A Randomized Placebo-controlled Trial of Methylphenidate in Veterans With a Diagnosis of Post Traumatic Stress Disorder and Recent Cerebral Stroke
Phase: PHASE1
Conditions: PTSD, Stroke
Sponsor: VA Office of Research and Development

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Protocol  
 
Protocol Title: A randomized placebo-controlled trial of methylphenidate in Veterans with a diagnosis of post-
traumatic stress disorder and recent cerebral stroke 
Protocol Version: 5 
Protocol Date:  7/11/24 
Principal Investigator: Chen Lin, MD 
 
 
1. Purpose - in nontechnical, lay language 
a. Summarize the purpose and objectives of this protocol in one short paragraph. Veterans with post-
traumatic stress disorder (PTSD) have an increased risk of developing ischemic stroke. Veterans 
enduring PTSD face difficulties in managing their PTSD severity after suffering from a stroke. 
Methylphenidate (MPH) is a central nervous system stimulant that blocks dopamine and 
norepinephrine transporters. MPH can improve PTSD symptoms: avoidance behaviors, social 
withdrawal, hyperarousal, and working memory. The high prevalence of PTSD in Veterans with 
stroke provides strong justification for development of interventions that effectively and 
simultaneously target both conditions. The overarching goal of our proposal is to understand how 
MPH improves PTSD severity in Veterans with comorbid stroke. 
 
b. Describe how outcomes will be measured for this protocol. We will collect outcome measures as listed 
in Table 1: Schedule of Events below. Additionally, we will collect feasibility metrics(recruitment, 
refusal, attrition, and retention rates) and safety outcomes. Finally, neuroimaging will be obtained 
for those without standard MRI contraindications, and we will perform structural and functional 
connectivity analysis of the pre- and post- intervention imaging.  
 
2. Background - in nontechnical, lay language 
Summarize in 2-3 paragraphs past experimental and/or clinical findings leading to the design of this 
protocol. Include any relevant past or current research by the PI. For drug and device studies, summarize 
the previous results (i.e., Phase I/II or III studies).  
 
Veterans with post-traumatic stress disorder (PTSD) have an increased risk of developing ischemic 
stroke. Veterans enduring PTSD face difficulties in managing their PTSD severity after suffering from a 
stroke. Currently, clinical trials in PTSD exclude patients with stroke and patients with significant 
premorbid psychological conditions like PTSD are usually excluded from stroke clinical trials. 
Methylphenidate (MPH) is a central nervous system stimulant that blocks dopamine and norepinephrine 
transporters, selectively increasing prefrontal cortex (PFC) activity. MPH can improve PTSD symptoms: 
avoidance behaviors, social withdrawal, hyperarousal, and working memory. The suspected mechanism 
is MPH activates PFC, enhancing fear extinction and improving PTSD symptoms. MPH can also improve 
post-stroke outcomes: mood, activities of daily living, and motor functioning. In clinical trials for PTSD or 
stroke, MPH has been shown to be well-tolerated with minimal adverse events. The high prevalence of 
PTSD in Veterans with stroke provides strong justification for development of interventions that 
effectively and simultaneously target both conditions. The overarching goal of our proposal is to 
understand how MPH improves PTSD severity in Veterans with comorbid stroke.   
 
This proposal is a single-site, phase 2, randomized double-blind placebo-controlled trial of MPH in the 
treatment of Veterans with a diagnosis of PTSD who are within 1-12 months of cerebral stroke. The 
purpose of the clinical trial is to evaluate the therapeutic effects on PTSD symptoms and post-stroke 
recovery of placebo-controlled MPH in Veterans diagnosed with PTSD and cerebral stroke. The outcome 
of the proposed work is expected to develop an intervention for patients with PTSD and stroke, thus 
improving their outcome by reducing symptom severity. Following successful screening and baseline 
randomization, eligible patients will be treated with a regimen of MPH vs placebo. 60 participants will 

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be randomized in a 1:1 ratio to placebo or MPH. We will perform a mechanistic study by examining 
changes in connectivity of the PFC pre- and post- MPH. Thus, we propose to conduct a randomized 
double- blind placebo-controlled trial of MPH to evaluate PTSD and stroke outcomes. 
 
 
3. Participants (Screening and Selection) 
a. How many participants are to be enrolled?  
Up to 300 patients will undergo the screening process. Our goal is to enroll 60 patients. We 
anticipate having to randomize 60 patients to reach the anticipated 50 patients that complete the 
study in entirety. 
 
b. Describe the characteristics of anticipated or planned participants (if multiple groups, repeat list for 
each group). 
Sex: both 
Race/Ethnicity: all 
Age: 40-75 
Health status: stroke patients with PTSD 
 
c. From what population(s) will the participants be derived? Patients with stroke and PTSD presenting to 
the Birmingham VA hospital will be recruited.   
 
