Clinical trial NCT02637895
Conditions: Post-Traumatic Stress Disorder
Keywords: PTSD, trauma stress disorder post-traumatic stress disorder anxiety disorder
Sponsor: University of Miami
Start date: 2016-12-01; Completion date: 2020-02-06
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Post-traumatic stress disorder (PTSD) can result from having experienced or witnessed a traumatic event. Patients with PTSD symptoms can sometimes experience symptom relief after treatment with antidepressants; however, few patients experience complete symptom relief. There is a need to develop new treatments for PTSD.

This study will evaluate if 12 weeks of using Vortioxetine relieves PTSD symptoms. Vortioxetine has been approved for the treatment of depression; however, Vortioxetine has not been approved by the Food and Drug Administration for the treatment of PTSD.

Detailed description:
Patients included in the study will either take the study medication or will take a placebo, a pill without the active medication. This will be determined by chance like a flip of a coin.

Study procedures will include taking study medication and coming to regular in-clinic visits. Depending on the study visit, study tests may include the following: medical evaluations, physical exams, body measurements, vital signs, blood and urine tests, pregnancy tests, genetic testing, heart function monitoring, clinical and psychiatric measures, neuropsychological testing (for example, investigators will test how well you remember words or how fast you perform a certain task), a function test (for example, investigators will test how well you perform certain daily tasks), and a test to measure your startle response. A startle response is an unexpected response by a sudden activity.

Arms: arm 1: Placebo pill once daily for 12 weeks of active treatment. arm 2: Vortioxetine pill 10mg once daily up to 4 weeks followed by 20mg once daily if tolerated for the rest of the study. Patients unable to tolerate the 20 mg/day dose may be reduced to 10 mg/day between weeks 4 and 8. The dose of study medication should remain stable for weeks 8-12.
Interventions: intervention 1: Placebo intervention 2: Vortioxetine
Intervention descriptions: intervention 1: Placebo pill matching Vortioxetine. intervention 2: Immediate Release 10 mg. Vortioxetine Pill

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
NCT02637895    
Unique Protocol ID 20150534 
 
Evaluation of the Efficacy of Vortioxetine for Posttraumatic Stress Disorder 
 
Miami PIs: Philip Harvey, Ph.D.  
Miami Co-Investigators: Donald J. Newport, M.D, Dante Durand, M.D 
 
Emory Sub-Investigators: Boadie W. Dunlop, M.D., Barbara Rothbaum, PhD, Kerry 
Ressler, MD, Ph.D.; Tanja Jovanovic, Ph.D. 
 
Version 8, January 22, 2019 
 
 
I. PROJECT ABSTRACT 
 
Posttraumatic stress disorder (PTSD) is a chronic and common anxiety disorder that follows 
exposure to an overwhelming traumatic event.  The majority of patients with PTSD also meet 
criteria for other psychiatric disorders and many attempt suicide. Despite its impact on society, 
little is known about the etiology or pathophysiology of this disorder. PTSD is responsive to 
pharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs), but 
response rates rarely exceed 60%, and even fewer patients (20-30%) achieve clinical 
remission. Thus, there is a clear need to develop novel and improved therapeutics for PTSD.  
 
We will assess the efficacy of vortioxetine using a 12-week, double-blind, parallel-group, 
placebo-controlled trial of adults with PTSD.  Although Vortioxetine has not been approved by 
the Food and Drug Administration for the treatment of PTSD, it has been approved for the 
treatment of major depressive disorder and its safety profile is well characterized. In addition to 
measures of symptomatic improvement in PTSD, we will also assess changes in cognitive 
function and quality of life. Furthermore, we propose to investigate longitudinally whether certain 
biological surrogate markers (neurophysiology, genotyping, mRNA) are predictive of treatment 
response. 
 
II. SPECIFIC AIMS 
 
1. Specific Aim 1 (Primary Aim): To determine the efficacy of Vortioxetine compared with 
placebo in improving PTSD symptoms.   
Hypothesis: PTSD patients randomized to acute therapy (12 weeks) with Vortioxetine will show 
more improvement in PTSD symptoms compared to patients randomized to placebo, as 
determined by mean changes in the Clinician-Administered PTSD scale (CAPS-5) score over 
the course of 12 weeks. 
 
2. Specific Aim 2 (Secondary Aim): To determine the efficacy of Vortioxetine in treating 
PTSD in terms of overall response rate.  
Hypothesis: PTSD patients randomized to acute therapy (12 weeks) with Vortioxetine will have 
a greater rate of treatment response compared to subjects randomized to placebo, as 
determined by at least 30% improvement from baseline in CAPS-5 total score and a Clinical 
Global Impression of Improvement (CGI-I) score of 1 or 2. 
 


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Updated January 22, 2019 
 
3. Specific Aim 3 (Secondary Aim): To determine the efficacy of Vortioxetine in reducing 
depressive symptoms in PTSD patients.  
Hypothesis:  PTSD patients randomized to acute therapy with Vortioxetine will show more 
improvement in depressive symptoms compared to subjects randomized to placebo, as 
determined by mean changes in the Montgomery-Asberg Depression Rating Scale (MADRS) 
score over the course of 12 weeks. 
 
4. Exploratory Aim 1: Startle: To assess fear potentiation, conditional discrimination 
(AX+/BX-), and fear inhibition using acoustic startle methodology in a classical 
conditioning paradigm in PTSD patients before and after treatment with Vortioxetine.   
Hypothesis: PTSD subjects randomized to 12 weeks of Vortioxetine will have improved fear 
inhibition as measured by the AX+/BX- paradigm compared to baseline, while placebo subjects 
will not show improvement. 
5. Exploratory Aim 2: Cognition, Functional Capacity, and Quality-of-Life: To assess 
neurocognitive performance (pre- and post-treatment) with tests shown to be sensitive to 
PTSD (e.g. learning and memory, concentration and attention, and executive 
functioning).  In addition, to explore performance-based measures of everyday living 
skills, and measure quality-of-life as indexed by subjective reports.  
Hypothesis: Statistically significant changes detected for these variables will be correlated 
across domains.   
6. Exploratory Aim 3: Genotyping and Gene Expression: To explore whether response to 
Vortioxetine is associated with certain candidate gene polymorphisms previously 
associated with PTSD, and whether treatment with Vortioxetine alters gene expression 
patterns differentially in treatment responders and non-responders. 
Hypothesis:  Polymorphisms of specific candidate genes previously identified as relevant to 
PTSD will be differentially distributed between responders and non-responders to vortioxetine. 
 
 
III. SIGNIFICANCE/BACKGROUND 
 
Significance of PTSD and Limitations of Current Pharmacotherapies  
PTSD is a common chronic anxiety disorder that is often debilitating and follows exposure to an 
overwhelming traumatic event. PTSD occurs in approximately 8%-14% of the U.S. population 
(Breslau et al 1998; Davidson et al 1991; Kessler et al 1995). Rates of PTSD among women in 
the US are higher than in men being approximately twice that of men 12%-18% (Breslau et al 
1998; Resnick et al 1993).  
The burden of PTSD on individuals and society is significant. First, the majority of PTSD 
sufferers also meet the diagnostic criteria for several other psychiatric disorders (Breslau et al 
1991; Resnick et al 1993), especially major depression (Koenen et al 2003; Neria and Bromet 
2000) and many also attempt suicide (Davidson et al 1991). Significant health problems are 
more likely to occur in individuals with PTSD than in those without PTSD, particularly 
hypertension, bronchial asthma, peptic ulcer (Davidson et al 1991), gastrointestinal problems 
(Leserman et al 1996), increased rates of surgery, and visits to the physician (Solomon and 
Davidson 1997; Zoellner et al 1999). Despite the devastating impact of PTSD on the lives of 
millions worldwide, little is known about the etiology or pathophysiology of this disorder. 
Although disruptions in the hypothalamic-pituitary adrenal (HPA) Axis, noradrenergic, and 
serotonergic systems have been proposed as neurobiological substrates in the development of 
PTSD, the exact underpinnings of the neurobiology of PTSD remain to be fully elucidated.  
 
U.S.-based practice guidelines for PTSD have recommended cognitive behavioral therapy 
(CBT) and selective serotonin reuptake inhibitors (SSRIs) as first-line treatments (APA, 2004; 


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Updated January 22, 2019 
 
VA/DoD 2003).  However, the 2 FDA-approved SSRIs paroxetine and sertraline have modest 
effects, limited efficacy in all 3 clusters of illness (avoidance/numbing, reexperiencing, and 
hyperarousal), and few patients develop remission (Davidson 2006a).  Many placebo-controlled 
trials of other medications in PTSD have failed, and even recent studies of approved 
medications (e.g. sertraline) have failed to show efficacy in specific subgroups of PTSD patients 
such as combat veterans  treated in Department of Veterans affairs clinics (Friedman et al. 
2007). There is therefore a tremendous need to identify new medications that are efficacious for 
PTSD. Vortioxetine, with its muti-modal action at multiple serotonin receptor subtypes in 
addition to serotonin transporter inhibition, offers a novel approach to the treatment of this 
recalcitrant disorder.   
Progress in treating PTSD will also require better understanding of the biological characteristics 
associated with improvement during treatment.  As detailed below, this proposal will use state-
of-the-art biological and psychological phenotype measurements to identify moderators and 
mediators of outcomes with vortioxetine treatment. Through this proposal we are seeking to 
enhance treatment approaches for PTSD by evaluating the novel compound, vortioxetine, and 
to apply biological signatures to identify treatment prediction and response. The combined 
expertise across these sites makes for a unique and complementary research approach.  We 
are not aware of any other research team using these state-of-the-art biological approaches 
along with expertise in prospective treatment prediction to address these seminal questions in 
PTSD.     
 
