Remediation of Impaired Self-Regulation in Patients With Mild TBI
Phase: EARLY_PHASE1
Conditions: Mild Traumatic Brain Injury
Sponsor: VA Office of Research and Development

 
 
Study Methods and  
Statistical Analysis Plan 
 
 
Clinical Trial Name: 
Remediation of Impaired Self-Regulation 
in Patients with Mild TBI 
 
NCT #02260570 
 
Date of Document Upload: May 12, 2022 
 
 
 

IRB (Institutional Review Board/Human Studies Subcommittee) 
DEPARTMENT OF VETERANS AFFAIRS 
NORTHERN CALIFORNIA HEALTH CARE SYSTEM 
SAC-5th Floor Conference Room; MTZ-Director's Conference Room 
IRB APPROVAL - Continuing Review 
Date: May 10,2018 
From: Jary Larsen, PhD, IRB Chairperson 
Investigator: Andrew Kayser, M.D., PhD 
Protocol: MERIT: Remediation of Impaired Self-Regulation in Patients with Mild TBI 
ID: 00720 
Prom#: 5838 Protocol#: 14-06-00720 
Expiration Date: 05/01/2019 
The following items were reviewed and approved at the 05/01/2018 meeting: 
•
Continuing Review Application (04/26/2018; 2018) 
•
Consent Form (05/11/2017) 
•
Flyer - mTBI (04/06/2017; Flyer with and without tear-off strips) 
•
Flyer - OIF/OEF (04/06/2017; Flyer with and without tear-off strips) 
•
Human Subject Enrollment Form - 03/16/2017 to 02/16/2018 (02/16/2018) 
Research Service has this on file. Nine Veterans at VANCHCS listed and six Veterans not at 
VANCHCS listed. 
•
MR/fMRI Research - Investigator Perfotmed (04/26/2018) 
•
Project Data Sheet (02/16/2018) 
•
Research Security Plan (02/22/2018) 
•
Research Project Abstract (02/16/2018) 
•
Authorization for PHI use for Research (05/05/2016) 
•
Research Data Use and Security Plan - Investigator (02/22/2018) 
•
Offsite Data Storage Waiver (02/22/2018) 
•
Research Financial Conflict of Interest Statement - 2018 
Andrew Kayser (02/16/2018), Mark D'Esposito (03/21/2018) 
Approval is granted for a period of 12 months and will expire on 05/01/2019. Your Continuing Review 
is scheduled for 04/02/2019, and the requirements are attached. 
The protocol was determined to have the following level of risk: 
Moderate 
The following other committee reviews are scheduled: 
SRS (Subcommittee for Research Safety) [05/14/2018] 
Research & Development Committee [05/23/2018] 
Page 1 of 2 
The Northern Cal VAMC IRB is not connected with, has no authority over, and is not responsible for human research conducted at 
any other institution, except where a Memorandum of Understanding specifies otherwise. Separate consent forms, initial reviews, 
continuing reviews, amendments, and reporting of serious adverse events are required if the same study is conducted at multiple 
institutions. 

Approval by each of the following is required prior to study continuation (unless Exempt): 
IRB (Institutional Review Board/Human Studies Subcommittee) 
Research & Development Committee 
Approval for study continuation is contingent upon your compliance with the requirements of the Research 
Service for the conduct of studies involving human subjects. 
Jary Larsen 
Digitally signed by Jary Larsen 
Date: 2018.05.10 09:13:24 -0700' 
Jary Larsen, PhD, IRB Chairperson 
Page 2 of 2 
The Northern Cal VAMC IRB is not connected with, has no authority over, and is not responsible for human research conducted at 
any other institution, except where a Memorandum of Understanding specifies otherwise. Separate consent forms, initial reviews, 
continuing reviews, amendments, and reporting of serious adverse events are required if the same study is conducted at multiple 
institutions. 

DEPARTMENT OF VETERANS AFFAIRS 
NORTHERN CALIFORNIA HEALTH CARE SYSTEM 
10535 Hospital Way • Mather & Martinez, CA 
Conditions of IRB Approval 
What Are the Conditions of IRB Approval?  
1. Adhere to ethical principles: (1) Respect for persons - consent, privacy, confidentiality, (2) 
Beneficence - maximize possible benefits to the subject and minimize possible harms, and (3) Justice - 
equitable selection. 
2. Obtain informed, written consent from each human subject or his legally qualified guardian or next-of-
kin, unless specifically waived by the IRB. If the subject lacks decision making capacity or has been 
declared incompetent, surrogate consent is required. You are required to place the original, signed 
consent foim in the medical record (and document it in the electronic record), provide a copy to the 
subject, provide a copy to the Research Office (if applicable), and keep a copy for your files. 
3. Promptly report all Serious Adverse Events or Serious and Unexpected Events to the IRB (both events 
at the VA and sponsor reports of events at other sites). The FDA defines Serious Adverse Events as: 
(1) death, (2) life-threatening, (3) hospitalization - initial or prolonged, (4) disability, (5) congenital 
anomaly, (6) required intervention to prevent permanent impairment/damage, or (7) serious and 
unexpected severity or frequency of expected events. 
4. Promptly report all deviations (including error and accidents) from the approved protocol and do not 
initiate any unapproved changes (amendments, consent form modifications, advertisements) without 
IRB review and approval, except where necessary to eliminate apparent immediate hazard to human 
subjects. 
5. Report Emergency Use of unapproved test articles to the IRB within 5 days. 
6. If applicable, provide a copy of each subject's consent form and the Investigational Drug Information 
Record (VA Form 9012) to the Investigational Pharmacist prior to your request to receive, store, and 
dispense study medications. (The Investigational Pharmacist is responsible for the storage and 
dispensing of investigational drugs.) 
7. Submit Continuing Review information to the IRB by the date specified and inform the IRB when your 
study is completed (federal law requires that every protocol must be reviewed a minimum of once per 
year). File a final report upon completion or termination of a study. 
What Are the Penalties for Non-Compliance?  • 
1. Non-compliance may result in suspension of approval or a particular project. Serious or continuing 
non-compliance may result in suspension of your privilege to conduct research at this VAMC. 
Printed: 05/10/2018 
Page 1 of 1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
D. STUDY DESIGN AND MERIT 
1. Estimated length of study: (in years or months) 
VA RR&D funding has been provided for this study for 5 years. 
2. Length of each participant's time in this study: (in hours, days, weeks, months, or years) 
Each participant will have 3 study visits: one screening visit for approximately 2 hours and two functional MRI visits 
of approximately 5 hours each. 
3. Purpose of study: 
a. State the research hypothesis. 
The purpose of this application is to develop adjunctive medication options for the treatment of self-regulatory 
deficits. Such deficits are thought to emerge from failures of top-down control — i.e. the ability of higher-order 
goals to constrain impulses, habits, and other more "stimulus-driven" responses. Convergent data from multiple 
fields, including examples from both our own human neuroimaging work and animal studies of related 
processes, argue that top-down control is reflected neurophysiologically in the ability of prefrontal cortex (PFC) 
to influence activity in behaviorally-relevant posterior cortical and subcortical brain regions. Given the clear need 
for new therapeutic approaches to self-regulatory impairments, this mapping from brain to behavior identifies a 
potential biomarker for self-regulatory failure, and points toward a strategy for developing treatments. As we 
detail below, both our work and other reports suggest that the brain-penetrant, FDA-approved, catechol-0-
methyltransferase (COMT) inhibitor tolcapone shows promise in improving the ability of PFC to influence 
posterior cortical and subcortical activity, and thus to improve self-regulation. 
b. Describe the research objectives. 
We propose to use behavioral tasks and functional MRI (fMRI) to directly test the hypotheses that self-regulatory 
deficits in veterans with mild traumatic brain injury (mTBI) result from diminished top-down control, and that 
administration of the FDA-approved, brain-penetrant COMT inhibitor tolcapone will improve self-regulation in 
human subjects. We will employ clinically-relevant tasks within a randomized, double-blind, placebo-controlled 
translational fMRI study to address behavioral, cognitive, and social-emotional self-regulation, respectively, 
including a delay discounting task to measure impulsivity, a visual perceptual task to assess attention, and a 
social-emotional task to evaluate social-emotional regulation. We hypothesize that these tasks will demonstrate  
V.09/13/2013 
Page 4 of 29 