Describe your ability to obtain access to the proposed population that will allow recruitment of the 
necessary number of participants: Dr. Lin is a stroke neurologist at the BVAMC and has access to all 
stroke patients admitted to the BVAMC.   
 
d. Describe the inclusion/exclusion criteria:  
 
Inclusion Criteria (all must be met): 
1. Male or female Veteran of US military [40 to 75] years of age; signed informed consent 
2. Criterion A Index Trauma(s) resulting in PTSD occurred during adulthood prior to stroke 
3. CAPS-5 score ≥23 at baseline visit 
4. Willing to refrain from antipsychotics, mood stabilizers, stimulants, and any formulation of MPH 
5. Most recent symptomatic ischemic stroke radiologically verified, occurring within past 1-12 months 
6. Females of child-bearing potential (i.e. not postmenopausal or surgically sterile) must be using a 
medically acceptable method of birth control and should not be pregnant nor have plans for pregnancy 
or breastfeeding during the study 
Exclusion Criteria (one or more will exclude the Veteran): 
1. Moderate to severe cognitive impairment (Montreal Cognitive Assessment score <16/30). 
2. Poor pre-stroke baseline function of a modified Rankin score >2. 
3. Current diagnosis of DSM-5-defined bipolar disorder I, schizophrenia, schizoaffective disorder, 
obsessive-compulsive disorder, or major depressive disorder with psychotic features in medical record 
review. 
4. Diagnosis of moderate or severe substance use disorder (except for caffeine and nicotine) during 
the preceding 3 months. Patients who utilize alcohol or cannabis but do not meet criteria for 
moderate or severe disorder are permitted at the discretion of the investigator. Participants must 
agree to abstain from illicit drugs during the study. 
5. Increased risk of suicide that necessitates inpatient treatment or warrants additional therapy 
excluded by the protocol; and/or intensity of suicidal ideation (Type 4 or Type 5) or any suicidal 
behavior in the past 3 months on Columbia Suicide Severity Rating Scale (C-SSRS). 
6. Use of any investigational drug, MPH formulation, antipsychotics, mood stabilizers, monoamine 
oxidase inhibitors, stimulants or any medication known to be a potent (strong) cytochrome P450 
subtype 3A4 inhibitor within 2 weeks of baseline. 
7. Treatment with evidence-based trauma-focused therapy for PTSD within two weeks of baseline 

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(If participant is receiving therapy, he/she must complete treatment prior to entering study). 
Supportive psychotherapy in process at time of Screening may be continued during the study. 
8. History of moderate or severe TBI as defined by the Ohio State University TBI Identification 
Method. Based on investigator’s clinical judgment, history of mild TBI is not excluded. 
9. Any clinically significant, uncontrolled, or medical/surgical condition or laboratory abnormality 
that would contraindicate use of MPH (see Human Subjects section) 
10. Severe allergic reaction, bronchospasm, or hypersensitivity to any MPH formulation. 
11. Litigating for compensation for a psychiatric disorder. Veterans who are in the process of applying 
for or receiving VA service-connected disability are eligible. 
12. Current enrollment in another intervention trial for PTSD or stroke 
13. Persons imprisoned, diagnosed with terminal illness, or require surrogate for consent. 
 
 
e. If participants will comprise more than one group or stratification, describe each group (e.g., 
treatment/intervention, placebo, controls, sham treatment) and provide the number of participants 
anticipated in each group. Up to 300 patients will undergo the screening process. Our goal is to 
randomize 60 patients with 30 in the placebo and 30 in the active medication group. We anticipate 
having to randomize 60 patients to reach the anticipated 50 patients.  
 
f. Indicate which, if any, of the special populations listed below will be involved in the protocol. Include the 
Special Populations Review Form (SPRF) if indicated. 
☐ Pregnant Women: Attach SPRF—Pregnant Women, Fetuses, Neonates/Nonviable Neonates 
☐ Fetuses: Attach SPRF—Pregnant Women, Fetuses, Neonates/Nonviable Neonates 
☐ Neonates/Nonviable Neonates: SPRF—Pregnant Women, Fetuses, Neonates/Nonviable Neonates 
☐ Prisoners: Attach SPRF—Prisoners 
☐ Minors (<18 years old): Attach SPRF—Minors 
☐ Employees or students at institution where research conducted 
☐ Persons who are temporarily decisionally impaired 
☐ Persons who are permanently decisionally impaired 
☐ Non-English Speakers 
For each box checked, describe why the group is included and the additional protections provided to 
protect the rights and welfare of these participants who are vulnerable to coercion: NA 
 
g. List any persons other than those directly involved in the protocol who will be at risk. If none, enter 
“None”: none 
 
 
h. Describe the recruitment process (e.g., medical record review, referrals, letter of invitation, existing 
patients) that will be used to seek potential participants (e.g., individuals, records, specimens). Research 
recruitment by non-treating physicians/staff may require completion of Partial Waiver of Authorization for 
Recruitment/Screening. Recruitment: Veterans with PTSD and Stroke will be recruited at the BVAMC 
through the inpatient neurology service, stroke clinic, mental health clinic, and self-referral from clinic. 
Flyers will be given by study team to providers to give to potential interested participants to contact study 
team. Letters will be sent to the patients (by the study team) from the clinics after they have been identified 
as potential candidates via mail or VA email. After 7 days from sending the study letter, the study team will 
call, text, and/or send a VA email to potential candidate(s) from the contact information listed on their 
health records to confirm if they received the study letter. Recruitment prospects are high, as the 
Birmingham region encompasses one of the largest catchment areas for stroke in Veterans in the United 
States. Dr. Lin is a neurologist at the BVAMC and has direct access to the study population through the 
inpatient neurology service and outpatient neurology clinic. We are requesting a waiver of documentation 
of the informed consent to perform a CAP-5 survey that will determine if a potential participant meets 
eligibility to participate in the research study. If the score reflects eligibility, the participant will be 
consented to participate in the study. 