IV. DRUG INFORMATION 
 
A. Investigational Drug: Vortioxetine  
Vortioxetine is a newly approved antidepressant with a unique pharmacological profile.  It is a 
potent SSRI and, in addition, has a high affinity for the 5HT1D, 5HTT3, and 5HT7 receptors where 
it acts as an antagonist.  It is also a 5HT1A agonist and 5HT1B partial agonist.  Of particular 
interest to this PTSD study is the finding that vortioxetine exhibits considerable positive effects 
on attention, memory, and executive function in patients with major depression, as well as 
improving performance-based measures of disability. 
 
V. RESEARCH DESIGN AND METHODS 
 
A. Overview of Study 
The study design is a 2-site, 12-week, randomized, double-blind, placebo-controlled, parallel-
arm, flexible dose trial evaluating the efficacy, safety, and tolerability of Vortioxetine for male 
and female adult outpatients with PTSD. The primary outcome assessment will occur at 12 
weeks.  A total of 60 patients will be randomized across the 2 study sites.  Subjects must have 
PTSD symptoms for at least 3 months prior to randomization, and have at least moderate PTSD 
symptom severity as measured by a score ≥ 28 on the CAPS-5 Past-month version at the 
screening and baseline visits for inclusion in the study.  The study population will be comprised 
of men and women with PTSD resulting from any form of DSM-5-defined trauma. Combat-
related PTSD will not be an exclusion, but no cases with pending litigation or disability claims 
associated with PTSD will be enrolled. 
  
The 4 study phases consist of the following: 
 
(1) Screening Phase and (if necessary) Medication-Washout: Informed consent will be 
signed at the initiation of the screening phase. As part of the informed consent process, 
participants will be asked whether they are willing to have their research assessments 
videotaped, and to indicate their authorization for Audio/Video/Photography Recording on the 


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Updated January 22, 2019 
 
consent form.  Patients refusing to consent to videorecording will still be permitted to participate 
in the study.  Recordings of study visits will be used by the study team for interrater reliability 
training and assessment. Screening for psychiatric and medical eligibility will involve vital signs, 
weight, blood tests, pregnancy test, drug screen, psychiatric interviews, medical and psychiatric 
history, physical exam and electrocardiogram (EKG). We will also draw the genotype sample at 
this visit for consenting subjects. 
 
If a patient is already taking medication for PTSD and has achieved therapeutic response, s/he 
will not be tapered off the effective medication(s) to participate in this study, and will not be 
eligible for the study. Patients who are taking a psychotropic medication that has proven 
ineffective for their PTSD symptoms will be tapered off the medication prior to randomization. 
Whenever possible, decisions to taper a patient’s medication for the purpose of study 
participation will be made in conjunction with the patients’ prescribing physician. Patients will be 
tapered off ineffective psychotropic medications over 7-21 days, though patients on fluoxetine or 
protriptyline will be required to be off those medications for 5 weeks prior to baseline. Risks 
associated with medication tapering will be discussed with the patient. This washout process will 
be conducted and monitored by the study physician. 
 
(2) Study Period I – Pretreatment Testing (Days –7 to –1): Visit 1. During this study period, 
subjects will undergo surrogate marker testing (psychophysiology, and neuropsychological 
testing). These visits will be conducted over a 7-day period prior to the day of randomization, 
following the successful completion of all the screening procedures in Phase 1 above.   We 
anticipate that these procedures can be completed in 1 study visit; however, we will be flexible 
to allow additional visits if required due to subject fatigue or time constraints. 
 
3) Study period II Treatment (Day 0 to 84): Visits 2 through 9. This is the 12-week period of 
double-blind placebo-controlled acute treatment.  At day 0, EKG for safety monitoring will be 
conducted. The baseline mRNA sample will be collected. All subjects who continue to meet 
eligibility criteria will be randomized to one of two groups: Vortioxetine or placebo. 
Randomization will be performed at a 1:1 ratio into two treatment groups, and both vortioxetine 
and placebo will be distributed to the patient in blister packs. If a participant is taking 10mg of 
vortioxetine they will be provided with 2 blister packs at each visit. If a participant is taking 
20mg, they will be provided with 4 blister packs.  Surrogate marker testing for 
psychophysiology, mRNA, and neuropsychological testing will be repeated at the completion of 
the double-blind treatment. Due to the amount of study procedures for certain study visits, we 
will allow study visits to be done over two days.  
 
4) Follow-Up (Day 84 to 98): Visit 10. Patients will return to the clinic two weeks after the last 
dose of study medication for assessment of psychiatric status, sucidality, follow-up of any 
abnormal laboratory or EKG results, and to assist with transition of psychiatric care, if indicated.   
 
 
See the Schedule of Events chart at the end of this section for details of the procedures 
performed during each visit. 
 
B. Justification of Sample Size 
Power Analysis:  
 
Samples of n=60 (2 groups) are associated with reduced but adequate power.  Between group 
differences in change scores of d=.70 are detectable with .80 power at p<.05.  Correlations of 


5 
 
Updated January 22, 2019 
 
.33 between two variables are detectable with power=.80 in the full sample of 60.  Within 
treatment conditions (n=30) correlations of r=.50 are detectable with the same level of power.  
 
 
C. Informed Consent, Regulatory and Ethical Considerations 
The study will be conducted in accordance with Good Clinical Practices (GCP), 21CFR Parts 50 
and 56 and all applicable regulatory requirements. Approval for conduct of the study will be 
obtained from the institutional review boards at both sites. 
 
Written informed consent will be obtained from each subject prior to any study procedures.  All 
potential subjects will be properly informed as to the purpose of the study and the potential risks 
and benefits known or that can be reasonably predicted or expected.  The subjects’ 
understanding of the study procedures will be tested in the form of oral questioning or written 
testing.  Investigators at each site will retain the original copy of the Informed Consent Form and 
HIPAA documents signed by the patient, and duplicates will be provided to the patient. 
 
D. Screening Phase 
The screening procedure includes an extensive phone interview and, if eligible, a screening 
visit.  Clinical staff members (bachelor’s or masters-level research assistant, Ph.D., or M.D.) 
trained in DSM diagnostic interviewing will conduct an initial phone interview to determine likely 
diagnostic suitability.  If the patient is deemed preliminarily eligible for participation, s/he will 
then be invited for an in-person screening visit.  If the potential participant is deemed ineligible 
after the brief phone interview or expresses interest in alternatives to study participation, the 
phone interviewer will give appropriate referrals. Upon arrival at the research clinic, the principal 
investigator or a trained delegate will briefly describe the details of the study procedures, risks 
and benefits, alternative treatments, and confidentiality of information. Potential participants will 
independently read and review the consent and HIPAA forms, and then the researcher 
obtaining consent will address any questions that the participant may have. Once the participant 
communicates his or her thorough understanding of the study and decides that s/he wishes to 
participate, he/she will be asked to sign and date the form. No study procedures will occur prior 
to the conclusion of the informed consent process.    
 
After patients consent to participate, they will undergo several procedures, which will occur over 
1-2 visits. These include: (1) psychiatric interview by a research psychiatrist or psychologist; (2) 
a structured clinical interview (the Mini International Neuropsychiatric Interview, “MINI,” Modules 
A and C through P); (3) administration of the CAPS-5, Columbia Suicide Severity Rating Scale 
(CSSRS), and Clinical Global Impression of Severity (CGI-S); (4) completion of several self-
report instruments; (5) collection of blood samples for safety testing and genotype analysis, 
pregnancy testing (if indicated), urine sample [urinalysis, toxicological screen]; (6) EKG; and (7) 
physical examination.  
 
A clinical researcher with specialized training in diagnostic assessment will perform the 
specified modules of the MINI and the rating scales. Appropriately trained study staff will 
conduct all medical tests and obtain biological samples for the following laboratories: blood 
samples for serum chemistries, liver function panel, free T4, thyroid stimulating hormone, 
hepatitis B surface antigen, hepatitis C antibody, serum pregnancy, gamma-glutamyl 
transferase (GGT), and complete blood count (CBC), urinalysis and urine drug screen.  At the 
conclusion of the screening process, the patient will be contacted within several days regarding 
preliminary eligibility.  All patients who are eligible will be scheduled for an in-person visit 
approximately one week after the initial evaluation. The participant will continue into Study 


6 
 
Updated January 22, 2019 
 
Period I at that time. If deemed ineligible for the protocol, a study physician will explain the 
reasons for disqualification, and these patients will receive appropriate research or treatment 
referrals. If symptoms worsen significantly during this period, as determined by the study 
physician’s assessment, subjects will be removed from the study and given appropriate referrals 
after meeting with the study investigators.  Options would include referral to the resident 
psychopharmacology clinic or referral back to their treating physician. 
 