behavioral impairments in veterans with mTBI, that these impairments will correlate with reduced top-down 
control as measured by fMRI, and that tolcapone will rennediate the behavior and underlying neurophysiology. 
In addition, we hypothesize that self-regulatory failures in each of the three domains — behavioral, cognitive, and 
social-emotional — will correlate with each other within subjects. 
c. Describe in detail the purpose of this study. 
Higher cognitive function — in particular, our capacity for self-regulation — enables us to plan for the future, to 
maintain our focus in the face of distractions, and to manage our emotions. Failures of self-regulation are an 
integral manifestation of mild traumatic brain injury (mTBI) and its comorbidities, including substance use and 
post-traumatic stress disorder (PTSD). Because of the importance of such functions in our daily lives, these 
impairments have profound effects on the lives of veterans with mTBI, who complain of poor decision making, 
diminished concentration, and inadequately controlled anxiety. Due to impediments to care including the 
severity of these comorbid symptoms, the remoteness of their homes, and concerns about disclosing the extent 
of their deficits, many of these veterans are poorly able to participate in behavioral/neurocognitive approaches to 
address these issues. In such circumstances, effective adjunctive medications to improve self-regulation are 
important to permit and/or to reinforce the ability of these veterans to manage their symptoms and to engage in 
behavioral therapies. Unfortunately, very few medications are effective for cognitive issues in patients with 
mTBI, and current agents are not effective for many symptoms and for many veterans. 
d. Describe the importance of resulting knowledge from this study. 
By testing tractable hypotheses supported by our preliminary data, these studies address a critical barrier to 
progress in the fields of cognitive rehabilitation and psychotherapy. Specifically, as our own clinical experiences 
and exclusion criteria in published reports indicate, not all veterans are capable of participating in behavioral 
paradigms addressing cognition and mental health. For such patients, pharmacological approaches are a 
much-needed adjunct that may enable other therapies. That potentially beneficial medications are already FDA-
approved for other indications increases both the rapidity with which these medications can be applied to mTBI, 
and the urgent need to obtain high quality, proof of principle results. Moreover, by using fMRI to evaluate the 
influence of tolcapone on brain activity related to relevant tasks, we gain insights into mechanism of action that 
can guide the development of other agents, whether pharmacological or otherwise (e.g. transcranial magnetic 
stimulation). This proposal thus represents an innovative, pragmatic approach to a problem — self-regulatory 
failure after mTBI — that is widespread, under-treated, and for which veterans desperately want new therapies.  
4. Check types of study design: 
Chart]Medical Records Review 
Prospective 
Retrospective 
1-1  Observational (the investigator observes the events without altering them): 
n Cross-sectional study (each participant examined only once) 
I I Longitudinal study (each participant followed over a period of time) 
Eg Experimental Intervention (the investigator observes the effect of the intervention on outcome): 
IM Randomized 
EI Blinded 
LII Retrospective 
El Prospective  
V.09/13/2013 
Page 5 of 29 

5. Describe statistical methods (For example: sample size estimation, power calculation, statistical tests or 
descriptive statistics, data analysis tools, etc.) 
Given our primary outcomes and preliminary data, we specify a sample size of 40 subjects per group, consistent 
with both seminal neuroimaging papers and our previous work. This number assumes certain standard estimates of 
signal-to-noise, spatial smoothing, and BOLD time series duration that are well-established in the fMRI literature 
across studies including perceptual, attentional, language-related, and executive tasks. Our sample size will provide 
80% power to detect a difference between treatment groups with a standardized effect size (observed effect divided 
by the standard deviation of the signal noise) of 0.71 at a corrected significance level (alpha) of 0.05 (two-tailed). 
This effect size corresponds to a 0.25% difference in the BOLD signal change between tolcapone / placebo 
conditions. We note that differences in BOLD signal in our tasks can sometimes be reliably present at higher levels 
(e.g. 0.5%), so it is possible that our estimated requirement for 40 subjects may be unduly conservative. Statistical 
analyses of neuroimaging results will be conducted within the AFNI suite of fMRI analysis programs. 
6. Describe appropriateness and rationale for elements warranting special attention (placebo, washout period, 
challenge study, radiation exposure, deception study, deviation from accepted standard of care). 
Subjects will receive both tolcapone and placebo in a randomized, double-blind, counterbalanced, cross-over 
design. The use of a placebo will permit each subject to serve as his/her own control, an important point given 
known individual differences in dopamine tone that can be obscured if only across group comparisons are possible. 
A washout period between the two fMRI sessions will be used. Tolcapone concentration peaks at 90 minutes, and 
when used for the treatment of Parkinson's disease (its FDA-approved indication), it is dosed three times per day. 
To ensure that the one-time dose of the drug is eliminated from each subject's system prior to the second scan, at 
least 5 days will elapse between MRI scans. Finally, MRI scanning is used because it noninvasively permits 
excellent spatial and temporal resolution of brain activity without the use of ionizing radiation.  
7. Have there been IRB approved protocol amendments modifying the study (including sponsor amendments) 
since the last review? 
121 Yes fl No 
•
If "YES", list approval date and summarize the nature and purpose of all protocol amendments made since 
the time of last Initial or Continuing Review: 
 
  
 
 
 
 
 
 
 
 
 
 
 
E. AMENDMENT REQUEST AT CONTINUING REVIEW 
1. Are any protocol amendments modifying the study (including sponsor amendments) being proposed at the 
time of this continuing review? 
Yes El No 
•
If "YES", complete the rest of this section, If No, skip the rest of this section 
2. Purpose and/or reason for modifying the protocol. 
3. Brief Description of Amendment. 
V.09/13/2013 
Page 6 of 29 

F. SUBJECT POPULATION 
1. Human 
a. 
Subject Enrollment 
How many total participants did VANCHCS IRB originally approve for accrual (sign consent forms) at 
VANCHCSNACCHCS? 40 
b. How many total participants are currently approved for accrual at VANCHCSNACCHCS? 80 
c. 
How many total participants did VANCHCS IRB originally approve for accrual at other sites under your 
responsibility? 40  
List other initial site names The UCSF Research Clinic, located at UC Berkeley 
d. How many total participants are currently approved for accrual at other sites under your responsibility? 80  
List other current site names The UCSF Research Clinic, located at UC Berkeley 
e. If this is a Multicenter trial with different sites and different Pls, how many total participants are currently planned 
to be enrolled for the entire project? N/A 
f. 
No contact with participants, authorization and consent waived: 11 
1) Enter total number of samples or charts originally approved 
2) Enter total number of samples or charts currently approved 
3) Enter total number of records extracted from VA Data Mart or VA Data Warehouse (National, Regional, or 
VISN) originally approved 
4) Enter total number of records extracted from VA Data Mart or VA Data Warehouse (National, Regional, or 
VISN) currently approved 
 
2. Status of subjects 
a. Number of subjects, samples or charts entered into study since project began? 55  
b. Number of subjects, samples or charts entered into study since last report to the IRB? 15 
3. Since 
a. Number 
b. Number 
c. Number 
d. Number 
the last report, to the IRB indicate: 
groups: 
of female subjects:2 
of male subjects: 13 
of subjects in each of the following 
Caucasian: 5 
African-American: 3 
Hispanic: 4 
Asian: 2 
Other: (indicate minority status and number) 1 - American 
Indian 
of subjects in each of the following vulnerable groups: 
0 None 
Children: 
Persons with HIV: 
Economically Disadvantaged: 
Employees: 
Prisoners: 
Educationally Disadvantaged: 
Homeless/Shelter: 
Students/Trainees: 
Impaired Decision Making Capacity: 
Mentally Disabled: 
Terminally III Patients: 
Pregnant Women & Fetuses: 
Non-English Speaking: 
Others: 
e. Number of subjects who signed consents 
f.
Total number of patients who withdrew or 
1) Summarize the reasons for withdrawal. 
g. Did all research subjects give written informed 
1) If no, provide explanation: 
but were dropped from study 
were withdrawn from the study: 
Subject unable to complete 
("screen failures"):3 
1 
study tasks 
No 
N/A - consent waived 
consent? 
I Yes 
V.09/13/2013 
Page 7 of 29 

4. Which of the following groups will be recruited for this study? (check all that apply) 
Inpatients 
E] Outpatients 
Li Pre-Operative patients 
III Nursing home patients 
El Healthy volunteers 
III Non-VA participants * 
* Recruitment of Non-VA Participants 
a.
Non-veterans may be entered into VA-approved research studies only when there are insufficient veterans 
available to complete the study in accordance with 38 CFR 17.45 and 38 CFR 17.92. 
b.
You must document how you will attempt to enroll veterans and outline how you will provide verification to 
Research Service that recruitment resulted in insufficient veteran enrollment. 
5. Are you recruiting and enrolling Non-VA participants? 
1- 1  Yes 
No 
•
If "YES", complete the following information: 
a.
Document how you will attempt to enroll veterans. 
b. Outline how you will provide verification to Research Service that recruitment resulted in insufficient 
veteran enrollment. 
6. Selection Criteria 
V.09/13/2013 
Page 8 of 29 

