05016. Epub 2006 Jul 16.