E. Study period I: Pre-Treatment Testing 
During this testing phase, which will be scheduled within one week of the day of randomization, 
we will examine neurobiological surrogate markers involving psychophysiology (startle) and 
neuropsychological testing.  
 
F. Study period II: 12-Week Randomized, Double-Blind, Placebo-Controlled Trial 
Study Period II is the 12-week double-blind treatment period. On the day of randomization, an 
EKG and laboratory tests (blood samples for CPK and a urine sample for pregnancy testing will 
be collected. 
 
Patients will be assessed in-person weekly or every other week from Visit 2 through Visit 9, 
using self-report and clinician-administered measures to gauge changes in symptomatology 
(see Schedule of Events chart below). In order to maximize patient retention and account for 
unpredictable schedules, the treatment window will consist of the target visit date plus/minus 2 
days for Visit 2 through Visit 4 and plus/minus 3 days for Visit 5 through Visit 10. Patients will be 
randomized at a ratio of 1:1 to receive either Vortioxetine at a starting dose of 10 mg /day or 
placebo. Concurrent treatment with other psychotropic medication will NOT be permitted during 
the study with the exceptions of the hypnotics zolpidem, eszopiclone, zaleplon, and 
diphenyhdramine. Patients taking diphenydramine will be instructed not to take any doses of 
this medication for three days prior to the visits that involve Neuropsychological testing or the 
Startle Task.  These hypnotics will be allowed up to 3 doses per week during the trial. The CBC, 
blood chemistries, serum pregnancy, thyroid function measures and urinalysis will also be 
repeated at week 12.  At the end of this study period, the neurophysiology, neuropsychological, 
and mRNA measures will be repeated. Patients will be outpatients for the duration of the study. 
Due to the amount of study procedures for certain study visits, we will allow study visits to be 
done over two days. 
 
Dosing of Study Medication: All patients will be started on 10 mg vortioxetine/day (or placebo 
equivalent) dosed in the morning with food.  Patients experiencing sedation from the medication 
may be switched to evening dosing at the discretion of the study psychiatrist.  If by Week 4 the 
patient has demonstrated inadequate benefit from the medication, the dose will be increased to 
20 mg/day.  Patients unable to tolerate the 20 mg/d dose may be reduced to 10 mg/day 
between weeks 4 and 8. Patients unable to tolerate 10 mg will be discontinued from the trial.  
The dose of study medication should remain stable for weeks 8-12. 
Medication compliance will be monitored by pill counts conducted at every visit during study 
period II. The patient will also maintain a medication diary to mark the date and time they took 
their medication. Women of child bearing potential will also use the diary to indicate the start 
date of their menstural cycles, as this information will inform analysis of the startle testing data.   
 
 
 
G. Follow-up 


7 
 
Updated January 22, 2019 
 
After participants completing the 12 week randomized treatment phase, they will return to the 
clinic 14 days later (Visit 10) for a follow-up evaluation.  All subjects who complete the trial or 
discontinue the study because of lack of response or side effects will receive assistance in 
transitioning to another care provider as clinically appropriate at the research site (if they choose 
to do so), or will be referred back to their referring physician.  Patients with clinically significant 
abnormal laboratory tests at Visit 9 will have those tests repeated at the follow-up visit. 
 
 
H. Early Termination from Protocol  
Medical or Administrative Reasons: Subjects will be terminated early if any of the following 
occur:  (1) Intolerance to study drug in the dose range required by the study; (2) worsening of 
PTSD or depressive symptoms such that the subject’s safety is endangered (e.g. suicidality); (3) 
If patient becomes manic or psychotic; (4) a serious adverse event (SAE) that is either: i) 
considered by the investigator to be possibly, probably, or definitely related to the study 
medication, or ii) places the subject at increased risk of harm if s/he were to continue in the 
study. 
 
Suicidal ideation is assessed at each study visit with the Columbia Suicide Severity Rating 
Scale (CSSRS), an instrument endorsed by the FDA for clinical trials.  This brief instrument 
systematically tracks suicidal ideation and behavior (e.g., suicide attempts, wish to die, thoughts 
of suicide, and plan and intent), and classifies events according to the following categories: 
Suicidal events – completed suicide, suicide attempt, preparatory acts toward imminent 
suicidal behavior and suicidal ideation. Non-suicidal events – self-injurious behavior, no 
suicidal intent and other, no deliberate self-harm. Indeterminate or potentially suicidal events 
– self-injurious behavior, suicidal intent unknown. Subjects who are considered by the study 
psychiatrist to be at high risk for suicide are discontinued from the study and referred for 
hospitalization and further treatment as clinically indicated. 
 
Poor Adherence:  Every effort will be made to encourage subject compliance with the dosage 
regimen as per the protocol.  A record of the supplies dispensed, taken and returned will be 
recorded at each visit.  Compliance will be monitored by pill counts. Subjects who miss three or 
more consecutive days of Vortioxetine during the study are considered non-compliant and will 
be counseled about need for adherence.  Patients found to miss three consecutive doses of 
study medication twice will be withdrawn from the study.  Non-adherent patients are classified 
as dropouts in the analysis. 
 
Drop-outs:  Drop-outs will be defined as randomized subjects lost to follow-up who do not 
complete the 12-week double-blind treatment period. Randomized subjects who drop out prior 
to completing one post-randomization efficacy assessment will not be included in the primary 
efficacy analysis.   


8 
 
Updated January 22, 2019 
 
 
SCHEDULE OF EVENTS  
Visit Number 
S1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Week  
(± 2 days for V2-V4, ± 3 days for V5-10) 
 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
Day  
 
-7 
0 
7 
14 
28 
42 
56 
70 
84 
98 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics/Hollingshead 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
Psych/Medical eval. by MD 
X 
 
 
 
 
 
 
 
 
X 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
 
12-lead EKG 
X 
 
X 
 
 
 
 
 
 
X 
 
MINI modules A, C-P 
X 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug & Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
  CBC 
X 
 
 
 
 
 
 
 
 
X 
 
  Blood Chemistry 
X 
 
 
 
 
 
 
 
 
X 
 
  Liver Function Tests 
X 
 
 
 
 
 
 
 
 
X 
 
  GGT 
X 
 
 
 
 
 
 
 
 
 
 
  Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
 
  Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
  Serum Pregnancy 
X 
 
 
 
 
 
 
 
 
X 
 
  Urine Pregnancy 
 
 
X 
 
 
 
 
 
 
 
 
  CPK 
 
 
X 
 
 
 
 
 
 
X 
 
  TSH, Free T4 
X 
 
 
 
 
 
 
 
 
X 
 
  Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
  Pharmacokinetics 
 
 
 
 
 
X 
 
X 
 
X 
 
Psychiatric Measures 
 
 
 
 
 
 
 
 
 
 
 
  CAPS  and CGI 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
  MADRS 
 
 
X 
 
X 
X 
 
X 
 
X 
 
  CSSRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
E-TRIP 
X 
 
 
 
 
 
 
 
 
 
 
  PCL-5/QIDS-SR 
 
 
X 
 
X 
X 
 
X 
 
X 
 
  CTQ & PDS Screen 
X 
 
 
 
 
 
 
 
 
 
 
  PSQI 
 
 
X 
 
 
X 
 
X 
 
X 
 
  SDS 
X 
 
X 
 
 
 
X 
 
 
X 
 
  Life Experiences Survey 
 
 
X 
 
 
 
 
 
 
X 
 
Safety Measures 
 
 
 
 
 
 
 
 
 
 
 
  PRISE/Con meds 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  FIBSER 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Exploratory Aim Testing 
 
 
 
 
 
 
 
 
 
 
 
  Startle Paradigm  
 
X 
 
 
 
 
 
 
 
X 
 
  Genotype/Methylation 
 
 
X 
 
 
 
 
 
 
X 
 
Neuropsychological Testing: 
BACS + UPSAB 
 
X 
 
 
 
 
 
 
 
X 
 
  mRNA 
 
 
X 
 
 
 
 
 
 
X 
 
 


9 
 
Updated January 22, 2019 
 
 
I. Efficacy and Safety Tests and Procedures 
1. Measures and Questionnaires 
See Appendix B for a brief description of the rating scales. 
 
2. Blood and Urine Tests for Safety 
2a. At the start of the study, participants will undergo specific laboratory tests, as outlined in the 
Schedule of Events above. Blood tests include: complete blood cell count (CBC) with 
differential, thyroid functioning (TSH), and free thyroxine, fasting blood sugar, liver function tests 
(LFTs), including total bilirubin, a hepatitis panel, and a serum pregnancy test in women of child-
bearing potential. Participants also undergo a urine toxicology screen, urine pregnancy test and 
urinalysis testing. Additional blood or urine tests for disallowed medications or drugs of abuse 
may be performed during the randomization phase at the discretion of the investigator. 
 
3.  Pharmacokinetics Testing  
3a. As outlined in the schedule of events, participants will undergo confirmatory laboratory 
testing at visits 5, 7, and 9. Blood will be drawn and tested to confirm the level of Vortioxitine in 
the participant’s system at the time of their study visit.    
 
