A Double-Blind, Placebo-Controlled Study of Vortioxetine in the Treatment of Binge Eating Disorder
Phase: PHASE2
Conditions: Binge Eating Disorder
Sponsor: University of Chicago

 
1 
 
IISR GUIDE (to be completed in English) 
STUDY INFORMATION 
Date:  April 19th, 2017 
Protocol Version:3.1 
Country(s) the study will be conducted 
in:  
United States 
Compound/Product: <Generic Drug 
Name> 
Vortioxetine 
Study Type :{ie, clinical interventional, 
clinical non-interventional, 
observational} 
Clinical interventional 
Study Title:  
A Double-Blind, Placebo-Controlled Study 
of Vortioxetine in the Treatment of Binge 
Eating Disorder. 
Indication:List therapeutic area: 
{Gastroenterology, Diabetes/Metabolism, 
Hypertension, Central Nervous System, 
Respiratory, Other} 
Central nervous system 
 
INVESTIGATOR CONTACT INFORMATION 
Number of Sites: (if there are sites 
multiple countries, name each country 
and number of sites in each country) 
1 – United States 
Principal Investigator Contact: 
 
Principal Investigator Name 
Jon Grant, JD, MPH, MD 
Organization Name 
University of Chicago 
Address 
5841 S. Maryland Avenue 
Telephone 
773-834-1325 
Fax 
773-834-6761 
E-mail address 
jongrant@uchicago.edu 
Co or Sub-Investigator(s) Contact (if 
applicable): 
 
Sub-Principal Investigator Name 
Royce Lee, MD 
Organization Name 
University of Chicago 
Address 
5841 S. Maryland Avenue 
Telephone 
773-834-5673 

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Fax 
E-mail address 
773-834-6761 
rlee@yoda.bsd.uchicago.edu 
Study Assistant(s)/Coordinator(s) 
Contact: 
 
Name 
(address, phone number, email) 
Eric Leppink 
5841 S. Maryland Avenue 
Tel: 773-834-3778 
Email: eleppink@yoda.bsd.uchicago.edu 
Institution’s Contracts or Grants office 
contact: 
 
Name 
(address, phone number, email) 
Ms. Janet Nelson  
Research Section Manager  
Department of Psychiatry and Behavioral 
Neuroscience 
The University of Chicago Biological 
Sciences 
5841 South Maryland Avenue  
Room B-354, MC 3077  
Chicago, Illinois 60637 
Tel: 773/834.1324 
Fax:  773/834.6761 
Email: jnelson@yoda.bsd.uchicago.edu 
Name and contact information of 
person completing this form: 
(name, address, phone number, email) 
Jon Grant, JD, MPH, MD 
University of Chicago 
5841 S. Maryland Avenue 
Tel: 773-834-1325 
Fax: 773-834-6761 
Email: jongrant@uchicago.edu 
 

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RESOURCES REQUESTED 
Resource Requested: {Drug, funding or 
drug & funding} 
Drug and Funding 
 
Estimated Study Budget: 
(Enter total here – including direct, indirect 
cost and institutional overhead)  
$401,776 
Do you have additional funding sources 
for this project? 
(If yes, please explain) 
No 
Dosage and Formulation: 
10mg tablets and 20mg tablets 
 
Estimated Total Drug Supply for Study:  
(number of tablets, capsules, vials)  
10mg po qday (or placebo) for the first 
week and 10mg po qday (or placebo) for 
the final taper week (this means 14 days 
total taking 10mg tablets for 80 subjects = 
1120 tablets [560 10-mg tablets and 560 
placebos]) and 
20mg po day for 11 weeks for 80 subjects 
(means 3080 tablets and 3080 placebos) 
Total # of Subjects:  
80 subjects (40 assigned to vortioxetine 
and 40 assigned to placebo) 

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Study Timeline: 
Planned StudyActivation: (month/year) 
Study activation is final regulatory authority 
approved protocol and fully executed 
contract  
 
September 1, 2015 
 
Study Activation to FirstPatient In (days, 
weeks, months):  
September 7, 2015 (within one week of 
study activation) 
First Patient In to Last Patient In  
(days, weeks, months) 
20 months 
Last Patient In to Last Patient Out 
(days,weeks, months) 
13 weeks 
Monthly enrollment rate:(days) 
4 subjects per month 
Treatment duration:(in months) 
3 months (12 weeks of treatment and 1 
week taper off) 
Number of Study Sites/Depots: (depots 
are defined as shipment facilities for sites) 
1 
Completion of Data Analysis: (# months) 
2 months 
Completion of Final Study 
Report/Manuscript: (month/year) 
October, 2017 
Publication Plan: (target journal, target 
conference) 
American Journal of Psychiatry 
ACNP 

