Evaluate the Effects of Tolcapone on Cognitive and Behavioral Dysfunction in Patients With BI and NCD

A Proof of Concept Open-label Study to Evaluate the Effects of Tolcapone on Cognitive and Behavioral Dysfunction in Patients With Traumatic Brain Injury (TBI), Other Acquired Brain Injuries (ABI), or a Diagnosis of Neurocognitive Disorder (NCD)

The experimental design is an open-label two-week trial of tolcapone to evaluate which clinical domains are affected by tolcapone treatment and to identify "responders" to tolcapone treatment in the two subject groups (BI and NCD)

Study Overview

• Status: Unknown
• Conditions: Neurocognitive Disorders; Brain Injuries; Brain Injuries, Traumatic
• Intervention / Treatment: Drug: Tolcapone

Detailed Description

Each patient will receive a two-week specified dosing amount of tolcapone (100mg TID on Day 1; 200mg TID on Days 2-14). The patient will be instructed to take the study drug three times daily. Tolcapone will be tapered after Day 14 to avoid potential withdrawal reactions.

Clinical Instruments for patients:

• Question banks from large patient-reported outcome measure initiatives will be used and administered and used by computerized-adaptive tests (CATs). These include the TBI-QoL for patients with TBI and question banks from the patient-reported outcome measure information systems (PROMIS) and neurology quality of life measurement initiative (Neuro-QoL). Patients will answer questions related to their mobility, fatigue, pain interference, positive affect and well-being, depression, anxiety, anger and irritability, and emotional and behavioral dyscontrol.
• Clinical Global Impressions Scale
• Geriatric Depression Scale-15
• State-Trait Anxiety Inventory
• Hopkins Adult Reading Test
• Frontal Systems Behavior Scale
• Montreal Cognitive Assessment
• Trails A&B
• Modified Wisconsin Card Sorting Test
• NIH Toolbox
• Perceptual Comparison Test
• Brief Test of Attention
• Hopkins Verbal Learning Test
• Brief Visuospatial Memory Test
• Calibrated Ideational Fluency Assessment
• Profile of Mood States
• Digit Span

Clinical Instruments for Informants:

• Neuropsychiatry Inventory
• Apathy evaluation scale
• Overt aggression scale
• Frontal Systems Behavior Scale

Laboratory Measures:

• Blood sample for genotyping
• Blood sample for assessing COMT activity.
• Blood sample for a laboratory profile including CBC, CMP, TSH, Hepatitis Panel (B and C), and RPR
• A urine analysis, urine drug screen, and a urine pregnancy test
• In addition for NCD patients: a blood sample for tests including Serum Calcium, B12, ESR, and C-reactive protein

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21204
      • Sheppard Pratt Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

TBI and ABI Patients Inclusion Criteria

• Age 18-70
• Diagnosis of mild, moderate, or severe TBI, or history of ABI with classification to be made based on parameters at the time of the index event or acquired brain injury.
• Index event resulting in Traumatic or Acquired Head Injury occurred >12 months prior to trial initiation
• A current or former patient at the clinics of the Sheppard Pratt Neuropsychiatry Program or another Sheppard Pratt outpatient clinic with medical documentation of TBI or ABI
• Proficient in the English language
• Available to come to Sheppard Pratt Towson for the baseline evaluation and testing and for the duration of the protocol
• Stable neurological and psychiatric symptomatology for 2 months prior to trial initiation as determined by the referring Sheppard Pratt physician.
• Stable medication dose and regimen for 2 months