J. Exploratory Biological and Neuropsychological Assessments 
 
In addition to the treatment outcome goals, we will examine previously identified genetic risk 
factors for predictors of treatment response.  We will also examine SNPs associated with PTSD 
which meet genome-wide significance within an ongoing cross-sectional n=8000 Genome Wide 
Association Study.  
 
Hypothesis 1: Based on our extensive prior experience in examining physiological markers of 
fear responding, we hypothesize that trauma-exposed individuals with PTSD will exhibit a higher 
likelihood of responding to PTSD treatment if they display differential physiological signatures of 
PTSD (e.g. increased dark-enhanced startle and decreased extinction of fear), compared to 
those without these physiological signatures of PTSD. 
 
Hypothesis 2: Based on our previous work in PTSD identifying significant cognitive and 
functional capacity deficits, we hypothesize that treatment of with vortioxetine will improve 
cognitive and functional capacity.  
 
Hypothesis 3: Based on our pilot data that interventions for PTSD can ameliorate genetic 
predisposition, we hypothesize that trauma-exposed individuals with PTSD will exhibit a higher 
likelihood of responding to PTSD treatment if they are carriers of risk alleles of the FKBP5, the 
ADCYAP1R1 gene and other genes (e.g., DAT, BDNF, COMT, CRHR1, 5-HTTLPR, RGS2, 
GABRA2), compared to non-carriers of risk alleles. We will also examine gene expression and 
epigenetic risk factors associated with PTSD as predictors of treatment response.   These will 
Abbreviations: CAPS = Clinician-Administered PTSD scale; CBC = Complete blood count; CGI I/S  = Clinical Global 
Impression Scale (improvement and severity); CSSRS = Columbia Suicide Severity Rating Scale; CTQ = Childhood 
Trauma Questionnaire; EKG = Electrocardiogram; ETRIP = The Emory Treatment Resistant Interview for PTSD;  
FIBSER = Frequency, Intensity and Burden of Side Effects Rating; GGT = Gamma glutamyl transpeptidase; 
Hollingshead= Hollingshead 4 Factors of Social Status Scale; MADRS= Montgomery Asberg Depression Rating Scale; 
PCL-5 =The Posttraumatic Stress Disorder Checklist for DSM-5; PRISE = Patient Rated Inventory of Side Effects; PSQI 
= Pittsburgh Sleep Quality Index;  PDS = Post-traumatic stress Diagnostic Scale;  PSSR = PTSD Symptom Scale Self 
Report; QIDS-SR = Quick Inventory of Depressive Symptoms; SDS = Sheehan Disability Scale; T4 = Thyroxine; TSH = 
Thyroid stimulating hormone;  
Notes: Patients who terminate early will complete the Visit 9 safety and efficacy procedures. 


10 
 
Updated January 22, 2019 
 
include differential mRNA expression and epigenetic (methylation) marks identified 
pretreatment, previously associated with differential PTSD risk to identify how modulators of 
gene function relate to treatment response.   
 
1. DNA 
We will draw DNA on all consenting subjects to evaluate whether carriers of identified 
risk alleles are associated with response or non-response to voritoxetine. 
 
2. mRNA 
We will draw 12 mls of blood at baseline and at week 12 to evaluate the expression of 
HPA-related mRNA expression.   
 
3. Neurophysiology: Startle Testing 
3a. Conditioning sessions. The following methods will allow us to assess fear acquisition, 
and conditional discrimination (learned safety), as well as the subjects’ awareness of 
reinforcement contingencies in the experiment. The aversive stimulus (US) in these studies will 
be a 250 ms airblast with an intensity of 80 p.s.i. directed to the larynx as described in similar 
human fear conditioning studies (Grillon & Davis, 1997; Jovanovic et al. 2005).  A compressed 
air tank connected to polyethylene tubing and controlled by a solenoid switch will emit the 
airblasts. The conditioned stimuli (CS’s) used in the AX+/BX- session (A, B, C and X) will be 
different colored shapes; in the fear acquisition and extinction sessions the CS’s will be neutral 
pictures. The CS’s will be presented on a computer monitor. The pictures and colored shapes 
will be counterbalanced across subjects. The stimuli will be presented using SuperLab 3.0 for 
Windows (Cedrus, Inc.) and synchronized with the psychophysiological data acquisition using a 
DIO card (Measurements Computing, Inc). The psychophysiological data will be collected with 
Biopac MP150 (Biopac Systems, Inc.). Skin conductance will be acquired concurrently with 
acoustic startle.   
3b. Acoustic startle. The acoustic startle response (eyeblink component) will be measured 
via electromyography (EMG) of the right orbicularis oculi muscle. Two 5 mm Ag/AgCl pre-gelled 
disposable electrodes will be positioned approximately 1 cm under the pupil and 1 cm below the 
lateral canthus. All resistances will be less than 6 kilo-ohms. EMG activity is acquired at a 
sampling rate of 1kHz, amplified and digitized. The startle probe (noise burst) will be a 108-dB 
[A] SPL, 40-ms burst of broadband noise with a near instantaneous rise time.   
3c. Response keypad. To assess subject awareness and US expectancy during each 
experimental session subjects will respond on a response keypad (SuperLab, Cedrus Corp.) in 
coordination with the EMG startle response monitoring system (SR-LAB, San Diego 
Instruments).  During the fear conditioning sessions subjects will press a button marked “+” if 
they expect a CS to be followed by the US, a button marked “-“ if they do not expect a CS to be 
followed by the US, and a button marked “0” if they are uncertain of what to expect.   
3d. Skin Conductance Level. The skin conductance level will be acquired at a sampling 
rate of 1 kHz using the GSR module of the Biopac system. Two 5 mm Ag/AgCl disposable 
electrodes filled with isotonic paste will be attached to middle phalanges of the second and 
fourth finger of the non-dominant hand.  
 
4. Neuropsychological Battery 
4a. Rationale and Test Descriptions. Cognitive function will be assessed by Brief 
Assessment of Cognition in Schizophrenia (BAC-S) test battery with measures in: (1) list 
learning, (2) digit sequencing task, (3) token motor task, (4) verbal fluency, (5) tower of 
London test, a n d  (6) symbol coding subtest. All BAC-S measures will be administered at 
specified time points, and the total composite z-scores will be compared to baseline total 
composite z-scores. 


11 
 
Updated January 22, 2019 
 
4b. Performance Based-Measures of Functional Capacity 
For the assessment of functional capacity, we will use instrumentation previously developed for 
use in schizophrenia: the UCSD performance-based skills assessment (UPSA; Patterson et al 
2001). The UPSA is the most widely used functional capacity measure in serious mental illness, 
but suffers from a lengthy assessment format (30 minutes), high-level reliance on props, and 
geographic specificity. The UPSA-B involves role-play tasks similar in complexity to those that a 
community-dwelling person is likely to encounter. Administration requires an average of 10 
minutes. The UPSA-B’s two domains result in a summary score ranging from 0 to 100 and we 
will use the summary score as the dependent variable.  
 
K. Clinical Care 
 
1. Discontinuation from study 
At the end of the treatment trial or when a patient discontinues the study prematurely, the 
efficacy evaluations will be repeated. In addition, a physical exam, 12-lead EKG, vital signs, 
weight, and laboratory measurements will be obtained. Patients will also be assessed for 
adverse experiences. All subjects who complete the trial or discontinue because of lack of 
response or side effects will receive treatment as clinically appropriate and will then be referred 
for appropriate follow-up care. 
 
Patients may withdraw at any time, or may be withdrawn by the investigator should medical 
contraindications to the assigned medication develop, intolerable adverse reactions occur, or 
mood or anxiety worsens to an extent that, in the clinicians’ judgment, further participation would 
put the patient at risk.  
 
Pregnancy 
The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study.  Any female subject who becomes pregnant while 
participating will be withdrawn from the study.  The investigator will record pregnancy 
information on the appropriate form and submit it to Dr. Philip Harvey at the University of Miami 
(Email: pharvey@med.miami.edu  Fax: 305-243-1619) and to Takeda (Email: 
(takedasafetytgrd.com iFax: 1-224-554-1052) within 24 hours of learning of a subject's pregnancy.  
The subject will also be followed to determine the outcome of the pregnancy.  Generally, follow-
up will be no longer than 6 to 8 weeks following the estimated delivery date.  Any premature 
termination of the pregnancy will be reported.  While pregnancy itself is not considered to be an 
AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be recorded as an AE or SAE. A spontaneous abortion is always considered an 
SAE and will be reported as such.  
 
SAE Reporting 
All SAEs will be reported to Dr. Philip Harvey and to Takeda within 4 calendar days of the site 
investigator becoming aware of the event. All fatal or life-threatening SAEs will be reported by 
facsimile within 24 hours. The appropriate SAE form will be completed and emailed or faxed to 
Dr. Harvey and Takeda using the contact information listed in the Pregnancy section.  
 