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STUDY PROPOSAL 
Background 
Binge-eating disorder recently included in the DSM-5, is now recognized as a serious 
public health problem (Kessler et al., 2013). Binge-eating disorder is associated with 
obesity and psychiatric comorbidities, including depression, and may be predictive of 
metabolic syndrome (Mathes et al., 2009). Many patients are undertreated despite 
functional impairments and personal and social difficulties leading to a poor quality of 
life (Hudson et al., 2007). Binge-eating disorder is characterized by recurrent episodes 
of excessive food consumption accompanied by a sense of loss of control and 
psychological distress but without the inappropriate compensatory weight-loss 
behaviors of bulimia nervosa. Binge eating is seen in 23–46% of obese individuals 
seeking weight loss treatment and its severity relates to body mass index and predicts 
regain of lost weight.   
Current treatments for binge eating disorder are often inadequate. Cognitive behavioral 
therapy has been shown to reduce binge eating but finding trained psychologists is 
difficult. Lisdexamfetamine was recently approved by the FDA for binge eating disorder 
(McElroy et al., 2015) but it carries risk of addiction and diversion and so will likely not 
be prescribed by most family physicians or psychiatrists. Other currently available 
medications, used off-label for binge eating disorder, include anticonvulsants, which 
may reduce binge eating but are often poorly tolerated (McElroy et al., 2012). Therefore, 
additional clinical trials are needed to identify effective pharmacotherapies. 
Consuming food is necessary for life and involves brain regions that are quite ancient in 
evolutionary terms. The intestinal tract itself is almost like a “second brain” in that it 
contains vast amounts of neurons used to transmit and process sensory information; 
indeed the intestinal tract contains more of the neurotransmitter serotonin than the brain 
itself. Peripheral signals from the body (including from the intestinal tract, but also from 
the blood stream – e.g. glucose levels) are transmitted to brain regions such as the 
hypothalamic nuclei to help regulate appetite/hunger and maintain equilibrium. Another 
key aspect of circuitry involved in eating involves the brain reward system, including the 
nucleus accumbens, which is regulated by neurotransmitters such as dopamine, 
opioids, noradrenaline, and serotonin. In humans, but to a lesser degree in other 
animals, there is also top-down control from the prefrontal cortices, which serve to 
regulate our behaviors and suppress our tendencies to crave rewards, and allow us to 
flexibly adapt our behavior rather than get stuck in repetitive habits. Thus, binge-eating 
most likely involves dysregulation of all three above domains regulating behavior: the 
primitive ‘peripheral-hypothalamic’ feedback system, reward circuitry, and top-down 
control circuitry. On a neurochemical level, binge eating may be related to dysfunction 
of the serotonergic, dopamine, glutamatergic, and norepinephrine systems (David et al., 
2009; Johnson and Kenny, 2010; Latagliata et al., 2010).  Thus, a medication to target 
binge eating needs to be multi-modal in terms of its pharmacology. 
Rationale:  
Rationale for evaluating this compound in this population/target organ. Provide overall 
reason the study is being proposed, including past study results that may have led to a 
decision to propose this study. 
Vortioxetine has distinctive properties that make it a promising option for patients with 

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binge eating disorder. In vitro studies indicate that vortioxetine is an inhibitor of the 5-HT 
transporter and is a 5-HT1D, 5-HT3 and 5-HT7 receptor antagonist, a 5-HT1A receptor 
agonist and a 5-HT1B receptor partial agonist. Animal and in vitro studies indicate that 
several neurotransmitter systems may be impacted by vortioxetine, with the drug 
enhancing levels of 5-HT, noradrenaline, dopamine, acetylcholine and histamine in 
certain areas of the brain, as well as modulating γ-aminobutyric acid and glutamate 
neurotransmission (Gibb and Deeks, 2014). In addition, vortioxetine appears to improve 
executive functioning which in turn has the potential to improve top-down cognitive 
control (Mahableshwarkar et al., 2015). This suggests that vortioxetine could improve 
the symptoms of binge eating disorder by two complementary pathways. Finally, 
because of low rates of side effects, low likelihood of sexual dysfunction, and the 
potential for improved cognitive performance, vortioxetine should be a well-tolerated 
and in fact desired medication approach to binge eating. 
Given the serious public health problems associated with binge eating disorder, and the 
likelihood of success of vortioxetine in treating the disorder, the aim of the present study 
was to examine the efficacy and safety of vortioxetine vs placebo in adults with 
moderate to severe Binge eating disorder, as indicated by at least 3 binge eating days 
per week for the 2 weeks before the baseline visit 
Hypothesis:  
State hypothesis for study objectives. 
We hypothesize that vortioxetine will be more effective than placebo in reducing the 
number of binge eating days per week after 12 weeks of treatment when compared to 
baseline. 
Primary Aim/Objective: 
For clinical studies– eg, To evaluate the safety and efficacy of interventions with test 
medication on symptoms, signs and quality of life in patients with target condition. 
The aim of the present study is to examine the efficacy and safety of vortioxetine vs 
placebo in adults with moderate to severe Binge eating disorder, as indicated by at least 
3 binge eating days per week for the 2 weeks before the baseline visit.  
 