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i. If you will use recruitment materials (e.g., advertisements, flyers, letters) to reach potential participants, 
attach a copy of each item. If not, identify the source (e.g., IRB Protocol Number for approved 
databases) from which you will recruit participants. Flyer/advertisement submitted for review. 
The following will be the texted from a VA phone sent to participant number: 
 
“Dear Mr./Mrs./Ms. _______, 
 
I am with the Birmingham VA Medical Center. I was reaching out to you to potentially discuss 
participating in a study evaluating how well an FDA-approved drug works to reduce symptoms of 
Post-Traumatic Stress Disorder (PTSD) in patients that have suffered recent stroke. Participation in 
this study is voluntary and a decision to join or not will have no impact on your VA healthcare or 
other benefits. Please let me know whether you are interested or not interested by texting or 
calling this number 205-240-6552.  Thank You!” 
 
The following will be the emailed from a VA email if a participant’s email is provided: 
 
“Dear Veteran: 
 
The Birmingham VA Medical Center invites you to consider participating in a research study evaluating 
how well an approved study drug works to reduce symptoms of Post-Traumatic Stress (PTSD) in patients that 
have suffered stroke. The symptoms of PTSD commonly include distressing memories, nightmares, or 
flashbacks of a prior traumatic event, significant avoidance of people or situations that remind you of the 
traumatic event, difficulty sleeping through the night, negative thoughts or feelings, difficulty experiencing 
positive feelings, poor concentration, anger and increased worry about your safety. 
If you are interested in participating, please contact a member of our team for a brief phone call that 
will help determine if you are potentially eligible. If you are still interested, we ask you to stop by our clinic for 
further evaluation located on the 2d floor of the Birmingham VAMC, in Clinic 2K, office 2819. All information is 
kept confidential. Participation in this study is completely voluntary and a decision to join or not will have no 
impact on your VA healthcare or other benefits. As an alternative to participating in the study, the VA Medical 
Center closest to you offers treatment for PTSD to eligible veterans.  
If you consent to be in the study, you will be evaluated by the medical research team. You will be 
treated with either the study drug or placebo for 12 weeks, and we will follow-up with you over a 16-week 
period as explained below.  
 
There are no costs for you to participate in this study. In return for your time, effort, and travel expenses, you 
will be paid for taking part in study assessments. If you stop participating for any reason, you will be paid for only the 
assessments that you complete. The total possible compensation for attending all visits is $300, as described below:  
• Screening and Eligibility Assessments, including an MRI: $50 
• Week 4 assessment: $50 
• Week 8 assessment: $50 
• Week 12 assessment: $50 
• Completion of final 1-month follow-up: $100 
  
For more information, to find out if you qualify, or if you wish to opt out from being contacted further, 
call 205-240-6552 or email megan.baker6@va.gov. If we have not heard from you within 7 days, a study 

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member may contact you to gauge your interest.  You can also stop by the Birmingham VAMC Research 
Service offices, located on the 2d floor of the Birmingham VAMC, in Clinic 2K, office 2819. Thank you for 
considering this invitation to participate in this study.” 
 
j. Describe the screening process/procedures for potential participants.  
Screening: The screening procedure includes informed consent, vital signs, demographics, disability 
status, medication history, neurologic and psychiatric diagnostic evaluation, imaging studies 
including CT and MRI scans, review of medical conditions, physical exam, ECG, and laboratory tests 
(hematology, chemistry, liver and thyroid function tests, blood chemistry, urinalysis, urine screen 
for drugs of abuse, lipid profile, and serum pregnancy test for women of child-bearing potential). If 
laboratory test or ECG is not available to review in the Veteran’s medical records, the study will 
obtain prior to randomization. Clinical characteristics including time since stroke and stroke location 
will be recorded. We will document recent PTSD therapies completed within last 6 months. A 
Veteran who is meeting eligibility criteria except for an excluded medication that is not tolerated or 
beneficial may undergo a tapered washout of the excluded medication if this plan is 
 
clinically indicated regardless of study participation. 
 
 
4. Protocol Procedures, Methods, and Duration - in nontechnical, lay language 
a. Describe the procedures for all aspects of your protocol. Tell us what you are doing.  
 