a. What are the inclusion/exclusion criteria? 
Inclusion Criteria: 
Ages 18-50 and in general good health 
Able to read English at a 6th grade level (as determined by WTAR) 
Able to provide written informed consent 
* Mild TBI (GCS 13-15, LOC < 30 min, and/or PTA <24 hours from onset) as confirmed by structured clinical 
history (TBI SUJECTS ONLY) 
* Greater than 6 months from the time of brain injury (TBI SUBJECTS ONLY) 
Normal or corrected-to-normal visual acuity 
Stable doses of all medications (2 weeks or greater) 
Exclusion Criteria: 
Contraindications to MRI (e.g. unremovable ferromagnetic metals, claustrophobia) 
Inability to complete basic fMRI requirements (e.g. making button presses, minimizing movement < 5mm) 
History of major brain surgery or penetrating brain injury (i.e. violating brain parenchyma) 
Severe low blood pressure or uncontrolled high blood pressure 
* History of mild, moderate, or severe TBI (CONTROL SUBJECTS ONLY) 
Contraindications to tolcapone use, including liver function tests (AST, ALT, Total Bilirubin, Direct Bilirubin, 
Alkaline Phosphatase) more than 2 times normal ranges, pregnancy, previous adverse reaction to tolcapone, or 
significant liver impairment including but not limited to chronic hepatitis, cirrhosis, hepatocellular carcinoma, 
parasitic liver infection, autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis, or any other liver 
condition obtained from patient history (and/or the medical record, if available) that is identified by the reviewing 
clinician 
Current use (within previous 30 days) of pharmacological agents with dopaminergic actions, including but not 
limited to tolcapone, levodopa/carbidopa, entacapone, amantadine, bromocriptine, pergolide, pramipexole, 
ropinirole, selegeline, isocarboxazid, phenelzine, tranylcypromine, clozapine, olanzapine, quetiapine, 
risperidone, ziprasidone, aripiprazole, fluphenazine, haloperidol, perphenazine, pimozide, thiothixene, 
trifluoperazine, loxapine, molindone, chlorpromazine, mesoridazine, thioridazine, promethazine, 
dextroamphetamine, dexmethylphenidate, dextroamphetamine, methylphenidate, cocaine, or methamphetamine 
Active alcohol dependence or alcohol abuse by DSM-IV-TR criteria (within previous 30 days) 
Active substance dependence or substance abuse by DSM-IV-TR criteria (including marijuana, opiates, 
stimulants (cocaine, amphetamines), hallucinogens within previous 30 days) 
Positive urine drug screen for illicit substances 
Past schizophrenia, ADHD, and/or other psychiatric diagnosis except depression or PTSD 
History of psychiatric hospitalization (last 1 year), suicide attempt (last 5 years), or current suicidal ideation 
Clinically severe medical illness requiring treatment 
Subject has received an investigational drug within 30 days of screening visit 
Seizures greater than 4 weeks after injury or requiring active pharmacological treatment 
History of brain tumor, stroke, demyelinating disease, encephalitis, or aneurysm rupture 
Diagnosis of Alzheimer's disease or other primary neurodegenerative disorder 
A history of substance abuse will be assessed via patient history, consistent with our previous studies in healthy 
and substance-abusing patient populations. As noted elsewhere in the protocol, we will also screen the urine 
for drugs of abuse in order to ensure that subjects are not engaging in active use of amphetamine, cocaine, and 
other drugs as listed in the protocol. A history of psychiatric illness will be assessed via patient history, 
consistent with our previous studies in healthy and substance-abusing patient populations. As noted elsewhere 
in the protocol, our questionnaires will also augment these data (e.g. the PCL to assess symptoms of post-
traumatic stress disorder).  
V.09/13/2013 
Page 9 of 29 

7. Research Setting: 
a.
Describe the research setting in context of equitable selection of subjects. 
Subjects will be screened on either the VA Martinez campus or at the UCSF Research Clinic located at U.C. 
Berkeley, depending on subject convenience. Both settings are designed to be accessible and available to 
subjects with a variety of backgrounds. By a similar token, the MRI scanner setting at U.C. Berkeley does not 
impact equitable selection of subjects. 
b. Where will participants be screened, enrolled, and followed? 
n VANCHCS Outpatient Clinics - Check all that apply: 
Chico VA Outpatient Clinic - Specify Clinic: 
Fairfield VA Outpatient Clinic - Specify Clinic: 
 Mare Island VA Outpatient Clinic - Specify Clinic: 
El McClellan VA Outpatient Clinic - Specify Clinic: 
El Martinez VA Outpatient Clinic - Specify Clinic: 
11] Oakland VA Outpatient Clinic - Specify Clinic: 
Fl  Oakland VA Mental Health and Substance Abuse Clinic - Specify Clinic: 
Redding VA Outpatient Clinic - Specify Clinic: 
Sacramento VA Mental Health Clinic - Specify Clinic: 
El Sacramento VA Medical Center — Check all that apply: 
El Outpatient Clinic: Specify: 
n Inpatient Ward: Specify: 
fl UC Davis CTSC Clinical Research Center (CCRC) 
VANCHCS Martinez: Center for Rehabilitation and Extended Care (CREC) 
n VANCHCS Martinez: UC Davis Alzheimers Disease Center (UCD ADC) 
E VANCHCS Research Space - Specify Site: Building 4 
El UC Davis Medical Center - Specify: 
University or College Campus - Specify: 
VACCHCS Outpatient Clinic - Specify Clinic: 
VACCHCS Research Space - Specify Site: 
E Other - Specify: the UCSF Research Clinic, located at UC Berkeley; UC Berkeley Brain Imaging Center 
I I 
I I 
I I 
b. How do the inclusion/exclusion criteria reflect the purpose of the study? 
The challenges of designing studies with a mTBI population in mind are many, not least of which is selecting as 
reasonably homogeneous a group of patients as possible. Our study will enroll mTBI and matched control 
OEF/OIF veterans between 18 and 50 years old who live independently and are in the chronic, stable phase of 
recovery -- at least 6 months removed from the time of their traumatic brain injury. These criteria reflect our goal 
of looking at patients in the chronic phase of mTBI whose symptoms are not potentially confounded by other 
significant neurological or psychological comorbidities. 
c.
How do inclusion and exclusion criteria impose fair and equitable burdens and benefits? 
These criteria attempt to balance the need to be broad enough to make the results generally applicable, but 
specific enough to ensure that other factors do not confound or negate possible results. For individual subjects, 
the inclusion and exclusion criteria balance safety, given the use of both MRI and tolcapone, with possible 
improvements (or not) in decision making.  
d. Describe the science and ethics of excluding groups that might benefit from the research. (If women or 
minorities are excluded, explain reasons for exclusion.) 
Gender and ethinicity/race do not interact with any of our hypotheses, and we will not exclude any subjects on 
either basis. 
V.09/13/2013 
Page 10 of 29 

8. How will participants be recruited for taking part in the study? Please review "Important Information for 
Researchers" for more information about acceptable recruitment methods. 
a. Check all that apply: 
' 
Investigator's patient population: Study investigators recruit their own patients directly in person and/or nurses 
working with researchers approach patients. 
n Scheduled visit: Study investigators provide their colleagues with an IRB approved "Dear Patient" letter 
describing the study. This letter can be signed by the treating health care provider and would inform the patients 
about how to contact the study investigators. The study investigators may not have access to patient names 
and addresses. 
E Physician referral: Study investigators send an IRB approved letter to colleagues asking for referrals of eligible 
patients interested in the study. The investigators may provide the referring physicians an IRB approved 
Information Sheet about the study to give to patients. If interested, the patient will contact the Pl. Or, with 
documented permission from the patient, the PI may be allowed to talk directly with patients about enrollment. 
a. Direct advertising: Interested participants will initiate contact with study investigators. (Submit an electronic 
copy of all recruitment media listed in this section to the IRB Coordinator who will forward it to VANCHCS Public 
Affairs Officer (PA 0) for review prior to IRB review and approval.) 
LI Newspaper: Name(s) 
Bulletin Board Poster: Posting Location(s) VA Martinez, Concord and Oakland Vet Centers 
Flyers: Posting Location(s) VA Martinez, UCSF Research Clinic located at UC Berkeley, UC Berkeley, 
Concord and Oakland Vet Centers, see attached approved amendment(3114116) for additional sites 
' Internet: Web site address Craiglist 
If using the media above, see VANCHCS Policy Statement PS-00-9 "Local Publications" or call VANCHCS 
HRPP  at 916 366-5369. 
 Radio: Station Name(s) 
I  I Television: Station Name(s) 
If using the media above, see VANCHCS Policy Statement PS-00-7 "Public Affairs Program." 
Other: 
il  Waiver of Authorization and Consent for recruitment purposes: This waiver is an exception to the policy but 
may be requested in exceptional circumstances such as: 
n Minimal risk studies in which participants will not be contacted, for example chart/database review only 
(Describe who and how): 
I I Review of charts/database is needed to identify prospective participants who will then be contacted 
(Describe who and how): 
LI Large-scale epidemiological studies and/or other population-based studies when participants may be 
contacted by someone other than personal health care provider (Justify and describe by who and how): 
I 
Direct contact: Potential participants have previously given consent to be contacted for participation in 
research. Clinic or program develops an IRB approved recruitment protocol that asks patients if they agree to 
be contacted for research (a recruitment database) or consent for future contact was documented using the 
consent form from a different study that was approved by the IRB. 
LI Potential participants unknown to investigators: Study investigators recruit potential participants who are 
unknown to them. Examples include direct approach in public situations, random digit dialing, use of social 
networks, Please explain here: 
LI NO contact: This study does not involve participant contact for recruitment. Examples include record review, 
use of specimens. 
V.09/13/2013 
Page 11 of 29 