 
Secondary Aim/Objective:(if applicable) 
A secondary aim of the study is to examine the effects of vortioxetine vs placebo con 
overall functioning and quality of life. 
 
Primary Endpoint(s):  
The primary efficacy measure is the number of binge eating days per week based on 
clinician interview and confirmation of identified Binge eating episodes in self-reported 
Binge eating diaries. The primary efficacy end point is the change from baseline to week 
12 on the log-transformed scale (Binge eating days per week) + 1. 
 

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Secondary Endpoint(s): (if applicable) 
Secondary efficacy measures include the number of Binge eating episodes per week, 1-
week Binge eating episode response status, and 4-week cessation from Binge eating 
(free from Binge eating episodes). Other secondary endpoints include the change in 
weight/BMI between baseline and study endpoint, the Clinical Global Impressions–
Improvement Scale (CGI-I) rated global improvement of symptoms over time (results 
will be dichotomized as improved [CGI-I ratings of 1 or 2 very much/much improved] or 
not improved [CGI-I ratings of 3-7]). The self-reported Eating Inventory, also known as 
the Three-Factor Eating Questionnaire, the self-reported Binge Eating Scale, the Yale-
Brown Obsessive Compulsive Scale modified for Bing Eating (YBOCS-BE), the Quality 
of Life Inventory, the Hamilton Depression Rating Scale and the Hamilton Anxiety 
Rating Scale. 
 
Study Plan: 
Eighty individuals with binge eating disorder will be recruited for a double-blind, 
placebo-controlled pilot study in which Vortioxetine or placebo is administered in a 1:1 
fashion. All 80 subjects will have binge eating disorder per DSM-5 criteria for at least a 
year. Following baseline measures, subjects will receive Vortioxetine (10mg for one 
week and then 20mg thereafter) or inactive placebo. Participants will be seen one week 
after the baseline visit (assessing the 10mg dose), one week after that (assessing the 
20mg dose), and then every 2 weeks for the remainder of the 12-week period. At week 
12, subjects will start a 1-week taper off the medication and will be seen at week 13. 
Efficacy and safety measures will be performed at each visit.   
 
The study will be conducted in accordance with the International Conference on 
Harmonization Guideline for Good Clinical Practice, all local ethical and legal 
requirements, and the World Medical Assembly (Declaration of Helsinki). The study 
protocol and procedures will be approved by the University of Chicago’s institutional 
review board prior to any  recruitment. Written informed consent will be required for 
study participation. 
Study Population 
80 male and female outpatients aged 18-65 with a primary diagnosis of binge eating 
disorder. 
 
Subjects 
 
Inclusion criteria:  
1) Men and women age 18-65;  
2) Primary diagnosis of Binge eating disorder;  
 
3) At least 3 binge eating days per week for the 2 weeks before the baseline visit; 
4) Ability to understand and sign the consent form. 

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Exclusion criteria:  
1) Unstable medical illness based on history or clinically significant abnormalities 
on baseline physical examination (history of medical illness which is currently 
stable is allowed such as diabetes well controlled, treated hypothyroidism, 
hypertension, etc)  
2) Current pregnancy or lactation, or inadequate contraception in women of 
childbearing potential 
 
3) Subjects considered an immediate suicide risk based on the Columbia Suicide 
Severity rating Scale (C-SSRS) (www.cssrs.columbia.edu/docs)  
4) Past 12-month DSM-5 major psychiatric disorder (psychotic disorder, bipolar 
disorder, major depressive disorder) 
5) Past 6-month alcohol or substance use disorders 
6) Illegal substance use based on urine toxicology screening  
7) Initiation of psychological or weight-loss interventions within 3 months of 
screening  
8) Use of any other prescription psychotropic medication (except a PRN hypnotic 
or PRN benzodiazepine) 
9) Previous treatment with Vortioxetine 
10) Currently taking OTC weight loss medications. If willing to stop these 
medications, the participant will not be excluded based on this criterion. 
10) Cognitive impairment that interferes with the capacity to understand and self-
administer medication or provide written informed consent  
Stable medical conditions (‘stability’ based on history and clinical and physical 
examination) will not be reason for exclusion. 
Concomitant medications, that have no psychotropic qualities, will be allowed.  
Participants can be receiving psychotherapy if they have been in treatment for at least 3 
months prior to study entry.  
Concurrent formal weight loss interventions will not be allowed. 
 