Participants who continue to meet eligibility criteria are randomized into Methylphenidate or placebo. Schedule 
of events are shown in Table 1. Following successful screening and baseline randomization described above, 
eligible patients will be treated with a regimen of MPH vs placebo and treated for 12 weeks. They are assessed 
in-person every 4 weeks (4, 8, 12) and conclude with a final follow-up at 30 days. The participant is assessed by 
telephone every 2 weeks when not evaluated in-person (week 2, 6, and 10) for treatment-emergent side effects. 
60 participants will be randomized in a 1:1 ratio to placebo or MPH. Specifically for the CAPS-5 measure, the 
measure will be recorded by a VA-approved audio recorder (Philips DPM-8000). Co-investigators will review the 
recording to ensure agreement in scoring.  
 
Table 1: Schedule of Events 
Assessments 
Scree
n  
Baselin
e  
Wk 
4 
 Wk 
8  
Wk 
12 
30 days 
after 
taper  
Informed Consent and HIPAA 
X 
 
 
 
 
 
Demographics, Medical History, 
Physical, Height, ECG, Labs.  
X 
 
 
 
 
 
Verify Eligibility Criteria in CPRS 
X 
 
 
 
 
 
Ohio State University TBI 
X 
 
 
 
 
 
Emory Treatment Resistance Interview 
for PTSD 
X 
 
 
 
 
 
Life Events Checklist 
X 
 
 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
CAPS-5  
X 
X 
X 
X 
X 
X 
PTSD Checklist for DSM-5 
 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
X 
X 
X 
X 
X 
X 
Patient Health Questionnaire 9 
 
X 
X 
X 
X 
X 
Fatigue Severity Scale 
 
x 
 
 
x 
x 
modified Rankin Score 
 
X 
X 
 
X 
X 
NIH Stroke Scale 
 
X 
 
 
X 
X 

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Montreal Cognitive Assessment 
 
X 
X 
 
X 
X 
Stroke Impact Scale-16 
 
X 
X 
 
X 
X 
Study Drug Adherence 
 
 
X 
X 
X 
 
Concomitant Medication  
 
 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
Review PTSD therapies completed 
X 
 
 
 
 
X 
Neuroimaging 
 
X 
 
 
 
X 
 
Medication Protocol: The study drug is dispensed from the VA pharmacy according to the assignment after 
the medication order is entered by the investigator. In this double-blind design, both participants and research 
team will remain blinded to drug/placebo for the duration of the trial; however, pharmacy has procedures for 
breaking blind for emergency situations to non-research provider of care. At randomization, the study 
personnel will provide participants the instructions for taking the drug.  The dose of MPH for this proposal will 
be similar to that used in prior PTSD trials. Study drug (MPH vs look-alike placebo) is initiated at 10 mg once 
daily for the first week, 10 mg twice daily for the second week. After the second week, participants will stay on 
the 20mg twice daily dosing until week 10. Participants start tapering at week 10 for a 2-week taper. The first 
week taper will be at 10 mg twice daily, followed by 10mg once daily for a week, and then stop the 
medication. If an adverse effect is believed to be associated with medication, participants’ dose will be held or 
decreased to a prior dose instead of proceeding with the scheduled increases. 
 
Outcome measures for subjects are collected per Table 1 schedule of Measures will be collected either while 
patients are in clinic during a standard of care visit at the VA Clinic, at a private preparation area either before 
or after their imaging at Highlands, or at a private clinic room in the 7th Floor VA Neurology Clinic. 
 
Data to be collected on subjects from the electronic medical record for this study includes demographics (sex, 
age, race, symptoms, medical history, smoking history, anatomical level/grade of intracranial stenosis); lab 
results, medications, inpatient records related to stroke, imaging results, and standard clinical assessment 
from rehabilitation stay and clinical visits.  
 
 
b. What is the probable length of time required for the entire protocol (i.e., recruitment through data 
analysis to study closure)? 5 years 
 
c. What is the total amount of time each participant will be involved? 4-5 months  
 
d. If different phases are involved, what is the duration of each phase in which the participants will be 
involved? If no phases are involved, enter “None.” none 
 
e. List the procedures, the length of time the procedure takes, the total # of times the procedure is 
performed.  See Table 1: Schedule of events 
 
 
f. Will an interview script or questionnaire be used? 
☒Yes ☐No 
If Yes, attach a copy. 
 
g. Will participants incur any costs as a result of their participation? 
☐Yes ☒No 
If Yes, describe the reason for and amount of each foreseeable cost.       
 
h. Will participants be compensated? 
☒Yes ☐No 
If Yes, complete i-v. 
i. Type: (e.g., cash, check, gift card, merchandise): Check or direct deposit 
ii. Amount or Value: $300 total 
iii. Method (e.g., mail, at visit): at visit 

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iv. Timing of Payments: (e.g., every visit, each month): $50 each after completing the  following: 
baseline visit, week 4, week 8, and week 12 visits. $100 for completing the final 1-month follow-up. 
v. Maximum Amount of Compensation per Participant: $300 
 
5. Benefits 
Describe the potential benefits of the research. There may or may not be direct benefit to participants no 
direct benefit to the subjects.  However, the investigators hope that knowledge gained in this study will 
help with patient with PTSD and stroke recovery outcomes.   
 
