Effects of Tolcapone on Frontotemporal Dementia

NCT00604591 | Completed Phase 2 Results

• 2 other identifiers: AAAF41515R00NS060766
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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.

Conditions

Frontotemporal Lobar Degeneration

Keywords

Dementia Treatment; Frontotemporal Dementia; Dopamine; Frontotemporal Lobar Degeneration

Outcome Measures

Primary Outcomes (2)

• 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.

  First intervention: Day 8 and Second intervention: Day 21

• Reaction Time on the N-back Cognitive Test (1-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 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.

  First intervention: Day 8 and Second intervention: Day 21

Secondary Outcomes (3)

• Score on Neuropsychiatric Inventory Questionnaire (NPI-Q)

  First intervention: Day 8 and Second intervention: Day 21

• Score on the Repeated Battery for the Assessment of Neurological Status (RBANS) for Dementia

  First intervention: Day 8 and Second intervention: Day 21

• Score on the Clinical Global Impressions (CGI) Scale

  First intervention: Day 8 and Second intervention: Day 21

Study Arms (2)

Placebo then Tolcapone

PLACEBO COMPARATOR

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; Drug: Placebo

Tolcapone then Placebo

EXPERIMENTAL

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; Drug: Placebo

Interventions

Tolcapone DRUG

200 mg by mouth three times a day

Also known as: Tasmar

Placebo then Tolcapone; Tolcapone then Placebo

Placebo DRUG

200 mg by mouth three times a day

Also known as: Sugar pill

Placebo then Tolcapone; Tolcapone then Placebo

Eligibility Criteria

• Age: 40 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Columbia University: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Related Publications (3)

• 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.

  PMID: 9708959 BACKGROUND

• 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.

  PMID: 17063156 BACKGROUND

• 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.

  PMID: 16862116 BACKGROUND

MeSH Terms

Conditions

Frontotemporal Lobar Degeneration; Frontotemporal Dementia

Interventions

Tolcapone; Sugars

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; TDP-43 Proteinopathies; Neurodegenerative Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Nitrophenols; Phenols; Ketones; Nitro Compounds; Carbohydrates

Limitations and Caveats

A modified and simplified version of the N-back task was used because patients with FTD were incapable of performing the original version. Another limitation was the relatively brief duration of treatment conditions and washout.

Results Point of Contact

• Title: Edward D. Huey, MD
• Organization: Columbia University

edh2126@cumc.columbia.edu

212-305-1134

Study Officials

• Edward Huey, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 19, 2008
• First Posted: January 30, 2008
• Study Start: January 30, 2008
• Primary Completion: June 16, 2016
• Study Completion: June 16, 2016
• Last Updated: August 28, 2024
• Results First Posted: August 28, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)