Study Drug(s):  
Drugs, Dosages, and Regimens  
Baseline visit will consist of all evaluations. For subjects who meet inclusion/exclusion 
criteria, they will be randomized at the end of their baseline visit.  
All 80 subjects who are randomized to Vortioxetine (1:1 randomization) will receive 
10mg/day or placebo during the first week of the study (the first dose will be started the 
day immediately after the baseline visit).  All subjects will receive 10mg or placebo for 7 
days and then will be evaluated with all measures at week 1 (7 days after baseline). 

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At the week 1 visit, subjects will be started on 20mg/day (or remain on placebo) for the 
remainder of the study. They will return at week 2 (corresponding to having been on 
20mg/day for one week) and be evaluated with all measures. After week 2 visit, all 
subjects will be seen every two weeks for the remainder of the 12-week study period 
(this corresponds to visits at week 4, 6, 8, 10, and 12). Week 12 evaluation will be the 
study endpoint for purposes of efficacy. 
All visits are as outpatients and include in-person assessments. 
After study conclusion (at week 12), the dose will be tapered off during a 1-week follow-
up period. All subjects will return at week 13 for final safety evaluation only. 
Dosage changes/reductions will not be permitted. Because nausea, and possibly 
headache, are the most likely side effects anticipated at the 20mg dose, participants will 
be allowed the use of over-the-counter options such as Tylenol prn for headaches, or 
bismuth subsalicylate for nausea. The use of over-the-counter options will be tracked at 
each visit. If side effects continue and are intolerable, the participant will have to 
discontinue treatment. If that occurs, a detailed ‘final visit’ assessment will be conducted 
and the participant will be contacted two weeks following to assess side effect 
outcomes. 
Treatment Duration, Visit Frequency, and Procedures   
This is a 13-week study (12 weeks of acute treatment followed by a 1-week tapering 
phase). Subjects will be seen for a total of 9 study visits. All visits will include the full 
battery of assessments except week 13 which is only a safety evaluation.  
 
Randomization 
Participants are randomized (1:1) to receive placebo or vortioxetine by the 
investigational pharmacy at the University of Chicago. The study blind will be 
maintained by over-encapsulation, making placebo and active treatments appear 
identical in size, weight, shape, and color. Dosage changes and reductions will not 
permitted during the study and participants will be discontinued if they experienced 
intolerance. 
 
Baseline Visit Assessments  
Those subjects who appear appropriate for the study, based on telephone screening, 
will be invited for a baseline assessment. The duration of the baseline assessment will 
be approximately 2-3 hours and will include the following: Informed consent, 
Demographic data, Concomitant medications (no psychotropic medications will be 
allowed), Family history data, Medical evaluation including physical examination, EKG, 
weight, and vital signs, Urine pregnancy test (for women of childbearing years) and 
urine drug screen, and a psychiatric evaluation (using the following measures: MINI 
International Neuropsychiatric Interview (Sheehan et al., 1998); Neurocognitive 
assessments of impulsivity; Depressive symptoms will be rated with the 24-item 
Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1960); Anxiety symptoms will be 
assessed using the Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1959); 
Psychosocial functioning will be evaluated using the patient-rated version of the 