b. Are participants 
participation? 
being paid (includes all types of reimbursement, such as parking fees, etc.) for 
, 
prohibits paying hum-an subjects to participate in research when the research is integrated with 
and when it makes no special demands on the patient beyond those of usual medical care. 
to question 1), 2), 3), 4), 5) and 6) below. 
to Section F.9. 
0 Yes I 
I No 
Note: VA policy 
a patient's care 
•
If "YES", continue 
•
If "NO", skip 
1) Payment may be permitted in the following circumstances 
Check all that apply 
11 No Direct Subject Benefit: When the study to be performed is not directly intended to enhance the 
or treatment of the medical condition for which the volunteer participant is being treated, and 
the standard of practice in affiliated non-VA institutions is to pay participants in this situation. 
diagnosis 
when 
I I Others Being Paid: In multi-institutional studies, when human participants at a collaborating non-VA 
institution are to be paid for the same participation in the same study at the same rate proposed. 
I I Comparable Situations: In other comparable situations in which payment of participants is 
appropriate. Describe: 
, Transportation Expenses: When transportation expenses are incurred by the participant that would 
incurred in the normal course of receiving treatment and which are not reimbursed by any other 
not be 
mechanism. 
2) Payment Amount: 
Total Amount $ Approximately $316, assuming study completion 
Prorated as follows: $12/hour for non-scanner time, $20/hour for scanner time, up to $40 for task-
related payments, and a $100 completion bonus to encourage returning for all 3 visits 
3) Method of Payment: 
n Cash 
I—I  Gift certificate Lii  Other: 
, Check 
4) Payment Schedule: 
Each visit 
completion 
LII Other: 
' 
Study 
5) Substantiate that proposed payments are reasonable and commensurate with the expected 
contributions of the participant. 
We anticipate that subjects will be present for 2 hours for the screening visit, and 5 hours for each of 
the MRI visits, of which 2 hours will consist of MRI scanner time. 8 hours of behavioral time x 
$12/hour = $96. 4 hours of MRI scanner time x $20/hour = $80. Including $40 related to performance 
of the economic games and the $100 completion bonus, the total payment would be $316. 
6) Substantiate that proposed payments are fair and appropriate and that they do not constitute undue 
pressure or influence to participate. 
These payments are consistent with our previous IRB-approved protocols at U.C. Berkeley and U.C. 
San Francisco. Payments of $12/hour for behavioral testing and $20/hour for MRI scanner time 
reflect ongoing subject payment rates at U.C. Berkeley. The maximum of $40 for bonus payments 
related to economic task performance is necessary to encourage veridical participation in the 
economic tasks. Finally, the $100 completion bonus ensures that subjects return for all 3 sessions, 
while balancing the concerns of undue influence to participate. 
9. Which of the following vulnerable populations will be recruited for this study? (Check all that apply). 
Children* 
ri Non-English Speaking 
L None 
Economically Disadvantaged* 
 Employees 
I 
I Persons with HIV 
T1  Educationally Disadvantaged* 
 Fetuses* 
I 
I Prisoners* 
ri  Impaired Decision Making Capacity* 
I I Homeless/Shelter 
Students/Trainees 
V.09/13/2013 
Page 12 of 29 