 
2. Suicide risk among patients treated with antidepressants 
Subjects with major depressive disorder or with depression as part of bipolar disorder may 
experience worsening of their depression and/or the emergence of suicidal ideation and 
behaviour (suicidality), whether or not they are taking antidepressant medications, and this risk 
may persist until significant remission occurs.  This guidance is consistent with global class 


12 
 
Updated January 22, 2019 
 
labelling for antidepressants. Although there has been a long-standing concern that 
antidepressants may have a role in inducing worsening of depression and the emergence of 
suicidality in certain subjects, a causal role for antidepressants in inducing such behaviours has 
not been established. Nevertheless, subjects being treated with study medication will be 
observed closely for clinical worsening and suicidality, especially at the beginning and end of 
the course of treatment, or at the time of dose changes, either increases or decreases. 
Consideration will be given to possibly discontinuing the investigational product in subjects 
whose depression is persistently worse or whose emergent suicidality is severe or abrupt in 
onset or was not part of the subject’s presenting symptoms. To assess suicidal ideation and 
behaviors, the CSSRS will be used in this trial. 
 
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility 
(aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, 
have been reported in patients being treated with antidepressants for major depressive disorder. 
Although a causal link between the emergence of such symptoms and either the worsening of 
depression and/or the emergence of suicidal impulses has not been established, consideration 
should be given to possibly discontinuing the investigational product in subjects for whom such 
symptoms are severe, abrupt in onset, or were not part of the subject’s presenting symptoms. 
 
2. Provision of Clinical Care 
 
All subjects who complete the trial or discontinue the study because of lack of response or side 
effects will receive assistance in transitioning their care to another provider.  
 
VII. DATA ANALYSIS AND STATISTICAL PLAN 
 
A. Approach to Data Management 
Case report forms are developed from adaptations of NIH and industry-funded clinical trial 
protocols in PTSD. Study data will be recorded on paper forms and translated to a digital format 
without specific patient identifying information. Patient identifiers will be maintained in a 
separate code book that will be kept in a locked cabinet in the Principal Investigator’s office at 
each site. These data will preserved on site with periodic monitoring by the primary site. At the 
end of the study, the databases for the different sites will be merged.  Data will be entered 
sequentially and within a timely manner so that any queries for missing information can be 
resolved. 
 
B. General Statistical Considerations  
Possible risk factors/confounders: We expect the randomization procedure to equalize risk 
factors across treatment groups; however, we will produce summary statistics to explore any 
unexpected differences in the values of covariates in the treatment groups. While we do not 
expect differences in covariates in the treatment groups, it is very likely that the response 
groups will be different on some relevant clinical variables (e.g., comorbid conditions). However, 
these should affect only the analyses that include treatment response, and not analyses such as 
group-related change in CAPS. Thus, we will formally assess response group differences in 
possible covariates of interest and incorporate any covariates identified that are considered both 
statistically and clinically relevant as additional main effects for the response-based analyses. 
Specific types of interaction effects, such as effect modifiers specified a priori, will be the subject 
of exploratory analysis. 
 
Site effects: Our assumption for the analysis plan and power calculations is that the protocols 
will be implemented sufficiently comparatively to avoid significant site effects in the results. 
Given that the randomization will be blocked by site, there is no reason to believe that the 


13 
 
Updated January 22, 2019 
 
subjects will have a different a priori probability of response or will be significantly different from 
a clinical perspective. However, we will test for site differences in all outcome measures with 
appropriate univariate comparisons to ensure that this is not a significant confounder. If there is 
evidence of significant site differences in response, we will proceed with stratified analyses in 
place of the proposed analyses. 
 
Missing data: For those subjects randomized who do not complete treatment, an intent-to-treat 
approach will be implemented using linear and categorical mixed model methods. More 
specifically, all participants who are randomized to treatment group and have baseline 
measures will be included in the analysis. If the probability of a missing observation depends on 
either observed covariates in the model or the previous observations of the outcome variable 
(e.g. CAPS), these models will provide the correct conclusions (Little & Rubin, 2002). Any other 
missing data would be the result of incomplete recording of information or refusal of a subject to 
give information. Thus, the assumption that missing data are in fact missing at random (MAR), 
or that other variables under consideration will contain enough information to effectively model 
the outcome of interest, will be reasonable for these analyses. 
Therefore, in the case of missing predictor variables, simple or multiple imputation methods 
(Little and Rubin, 2002) will be sufficient to provide “fill-in” methods so we can perform analyses 
of the full data set. All analyses described below will be performed on the complete data sets 
that result from this process. We will compare dropout patterns between groups and if there are 
concerns of informative dropout and/or informative intermittent missing data, we will perform 
sensitivity analyses to determine the effects of these assumptions on our main analyses 
(Molenberghs et al., 2004). 
 
Analytic details: Continuous variables will be fit using SAS PROC MIXED, and categorical data 
will be fit using the gllamm add-on to Stata (Rabe-Hesketh et al; 2002). The gllamm method is 
preferred to SAS PROC GLIMMIX in that is a full likelihood method which uses numerical 
integration for the random effects rather than a partial likelihood approximation. In addition, it 
provides empirical Bayes estimates of the random effects for model checking. Prior to model 
fitting, we will examine the distributions of the continuous outcome variables using visual 
inspection of histograms and boxplots to identify potential outliers. If variables are not normally 
distributed or contain outliers, then log transformations will be considered or appropriate 
nonparametric procedures will be substituted for the analyses stated. 
 
Multiple outcome measures: To address the possible increase in Type I errors due to multiple 
outcome variables, we have a priori selected a single outcome measure (CAPS total) which will 
maintain the significance level (α) 0.05 for the primary analysis. For secondary outcome 
measures, we will adjust p-values by controlling for the false discovery rate (Benjamini & 
Hochberg, 1995) and report both unadjusted and adjusted p-values. 
 
Random effects: Given that the majority of outcomes are behavioral in nature, we expect that 
there will be significant individual level variance that will need to be incorporated into the model. 
Thus our overall analysis approach will be to use linear 2-level mixed models or generalized 
linear mixed models, as appropriate, to analyze the repeated measures data with at least a 
random intercept to incorporate individual level variation. We will also incorporate a random 
slope if necessary however, it is not always necessary in our experience, particularly with scales 
with a limited range such as MADRS.  
 
 
VIII. HUMAN SUBJECTS 
 


14 
 
Updated January 22, 2019 
 
A. Subject Recruitment 
Men and women between the ages of 18-65 with a primary diagnosis of PTSD using the DSM-V 
criteria will be eligible for the study.  A total of 60 subjects will be randomized (30 to Vortioxetine 
and 30 to placebo).  These subjects will be enrolled at 2 sites, Emory University School of 
Medicine and Miami Miller School of Medicine.  Subjects will enter this study having been 
recruited through referrals from outpatient clinics, or referrals from other community clinics and 
community clinicians (psychiatrists, psychologists, and social workers) in the greater Atlanta and 
Miami regions.  In addition, we will advertise locally in newspapers and radio and will post 
recruitment messages on internet sites.   
 
Subjects will meet all inclusion/exclusion criteria outlined below. We will exclude subjects with 
history of bipolar disorder, psychosis, substance abuse or dependence that is current or existed 
3 months prior to screening, history of borderline intellectual functioning or mental retardation, 
and clinically significant suicidal risk.  We will exclude individuals with the following medical 
conditions, as evidenced by use of daily medications or prior treatment: cancer in past year, 
stroke, heart attack, angina, neurological disease (MS, epilepsy, Parkinson’s), CNS lesions 
(head trauma), dementing illness, liver/kidney disease. The completion of self-report scales and 
cognitive tests requires a level of understanding that may not be present in those with low IQ.  
Medical illnesses and use of medication that may interfere with biological, and possibly 
psychological assessments, and current suicidality that requires immediate clinical intervention 
will be exclusionary for participation.  
 
B. Inclusion/ Exclusion Criteria 
 
Inclusion 
CRITERION                                                                    METHOD OF ASCERTAINMENT 
1. Males and Females between the ages of 18 
and 65 
History 
2. Fulfills DSM-5 criteria for primary diagnosis of 
PTSD.  
MINI 
3. Willing and able to give consent 
Clinical interview 
4. A negative urine toxicology 
Urine toxicology 
5. For females of reproductive age, use of an 
effective birth control method* for the duration 
of the study or abstinence. 
History 
6. Duration of illness of PTSD for at least 3 
months 
History 
7. An initial score at Screening, and Visit 2 
(randomization) of ≥ 28 on the CAPS-5 for 
PTSD Studies 
CAPS-5 
*See specific criterion for effective birth control methods. 
 