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Sheehan Disability Scale (SDS) (Sheehan, 1983); Quality of Life Inventory (QOLI) 
(Frisch et al., 1993); Compulsivity will be assessed using the Cambridge Chicago Trait 
Scale (Cambridge CHI-T Scale) (Grant & Chamberlain, 2016), the Lie Acceptability 
Scale (Goosie, 2014), The Narcissistic Personality Inventory (Raskin & Terry, 1988), 
The Social Desirability Scale (Crowne & Marlowe, 1960), and the Columbia Suicide 
Severity Rating Scale (C-SSRS)). If subjects consent, a blood sample will be collected 
to check for diabetes by measuring blood glucose levels. 
At baseline, binge eating will be assessed using the following: Binge eating diary, 
Clinical Global Impressions–Severity Scale, the Three-Factor Eating Questionnaire, 
Self-Reported Binge Eating Scale, and the Yale-Brown Obsessive Compulsive Scale 
modified for Binge Eating (YBOCS-BE). Baseline labs, as well as interim labs, may be 
ordered based on clinical and medical evaluation. 
Weight will be recorded using a calibrated scale with the participants not wearing shoes, 
rounded to the nearest 0.5 pounds, and converted to kilograms (to convert, multiply by 
0.45) for data reporting. 
Following-Up Visit Assessments 
All follow-up visits will include safety measures (adverse events, vital signs, C-SSRS), 
weight, binge eating measures, Clinical Global Impressions–Improvement Scale, and 
other psychiatric measures. 
Medical evaluation including physical examination will be performed again at study 
endpoint. 
At study completion, participants will be made aware of all available options for follow-
up care in the community. 
 
Safety Assessments 
Safety and tolerability will be assessed using spontaneously reported adverse events 
data, Columbia–Suicide Severity Rating Scale (C-SSRS) vital signs, and by evaluating 
premature termination. Safety assessments (C-SSRS, sitting blood pressure, heart rate, 
adverse effects, and concomitant medications) will be documented at each visit. 
Subjects who are an immediate suicide risk will be removed from the study and 
appropriate clinical intervention (e.g. hospitalization) will be arranged. Urine pregnancy 
tests will be performed at the initial visit. Subjects who have a positive urine pregnancy 
test will be excluded from the study. Assessment of side effects will be done at each 
visit. AEs will be coded by system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary for Regulatory Activities (Med- DRA) Version11.1. The incidences of 
all AEs will be summarized descriptively. 
 
Safety Reporting (please do not change the safety section of the template) 
Institution/Investigator is solely responsible for reporting all Adverse Events and Serious 
Adverse Events to regulatory authorities, investigators, IRBs or IECs and Takeda, as 
applicable, in accordance with national regulations in the countries where the study is 
conducted.  

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Regardless of expectedness or causality, all SAEs and pregnancy reports must also be 
reported in English by facsimile to Takeda Pharmacovigilance or designee: 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
All other serious (non-fatal/non-life threatening) events within 4 calendar 
days of the sponsor-investigator’s observation or awareness of the event 
 
Takeda Safety Reporting Contact Information 
 
Takeda requires that all information be communicated to Takeda’s 
Pharmacovigilance Department as outlined in the study contract. 
 
All reported adverse drug reactions and safety issues related to Takeda compound 
must be included in the final study report. 
Describe procedures for reporting Adverse Events and Serious Adverse Events. 
 
Reporting Adverse Events and Serious Adverse Events 
 Any unanticipated problem will be reported by telephone within 24 hours to 
Takeda.  A full written report will be sent to the Institutional Review Board (IRB) 
at the University of Chicago and Takeda within 10 working days of the event. 
 Any other adverse event will be summarized in the IRB and Takeda annual 
progress reports. 
 The PI will inform either Takeda or the IRB at the University of Chicago of actions 
taken by the other organization as a result of their continuing review. 
 
Definitions: 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a medicinal product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product 
whether or not it is related to the medicinal product.  This includes any newly occurring 
event, or a previous condition that has increased in severity or frequency since the 
administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
 
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious 
and unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. This 
includes adverse reactions which arise from: use of a medicinal product within the terms 
of the marketing authorization; use outside the terms of the marketing authorization, 

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including overdose, misuse, abuse and medication errors; and occupational exposure*. 
* This corresponds to the exposure to a medicinal product for human use as a result of 
one’s occupation, such as nurses who may handle products routinely in their 
occupational setting. 
 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
 Results in death. 
 Is life-threatening (refers to an AE in which the patient was at risk of death at 
the time of the event.  It does not refer to an event which hypothetically might 
have caused death if it were more severe). 
 Requires inpatient hospitalization or prolongation of an existing 
hospitalization . 
 Results in persistent or significant disability or incapacity. (Disability is 
defined as a substantial disruption of a person’s ability to conduct normal life 
functions). 
 Is a congenital anomaly/birth defect. 
 Is a medically important event.  This refers to an AE that may not result in 
death, be immediately life threatening, or require hospitalization, but may be 
considered serious when, based on appropriate medical judgment, may 
jeopardize the patient, require medical or surgical intervention to prevent 1 of the 
outcomes listed above, or involves suspected transmission via a medicinal 
product of an infectious agent.   Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting 
Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.   
 
