A Pilot Dose-Response Biomarker Study of Brexpiprazole Treatment in PTSD
Phase: PHASE2
Conditions: Post Traumatic Stress Disorder
Sponsor: Duke University

 
Version:  2/3/2017 
 
 
 
 
 
A Pilot Dose-Response Biomarker Study of Brexpiprazole Treatment in PTSD 
(Terminated) 
 
NCT02934932 
 
Document Date: February 3, 2017 
 

 
V er si o n:  2/ 3/ 2 0 1 7  
 
1. Title: A Pil ot D ose - Res p o nse Bi o mar k er St u d y of Bre x pi praz ole Treat m e nt i n P T S D  
2. P ur p ose of t he St u d y : T o deter mi ne if br e x pi praz ole treat me nt will be ass ociate d wit h a d ose- d e p e n de nt 
re d ucti o n i n resti n g p u pil dia meter as a reflecti o n of l oc us c oer ul e us ( L C) n ore pi ne p hri ne ( N E) n e ur o n tar get 
e n ga ge me nt i n a gr o u p of s u bjects wit h P T S D. T o deter mi ne if bre x pi praz ole t hera p y will als o be ass ociate d 
wit h a d ose- de p e n de nt de creas e i n t he cli nicia n a d mi nistere d P T S D scale ( C A P S - 5) sc ores.  T o deter mi ne if the 
pre -p ost treat me nt c ha n ge i n resti n g p u pil dia meter will be statisticall y si g nifica ntl y c orrelate d wit h t he p re- p ost 
c ha n ge i n C A P S -5 sc ore.  
 
3. Pri m ar y O bjecti ves:  
 
S pecific Ai m 1:  E val u ate t he effects of t w o  d os es of bre x pi praz ole o n l oc us c oer ule us ( L C) n ore pi n e p hri ne 
( N E) ne ur o n acti vit y.  
 
S pecific Ai m 2:  D eter mi ne t he effect of bre x pi praz ole t hera p y o n P T S D s y m pt o m se verit y.   
 
S pecific Ai m 3:  1) E v al uate w het her de pr essi o n se verit y i m pr o ves wit h treat me nt a n d assess h o w t his relates t o 
P T S D res p o nse; 2) S pecificall y e val uat e t he de gree t o w hic h treat me nt i m pr o ves ni g ht mares; 3) E v al uate t he 
effects of treat me nt o n slee p dist ur ba nce. 
 
4. B ac k gr o u n d & Si g nific a nce: P ost- tra u matic stress dis or der ( P T S D) a d v ersel y affects a n i n di vi d ual’s 
e m oti o nal a n d p h ysical well -bei n g, q ualit y of life, a n d f u ncti o nal a bilities, a n d i ncreases s uici de ris k ( Fi nle y et 
al., 2 0 1 5).  T he lifeti me pre vale n ce of P T S D varies s u bsta ntiall y d e pe n di n g o n t he p o p ulati o n ( militar y, p olice, 
ge n eral a d ult p o p ulati o n), b ut lifeti me esti mates are re p ort e d t o be at ar o u n d 1 0 % ( 7. 8 % i n t he U nite d States, 
9. 2 % i n Ca na da a n d 1 2. 2 % i n A ustralia).  H y p er -ar o usal is e xtre mel y c o m m o n i n i n di vi d uals wit h P T S D a n d is 
c o nsi dere d a hall mar k of t he dis or der.  L oc us c oer ule us ( L C) n ore pi ne p hri ne ( N E) n e ur o n d ysre g ulati o n is 
belie ve d t o c o ntri b ute t o d ysf u n cti o nal ar o usal i n patie nts wit h P T S D a n d is a ne ur o bi ol o gical tar get of 
i nterest.  F or i nsta n ce, L C N E re u pta ke tr a ns p orter la beli n g usi n g P E T sca ns c orres p o n d wit h a n xi o us-ar o usal 
s y m pt o ms s uc h as h y per vi gila nce i n s u bjects wit h P T S D.  Bre x pi praz ole is of i nterest as a treat me nt f or 
re d uci n g d ysf u n cti o nal ar o usal i n P T S D patie nts base d o n its rece pt or bi n di n g pr ofile w hic h i ncl u des 5-H T 1 A 
rece pt or acti vati o n a n d 5- H T 2 rece pt or a nta g o nis m. T he brai nste m circuit w hic h i n v ol ves 5- H T ne ur o n 
re g ulatio n of L C N E ne ur o n acti vit y is c o m ple x a n d i ncl u des 1) acti vati o n of 5-H T 1 A rece pt ors t hat decrease  5-
H T ne ur o n acti vit y me di ate d 5- H T r eleas e a n d 2) 5- H T 2 rece pt or a nta g o nis m o n G A B A er gic pr oj ecti o n ne ur o ns 
t o t he L C, w hic h 3) re n d ers a n i ncr eas e i n 2-a ut orece pt or me diate d re g ul ati o n of N E ne ur o ns ( Bli er a n d Sza b o, 
2 0 0 5).  H o we v er, t he eff ects of t his  a ge nt o n patie nts wit h P T S D ha ve n ot bee n e v al uate d.  A fact or 
c o nf o u n di n g p urs ui n g a st u d y of t he eff ects of bre x pi praz ole i n patie nts wit h P T S D is precli nical data w hic h 
s u g gest t hat t her e mi g ht be a n i ncr ease i n L C f u n cti o n wit h bre x pi praz ole at least wit h s o me d oses s u g gesti n g 
t hat t his a ge nt ma y h a ve i m p orta nt d ose- de pe n d e nt effects o n L C f u n cti o n w hic h, i n t ur n, s u g gests t hat t he 
t hera pe utic eff ects i n patie nts wit h P T S D mi g ht be hi g hl y d ose-d e pe n de nt.  H o we ver, w het her t here is a d ose-
de pe n de n ce t o t he effects o n L C f u n cti o n i n h u ma ns has yet t o b e deter mi n e d.   It is critical t hat t he u ncertai nt y 
as t o t he a p pr o priat e d osa ge b e a d dr esse d b ef ore carr yi n g o ut siza ble st u dies of t he effects of bre x pi praz ole o n 
patie nts wit h P T S D t o pre ve nt s uc h st u dies fr o m b ei n g f utile.   I n or der t o a d dress t his u ncertai nt y w e pr o p ose 
t o carr y o ut a bi o mar ker st u d y t o esta blis h t he effects of bre x pi praz ole o n L C N E acti vit y as a f u ncti o n of d ose 
w here p u pill o metr y will be e m pl o ye d as a n i n dicat or of L C N E acti vit y.  
 