6. Risks - in nontechnical, lay language 
a. List the known risks for participants as a result of participation in the research. This should not include 
the minimal risk of loss of confidentiality. However, it should include any physical, psychological, social, 
economic, and/or legal risks. If there is a greater than minimal risk of loss of confidentiality describe 
why this is so. Do not list risks associated with the standard-of-care procedures. 
NOTE:  Risks included here should be included in the consent form or information sheet, as applicable. 
Physical Risks 
 
Methylphenidate: Participants will be screened by the eligibility criteria and be excluded if 
participants have any contraindications to methylphenidate including hypersensitivity reactions such 
as angioedema and anaphylactic reactions to methylphenidate. 
 
Nervousness and insomnia are the most common adverse reactions reported in clinical trials and 
post-marketing surveillance. In addition, patients have reported loss of appetite, abdominal pain, 
weight loss during prolonged therapy, and tachycardia. Other potential side effects include: 
 
• Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia. 
• Gastrointestinal: abdominal pain, nausea. 
• Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative 
dermatitis, erythema multiforme, and thrombocytopenic purpura. 
• Metabolism/Nutrition: anorexia, weight loss during prolonged therapy. 
• Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, 
toxic psychosis 
• Vascular: blood pressure increased or decreased; cerebrovascular vasculitis; cerebral occlusions; 
cerebral hemorrhages and cerebrovascular accidents. 
• Blood/Lymphatic: leukopenia and/or anemia 
• Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma 
• Psychiatric: transient depressed mood, aggressive behavior 
• Skin/Subcutaneous: scalp hair loss 
 
Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of 
these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-
year-old boy who had been taking methylphenidate for approximately 18 months experienced an 
NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether 
this case represented a drug-drug interaction, a response to either drug alone, or some other cause. 
 
 
The investigators will closely monitor the veteran for all possible side effects and adverse events. 
This study uses a low dose and duration of methylphenidate, which reduces the chances of an 
adverse event.  
 

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Clinical Testing: The functional assessments used in the proposed study are routine, clinical 
assessments of gait and stroke impairments used in stroke outpatient and therapy clinics. The 
experimental protocol to be used in this portion of the proposal involves minimal risk and is 
considered standard clinical practice. 
 
MRI Neuroimaging: MRI will be obtained in patients that pass routine MRI screening. The MRI 
scanner contains a very strong magnet. Therefore, participants may not be able to have the MRI if 
they have certain types of metal implanted in their body, for example, any 
pacing device (such as a heart pacer), any metal in their eyes, or certain types of heart valves or brain 
aneurysm clips. Although there is no indication that MRI is unsafe during pregnancy, if the 
participant is female, she will be asked to take a urine pregnancy test to verify that she is not 
pregnant. There is not much room inside the MRI scanner. The participant may be uncomfortable if 
they do not like to be in close spaces ("claustrophobia"). If the participant becomes uncomfortable 
at any time, they can request that the scan be stopped. All participants will pass an MRI screen to 
decrease risk of adverse events. 
 
b. Estimate the frequency, severity, and reversibility of each risk listed. Possible serious physical risks 
would be possible and not reversible but are highly unlikely and rare. The transient milder symptoms 
associated with methylphenidate (i.e., nervousness, insomnia) are more likely and frequent based 
on post-marketing surveillance data as noted above. These are reversible symptoms and should not 
be persistent. There is a minimal risk for muscle strains during the testing and training. 
 
 
Assessments/Questionnaires: Risk is minor and readily reversible.   
 
c. Is this a therapeutic study or intervention? 
☒Yes ☐No 
If Yes, complete i.-iii. 
i. Describe the standard of care in the setting where the research will be conducted: these patients 
would typically be followed in the Mental Health or Stroke clinic and be given pharmacologic options 
to treat their PTSD symptoms. No known a pharmacologic treatments exist to improve outcomes for 
the combination of patients with PTSD symptoms and stroke recovery.  
ii. Describe any other alternative treatments or interventions: continued standard of care treatments 
with pharmacologic approaches. 
iii. Describe any withholding of, delay in, or washout period for standard of care or alternative 
treatment that participants may be currently using: N/A 
 
d. Do you foresee that participant might need additional medical or psychological resources as a result of 
the research procedures/interventions? 
☒Yes ☐No 
If Yes, describe the provisions that have been made to make these resources available.       
 
From the screening point forward, diphenhydramine or a nonbenzodiazepine hypnotic  
may 
 
be used sparingly (not to exceed three times per week) for severe insomnia or  agitation.  
 
 
e. Do the benefits or knowledge to be gained outweigh the risks to participants? 
 
☒Yes ☐No 
If No, provide justification for performing the research:       
 
7. Precautions/Minimization of Risks 
a. Describe precautions that will be taken to avoid risks and the means for monitoring to detect risks.  
 