Exclusion: 
CRITERION                                                                 METHOD OF ASCERTAINMENT 
1.  Lifetime or current diagnosis of schizophrenia 
or other psychotic disorder, dementia, bipolar 
disorder.    
MINI and Clinical Evaluation 
2.   Subject is currently participating in another 
clinical trial in which s/he is or will be exposed to 
an investigational or non-investigational drug or 
Clinical Interview 


15 
 
Updated January 22, 2019 
 
device, or has done so within the preceding 
month.  
3. Subject has a prior unsuccessful trial of 
Vortioxetine at 20 mg/day or higher for 8 weeks or 
more 
History 
4.   Current evidence or history of significant 
unstable medical illness or organic brain 
impairment, including stroke, CNS tumor, 
demyelinating disease, cardiac, pulmonary, 
gastrointestinal, renal or hepatic impairment that 
would likely interfere with the action, absorption, 
distribution, metabolism, or excretion of 
Vortioxetine.  History of moderate or more severe 
TBI will also be exclusionary. 
Medical chart review, clinical 
interview, physical exam, and 
laboratory testing 
5.  Patients who in the investigator’s judgment 
pose a current suicidal or homicidal risk 
Clinical Interview 
6. DSM-5 substance abuse or dependence within 
the past 90 days. Subject has a positive urine 
toxicology test for illegal substances.  
History, Urine Toxicology 
7. Diagnosis of anorexia nervosa or bulimia in the 
past year. 
MINI, History 
8. Subject has a documented history of hepato-
biliary disease including a history of, or positive 
laboratory results for hepatitis (hepatitis B surface 
antigen and/or hepatitis C antibody), AND  
clinically significant hepatic enzyme elevation, 
including any one of the following enzymes 
greater than 3 times the upper limit of normal 
(ULN) value (ALT, AST, ALP), or total bilirubin > 
1.5 x ULN, unless consistent with presumed or 
diagnosed Gilbert’s disease 
History, Laboratory testing 
9. Subject has taken systemic corticosteroids 
within 2 weeks of the Randomization Visit 
History 
10.  Treatment with any other psychoactive 
medication within 2 weeks of Visit 1, including all 
antidepressants, psychoactive herbal or nutritional 
treatment (St Johns Wort, SAM-e), lithium, other 
mood stabilizers, oral antipsychotics, depot 
antipsychotics within 12 weeks, beta blockers, 
thioridazine, pimozide, opiates, anxiolytics, and 
sedatives (with the exception of zolpidem, 
eszopiclone, zaleplon, and diphenhydramine).  
Also any treatment with any medication that the PI 
judges not acceptable for this study. 
History 
11.  Pregnancy or lactation* 
Pregnancy test, assessment 
12. Subjects who, in the opinion of the 
investigator, would be noncompliant with the visit 
schedule or study procedures (e.g. illiteracy, 
planned vacations, or planned hospitalizations 
during the study). 
Interview/History 


1 6  
 
U p d at e d J a n u ar y 2 2, 2 0 1 9  
 
1 3 . A n y l a b or at or y a b n or m alit y t h at i n t h e 
i n v e sti g at or’ s j u d g m e nt i s c o n si d er e d t o b e 
cli ni c all y si g nifi c a nt ( bl o o d pr e s s ur e, E C G, T S H, 
L F T,  et c.)  
L a b or at or y t e sti n g  
1 4 .  P ati e nt s w h o ar e r e c ei vi n g e x p o s ur e-b a s e d 
p s y c h ot h er a p y t h at t ar g et s P T S D s y m pt o m s  
Tr e at m e nt Hi st or y  
1 5 . C urr e nt or pl a n n e d liti g ati o n or ot h er a cti o n s 
r el at e d t o s e c o n d ar y g ai n r e g ar di n g t h e tr a u m ati c 
e v e nt  
I nt er vi e w 
1 6 . S u bj e ct h a s cli ni c al e vi d e n c e of, or E K G 
r e s ult s i n di c ati n g a n y of t h e f oll o wi n g at eit h er 
s cr e e n or R a n d o mi z ati o n Vi sit u nl e s s r e p e at E K G 
s h o w s t h at t h e p ar a m et er h a d r et ur n e d t o wit hi n 
n or m al r a n g e b y t h e R a n d o mi z ati o n Vi sit:  
� Q T c > 4 5 0 m s e c  f or m e n, or >  4 7 5 m s e c f or 
w o m e n ; 
� A n y  c ar di a c c o n diti o n or E K G e vi d e n c e t h at t h e 
i n v e sti g at or f e el s m a y p o s e a p ot e nti al s af et y 
c o n c er n.  
E K G  
 
* A s er u m pr e g n a n c y t e st i s p erf or m e d d uri n g t h e s cr e e ni n g.  Si n c e t hi s t e st mi g ht n ot d et e ct t h e 
v er y e arl y st a g e of p r e g n a n c y (i. e. m a xi m u m of 1 0 d a y p eri o d b et w e e n f ertili z ati o n a n d 
i m pl a nt ati o n), w o m e n of c hil d-b e ari n g a g e ar e e x cl u d e d fr o m t h e st u d y if t h e y d o n ot u s e a n 
eff e cti v e birt h c o ntr ol m et h o d f or 1 5 d a y s pri or t o r e c ei vi n g t h e st u d y dr u g.  A c c e pt a bl e m et h o d s 
of birt h c o ntr ol i n cl u d e:  s ur gi c al st erilit y; p o st m e n o p a u s al st at u s ( d efi n e d a s n o m e n s e s f or at 
l e a st 1 2 m o nt h s) ; a d o u bl e -b arri er m et h o d ( c o n d o m s pl u s di a p hr a g m); h or m o n al c o ntr a c e pti v e s 
pl u s si n gl e b arri er ( birt h c o ntr ol pill s, i m pl a nt s [ N or pl a nt] or i nj e cti o n s [ D e p o -Pr o v er a]), 
I ntr a ut eri n e D e vi c e (I U D), or a b sti n e n c e ( n o s e x u al a cti vit y).   
 
E. Ri s k s  
1. G e n er al   
B y a gr e ei n g t o p arti ci p at e i n t hi s st u d y, s u bj e ct s will b e t e m p or aril y f or g oi n g t h e o p p ort u nit y t o 
r e c ei v e r o uti n e cli ni c al c ar e i n t h e c o m m u nit y. T hi s will b e cl e arl y e x pl ai n e d t o all p ati e nt s, al o n g 
wit h t h e tr e at m e nt str at e gi e s t h at ar e g e n er all y u s e d i n p ati e nt s wit h P T S D. P ati e nt s will b e t ol d 
t h at st a n d ar d alt er n ati v e tr e at m e nt s e xi st f or P T S D.  
 
2. S cr e e ni n g a n d E v al u ati o n  
T h e ri s k s a n d di s c o mf ort s of t h e s cr e e ni n g a n d b a s eli n e e v al u ati o n s ar e mi ni m al. N o di s c o mf ort 
i s e x p e ct e d t o b e a s s o ci at e d wit h t h e p h y si c al e x a mi n ati o n or t h e cli ni c al i nt er vi e w. 
V e ni p u n ct ur e m a y b e a s s o ci at e d wit h t h e m o m e nt ar y di s c o mf ort of t h e n e e dl e sti c k, a s w ell  a s a 
s m all ri s k of h e m at o m a ( br ui s e). S u bj e ct s will b e e x p o s e d t o t h e di s c o mf ort of a n s w eri n g 
p er s o n al q u e sti o n s t h at t h e y m a y fi n d di str e s si n g.  
 
3. Dr u g -fr e e p eri o d a n d tr e at m e nt tri al 
Si n c e it i s u n k n o w n w h et h er t h e c a n di d at e i s eff e cti v e i n t h e tr e at m e nt of P T S D, p arti ci p ati o n i n 
t hi s tri al c o ul d d el a y p ot e nti all y eff e cti v e t h er a p y b y 1 2  w e e k s. T h er e m a y b e a si g nifi c a nt 
w or s e ni n g of s y m pt o m s a s t h e p ati e nt’ s m e di c ati o n s ar e b ei n g di s c o nti n u e d, d uri n g t h e dr u g -
fr e e p eri o d or d uri n g t h e st u d y it s elf. If t h e p ati e nt i s di s c o nti n u e d fr o m t h e st u d y d u e t o a 
w or s e ni n g of t h eir ill n e s s, t h e y will b e r ef err e d f or st a n d ar d c ar e.  
 


17 
 
Updated January 22, 2019 
 
 
F. Procedure Specific Risks 
Research interviews or study procedures will be interrupted if subjects become distressed or 
object to answering questions. We will not taper off medications that are clearly effective for the 
patient’s current depression or PTSD.  
 
Patients may withdraw at any time or be dropped from the study at the discretion of the 
investigator should medical contraindications to the assigned medication develop, if intolerable 
adverse reactions occur, if mood or anxiety worsens, or if in the clinician’s judgment the patient 
has worsened to such a degree that further participation would put the patient at risk. If stopping 
criteria established by University of Miami guidelines are met, participants will be exited from the 
study and appropriately monitored.   
 
In the startle testing, participants will be exposed to a Lemon Prep mild abrasive skin prepping 
lotion and gel for the electrodes. It is possible that subjects may experience allergic responses 
to the ingredients of the lotion or gels.  
 
Risks Associated with Donation of Genetic Material  
There are no physical risks associated with participation in genetic studies, apart from those 
routinely associated with phlebotomy, which are minimal. Psychological and social/economic 
risks associated with genetics studies of the kind described here are difficult to define, and 
remain the subject of heated controversy in the ethics community. The major risk, to the degree 
that any exists, is that a breech of confidentiality regarding genetic studies that resulted in third 
parties finding out genetic information about a person could theoretically place a person at risk 
for loss of insurance, loss of employment, etc. because of genotype-based discrimination. To 
our knowledge, no person has ever suffered harm for the reasons just described as a result of 
participating in a genetics research study. Regardless, our written informed consent process 
goes over these risks carefully. In addition, subjects have the right to “withdraw” from the 
research by having their DNA sample destroyed. Finally, all research records containing any 
subject-identifying information are stored under lock and key, or in secured computing 
environments. Personal identifiers are never associated directly with genotypes in the same 
data file—all genotype information is indexed only to de-identified subject codes. With these 
safeguards in place, we are confident the research is virtually without psycho-social-economic 
risk to subjects. 
 