n Pregnant Women* 
 Mentally Disabled* 
 Terminally III Patients 
 Others: 
* listed in the Federal regulations; VHA Handbook 1200.5 Appendix D lists special requirements 
a. 
Describe the scientific and ethical reasons for including vulnerable populations in the research. (Why 
are vulnerable populations necessary in this research study?) 
N/A 
b. Describe the extra protections and additional safeguards that protect the rights and welfare of 
vulnerable groups. (How are the vulnerable populations being protected?) 
N/A 
c. 
Describe the procedures that you have devised to ensure that participant's representatives are well 
informed regarding their roles and obligations to protect incompetent participants or persons with 
impaired decision making capacity. 
N/A 
G. RESEARCH PROCEDURES 
1. Check all procedures to be performed on human participants, samples or charts: 
Analysis of Existing Biological Specimens 
Interview 
n Analysis of Existing Data 
Invasive Procedures — Diagnostic (e.g. biopsy, catheters, etc.) 
II Biological Specimen Collection (urine, sputum, 
Invasive Procedures — Therapeutic (e.g. infusions, catheters, 
etc.) 
tissue, etc.)  
I Blood Collection 
fMRI: Clinical Research 
I 
Chart Review 
Fl MRI: Clinical Research 
Cognitive or Perceptual Experiment 
MRI: Diagnostic 
Commercial Product Development Potential 
from Human Biological Specimens 
Placebo 
Deception 
2 Physical Measurements: Non-Invasive (e.g. vitals signs) 
I I Device(s): FDA approved 
n Public Behavior Observation 
I I Device(s): Investigational 
I 
Questionnaire 
I Drug(s): FDA approved 
 Radiation: Clinical Research (e.g. PET) 
Drug(s): FDA approved Controlled Substance 
 Radiation: Diagnostic (e.g. X-ray) 
LI Drug(s): Investigational 
TI  Radiation: Therapeutic 
I I Drug(s): Investigational Controlled Substance 
III Specimen Collection for Future Use (tissue banking) 
I I ECG 
r
 Specimen Use from Tissue Bank (stored samples) 
LI EEG 
l_.] Surgery 
EMG 
LI Survey 
LI Evaluation of Program or Services 
LI Taste Test 
I 
Gene therapy 
I- 1  VA Data Record Search (Data Mart, Data Warehouse, etc.) 
I 
Genetic/DNA Research 
 Other 
V.09/13/2013 
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2. Describe research procedures to be performed on participants, samples or charts. 
a. Describe all interactions with participants or their identifiable samples or data in detail. 
For subjects who potentially meet eligibility criteria, we will use the initial phone screening performed by Dr. 
Kayser, Dr, D'Esposito, their postdoctoral fellows, graduate students, or research assistants to verify that 
subjects meet the criteria specified in the advertisement. Specifically, interested subjects will contact the study 
via the contact information provided in the study advertisements. Dr. Kayser, Dr. D'Esposito, or their research 
associates will then contact each potential subject by phone (or by each subject's preferred method of 
communication) in order to set up a brief phone interview, during which the requirements for the study will be 
reviewed. For control subjects, research assistants, graduate students, or postdoctoral fellows may perform the 
initial phone screening. Information collected during this phone screening is not written down. 
For subjects who state that they are potentially eligible for enrollment, we will arrange an initial visit, at the 
subject's convenience, to perform further screening and to gather initial behavioral data. The Subject Health 
screening sheets will be filled out immediately (and only) after obtaining written informed consent. We will 
additionally administer an extensive questionnaire listing contraindications to MRI scanning. Because the MRI 
scanner attracts certain metals, subjects who may have metallic objects in their bodies will be excluded. (As an 
additional measure of protection, we will use a hand-held metal detector to screen subjects before entering the 
scanner. This screening visit will take place either at the VA NCHCS Martinez campus or at the U.C.S.F. 
Research Clinic located at U.C. Berkeley, whichever is more convenient for subjects. 
After the study is explained to them and informed consent is obtained, subjects will participate in a blood draw in 
order to determine liver function tests. A hepatic screen will assay total protein, albumin, globulin, A/G ratio, 
bilirubin (total, direct, and indirect), alkaline phosphatase, AST (SGOT), and ALT (SGPT). These tests will be 
performed in the VA NCHCS system or at Quest Diagnostics. Elevation of plasma bilirubin, AST (SGOT), ALT 
(SGPT), or alkaline phosphatase consistent with liver disease and greater than 2.5 times the upper limit of 
normal will be grounds for subject exclusion. (Note that ongoing monitoring of liver enzymes will not be 
necessary, as only a single, counterbalanced dose of tolcapone will be administered to each subject.) If 
subjects have had liver function tests evaluated within the previous 6 months, subjects may sign a waiver to 
allow us to obtain those laboratory results. This step has the benefit of minimizing the use of even minimally 
invasive procedures for each subject. Subjects will also provide a salivary sample so that COMT genotype --
specifically, SNPs within the COMT gene -- can be obtained. Importantly, COMT genotype may modulate the 
effect of tolcapone, which inhibits COMT, and will therefore provide additional information that may potentially 
impact how the drug affects each subject. DNA extraction and analysis will be conducted using standard 
methods on saliva samples obtained just prior to the first MRI session. The UC Genomics Core will carry out 
genotyping of the COMT gene using Taqman and other assays with which they have extensive experience. 
Examiners and researchers outside of the Genomics Core will remain blinded to genotype until the end of the 
study. 
Female subjects will also be screened for pregnancy, as the effects of the drug during pregnancy are not 
adequately known and the drug can appear in breast milk. (Pregnancy is also a contraindication to MRI 
scanning; see below.) Since subjects may not know they are pregnant, all female subjects recruited to 
participate in the study will be required to have a urine pregnancy test prior to each session of the study. They 
will self-administer the test after coming into the research lab. These pregnancy tests have been in reliable use 
at the UC Berkeley Brain Imaging Center and Research Clinic for approximately 20 years without any reported 
failures. These requirements will not apply to any female subjects who are post-menopausal. 
Finally, at the screening visit subjects will complete a number of questionnaires (attached). They will also 
complete the VA NCHCS multi-center core TBI protocol. 
V.09/13/2013 
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b. Describe the research methods, including how the study will be implemented locally. 
This study is a randomized, double-blind, counterbalanced, crossover, behavioral and resting state fMRI study 
designed to test the effect of tolcapone on decision-making and neural activity. Tolcapone is an orally active, 
selective and reversible inhibitor of catechol-O-methyltransferase (COMT), an enzyme that catabolizes 
extracellular dopamine. Consequently, tolcapone prolongs the effect of endogenous dopamine release. It was 
FDA-approved in 1998 for treatment of Parkinson's disease as an adjunct to levodopa-containing medications 
Following screening, subjects will participate in two sessions (on separate days), and will be administered either 
placebo or tolcapone at the start of each session. Each session will last approximately 5-6 hours. Combining 
tolcapone challenge with task-active fMRI allows us to examine the impact of tolcapone on the neural circuits 
underlying decision-making during task performance. 
In keeping with our previous protocols and published reports, the randomization of drug across subjects 
(tolcapone versus placebo) is accomplished via a true random number generator utilizing atmospheric noise and 
accessible at the website www.random.org. The dispensing record is now attached. Utilizing the (blinded) 
medication assignment, the clinician identifies the study drug, logs the drug into the dispensing record, notes the 
drug administered in the subject's documentation, and administers the drug to the subject. 
V.09/13/2013 
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c. Provide detailed information about all study procedures, including the approximate duration and 
frequency of each procedure. It is not necessary to repeat descriptions of non-human related 
procedures from the protocol narrative (e.g. you should describe how much and how frequently blood is 
drawn, but not the methods for performing tests on the blood, if already stated elsewhere). 
For the MRI component of the study, subjects will participate in 2 days of testing — one each for tolcapone and 
placebo administration. The structure of each session of the 2 days will be identical: subjects will participate 
while seated in a well-lit, comfortable room in the Brain Imaging Center on the UC Berkeley campus where the 
MRI scanner is located. Light snacks and reading material will be provided. The sequence of events during a 
session will be as follows: 
-10 minutes: Subjects will be urine-screened for illicit drug use (Biotechnostix) and for alcohol intoxication via 
breathalyzer (Lifeloc Technologies). Female subjects will be screened for pregnancy as described above. 
Active use of substances other than alcohol or tobacco, use of alcohol on the day of the study as assessed by 
breathalyzer testing, and/or a positive pregnancy test, will be grounds for exclusion. 
-5 minutes: Subjects perform a baseline testing mini-battery and have their blood pressure taken. The mini-
battery will consist of the backwards digit span, visual analog scales (anxious, happy, sad, nauseous, drowsy, 
jittery, fatigued, and dizzy), a time perception task, and/or a motor tapping test, all of which are designed to 
assess changes in dopaminergic tone. 
0 minutes: Subjects will be administered either 200mg of tolcapone or placebo, prepared by the compounding 
pharmacy to match tablet appearance, in randomized, double-blind, counterbalanced fashion. Because 
tolcapone can discolor the urine, and therefore unblind participants, both tolcapone and placebo will be co-
administered with riboflavin, a naturally-occurring B-vitamin that also discolors the urine and therefore masks 
this tolcapone effect. 
+60 minutes: Tolcapone concentration is known to peak in the bloodstream at approximately 90 minutes after 
oral ingestion. At approximately 60 minutes, subjects will be brought to the MRI scanner suite. They will be 
provided with ear protection, lumbar support, and head cushioning to ensure that they are comfortable in the 
scanner. They will also be given a response box in order to respond during task performance, and they will be 
provided with a mirror in order to see a rear-projection screen. These procedures will be performed in time for 
subjects to be ready for testing that includes the time of peak drug concentration. Behavioral and MRI tasks are 
described in more detail below. 
+210 minutes: Subjects will undergo additional behavioral testing outside the scanner. 
+300 minutes: Subjects will complete the testing day. 
The primary cognitive tasks are three. The first is a computer-based delay discounting task in which subjects 
choose between hypothetical monetary rewards available immediately versus lesser ("discounted") rewards 
available at one of a range of future time points or "delays". The second is a computer-based visual attention 
task in which subjects respond to pictures of faces and houses. The third is a computer-based social-emotional 
task in which subjects view pictures of emotional faces and from the IAPS set. They are required to react to the 
images, or to reframe the context of the picture to reduce the emotional response. Other tasks to measure 
impulsivity or decision-making may also be employed. Specifically, we will measure reaction time and response 
inhibition (i.e. motor impulsivity) directly, assess memory and higher-order problem-solving, ask subjects game 
theory-style decision-making questions, or determine how cognitive set modifies decisions about monetary 
reward and risk. 
d. Distinguish procedures that are for research from those that are clinically indicated and/or standard of 
care. 
All of the procedures included in this protocol are employed for research purposes only.  
V.09/13/2013 
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e. Will any study procedures (including analysis of subject samples or data) be conducted at any site other 
than VANCHCSNACCHCS? 
[SI Yes in  No 
•
If "YES", complete the following information: 
1) Site(s): UCSF Research Clinic, located at UC Berkeley, and UC Berkeley Brain Imaging Center 
2) What study procedures will be performed there? Screening visits will be performed at the UCSF 
Research Clinic, located at UC Berkeley, for subjects who find the site more convenient than the VA Martinez 
campus. The U.C. Berkeley Brain Imaging Center represents the site for MRI scanner visits. Blood testing for 
liver function and complete blood counts may be performed at Quest Diagnostics. The UC Genomics Core will 
perform genetic analyses.  
H. RISK 
V.09/13/2013 
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1. Expected risks 
•
Describe all known risks to subjects of study-related procedures and products and their expected frequency and 
severity. 
•
Assess the likelihood and seriousness of identified risks. 
a. Physical Risks: There are no known risks of functional MRI studies. This noninvasive technique involves no 
catheterizations or introduction of exogenous tracers. A multitude of subjects have now undergone magnetic 
resonance studies without apparent harmful consequences. Radiofrequency power levels and gradient 
switching times used in these studies are within the FDA-approved ranges. Some people become 
claustrophobic while inside the magnet, and in these cases the study will be terminated immediately at the 
subject's request. The only absolute contraindications to MRI studies are the presence of either intracranial or 
intraocular metal, or a pacemaker. Relative contraindications include pregnancy and claustrophobia. 
Participants who may be pregnant, who may have metallic foreign bodies in the eyes or head, or who have 
cardiac pacemakers will be excluded because of potential contraindications of MRI in such subjects. A negative 
pregnancy test will be required for female subjects. 
b. Tolcapone, the medication being used in these studies, has previously been associated with one very serious 
adverse effect. Three elderly parkinsonian women who were also taking tolcapone suffered fatal fulminant 
hepatic failure when liver function tests were either unmonitored or not used to discontinue the medication. 
Since this issue was raised in 1998, during 40,000 subsequent patient years of treatment only 3 cases of severe 
but reversible liver injury have occurred with chronic use. Reviews have concluded that "severe liver injury as a 
result of tolcapone is not greater than that observed with other routinely prescribed drugs such as 
carbamazepine, valproate and phenytoin". We note that this study will involve only a one-time dose of this 
medication, and that it will only be administered to subjects with liver function tests within a defined range prior 
to participation. Additionally, the current study population is significantly younger and has been selected to be 
physically healthy. No case reports or other studies have reported abnormalities in liver function that have 
developed after one dose. It is therefore very likely that our current study population will be at much less risk. 
Nonetheless, all subjects will be informed of this risk, and subjects with liver function tests elevated above twice 