Overall Protection: The investigators are experienced neurologists and a psychiatrist who are operating in a 
supportive medical center environment where medical, mental health, and PTSD specialists are 

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conveniently located for immediate consultation if needed. Before any tests are conducted, the protocol 
and tests to be used in this study and the potential risks and benefits of participation will be explained to 
each potential subject. All participants will review and sign an informed consent form approved by the local 
Institutional Review Board prior to initiating any portion of the study. While we do not anticipate any 
serious adverse events, participants will be given detailed information (verbal and written) regarding the 
steps to take in the event of a serious side effect or emergency. A physician will be available 24 hours and 7 
days per week for the participant to contact or be evaluated by in the event of a serious adverse event or 
emergency. Inpatient medical or psychiatric care is available at our study site.  
Adverse Event Monitoring: Common side effects are listed in the informed consent and are reviewed by the 
participant at screening visit. Adverse events, weight, and vital signs are evaluated at each assessment visit. 
All adverse events are recorded at each visit (description, severity, relationship to study medication, 
intervention, date onset, date resolution) regardless of relationship to study medication, and are MedDRA 
coded. Serious adverse events are reported to the data monitoring committee (DMC) and IRB.  
 
Data and safety monitoring for this study will be provided by the Clinical Science Research & Development 
(CSR&D) centralized Data Monitoring Committee (DMC). The DMC is provided by CSR&D to ensure 
independent oversight of the safety and integrity of the project. The DMC is an independent 
multidisciplinary group, whose members have collectively – through research, education, training, 
experience, and expertise – the requisite knowledge pertinent to the subject areas to be reviewed. 
Membership details are available on the CSRD website. The DMC will provide an ongoing independent 
evaluation of this study focused on safety and feasibility, including participant accrual and retention, 
adverse events monitoring, and data analyses. Meetings will be held two times per year at which time 
recommendations will be made to the Director of CSR&D for endorsement. These recommendations will 
range from approval to continue (unconditionally or with conditions to be addressed) to probation or 
possibly termination, if there are problems with enrollment or safety concerns. 
 
Concomitant Medication and Psychotherapy: Participants may remain on antidepressants, prazosin, or 
sleep medications if every effort is made for the doses to remain stable during the study. Opiates and other 
medications for pain conditions will be allowed and recorded in the concomitant medication inventory. All 
concomitant medication use will be carefully documented. While dose stability is the goal, any changes in 
dosages during participation that are medically warranted are recorded and  
may be leveraged in outcomes data interpretation. The following psychotropic medications are not allowed 
during the study: mood stabilizers (lithium, carbamazepine, valproate, lamotrigine), benzodiazepines, and 
neuroleptics. Treatment with trauma-focused therapy (e.g., CPT, PE, or EMDR) for PTSD within two weeks of 
baseline (if participant is receiving therapy, he/she must complete treatment prior to entering study) is not 
allowed. Veterans who want this type of treatment may enroll in a course of treatment and complete it 
prior to study participation. Participants may attend supportive-educational appointments that were 
initiated prior to entry.  
 
Allowed Rescue Medication: From the screening point forward, diphenhydramine or a nonbenzodiazepine 
hypnotic may be used sparingly (not to exceed three times per week) for severe insomnia or agitation. We 
considered the use of other low dose psychotropics, but for safety reasons it is important to avoid 
benzodiazepines in this population.  
 
Protections Against Physical Risks of Methylphenidate or Placebo: The eligibility criteria will exclude 
patients who have contraindicated conditions. The investigators will closely monitor the veteran for all 
possible side effects and adverse events. This study uses a low dose and duration of methylphenidate, 
which reduces the chances of an adverse event. The Principal Investigator will evaluate adverse events at 
the study assessments and is available for consultation as needed by the participant or the family. Further, 
the Co-Investigator, Dr. Davis, is board certified in psychiatry with many years of experience developing 

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psychopharmacologic clinical trials for veterans with PTSD. Common side effects will be listed in the 
informed consent and will be reviewed by the participant at screening visit. Adverse events, weight, and 
vital signs are evaluated at each visit.  
 
Contraindications and monitoring requirements for the study: hypersensitivity reactions such as 
angioedema and anaphylactic reactions to methylphenidate, marked anxiety, tension and agitation since  
drug may aggravate, glaucoma, motor tics, concomitant use of monoamine oxidase inhibitors or within 14  
days after their discontinuation. Sudden deaths, stroke, and myocardial infarction have been reported in  
adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is  
also unknown, adults have a greater likelihood than children of having serious structural cardiac  
abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious  
cardiac problems. Administration of stimulants may exacerbate symptoms of behavior disturbance and  
thought disorder in patients with a preexisting psychotic disorder such as bipolar illness, emergence of new  
psychosis or manic symptoms. Patients that develop seizures, gastrointestinal obstruction, need for surgery  
that might interfere with participant’s ability to participate, and/or oral/dental condition that interferes with  
oral administration, priapism, peripheral vasculopathy including Raynaud’s Phenomenon will be monitored  
during the study. Clinically significant cardiac disease, (e.g., significant arrhythmia or heart block, heart  
failure, or myocardial infarction within the past 2 years) or QTc >450 msec (male) or >470 msec (female) on  
electrocardiogram (ECG) will be excluded. Stimulant medications cause a modest increase in average blood  
pressure (about 2 to 4 mm Hg) and average heart rate (about 3 to 6 bpm), and individuals may have larger 
increases. Blood pressure and heart rate will be monitored after initial methylphenidate dosing. Patients who  
develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of  
cardiac disease during stimulant treatment will be asked to undergo a prompt cardiac evaluation. 
 