An IMPORTANT MEDICAL EVENT also includes any event described in Takeda 
Medically Significant AE List below: 
Acute respiratory failure/acute respiratory distress 
syndrome 
Anaphylactic shock 
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia 
Acute renal failure 
Malignant hypertension 
Pulmonary hypertension 
Convulsive seizures 
Pulmonary fibrosis 
Agranulocytosis 
Confirmed or suspected endotoxin shock 
Aplastic anemia 
Confirmed or suspected transmission of infectious agent 
by a medicinal product 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Neuroleptic malignant syndrome/malignant hyperthermia 
Hepatic necrosis 
Spontaneous abortion/stillbirth and fetal death 
Acute liver failure 
  
 
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 

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synonymous.  The general term severe is often used to describe the intensity (severity) 
of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache).  This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually 
associated with events that pose a threat to a patient’s life or ability to function.  A 
severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  For 
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations. 
 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in 
this study, she must inform the investigator immediately and permanently discontinue 
study drug.  The sponsor-investigator must fax a completed Pregnancy Form to the 
Takeda Pharmacovigilance or designee immediately.  The pregnancy must be followed 
for the final pregnancy outcome (i.e., delivery, still birth, miscarriage)and Takeda 
Pharmacovigilance or designee will request this information from the sponsor-
investigator. Please refer to study contract for Takeda pharmacovigilance contact 
information. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a 
completed Pregnancy Form to the Takeda Pharmacovigilance or designee. Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. Please refer 
to study contract for Takeda pharmacovigilance contact information. 
 
Product Complaints and Medication Errors  
A product complaint is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug 
product.  Individuals who identify a potential product complaint situation should 
immediately contact Takeda and report the event.   
A medication error is a preventable event that involves an identifiable patient and that 
leads to inappropriate medication use, which may result in patient harm.  While 
overdoses and underdoses constitute medication errors, doses missed inadvertently by 
a patient do not.  Individuals who identify a potential medication error situation should 
immediately contact Takeda (see below) and report the event. 
 
Phone: 1-877-TAKEDA7 (1-877-825-3327) 
E-mail: medicalinformation@tpna.com 
FAX: 1-800-247-8860 
Product complaints and medication errors in and of themselves are not AEs.  If a 
product complaint or medication error results in an SAE, an SAE form should be 
completed and sent to Takeda Pharmacovigilance. 

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Statistical Analysis: 
Design/Randomization 
The study is a double-blind, placebo-controlled study. Participants will be randomized 
(1:1) to receive vortioxetine or placebo by the University of Chicago Investigational 
pharmacy in block sizes of eight, using computer-generated randomization with no 
clinical information.  
Efficacy Analysis 
For statistical analysis, the full-analysis set will be defined as all participants who took at 
least 1 dose of the study drug and had at least 1 post-baseline primary efficacy 
assessment. The safety-analysis set will be defined as all randomized participants who 
took at least 1 dose of the study drug and completed at least 1 follow-up safety 
assessment.  
We will compare the baseline characteristics of both groups using Fisher’s exact test for 
categorical variables and the t test for continuous variables. We will calculate 
adherence to treatment, based on the number of capsules returned at each visit, as the 
number of capsules taken divided by the number of days in the study × 100%. 
 
Primary endpoint analysis 
 
The primary outcome measure will be the change from baseline in frequency of binge 
eating episodes (binges/week), defined as the mean number of binges per week in 2-
week intervals. If the visit interval is less than 2 weeks, the mean number of binges 
per week will be estimated based on the number of binge days in the interval since the 
last visit.  
 
Between group comparisons will use a mixed-effects model for repeated measures, 
including fixed factors for treatment and visit, the interaction of treatment and visit, a 
covariate of the log-transformation ([baseline number of BE days per week] + 1), and the 
interaction of the baseline covariate and visit using visit as a categorical variable. 
Mixed-effects models for repeated measures estimates differences from placebo in the 
change from baseline of the log-transformed scale ([BE days per week] + 1) at week 12 
(primary end point). Based on previous research, log-transformation should reduce 
skewness (McElroy et al., 2007).  
 
Secondary endpoints analyses 
 
Secondary outcome measures will include the change from baseline in frequency of 
binge days (or mean days per week when the participant had one or more binges), 
weight, body mass index, global improvement, Three-Factor Eating Questionnaire, and 
Impact of Weight on Quality of Life.  
We will also analyze changes from baseline in log-transformed BE episodes, TFEQ 
factor scores, and YBOCS-BE total score to week 12 using the mixed-effects model for 
repeated measures. Pairwise χ2 statistical tests will evaluates dichotomized CGI-I 
ratings at week 12 for placebo vs treatment group. 
 

