A Trial Evaluating Effects of COMT Inhibition in Patients With Acquired Brain Injury

The proposed study is a follow-up study for an ongoing open label trial conducted by the Sheppard Pratt-Lieber Research Institute utilizing the catechol-O-methyl-transferase (COMT) inhibitor Tolcapone to evaluate its effects on cognition and neuropsychiatric symptoms in patients with brain injuries (BI).

The outcome measures utilized in this study were chosen based on the available data from the currently ongoing open-label clinical trial. The proposed study will utilize the same study medication at the same dose and frequency. In addition, the length of administration of study medication (two weeks) is identical. In the proposed study, investigators will conduct a double-blind, placebo-controlled clinical trial utilizing a crossover design to study the effects of two weeks of Tolcapone 200mg administered three times a day (total of 600mg/day) on cognitive performance. Physical, emotional, cognitive and social functioning will be evaluated through participant and proxy report. The investigators are planning to randomize a total of 12 patients with BI.

The cross-over design requires two 2-week long study periods during which the participant receives either Tolcapone two 100mg capsules three times a day (total of 600mg/day) or placebo. Participants will be randomly assigned to two sequence groups either starting with Tolcapone treatment (T-P group) or placebo (P-T group). Investigators and participants will be blind to the study group assignment and hence blind to the treatment (Tolcapone vs. placebo) that subjects receive at a given time. The study periods are separated by a "washout period" that is at least two weeks and maximally 4 weeks long to reduce the potential for carryover effects. Patient reported outcomes will be obtained a total of four times, twice prior to the start of each respective study period (Pre-Study Period Visits I \& II) as well as at the end of each study period (Outcome Measures Visits I \& II). Cognitive outcome measures will be obtained twice throughout the study, at the end of each respective study period (Outcome Measures Visits I \& II).

• Tolcapone 200 MG (Drug), also known as Tasmar: Tolcapone 200 MG TID
• Placebo (Other): Placebo, TID Placebo will be in capsules that are identical in appearance to intervention drug, Tolcapone.

Primary outcomes

• NIH Toolbox Fluid Cognitive Battery [Administered on the 14th day of Tolcapone or Placebo treatment (i.e. during each Outcome Measures Visit).]: This battery is a measure of cognitive performance derived from a battery of five cognitive assessments.

Secondary outcomes

• TBI Quality-of-Life Measurement System [Administered prior to the start of Tolcapone oe Placebo treatment (i.e. during each Pre-Study Visit) and on the 14th day of Tolcapone or Placebo treatment (i.e. during each Outcome Measures Visit).]: A patient reported outcome measure assessing physical, emotional, cognitive and social functioning. Quality of Life Measure is a computer adaptive questionnaire.
• Frontal Systems Behavior Scale [Administered prior to the start of Tolcapone oe Placebo treatment (i.e. during each Pre-Study Visit) and on the 14th day of Tolcapone or Placebo treatment (i.e. during each Outcome Measures Visit).]: A patient reported outcome measure, and proxy reported outcome measure, assessing neuropsychiatric symptoms associated with prefrontal cortical dysfunction

Sex: All, ages: 18 Years to 70 Years, accepts healthy volunteers

Inclusion Criteria:

* Capacity for written informed consent
* Ages 18-70 years, inclusive
* Diagnosis of a BI including mild, moderate, or severe TBI, or other acquired BI and post-BI development of neuropsychiatric complaints.
* Index event resulting in Traumatic or Acquired Brain 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 BI
* 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 two months prior to trial initiation as determined by the referring Sheppard Pratt physician.
* Stable medication dose and regimen for two months prior to trial initiation (based on a review of medical chart)

Exclusion Criteria:

* 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
* Uncontrolled hypo-or hypertension based on Joint National Committee criteria (JNC7) Hypotension: Systolic <90mmHg or diastolic <60mmHg Hypertension: Systolic >140mmHg or diastolic >90 mmHg)
* Active alcohol use disorder, as defined by DSM-5, of any severity mild, moderate, or severe
* 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 event: 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 within the past 30 days.
* Pregnant or planning to become pregnant during the study period
* Breastfeeding or planning to breastfeed during the study period.
* Presence of severe pre-morbid/pre-BI cognitive impairment or behavioral dysfunction, as per informant or medical documentation

• Robert J Schloesser, MD, Principal investigator, Sheppard Pratt Health System