the normal range will be excluded from participation. Notably, the other drug in its class — entacapone — works 
only peripherally, as it does not cross the blood-brain barrier. In placebo-controlled trials of tolcapone, common 
side effects that occurred at a greater rate than for placebo included nausea, anorexia, orthostasis, and fatigue. 
Each of these side effects is uncommon at the single dosage being utilized in these studies, and subjects with 
contraindications to tolcapone use are excluded in our screening procedures. Moreover, in our sample of 
greater than 100 subjects who have taken tolcapone for other studies, no subject has reported such side effects, 
and subjects have been unable to identify placebo versus tolcapone. 
c. 
Psychological Risks: There are no risks associated with cognitive testing except for the occasional possibility 
of fatigue or frustration with poor performance. Testing will stop if a subject becomes too tired or frustrated. 
Subjects who become anxious during testing (e.g. due to PTSD symptoms) will have access to drop-in Mental 
Health care within the VA system, and a physician or nurse practitioner will be on-site at all facilities. 
d. Social Risks: There are no known social risks of these studies. 
e. 
Economic Risks: There are no known economic risks of these studies. Subjects will be reimbursed for their 
travel and participation. 
f. 
Legal Risks: There are no known legal risks of these studies. 
V.09/13/2013 
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2. Risk minimization 
a. Describe the impact of study design on risk. (e.g. does observational design impact on risk; or does 
observational design only impact privacy risks; or does placebo controlled design impact risk, or do all patients 
receive therapy; or does single blind placebo washout period increase risk of uncontrolled symptoms?) 
Because the study is performed in double-blind fashion, researchers will not be immediately aware of the drug 
condition should subjects have a side effect. If in the judgment of the on-site clinican this side effect requires 
knowledge of the medication provided, the blind can be broken .  
b. Describe study procedures that minimize risks. 
All subjects will be screened by the experimenter to ensure they do not have any metallic implants, shrapnel, 
pacemakers, or other contraindications to MRI. All subjects will be under close supervision on the days of the 
study. Also, for each subject's protection, access to the scanner is restricted to members of the research team. 
Information obtained from the studies in the research plan will be strictly confidential, except as required by law, 
but will be made available to the subject and his/her physician in response to a specific request from the 
participant. There will be no personal identification of subjects in scientific communications. fMRI studies are not 
given a clinical interpretation. In the event that a significant abnormality is detected on an anatomical MRI scan, 
a recommendation to seek further medical consultation will be made. However, it is stressed that the MRI 
evaluation performed for these studies does not represent a complete clinical MRI evaluation, and it is not being 
performed for clinical diagnostic purposes. All complications of treatment, as well as adverse and severe 
adverse events, will be promptly reported to the local institutional review board for human subjects. Timely 
contact will be made with the subject's physician, and care will be provided within the VA system, where 
applicable.  
c. Describe standard of care procedures that minimize risks. 
As described in section (b) above, study procedures will minimize risks. These research studies are operating 
in an area of study for which standard of care procedures are otherwise defined.  
I. 
RISK BENEFIT RATIO 
1. 
Risks in Relation to Benefits 
a. What are the direct benefits to the participants? 
Healthy adults and TBI patients may gain some insight into the scientific process of learning about human 
cognitive function; they may also note changes in their performance on the behavioral tasks. In addition, 
subjects may benefit psychologically from knowing that they are participating in research designed to benefit 
veterans. In addition, subjects will be reimbursed for their participation. The potential benefits anticipated in 
improved treatment and management of patients with cognitive disorders are expected to far outweigh the 
minimal associated risks. 
b. 
Why do you believe the risks are reasonable in relation to the potential benefits to the participants? 
The behavioral and MRI procedures are well-known to subject participants to minimal risks. The study drug has 
been very well tolerated in our previous studies of greater than 75 subjects. Study procedures described above 
minimize risks of each of these exposures. Given these small risks, and the above benefits, we believe the 
benefits outweigh risks. 
c. 
What are the benefits to society? 
Both awareness and incidence of mTBI have increased dramatically in recent years. To date the 
pharmacological treatments of mTBI are extremely limited. If this study points toward a benefit of tolcapone, this 
drug could improve the treatment of these individuals. We anticipate that the results of these studies will help in 
the overall understanding of cognitive function and may lead to improved treatments for patients with traumatic 
brain injury and other brain injuries. 
Why do you believe the risks are reasonable in relation to the potential benefits to society? As above, 
minimal risks and potentially significant benefits argue that the risk-benefit analysis represents a reasonable 
tradeoff. 
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2. Alternatives to participation 
a. Describe appropriate alternative procedures or courses of treatment, if any, which might be 
advantageous to the participant. (If no alternatives exist or if this is not a treatment study, state so.) 
Because this study is a research study, not a treatment study, the alternative for subjects would be not to 
participate.  
. MONITORING SAFETY 
1. Describe the Data and Safety Monitoring Plan that ensures the safety of participants in this research study. 
(e.g. what labs to monitor for abnormalities, what questionnaire responses to monitor for suicide) 
Subjects will be closely monitored while MRI scans are underway, and they will be able to communicate with the 
scanner operator at any time. Only scanner operators who have received both MRI safety and operator training will 
be allowed to scan subjects. Tolcapone administration will be observed, and subjects will remain in the laboratory 
setting for 6 hours after tolcapone (or placebo) ingestion so that any immediate side effects will be noticed. The drug 
is only administered in the UCSF Research Clinic located at UC Berkeley, and only under the supervision of an on-
site study physician (currently either Dr. Kayser or Dr. D'Esposito). Currently either Dr. Kayser or Dr. D'Esposito 
(both neurologists within the VA system), or in the future another trained prescribing clinician, will be on-site 
whenever a subject is administered a medication. Tolcapone will be kept in a secure, locked location in the UCSF 
Research Clinic located at UC Berkeley, and all use will be logged. Finally, a monitoring board headed by a 
physician independent of the study will review study procedures and outcomes. 
Numerous procedures ensure that the study drug is safe for use. All ingredients used are weighed and compared 
with the weight of the final product to ascertain that the strength of the drug in milligrams is as expected. Tolcapone 
is supplied as 100mg tablets, allowing the pharmacist to easily verify that the final weight of the compounded 
product is equal to the weight of the 2 x 100mg tablets, the incorporated riboflavin, and inert compounding 
ingredients. Tolcapone is supplied with a 2-year expiration date. The compounded bottles are labeled with a 
standard six month expiration date after compounding to ensure stability even though the tablets are given a two 
years expiration by the manufacturer. Consistent with the package insert for tolcapone, the original tolcapone tablet 
is not specially formulated (e.g. as some delayed-release formulations of other medications may be). Similarly, it is 
not resolubilized during the compounding process. Tolcapone is currently purchased by Abbotts Compounding 
Pharmacy from Bellco, a licensed wholesaler and subsidiary of AmerisourceBergen Corp. The placebo capsule 
contains microcrystalline cellulose and riboflavin that are both obtained from Medisca, an FDA-registered chemical 
wholesaler. Both tolcapone and placebo will be stored in a locked cabinet, in a secured office, away from light and 
moisture sources, in space occupied by the UCSF Research Clinic located at UC Berkeley. 
V.09/13/2013 
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2. Does this  study have a Data and Safety Monitoring Board (DSMB)? 
a Yes 
No 
•
If "YES": 
. 
a. What is the nature and expected role of the DSMB? An independent DSMB will examine accumulating data 
to assure protection of patients' safety while the study's scientific goals are being met. The DSMB is responsible 
for conducting periodic reviews of accumulating safety and efficacy data. It will determine whether there is 
support for continuation of the trial, whether there is evidence that study procedures should be changed, or 
whether the trial should be halted for reasons relating to the safety of the study patients. Adverse event data 
and other data intended for safety monitoring will be reported through the study Principal Investigator to the 
DSMB. After each meeting, the DSMB will communicate its recommendations and a summary report of all 
'possibly' related serious adverse events (SAEs) to the Principal Investigator, to be conveyed to the IRBs 
involved in the study. While interim efficacy analysis is not planned, the DSMB may request such analysis to 
•
permit proper evaluation of safety data. If an unscheduled interim efficacy analysis is necessary, the DSMB will 
specify the question, the analysis required, the critical values for a decision, and the statistical procedures 
necessary to control the overall type 1 error at p<0.05. A protocol amendment will be included in the DSMB 
report of the analysis describing the necessary changes in the statistical plan. 
b. How often will the findings of the DSMB be reported to the IRB? Our first subject was enrolled in July of 
2015, a report will be generated yearly from this date. 
3. 
Explain how researchers will manage adverse events and research-related injuries. 
Serious adverse events related or unrelated to the research, and serious unanticipated problems related to the 
research, will be reported directly to the Director of the Office for Protection of Human Subjects. These problems or 
events Will be reported as soon as possible, and at most within one week (seven calendar days) of the Lead 
Investigator learning of the incident. All MRI studies performed at the UC Berkeley Brain Imaging Center are part of 
research protocols and are not intended to provide comprehensive clinical MRI examinations of the brain. If, 
however, a potential abnormality is identified on the MRI scan, one of the two study neurologists — Dr. Kayser or Dr. 
D'Esposito — will notify the subject and the subject's physician. 
4. 
Describe the circumstances under which a participant may be withdrawn prematurely from, the study and 
the potential risks of such early withdrawal. 
Subjects who do not return for follow up visits or who are unable to otherwise comply with study procedures will be 
withdrawn from the study. In addition, if subjects do not wish to continue with the study or suffer a severe adverse 
event, they will be removed from the study. There are no risks in this study of early withdrawal per se. 
5. Describe the procedures for reporting adverse events. 
Serious adverse events related or unrelated to the research, and serious unanticipated problems related to the 
research, will be reported directly to the Director of the Office for Protection of Human Subjects. These problems or 
events will be reported as soon as possible, and at most within one week (seven calendar days) of the Lead 
Investigator learning of the incident. 
K. SAFETY REPORT (refer to OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to 
Subjects or Others and Adverse Events" dated January 15, 2007) 
V.09/13/2013 
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1. Adverse Events 
a. Local (Internal) Adverse Events and Serious Adverse Events (AE/SAE): Have ALL complications, untoward 
side effects, or adverse events related or possibly related to research at this site been reported to the IRB since the 
last review? 
P1 Yes n No i1 N/A = none occurred 
•
If "YES": 
Attach a Local Adverse Event spreadsheet summarizing all AE/SAE's which occurred at this site since 
the last report to the IRB. 
•
If "NO": 
Submit the missing report to the IRB and attach a Local Adverse Event spreadsheet summarizing all 
AE/SAE's which occurred at this site since the last report to the IRB. 
b. Global (External) Adverse Events and Serious Adverse Events (AE/SAE): Have any complications, 
untoward side effects, or adverse events been reported at other sites (SAE or IND Safety Reports) since last 
report? 
Lil Yes LIINo I 
N/A 
•
If "YES": 
Attach a Global Adverse Event spreadsheet summarizing all AE/SAE's which occurred at other sites 
since the last report to the IRB. 
NOTE: Definition of SAE and AE: 
•
Serious Adverse Event — any adverse experience that results in the following: Death; Hospitalization; 
Disability/Incapacity; Congenital Anomaly/Birth Defect; Requires Intervention; or is Life-threatening 
•
Adverse Event— any adverse experience temporally associated* with the investigational treatment not meeting the 
definition of serious adverse event. 
* temporally associated — during the time period the subject participates in the study 
2. Have unanticipated problems* (local or global) involving risks to subjects or others, or significant new findings 
(that have not been previously reported) been discovered since the previous IRB review that might affect the 
subject's willingness to continue participation? 
[I] Yes [A No 
•
If "YES", complete the following: 
a. Attach a spreadsheet summarizing all unanticipated problems which occurred since the last report to the 
IRB. 
b. Explain the risks or findings in detail: (a clear explanation of why the adverse event or series of adverse events 
has been determined to be an unanticipated problem) 
c. Describe any proposed protocol changes or other corrective actions to be taken by the investigators in 
response to the unanticipated problem: 
d. Do these risks or findings require modification of the informed consent form? 
Yes 111 No 
•
If "YES", have the modifications been submitted to the IRB? 
El Yes El No 
e. Were subjects notified of these risks or findings? 
fl Yes n No 
f.
Were subjects re-consented? 
n Yes LINo 
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3. Have other unanticipated problems (not related to adverse events) been discovered since the previous IRB 
review? 
fl Yes El No 
•
If "YES", complete the following: 
a.
Attach a spreadsheet summarizing all unanticipated problems which occurred since the last report to the 
IRB. 
b.
Explain the findings in detail: 
c.
Describe any proposed protocol changes or other corrective actions to be taken by the investigators in 
response to the unanticipated problem not related to an adverse event:  
* NOTE: Unanticipated problems are any incident, experience, or outcome that meet all of the following criteria: 
•
Is unexpected in terms of nature, severity, or frequency 
•
Is related or possibly related to participation in the research 
•
Suggests that the research places the subject or others at a greater risk of harm than was previously known or 
recognized 
 