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Response categories will be tabulated based on the percentage decrease in frequency 
of binges from baseline to endpoint, which will defined as follows: complete=cessation 
of binges; marked=75% to <100% decrease; moderate=50% to <75% decrease; and 
none=<50% decrease.  
 
We will calculate effect sizes for the primary analysis of binges per week and weight 
using Cohen’s d. Finally, we will perform a Spearman rank correlation to assess the 
association between the change in frequency of binges from baseline to week 12 and 
the change in weight from baseline using completers. 
 
Safety analyses 
 
Adverse events will be collected at baseline visit. We will evaluate differences between 
groups in the incidence of treatment-emergent adverse events using Fisher’s exact test. 
Descriptive statistics will be used to evaluate changes in laboratory values, blood 
pressure and heart rate.  
 
Sample Size 
The sample size was calculated for the primary endpoint of change from baseline in 
binge eating days per week. For 80% power to compare the change from baseline in 
binge eating days per week on the log-transformed scale, assuming an effect size of 0.6 
to 0.7 between treatment group and the placebo group, 40 participants will needed in 
each treatment group based on a 2-group t test at the .05 level of significance. Given 
the particularly low rates of adverse events reported with Vortioxetine, as well as its 
more positive side effect profile in terms of sexual side effects compared to other 
antidepressants used in binge eating disorder, we expect few drop-outs from the study 
and therefore a smaller sample is needed.  
 
Feasibility 
Given our past experience and the pacing of the study, we feel the goal to enroll 80 
subjects in 20 months is practical and attainable. Given no-shows and rescheduling, 
and the time required for recruitment, telephone and in-person screening, and related 
issues inherent in any human study, the current goal of averaging at least 4 subjects 
per month is reasonable based on the fairly high prevalence of binge eating disorder, 
the number of subjects calling our outpatient clinic, and the large recruitment area of 
metropolitan Chicago. We will also employ our standard participant friendly provisions, 
including scheduling sessions in late afternoon/early evening and weekends, 
incorporating technological advances for contacts and reminders, and providing 
adequate compensation for participants’ time.  
 
 Data Management Plan: 
Data collected will consist of demographic data, subjective (self-report questionnaires, 
interview responses, ratings), and physiological (weight, heart rate and blood pressure). 
Access to individually identifiable private information about human subjects will be 
limited to Drs. Grant and Lee and their staff and will be collected specifically for the 
proposed research project. All collected data will be stored utilizing a 4-digit subject 
identification code, linked to separately stored identifying information via a coded log 

updated 19APR2017 
Page 17 of 19 
only available to the PIs.  
The gender ratio of adult binge eating disorder has been estimated to be approximately 
1:1  We will also make every effort to include a racially/ethnically diverse study 
population. The year 2010 Chicago census is 2,695,598 (US Census Bureau, 2011).  
The year 2010 Chicago race distribution is as follows: white 47.1%, African/African-
American 33.9%, Asian/Asian-American 6.2%, Native American 1.0%, or other race/not 
identified (11.8%). A total of 28.9% of the population also identified as Hispanic/Latino 
allowing for a diverse population sample (year 2010, US Census Bureau, Chicago, IL). 
We will make every effort to ensure that members of both genders and diverse racial, 
ethnic, and socioeconomic groups are adequately represented in the proposed study. 
The PI will implement the following procedures to ensure data integrity and the safety of 
participants during the study: A number of elements of the research plan are intended to 
minimize the risks of study participation. For example, the study exclusion criteria 
exclude patients who are experiencing clinically significant suicidality or require a higher 
level of care than outpatient. If this is indicated, the PI will evaluate them and refer them 
for immediate non-study treatment (for example, inpatient or additional pharmacologic 
treatment).  The PI will carefully monitor ratings on the Columbia Suicide Severity 
Rating Scale and the Hamilton Depression rating Scale; any participant endorsing 
suicidal thoughts, will be immediately evaluated by the PI and referred to a higher level 
of care if clinically indicated. The PI will evaluate patient safety at each visit and resolve 
any safety issues more frequently if necessary, as such issues arise.  The PI will also 
be responsible for preparing written summary reports of adverse events and will 
prepare a written report summarizing any decisions that are made pertaining to 
participant disposition. Data integrity and confidentiality will be safeguarded as 
discussed above in the Data Management and Statistical Analysis section under 
Methods. 
Timetable: Our research team has a history of excellent recruitment for research 
studies Our university clinic has active impulsivity and eating disorders clinics. The 
current goal of averaging at least 4 subjects per month is based on the number of calls 
we receive each month asking for treatment for this disorder. Generally the clinic 
received 10-15 calls per month for BED. Of these calls, we anticipate that approximately 
30% would meet criteria for study entry.  The study will recruit in month 1 of YR1 and 
end recruitment in month 20 of YR2. We estimate that immediately upon having IRB 
approval, we will embark on full data collection, including recruitment, telephone and in-
person screening. We estimate averaging 4 subjects per month. Recruitment will be 
until month 20 for 80 subjects.  
 