The UAB Highlands facility screens for any MRI safety concerns to reduce imaging risks.  Subjects that 
are fatigued during assessment will be offered breaks.    
 
If the protocol involves drugs or devices skip Items 20.b. and 20.c. and go to Item 21. Instead include this 
information in the Drug Review Sheet or Device Review Sheet, as applicable. 
 
 
b. If hazards occur to an individual participant, describe (i) the criteria that will be used to decide whether 
that participant should be removed from the protocol; (ii) the procedure for removing such 
participants when necessary to protect their rights and welfare; and (iii) any special procedures, 
precautions, or follow-up that will be used to ensure the safety of other currently enrolled participants.  
 
A participant will be able to withdraw from the study at any time, at their request. If for any reason an 
unforeseen hazard arises with an individual participant, the session will be terminated, and the 
protocol will be modified to prevent the hazard with other participants. The investigators are 
experienced neurologists and psychiatrists who are operating in a supportive medical center 
environment where medical, neurologic, and mental health specialists are conveniently located for 
immediate consultation if needed. Before any tests are conducted, the protocol and tests to be used 
in this study and the potential risks and benefits of participation will be explained to each potential 
subject. All participants will review and sign an informed consent form approved by the local 
Institutional Review Board prior to initiating any portion of the study. A physician will be available 
24 hours and 7 days per week for the participant to contact or be evaluated by in the event of a 
serious adverse event or emergency. Inpatient medical or psychiatric care is available at our study 
site. 
 
If medical assistance is required during the MRI, researchers will follow the CINL protocol for 
emergencies: 1) Remove participant from the magnet, 2) Call UAB Police and Security (205-934-3535) 
who will page Health and Safety, 3) Once the immediate safety of the participant has been assured, 

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researchers will contact CINL staff (MRI technologist and director). As the scanner is housed in the 
UAB Highlands Hospital, medical staff will also be accessible. 
 
 
c. If hazards occur that might make the risks of participation outweigh the benefits for all participants, 
describe (i) the criteria that will be used to stop or end the entire protocol and (ii) any special 
procedures, precautions, or follow-up that will be used to ensure the safety of currently enrolled 
participants. If such adverse events occur the PIs will discuss the issues with IRB staff and consider 
terminating the entire study.  
 
In the event of incidental findings on imaging, researchers will follow CINL policy. 
 
 
8. Informed Consent 
a. Do you plan to obtain informed consent for this protocol? 
☒Yes ☐No 
If Yes, complete the items below. 
If No, complete and include the Waiver of Informed Consent or Waiver of Authorization and Informed 
Consent, as applicable. 
 
b. Do you plan to document informed consent (obtain signatures) for this protocol? 
☒Yes ☐No 
If Yes, complete the items below. 
If No, complete the items below and include the Waiver of Informed Consent Documentation. 
 
c. How will consent be obtained? Consent will occur in person in a private setting.  The consent 
discussion will occur for as long as necessary for the participant to understand the study. The participant 
will be able to ask questions and take as much time as needed to consider whether to participate. 
Participants will be able to review the consent form at their leisure and not be pressured by the research 
team to participate. 
 
 
d. Who will conduct the consent interview? Only members of the research team. 
 
e. Who are the persons who will provide consent, permission, and/or assent? Participants  
 
 
f. What steps will be taken to minimize the possibility of coercion or undue influence? Participants will be 
able to review the consent form and be given adequate time to consider whether they want to 
participate. 
 
 
g. What language will the prospective participant and the legally authorized representative understand? 
English 
 
h. What language will be used to obtain consent? English 
 
i. If any potential participants will be, or will have been, in a stressful, painful, or drugged condition before 
or during the consent process, describe the precautions proposed to overcome the effect of the 
condition on the consent process. If not, enter “None.” none 
 
j. If any protocol-specific instruments will be used in the consenting process, such as supplemental  
handouts, videos, or websites,  describe these here and provide a copy of each. If not, enter “None.” 
none 
 
k. How long will participants have between the time they are told about the protocol and the time they 
must decide whether to enroll? If not 24 hours or more, describe the proposed time interval and why 

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the 24-hour minimum is neither feasible nor practical. 24 hours unless the subject would like to enroll 
sooner at the time they are approached for their own convenience. 
 
 
 
9. Procedures to Protect Privacy 
Describe how you will protect the privacy interest of the participants. Include how you will make sure 
others cannot overhear your conversation with potential participants and that individuals will not be 
publicly identified or embarrassed. Other will not be able to overhear conversations about or with 
potential participations.  No participants will be publicly identified or embarrassed.  Study discussions 
will occur in private.   
 