4.
Describe any complaints about the research since the last IRB review. 
[S] N/A — none occurred 
5.
Describe any unanticipated protocol deviations (including errors and accidents) since the last review. 
121 N/A — none occurred 
L. PRIVACY AND CONFIDENTIALITY 
1. Research Data 
a. Identifiers: Please indicate all identifiers that may be used by researchers or included in study research 
records. 
Li NO identifiers used by researchers (skip to item L.1.d. "Medical Records or Health Information') 
Check all that apply: 
I Names 
II Social Security Number 
LI Device Identifiers 
a Dates 
I Medical Record Number 
n Web URLs 
a Postal Addresses 
Health Plan Numbers 
I I  IP Address Numbers 
V Phone Numbers 
Account Numbers 
I I  Biometric Identifiers 
•
Fax Numbers 
LI License/Certificate Numbers 
Photos and Comparable Images 
I Email Addresses 
Vehicle ID Numbers 
[I Any Other Unique Identifier 
b. 
Source of Identifiers Listed 
Check all that apply: 
Above: Please indicate the sources of the information listed in part 1(a) above 
as part of health care, collected as part of health care, added to the medical 
the medical record, or used to make health care decisions) 
including Interviews, Questionnaires 
Public 
a Medical Records (created 
record, extracted from 
I 
Directly from the Participant, 
11 Records Open to the 
n Other: 
c. 
Describe how identifiers will be used to screen and/or recruit participants for the trial. 
These identifiers will be used to contact subjects and to pay subjects. In addition, as indicated below, subjects 
may also allow researchers to obtain recent (previous 6 months) laboratory results for liver function testing. 
d. 
Medical Records or Health Information: Please indicate all information that may be used by researchers or 
included in study research records. 
Li NO medical record or health information used by researchers (skip to Section M. "Research Data Security') 
Check all that apply: 
V.09/13/2013 
Page 23 of 29 