 
 

updated 19APR2017 
Page 18 of 19 
Ethical and Regulatory Considerations: 
Prior to initiating the study, the Investigator must obtain written approval to conduct the 
study from appropriate institutional ethical and/or regulatory committee and send a copy 
to Takeda (gma.externalresearch@takeda.com). Should changes to the study become 
necessary, copies of written approvals from appropriate institutional ethical and/or 
regulatory committees must be sent to Takeda (gma.externalresearch@takeda.com). 
If research involves human subjects, the Investigator must register the study with 
clinical trials.gov and other appropriate entities, as necessary. 
An IND or CTA may be required.  The investigator is responsible to work with regulatory 
authority to obtain or prove exemption 
References: 
Davis  CA, Levitan  RD, Reid  C,  et al. (2009). Dopamine for “wanting” and opioids for  
“liking”: a comparison of obese adults with and without binge eating. Obesity (Silver 
Spring). 17(6):1220-1225. 
 
Frisch MB, Cornell J, Villaneuva M (1993). Clinical validation of the Quality of Life 
Inventory: a measure of life satisfaction for use in treatment planning and outcome 
assessment. Psychol Assess 4:92-101. 
 
Gibb A, Deeks ED. (2014) Vortioxetine: first global approval. Drugs. 74(1):135-45. 
 
JE, Chamberlain SR. (2016) Cambridge Chicago Trait Scale (Cambridge CHIT-T Scale). 
Available Upon Request. 
ton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:50-55  
 
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-
62.  
 
Hudson  JI, Hiripi  E, Pope  HG  Jr, Kessler  RC. (2007) The prevalence and correlates 
of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 
61(3):348-358. 
 
Johnson  PM, Kenny  PJ. (2010). Dopamine D2 receptors in addiction-like reward 
dysfunction and compulsive eating in obese rats. Nat Neurosci 13(5):635-641. 
 
Kessler  RC, Berglund  PA, Chiu  WT,  et al. (2013). The prevalence and correlates of 
binge eating disorder in the World Health Organization World Mental Health Surveys. 
Biol Psychiatry. 73(9):904-914. 
 
Latagliata  EC, Patrono  E, Puglisi-Allegra  S, Ventura  R.  Food seeking in spite of 
harmful consequences is under prefrontal cortical noradrenergic control. BMC Neurosci. 
2010;11:15. doi:10.1186/1471-2202-11-15. 
 
Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A Randomized, 

updated 19APR2017 
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Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the 
Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder. 
Neuropsychopharmacology. 2015 Jul;40(8):2025-37 
 
Mathes  WF, Brownley  KA, Mo  X, Bulik  CM.  The biology of binge eating. Appetite. 
2009;52(3):545-553. 
 
McElroy  SL, Hudson  JI, Capece  JA, Beyers  K, Fisher  AC, Rosenthal  NR; 
Topiramate Binge Eating Disorder Research Group.  Topiramate for the treatment of 
binge eating disorder associated with obesity: a placebo-controlled study. Biol 
Psychiatry. 2007;61(9):1039-1048. 
 
McElroy  SL, Guerdjikova  AI, Mori  N, O’Melia  AM.  Pharmacological management of 
binge eating disorder: current and emerging treatment options. Ther Clin Risk Manag. 
2012;8:219-241. 
 
McElroy SL, Hudson JI, Mitchell JE, Wilfley D, Ferreira-Cornwell MC, Gao J, Wang J, 
Whitaker T, Jonas J, Gasior M. Efficacy and safety of lisdexamfetamine for treatment of 
adults with moderate to severe binge-eating disorder: a randomized clinical trial. JAMA 
Psychiatry. 2015 Mar;72(3):235-46 
 
Sheehan DV (1983). The Anxiety Disease. New York: Scribner's. 
 
Supporting documentation/tables and graphs: 
Timetable of visits is attached. 
Detailed Budget for all study related costs: 
Please refer to the budget template accompanied with the notification letter from 
Takeda and include with your protocol submission.