 
10. Procedures to Maintain Confidentiality 
a. Describe how you will store research data to maintain confidentiality (both paper records and electronic 
data), including how access is limited. If data will be stored electronically anywhere other than a server 
maintained centrally by UAB, identify the department and all computer systems used to store protocol-
related data. Names, contact information, and MRI will be necessary to ensure safety and to allow 
follow-up. No PHI will be disclosed outside our research group. Research paperwork data will be 
kept in Dr. Lin’s locked office in BVAMC Room 8305. All electronic data will be identified by a study 
code number. The coded data will be stored on a password- and firewall-protected VA server on a 
VA computer. The research data, including any audio recordings, will only be accessible to study 
personnel. All private data will be stored behind a VA firewall- and password-protected on VA 
computers in a research folder. The document linking the subject id to subject PHI will be kept in a 
separate secure location from the study database with access to study personnel only.  
 
Since the MRI images are created at UAB for research purposes, UAB agrees to provide a copy of the 
imagery, via a CD, to the VA PI for record retention. At the completion of imaging for each patient, a 
report will be documented in their medical record stating: “A MRI Brain was performed at UAB 
Highland for research purposes only.” Along with the study team information.  
 
 
b. Will any data from this protocol be given to any person, including the subject, or any group, including 
coordinating centers and sponsors? 
☒Yes ☐No 
If Yes, complete i-iii. 
i. Who will receive the data? publications 
 
ii. What data will be shared? Aggregate data 
iii. How will the data be identified, coded, etc.? de-identified 
 
c. Records Management: Research records maintained by the investigator that span the entire lifecycle 
of the project and the records required by regulations such as the investigator's regulatory file will be 
maintained and destroyed per the VHA Records Control Schedule (RCS 10-1). 
 
11. Statistical Analysis 
Based on feasibility of enrollment within the time period and budget allowed, 60 Veterans (30 in each 
group) will be randomized and included in the analysis. Since the effect sizes estimated from Lin’s study 
will be used to help design future large-scale efficacy studies, we follow the recommendations derived via 
simulation by Whitehead et al. to justify our sample size. Our sample is sufficient to generate estimates to 
be used in designing a subsequent larger trial that will have approximately 85% power to detect even small 
effect sizes (d = 0.1 to 0.3). An effect size of Cohen’s d = 0.43 which we shall approximate represents the 
minimum significant effect size reported in previous PTSD clinical trials (range = 0.43-1.3) and is greater 
than the minimum effect size needed to achieve clinically meaningful changes in symptoms on the CAPS-5 

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(d = 0.39). While these trials are PTSD-specific and do not account for PTSD comorbid with stroke, we 
expect the averages of outcome measures to be different but the variability and deviation of measures to 
be the same.  
 
The investigators estimate that with equal numbers of subjects randomized to each of two treatments 
groups the samples size will have about an 80% power to detect a moderate effect size=0.41, two-sided 
alpha level of 0.05) at 12 weeks for CAPS-5. In the PTSD and TBI study by McAllister et al (2016), 
MPH (n=9) was shown to have significant differences in decreasing the PTSD symptoms compared to 
placebo (n=12) with an effect size of 0.88 at week 12 and with similar effects for PTSD symptom clusters. 
According to McAllister et al. (2016) the effect sizes for the improvement of MPH over Placebo for the 
PTSD are well above 0.41 which would increase the power to close to 0.80 with a moderate effect size for 
the change in endpoint results over the baseline to final assessment. In addition, we theoretically will see 
synergistic effects of the combination treatment that further amplifies the effect size. 
 
Analytic Approach: The analyses will include all available observations (i.e. from the various assessment 
times) from each subject. Mixed-Effect Model of Repeated Measure (MMRM) provides valid inference 
under the assumption of ignorable missingness. No imputation processes will be used to replace missing 
data. However, every effort will be made to minimize missing data. Because missing observations have the 
potential to alter the results of analyses, the analysts will examine whether the pattern of missing data is 
different among the two groups. The analysts will also examine the distribution of baseline covariates 
between those with and without missing outcome data. If there are no systematic differences between 
those with and without missing data, the data will be considered to be missing at random. If there are 
significant differences in dropout or missing data patterns between treatment arms, the analysts will 
conduct sensitivity analyses to determine the impact of missing information on the treatment 
comparisons. Continuous data will be analyzed using MMRM with treatment group (adjusting if needed for 
age, gender, site, presence/absence of concomitant antidepressants, and other potential confounders) as 
between-subject factors and visit as a within-subject repeated measure. The model will also include the 
two-way interaction between treatment group and visit. When appropriate, significant differences 
between treatment groups will be further analyzed with post-hoc comparisons. Adjusted marginal means 
(also called LS means) will be used to report and test for differences in mean change at 12 weeks for the 
placebo and MPH groups providing 95% confidence intervals and a p-value for the difference between 
them. If our attrition rate is larger than proposed, a secondary analysis will be performed based on 
patients who completed at least 4 weeks of treatment to determine if it would be worthwhile to conduct a 
future study where attrition due to causes other than adverse effects of MPH were better controlled.