NCD Patients Inclusion Criteria

• Age 60-75
• NCD diagnosed by a Sheppard Pratt physician, per DSM-5
• No abnormalities on other serum tests to rule out other cause of cognitive impairment: TSH, B12, CBC, Chemistry screen, and RPR.
• Recent structural neuroimaging (within 1 year or since the time of the onset of cognitive complaint)-noncontrast head CT or MRI-to rule out any gross lesion inconsistent with the diagnosis of MCI (e.g. subdural hematoma, normal pressure hydrocephalus, demyelinating lesion, infarct, or mass lesion)
• Proficient in the English language
• A current or former patient at the clinics of the Sheppard Pratt Neuropsychiatry Program or another Sheppard Pratt outpatient clinic with medical documentation of NCD
• Available to come to Sheppard Pratt Towson for the baseline evaluation and testing and for the duration of the protocol
• Stable neurological and psychiatric symptomatology for 2 months prior to trial initiation as determined by the impression of the referring Sheppard Pratt physician.
• Stable medication dose and regimen for 2 months

Exclusion Criteria for All Patients:

• History of, or active, liver disease or abnormal liver function tests--if the patient currently has elevated Alanine Transaminase (ALT) or Aspartate Transaminase (AST) levels that exceed 2 times the upper limit of normal [Normal Reference Ranges ALT (Male: 4-40 IU/L, Female: 4-40 IU/L), AST (Male: 4-31 IU/L, Female: 4-37 IU/L) or the ratio of AST:ALT has exceeded 2:1
• Active alcohol use disorder, as defined by DSM-5, of any severity mild, moderate, or severe
• History of, or active, cardiovascular disease defined as: coronary heart disease, manifested by myocardial infarction, angina pectoris, or heart failure
• Uncontrolled hypo-or hypertension based on Joint National Committee criteria (JNC7) Hypotension: Systolic<90mmHg or diastolic<60mmHg Hypertension: Systolic >140mmHg or diastolic>90 mmHg)
• History of extra-pyramidal symptoms (e.g. tardive dyskinesia, neuroleptic malignant syndrome, or QT prolongation) while on a first-generation anti-psychotic
• Active illicit substance use, resulting in a substance use disorder as defined by DSM-5, of any severity mild, moderate, or severe
• Patient is currently taking tolcapone or any of the following medications that can interact with tolcapone resulting in an adverse events: another COMT inhibitor, benserazide, α-methyldopa, dobutamine, apomorphine, isoproterenol, clozapine, MAO inhibitor
• Known allergy or serious adverse reaction to tolcapone
• Participated in any investigational drug trial in the past 30 days.
• Pregnant or planning to become pregnant during the study period
• Breastfeeding or planning to breastfeed during the study period.

Other Exclusion Criteria for TBI Patients

• Presence of pre-morbid/pre-TBI cognitive impairment or behavioral dysfunction, as per informant or medical documentation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-Label; Each patient will receive a two-week specified dosing amount of tolcapone (100mg TID on Day 1; 200mg TID on Days 2-14). The patient will be instructed to take the study drug three times daily. Tolcapone will be tapered after Day 14 to avoid potential withdrawal reactions.	Drug: Tolcapone; Other Names: Tasmar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline Clinical Global Impression Scale (CGI) to two weeks after medication administration	Up to 2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline TBI-QoL to two weeks after medication administration	Questions from the TBI-QoL battery, which consists of tests to assess items on domains of emotion, social activity, physical activity, and cognition	Up to 2 weeks
Change from Baseline NIH Toolbox Cognition Battery to two weeks after medication administration	A cognition battery developed by NIH, which consists of tests to assess Executive Function, Attention, Episodic Memory, Language, Processing Speed and Working Memory.	Up to 2 weeks

Collaborators and Investigators

• Sponsor: Sheppard Pratt Health System
• Collaborators: Lieber Institute for Brain Development (LIBD)
• Investigators: Principal Investigator: Robert J Schloesser, MD, Sheppard Pratt Health System

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Anticipated): January 1, 2020

Study Registration Dates

• First Submitted: January 6, 2016
• First Submitted That Met QC Criteria: January 8, 2016
• First Posted (Estimate): January 12, 2016

Study Record Updates

• Last Update Posted (Estimate): January 19, 2017
• Last Update Submitted That Met QC Criteria: January 17, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Neurocognitive Disorders; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antiparkinson Agents; Anti-Dyskinesia Agents; Catechol O-Methyltransferase Inhibitors; Tolcapone
• Other Study ID Numbers: 805704