0 History and Physical Exam 
I Progress Notes 
n Operative Report(s) 
n Discharge Summary(ies) 
IM Diagnoses 
' Drugs/Medications 
0 Radiology Images 
Radiology Reports 
ri  Pathology Reports 
I 
Laboratory Reports 
1:1 ECG Reports 
•
Consult Reports 
[Z] Drug Abuse 
2 Alcoholism or Alcohol Abuse 
Fl  Testing for or Infection with HIV 
•
Sickle Cell Anemia 
n Psychological Tests 
•
Mental Health (not psychotherapy notes) 
TI  Patient Demographics 
I-1 Only the following records of types of health information: 
e. Describe who will access protected health information (PHI) (i.e. medical record) and for what purpose. 
Researchers will not access PHI except in one circumstance. During the screening procedures, a blood draw is 
required in order to assess liver function tests (AST, ALT, T.Bili, D.Bili, Alk Phos). Some subjects may have 
obtained liver function tests within the previous 6 months, and may therefore be able to avoid an 
unnecessary venipuncture. If so, subjects may sign a disclosure of PHI form so that the research team may 
obtain a record of these results for determination of eligibility. Dr. Kayser will access the PHI 
In keeping with their roles in monitoring the study, the following entities may access or use PHI: VA RR&D, UC 
Berkeley IRB, UC San Francisco IRB, the FDA, and the VA NCHCS IRB. 
f. 
Disclosure of Protected Health Information 
of the information listed above as part of the study 
Check all that apply: 
n We do not plan to share any of the PHI 
(PHI): Please indicate to whom or where you may disclose any 
process. 
listed above outside the research team. 
Committee and Subcommittees 
-Profit Corporation 
Services Office for Human Research Protection (OHRP) 
Review Boards 
r VANCHCSNACCHCS Research & Development 
LI VAN CHCSNACCHCS Designated Non
.12 U.S. Food and Drug Administration (FDA) 
E] U.S. Department of Health and Human 
1-1  U.S. Government Accounting Office (GAO) 
11 Participant's Medical Record 
I 
Study Sponsor: VA RR&D 
I 
Others UCSF and UC Berkeley Institutional 
g. 
Identify who will disclose information. 
If required by the organizations noted in (f), Dr. Kayser will disclose the requested information. 
V.09/13/2013 
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2. Data Protection 
a. Describe the provisions that exist to protect participant privacy during and after the research. 
We will collect only the minimum amount of the individual's private information required to complete our study. 
To protect privacy, we will advise potential subjects of the minimum amount of personal information that would 
be required of them in order to participate in our study. Furthermore, we will provide information about the 
logistics of participating in our research study (e.g., location of testing) to ensure that each subject can decide 
whether logistics will impinge on his/her privacy. Finally, all participants will be informed regarding how 
information is secured and stored to protect confidentiality. Based on this information, the potential subject can 
determine for him/herself if he/she wishes to provide this information to us and whether he/she wishes to 
participate in our research study 
b. Describe the provisions in place to protect participant confidentiality during and after the research. 
Identifiable personal information will be obtained from each subject. Each participant will then be given a unique 
identifier that will not contain any identifying personal information. Information gathered using this unique 
identifier will be kept in a separate locked file cabinet. Only members of the research team who have been 
identified as key research personnel will have access to the subject information and study data. In the event 
that a potential subject is deemed ineligible for the study, all personal, identifiable information will be destroyed. 
Questionnaire data are stored in a separate cabinet in Dr. Kayser's office, and do not include subject personal 
identifiers. Behavioral, imaging, and genetic data do not include personally identifiable information. Data are 
stored in password-protected data files. The fMRI data are collected at U.C. Berkeley and are temporarily stored 
in a password protected directory on the UCB Brain Imaging Center network, which is also behind a firewall. No 
subject personal identifiers are ever associated with these data on either network. 
The data are to be presented in tables or MRI scans in peer-reviewed publications. Individual subjects are never 
identified. We have found that some subjects are interested in the published data and we provide them with 
copies of publications where their data is included. The consent forms and screening sheets of subjects 
excluded from the study will be destroyed. 
M. INTERIM FINDINGS 
1. Provide a summary description of study progress, subject experiences, research results obtained thus far, 
and any new information since the IRB's last review. 
Currently we are actively recruitng potentially eligible subjects. Because we are still in the process of collecting data 
there are no research results at this time. 
2. Provide a summary of any relevant recent literature since the IRB's last review. (Attach copies of any relevant 
publications.) 
3. Attach any relevant multi-center trial reports. 
N. INFORMED CONSENT PROCESS 
1. Will all participants taking part in this study be consented on VA Form 10-1086? 
N Yes 1-1  No 
•
If "YES", continue to question #2 and #3 below. 
•
If "NO", submit the document entitled "Request to Waive Consent and Authorization for a Research Study" and 
skip Sections 02 and 03. 
V.09/13/2013 
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2. Describe the process of obtaining informed consent. 
a. Describe who conducts the consenting process. 
. 
Andrew Kayser, M.D. Ph.D., Mark D'Esposito M.D., or Nick Rodriguez, BA in conjunction with their post-doctoral 
fellows, graduate students, and/or research assistant(s), will obtain informed consent from the subjects. All 
researchers participating in the consent process, and in the study as a whole, will be certified to work with 
human subjects. 
b. Describe when it occurs. 
Informed consent will take place at the beginning of the screening visit. 
c. Describe where it occurs. 
Informed consent will be obtained at the research lab in Martinez or in the UCSF Research Clinic located at UC 
Berkeley. 
d. Describe how you will assure an acceptable level of comprehension before consent. 
If a subject has difficulty reading, the researcher will read the consent to the participant in the presence of a 
spouse, family member, or other subject-designated individual. As in our other active protocols outside the VA, 
subjects will be asked to repeat in their own words what goals and procedures the study involves, including risks 
and benefits of participation. As in our other active protocols outside the VA, all subjects will be given the 
opportunity to ask any questions about the goals and procedures the study involves, including risks and benefits 
of participation. If the subject indicates that s/he cannot adequately understand the study goals and procedures, 
or the researcher believes that s/he cannot adequately understand the study goals and procedures, the subject 
will be excluded from participation. 
e. For participants who may have impaired decision-making capacity to give informed consent: 
1) Describe the likely range of impairment. 
Subjects with impaired decision-making capacity to give informed consent will not be enrolled in the study. 
2) Describe how the participants' decision-making capacity to consent will be determined. 
As noted in section 2d, subjects will be required to demonstrate an understanding of the goals and 
procedures of the study, including risks and benefits. 
3) Who will determine whether or not the participant has decision-making capacity to consent? 
We will not recruit patients who have impaired decision-making capacity. If such a subject is inadvertently 
screened and the researcher who is obtaining consent notes that the subject cannot explain goals, 
procedures, risks, and benefits of the study, the researcher will be instructed to call Dr. Kayser or Dr. 
D'Esposito to confirm. If confirmed, these subjects will be excluded. 
f. 
If any vulnerable populations will be recruited, describe what precautions will be taken to insure their 
protection from undue influence. 
No vulnerable populations will be recruited. 
g. If surrogate consent is likely to be required, describe your procedure for obtaining consent from the 
legally authorized representative. 
Surrogate consent will not be required. 
3. After Hours Contact Information (to be included in the consent form) 
a. The VA approved after-hours telephone number for research studies is (916) 843-7000 extension 6051. 
V.09/13/2013 
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b. This study will use the VA approved after-hours telephone number for research studies. 
El Yes fl No 
•
If "YES", complete the following: 
1) Designated Service (department): 
OR 
1) Designated Contact Person: Andrew Kayser MD 
2) After-hours telephone number for the designated contact person (to be given to the VA after-hours 
operator): 415-302-0303  
b. This study will use a Designated Contact Person. 
IZ Yes fl No 
•
If "YES", complete the following: 
1) Designated Contact Person: Andrew Kayser MD 
2) After-hours telephone number for the designated contact person: 415-302-0303 
V.09/13/2013 
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Initial beside each statement to confirm your knowledge and agreement. 
AK  1. I assure that the rights and welfare of human subjects participating in this research project will be protected at all 
times and that the benefits to be gained from this study are commensurate with the risks involved. 
I will obtain, (unless a waiver of consent and authorization is approved) an authorization to use PHI for research 
and a fully documented research informed consent on a VA Form 10-1086 for each subject enrolled. 
AK 3.
I will document the consent process in the progress notes for each research subject, unless a waiver of consent 
and authorization is approved. 
AK 4. I certify that I will report all serious adverse events and unexpected adverse experiences as required. 
AK 5. I acknowledge that I will immediately report any complications arising from this study to the Human Studies 
Subcommittee/IRB through the Research Office. 
AK 6. I understand that any research project utilizing VA resources (i.e. space, personnel, services) must be 
approved by VANCHCSNACCHCS Research and Development (R&D) Committee prior to commencement of 
the project. 
AK 7. I understand that any research involving VANCHCSNACCHCS patients must be approved by 
VANCHCSNACCHCS R&D Committee. 
AK 8. I will not begin any research project using human subjects before it has been fully approved by VANCHCS IRB 
and VANCHCSNACCHCS R&D Committees. 
AK 
9. I understand that I am required to annually complete an educational course or web-based training on both the 
protection of human subjects in research and Good Clinical Practice (GCP). ORD and Collaborative IRB  
Training Initiatives (CITI) have developed a VA training curriculum to satisfy this annual training requirement. 
AK 
(http://www.appc1.va.gov/resdev/fr/PRIDE/training/) 
 10. 1 understand that the research staff working for me who are involved in human studies are required to annually 
complete an educational course or web-based training on both the protection of human subjects in research 
AK 
and Good Clinical Practice. A single combined course will satisfy this requirement. 
 11.1 understand that there may be specific training requirements for me and my research staff regarding animal 
research, laboratory safety, and security. 
AK 12.1 understand that I am to cooperate fully with VANCHCS Research Compliance Officer regarding compliance in 
research. 
13.1 understand that any research involving radiation must be approved by VANCHCS Radiation Safety 
Committee. 
14.1 agree to abide by the requirements of VHA Handbook 1200.18, Intellectual Property. 
(http://www.va.gov/publ/direc/health/Handbook/1200-18hk.pdf) 
15.1 agree to abide by the requirements of VANCHCS PS-151-9, Publication of Professional Papers 
(http://vaww.northern-california.med.va.gov/policies/ResearchIndex.html) and VHA Handbook 1200.19 
Presentation of Research Results Handbook. (http://www.va.gov/publ/direc/health/handbook/1200.19hk.pdf) 
16.1 agree to abide by the requirement of VANCHCS PS-151-7, Administration of Non-VA Funded Research 
Grants. (http://vaww.northern-california.med.va.gov/policies/ResearchIndex.html) 
17.1 agree to abide by the requirements of VANCHCS PS-151-2, Detecting and Managing Conflicts of Interest in 
Research (http://vawvv.northern-california.med.va.gov/policies/ResearchIndex.html). 
18. I agree to abide by the requirements of VHA Handbook 1200.8, Safety of Personnel Engaged in Research and 
the Chemical Hygiene Plan for Medical Research. 
(http://www.va.gov/publ/direc/health/Handbook/1200.8hk.pdf)  
AK 2. 
AK 
AK 
AK 
AK 
AK 
AK 
0. PRINCIPAL INVESTIGATOR'S KNOWLEDGE ATTESTATION 
V.09/13/2013 
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P. PRINCIPAL INVESTIGATOR'S ASSURANCE 
As the Principal Investigator, I have ultimate responsibility for the performance of this study, the protection of 
the rights and welfare of the human subjects, and strict adherence by all co-investigators and research 
personnel to all requirements of the Human Subjects Subcommittee (IRB), the Research and Development 
Committee, federal regulations, and state statutes for human subjects research. 
I hereby assure the following: 
All named individuals on this project have read and understand the procedures outlined in the protocol. All 
experiments and procedures involving human subjects will be performed under my supervision or that of another 
qualified professional listed on this protocol. 
I understand that, should I use the project described in this application as a basis for a proposal for funding (either 
intramural or extramural), it is my responsibility to ensure that the description of human subjects used in the funding 
proposal(s) is identical in principle to that contained in this application. 
I will submit modifications and/or changes to the IRB as necessary to ensure these are identical. 
I and all the sub-investigators and research personnel agree to comply with all applicable requirements for the 
protection of human subjects in research including, but not limited to, the following: 
•
Obtain legally effective informed consent of all human subjects or their legally authorized representatives, and use 
only the currently approved, stamped consent form (if applicable); 
•
Make no changes to the approved protocol or consent form without first having submitted those changes for 
review and approval by VANCHCS Institutional Review Board; 
•
Within 24 hours of investigator awareness, communicate any Local Research Subject Deaths to the IRB and 
submit a written follow-up report to the IRB within 5 working days; 
•
Communicate other Local Serious Adverse Events, except death, in writing to the IRB within 5 working days after 
investigators learn of the event; 
•
Promptly provide the IRB with any information requested relative to the project; 
•
Promptly and completely comply with an IRB decision to suspend or withdraw its approval for the project; 
•
Submit an application for continuing review within 60 days prior to the date on which the approval for the study 
expires. I understand if I fail to apply for continuing review, approval for the study will automatically expire, and 
study activity must cease until IRB current approval is obtained; 
•
Submit a final report, within 60 days, to VANCHCS Research Office at the conclusion of this project; 
•
If I am unavailable to direct this research personally, I will arrange for an investigator to assume direct 
responsibility as principal investigator in my absence. I will submit a protocol amendment to the IRB in advance of 
such arrangements requesting this modification. 
I understand my obligations as an investigator and agree to fulfill them. 
The information contained in this application is complete to the best of my knowledge. 
By signing this document, I attest that all the information I have provided is accurate to the best of my knowledge. 
Digitally signed by Andrew Kayser 
DN cn=Andrew Kayser, o=1.1CSF, 
A ncl rew Kayser ou=Neurology, emall=akayser@gallo.ucsfedu, 
c=U5 
Principal Investigator 
Date: 2018.04.26 16:05:26 -07'00' 
Date 04-26-2018 
V.09/13/2013 
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