G. Protection against Risk 
There are four areas in which safeguards to protect subjects from undue risk require discussion 
for study-related activities. These include the procedures used to obtain informed consent, 
procedures used to ensure confidentiality of the subjects’ data, procedures used to minimize 
risks associated with study procedures, and risks associated with participating in the treatment 
study. 
 
Informed Consent 
In the consent form and discussion with an investigator, subjects are advised fully of the 
procedures to be used, the amount of time required of them, the possible risks and benefits of 
the procedures, their right to refuse participation in the study without prejudice, their right to 
terminate participation at any moment without prejudice, and the name and telephone number 
of the Principal Investigator. 
 
Confidentiality of Subjects’ Responses 


18 
 
Updated January 22, 2019 
 
In the informed consent form, subjects are told that the information they provide and all findings 
will be kept strictly confidential, with access limited to the research staff at the research sites 
and the possible exception of state or federal regulatory personnel. All data will be carefully 
stored in a limited access, locked room. No names will be associated with computer files or 
data, and no names will be associated with any published reports. Access to participant data will 
be limited to study staff, on an as-needed basis. Results are published as group data without 
the use of characteristics that would identify individual subjects. We quote information only by 
number in conference discussions, scientific reports, or publications, in order to maintain 
anonymity.  Confidentiality may need to be broken in certain cases, such as when the subjects’ 
safety is endangered. 
 
Research Procedures 
We have described above the potential risks of the research procedures and the safeguards 
that will be used to minimize risks. Additionally, interviewers will receive training in the 
importance of study information confidentiality, and in how to manage any participant distress 
that may be associated with responding to research questions and interviews. Subjects will be 
observed closely during startle testing and the procedure will be stopped immediately if a 
subject indicates it is too aversive. Only one subject out of approximately 600 test sessions in 
the Duncan lab has requested that startle testing be stopped. We will terminate subjects from 
research participation if it is believed that such participation endangers their welfare. Any 
adverse events will be reported in compliance with IRB policies at Emory and Miami. If a 
clinically significant physical condition is identified during the course of participation, an 
appropriate referral to a medical treatment facility will be offered. 
 
Study Medication 
Subjects are monitored for potential reactions during the clinical trial. A physician is on call at all 
times between clinic visits so that adverse reactions can be evaluated and treated promptly.  
 
H. Risk-Benefit Ratio 
The potential risks detailed above are non-significant, and the investigators will make every 
effort to minimize their occurrence. The direct benefits from participating in this study may be 
decreased PTSD and depressive symptoms, but there may be no direct benefits to individual 
patients. Information obtained from the study will benefit society by increasing knowledge about 
PTSD. 
 
I. Confidentiality of Data  
All electronic records will be kept confidential to the extent permitted by law.  Participants’ 
names and other personal identifying information will be stored in electronically secured 
databases at the study sites.  These databases are password protected and only study 
personnel will be given the password.  Results will be published as group data without the use 
of characteristics that would identify individual subjects. The results of the genetic assessments 
will also be addressed in the same way. 
 
J.  Data and Safety Monitoring Plan 
In compliance with local IRB guidelines, PIs will prepare a report annually that summarizes 
adverse event and protocol deviation data for the Data Safety Monitoring Board for the study. 
Each site will develop its own DSMB for the study.   
 
K. Adverse Event Monitoring 
Adverse events will be monitored throughout the study using the FIBSER and PRISE self-report 
forms, and through open-ended clinician inquiries. Monitoring will include assessment of 


19 
 
Updated January 22, 2019 
 
intensity (mild, moderate, severe) and assessment of causality (drug related, not drug related). 
All events will be followed to resolution or stabilization. All serious adverse events (SAE) will be 
collected and reported as appropriate per each site’s IRB-requried reporting guidelines.  
 
A serious adverse event is one that meets any of the following criteria: 
--Fatal or life threatening 
--Requires or prolongs inpatient hospitalization 
--Results in persistent or significant disability/incapacity 
--Congenital anomaly 
--Important medical event that may jeopardize the patient or require intervention to prevent a 
serious outcome 
--Cancer 
 
An Adverse Event is: 
--any abnormal laboratory test and felt to be clinical significant 
--exacerbation of chronic/intermittent pre-existing condition 
--New conditions detected or diagnosed 
--Signs, symptoms or clinical sequelae of a suspected interaction 
 
 
The University of Miami as the lead site will establish a Data Safety Monitoring Committee 
(DSMC) for the duration of this study in order to oversee the safety of study participants in the 
study. As part of the Clinical Operations Committee, the principal investigators and sub-
investigators will be having conference calls monthly and will review all data and procedures on 
a monthly basis. Each site PI will be ultimately responsible for monitoring the data and safety at 
that site and will provide continuous, close monitoring of adverse events.   In addition, the 
investigators and study coordinators will evaluate the progress of the study, including periodic 
assessments of data quality and timeliness, participant recruitment, accrual and retention, 
participant risk versus benefit, performance of the various sites, and other factors that can affect 
study outcome. They will also consider factors external to the study, such as scientific or 
therapeutic developments that may have an impact on the safety of the participants or the ethics 
of the study. 
 
L.  Financial Responsibilities of Subjects 
Takeda intends to supply Vortioxetine and matching placebo tablets and will finance all aspects 
of the study. The subjects will not bear responsibility for any costs associated with study 
participation. 
 
M. Subject Compensation 
Participants will receive $40 for each post screening, in-office visit they attend, to compensate 
for their time and inconvenience in participating in the trial. 
 
N. Site Monitoring 
The Miami lead coordinator will be responsible for ensuring uniformity of study procedures 
across the two sites. The University of Miami as the lead site will establish a Data Safety 
Monitoring Committee (DSMC) for the duration of this study in order to oversee the safety of 
study participants in the study. The Committee will consist of members of the University of 
Miami’s Department of Psychiatry and Behavioral Sciences. The committee will convene 
annually and will review the study activities by both study sites in a combined report. The Emory 
site will report their adverse events and all necessary events to the Miami site in a timely 
manner prior to the Miami site submitting to the Miami DSMC. Any communication, including 


20 
 
Updated January 22, 2019 
 
approval letters, from the DSMC will be distributed to the study sites and the study sponsor, as 
needed. The committee will also convene ad hoc as deemed necessary. 
 
Responsibilities of a DSMC: 
1.  The primary responsibility of the DSMC is to review interim analyses of outcome data and to 
recommend whether the study needs to be changed or terminated based on these analyses. 
 
2.  The DSMC reviews interim toxicity data. 
 
3.  The DSMC reviews major modifications to the study prior to their implementation (e.g. 
termination, dropping an arm based on toxicity results, increasing target sample size). 
 
 
 
IX. SOURCE OF RESEARCH MATERIALS  
 
Blood will be collected and analyzed for the screening tests and genetic analyses. Urine 
samples will be collected and analyzed with a toxicology screen. We will also collect physical 
records in the form of questionnaires, phone screenings, and psychiatric interviews. We will 
request access to patient’s medical records only for reasons related to patient safety. Patient 
charts will be kept in locked file cabinets in the offices of each study site. 
 
Biological specimens are linked to the individual patient only through a unique research code. 
All documents that directly reveal the patient’s identity, such as signed consent forms, are 
stored in charts that are marked on the outside only with the patient’s code number.  


21 
 
Updated January 22, 2019 
 
Appendix A. Drugs Allowed (Y) and Drugs not Allowed (N) for Study Periods I and II 
Drug Class 
Episodic Use 
Chronic Use 
Alpidem 
N 
N 
Amantadine 
N 
N 
Analgesics (except narcotics) 
Y 
N 
Anorexics 
N 
N 
Antianginal agents (except calcium channel 
blockers) 
Y 
Y 
Antiarrhythmics 
N 
N 
Anticholinergics 
Y 
Y 
Anticholinesterase inhibitors 
N 
N 
Anticonvulsants 
N 
N 
Antidepressants 
N 
N 
Antidiarrheal preparations 
Y 
N 
Antiemetics 
Y 
N 
Antihypertensives 
 
N 
Y 
Antipsychotics 
N 
N 
Benzodiazepines 
N 
N 
Buspirone 
N 
N 
Carbamazepine 
N 
N 
Chloral hydrate 
N 
N 
Clonidine 
N 
N 
Codeine 
Y 
N 
Cough/Cold preparations  
Y 
N 
Cyclosporine 
N 
N 
DHEA 
N 
N 
Ginko 
N 
N 
Ginseng 
N 
N 
Guanfacine 
N 
N 
Loperimide 
Y 
N 
Methyldopa 
N 
N 
Metyrosine 
N 
N 
Narcotics 
N 
N 
Phenytoin 
N 
N 
Pimozide 
N 
N 
Prazosin 
N 
N 
Psychostimulants 
N 
N 
Quinidine 
N 
N 
Reserpine 
N 
N 
Rifampin 
N 
N 
St. John’s Wort 
N 
N 
Steroids (oral) 
Y 
N 
Thyroid hormone supplementa 
N 
Y 
Tryptophan 
N 
N 
aSubjects needing supplements must be on a stable thyroid supplement dose for at least 2 
weeks prior to Visit 1.  
Subjects may use zolpidem, eszopiclone, zaleplon, or diphenhydramine up to 3 nights per week 
during the trial.  


