Effects of Tolcapone on Frontotemporal Dementia

Investigation of the Dopamine System in Frontotemporal Dementia

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.

Study Overview

• Status: Completed
• Conditions: Frontotemporal Lobar Degeneration
• Intervention / Treatment: Drug: Tolcapone; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center, 622 West 168th Street

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
A difference in the normalized BOLD signal intensity between subjects on placebo vs. tolcapone.	To complete over the next 3 years.

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Edward Huey, MD, Columbia University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: January 19, 2008
• First Submitted That Met QC Criteria: January 19, 2008
• First Posted (Estimate): January 30, 2008

Study Record Updates

• Last Update Posted (Actual): August 19, 2019
• Last Update Submitted That Met QC Criteria: August 15, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Dopamine; Dementia Treatment; Frontotemporal Dementia; Frontotemporal Lobar Degeneration
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Language Disorders; Communication Disorders; Speech Disorders; Aphasia; Dementia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Frontotemporal Lobar Degeneration; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antiparkinson Agents; Anti-Dyskinesia Agents; Catechol O-Methyltransferase Inhibitors; Tolcapone
• Other Study ID Numbers: AAAF4151; 5R00NS060766 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No