22 
 
Updated January 22, 2019 
 
Appendix B. Description of Scales 
Brief Assessment of Cognition in Schizophrenia (BACS) 
The Brief Assessment of Cognition in Schizophrenia (BACS) is a clinician-rated instrument that 
measures cognitive function. The domains of cognitive function that are assessed by the BACS 
include verbal memory, working memory, motor speed, attention, executive functions and verbal 
fluency. It is designed to require about 30 min of testing time. BACS A will be performed at V1 
and Version B will be peformed at V9.  
 
UCSD Performance-Based Skills Assessment- Brief Version (UPSA-B)  
The UCSD Performance-Based Skills Assessment (UPSA-Brief) is a role-play test designed to 
evaluate a person’s functional capacity in two selected areas of basic living skills. The UPSA-
Brief (UPSA-B) was developed as an abbreviated alternative to the full version of the UPSA 
(Mausbach et al., 2007) and contains 2 of the original 5 subscales of the full UPSA (i.e., finance 
and communications subscales), which allows for shorter administration time (10–15 minutes) 
and reduced reliance on testing props. An UPSA-Brief Total Score (range = 0–100) is then 
obtained by summing the subscale scores.  
 
Clinical Global Impressions Improvement Scale (CGI-I) and Severity Scale (CGI-S) 
 
The CGI-I (Guy 1976) is a clinician-rated instrument that measures the degree of the 
patient’s improvement. It is a 7-point scale where 1 = very much improved; 4 = no change; and 
7 = very much worse. Baseline for assessing improvement for the CGI-I ratings will be the 
patient’s clinical status at Visit 3. The CGI-S is a similar clinician-rated instrument that measures 
the overall severity of the patient’s illness as compared to the overall study population. It is also 
a 7-point scale where 1= normal, not at all ill; 4 = moderately ill; and 7 = among the most 
extremely ill patients. 
 
Clinician-Administered PTSD Scale (CAPS-5)  
 
The CAPS is a structured clinical interview designed to assess the essential features of 
PTSD as defined by the DSM-5. The CAPS can be used to provide categorical ratings of 
diagnostic status as well as a quantitative index of symptom severity. The CAPS-5 Past-month 
version to be used in this study will include 22 items that assess the DSM-5 symptoms of PTSD 
during the screening visit and 20 items for all post screening visits, with each item scored from 
0-4. Scores reflect an integration of each symptom’s severity and frequency.  The total score 
range is 0-80. Higher scores reflect a greater degree of symptoms severity.  
 
 
Childhood Trauma Questionnaire (CTQ) 
 
The CTQ (Bernstein, 2003) is a 28-item self-report instrument that assesses childhood 
trauma in the following areas: physical, sexual and emotional abuse and physical and emotional 
neglect. Each item is rated on a scale of 1 (never true) to 5 (very often true). The 5 subscales 
are then totaled, with scores ranging from 5-25 for each traumatic category.  
 
Columbia Suicide Severity Rating Scale (CSSRS) 
 
The CSSRS (Posner et al., 2007) is a brief, standardized, clinician-administered 
measure that uniquely assesses the essential information (behavior, ideation, lethality and 
severity) and distinguishes between suicidal occurrences and non-suicidal self-injury.  The 
CSSRS is composed of 3 questions addressing suicidal behavior and 5 questions assessing the 
severity.  
Emory Treatment Resistance Interview for PTSD (E-TRIP) 
 
The E-TRIP (Dunlop et al. 2014) is a clinician administered measure that assesses the level 
of treatment resistance in an individual with PTSD by evaluating past treatments and their 


23 
 
Updated January 22, 2019 
 
effectiveness, symptom onset, and primary symptoms. All past treatments are recorded and 
evaluated through 8 questions to determine whether the past treatment received an adequate 
trial and to determine the efficacy of any past adequate trials.  
Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) 
 
The FIBSER (Wisniewski et al., 2006) is a self-report measure used to quantify the 
overall side effect burden a patient is experiencing over the previous 7 days, used in 
combination with the PRISE. It uses 3 global ratings on a 7-point Likert-type scale to estimate: 
1) the frequency of side effects; 2) the intensity of side effects the patient believes stem from the 
study treatment; and 3) the overall burden or degree of interference in day-to-day activities and 
functioning due to side effects.  The form takes less than 5 minutes to complete. 
 
Hollingshead Four Factor Index of Social Status 
      The Hollingshead is a self-report measure assessing the socio-economic status (SES) of the 
participant as well as the participant’s parents.  The participant indicates the level of education 
obtained by their father, mother, and self using a scale ranging from 1 (less than 7th grade 
completed) to 7 (Graduate degree); in addition, the occupation of each of the three people is 
also indicated along the scale, where 1 is equivalent to a farm or day laborer, and 9 is a senior 
manager or professional.  The raw scores obtained for each individual are weighted (and in the 
case of the parents, averaged), yielding total Hollingshead scores for the participant and the 
parents. 
 
Life Experiences Survey 
 The LES (Sarason et al, 1978) is a 43 item scale that lists numerous events which individuals 
may experience and call for social readjustment. Subjects are asked to indicate events which 
they have experienced during the previous reporting period and whether these events were 
perceived as positive or negative. Additionally, subjects are asked to rate on a 7-point scale the 
degree of impact these events have on their lives. From these responses it is possible to derive 
three life change scores: positive, negative, and total.  
 
Montgomery-Asberg Depression Rating Scale (MADRS)  
 
The MADRS (Montgomery and Asberg 1979) is a 10-item instrument used for the 
evaluation of depressive symptoms in adults and for the assessment of any changes to those 
symptoms. The estimated time to administer this scale is 20 minutes. Each of the 10 items is 
rated on a scale of 0 to 6, with differing descriptors for each item. These individual item scores 
are added together to form a total score, which can range between 0 and 60 points.   
 
Pittsburgh Sleep Quality Index (PSQI) 
 
The PSQI (Buysse et al., 1989) is composed of 19 self-rated questions and 5 questions 
rated by a bed partner (if available). The self-administered scale contains 15 multiple-choice 
items that inquire about frequency of sleep disturbances and subjective sleep quality and 4 
write-in items that inquire about typical bedtime, wake-up, sleep latency and sleep duration. The 
PSQI generates seven scores corresponding to sleep domains. Each component score ranges 
from 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a 
global score (Range 0-21). A PSQI score >5 is considered to be suggestive of significant sleep 
disturbance.  Most patients can complete the PSQI in 5-10 minutes.  
 
 
The PTSD Checklist for DSM-5 (PCL-5) 
 
The PCL-5 (Blevins et al. 2015) is a 20-item self-report measure that assesses the 20 
DSM-5 symptoms of PTSD. All items are answered on a 5 point scale from 0 (not at all) to 4 
(extremely). Scoring can be done to measure overall symptom severity or cluster symptom 


24 
 
Updated January 22, 2019 
 
severity by dividing the questions into the following groups: Cluster B (items 1-5), Cluster C 
(items 6-7), Cluster D (items 8-14), and Cluster E (items 15-20).  
 
The Patient Rated Inventory of Side Effects (PRISE) 
 
The PRISE (Rush et al., 2004) is a 7-item self-report assessment of side effects in the 
following symptom domains: gastrointestinal, heart, skin, nervous system, eyes/ears, 
genital/urinary, sleep, sexual functioning, and other.  Each domain has multiple symptoms which 
may be endorsed, and for each domain the patient rates whether or not the symptoms are 
tolerable or distressing. The time frame evaluated is the past 7 days. The form takes less than 5 
minutes for the patient to complete. 
 
Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) 
 
The QIDS (Rush et. al., 2003) is a 16-item self rated instrument designed to assess the 
severity of depressive symptoms present in the past seven days. The 16 items cover the nine 
symptom domains of major depression, and are rated on a scale of 0-3. Total score range from 
0 to 27, with ranges of 0-5 (normal), 6-10 (mild), 11-15(moderate), 16-20 (moderate to severe), 
and 21+ (severe). 
 
Sheehan Disability Scale (SDS)  
 
The SDS (Leon et al 1997) is a patient-rated instrument designed to assess the impact 
of perceived problems on work productivity, social/leisure activities, and family life/home 
responsibilities. The Sheehan Disability Scale consists of 3 questions rated on a visual analog 
scale (0 to 10). Higher scores represent greater impairment of activity. 
 
Mini International Neuropsychiatric Interview (MINI)  
 
The MINI is an abbreviated neuropsychiatric diagnostic interview.  It examines all of the 
conditions that are included as both inclusion and exclusion criteria in this trial.  The MINI 
generates diagnoses with high reliability and is easy to train raters to administer with high 
fidelity. We will use modules A, and C through P in this study to evaluate the inclusion and 
exclusion criteria. Module B for Suicidality will be excluded, as the CSSRS will be performed at 
screening and every study visit from randomization onward.  


25 
 
Updated January 22, 2019 
 
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