P u pill o metr y is a well -esta blis he d, n o n-i n vasi ve, i ne x pe nsi ve i n dicat or of L C N E acti vit y.  L C N E ne ur o n 
acti vit y i ncr eases p u pil si ze t hr o u g h acti vati o n of E di n ger- West p hal ne ur o ns w hic h pr oject t o s y m p at hetic 
ga n glia c o ntr olli n g p u pil dia meter.  Rece nt w or k h as vali date d p u pill o metr y as a meas ure of L C N E acti vit y b y 
si m ulta ne o usl y o btai ni n g E E G, f M RI, a n d p u pill o metric data .  F urt her m ore, t he utilit y of p u pill o metr y as a 

 
Version:  2/3/2017 
 
biomarker of PTSD is suggested by a recent study which found increased pupil responses to threatening pictures 
in subjects with PTSD compared to those without PTSD.   Thus, we propose to carry out a study employing 
pupillometry as a means of establishing the dose-response function of brexpiprazole on a key target of PTSD 
therapy as a means of addressing the uncertainty in dose generated by preclinical work indicating that, at least at 
some dosages, brexpiprazole may increase LC NE activity.  We will also collect preliminary data on the dose-
response effects of brexpiprazole on the clinical symptomatology of PTSD.  Overall, this study is intended to 
provide a basis for determining the potential of brexpiprazole to be an effective therapy for PTSD.  If 
brexpiprazole appears to be a promising therapy for this condition, our study will also serve as a basis for 
indicating how best to carry out clinical trials.  
  
The broad impetus for this effort is the urgent need to develop improved therapeutics for PTSD.  Treatments for 
this condition are extremely limited and none have demonstrated robust efficacy.   It is hoped that the proposed 
study will serve as a key step towards evaluating whether brexpiprazole could be a much needed efficacious 
treatment for the many patients suffering from PTSD.  
 
5. Design & Procedures 
 
5.1 Subject recruitment: Participants will be recruited by running approved study specific advertisements in 
local newspapers and posting study flyers.in the local area.  We plan to consent up to 100 subjects to recruit 36 
study qualifiers.  Single site, double-blind, within-subjects, cross-over, dose-response study of brexpiprazole in 
subjects with PTSD to evaluate the effects of brexpiprazole dose on LC NE neuron activity using pupillometry 
and CAPS-5 ratings.  
 
Inclusion/Exclusion Participants will be 18-65 years of age.  All subjects will be evaluated by physical 
examination, ECG, standard blood chemistry, hematologic labs, toxicology testing, Compliance Panel and 
urinalysis at baseline and end of study. Results of these studies must demonstrate a lack of clinically significant 
abnormalities prior to enrollment.  If results are outside of the normal reference range the study physician will 
be consulted to assess if clinically significant. Subjects will need to satisfy DSM-5 criteria for PTSD and 
receive a CAPS-5 score of 33 or greater on testing for study enrollment. Subjects will need to be free of 
psychotropic medications or treatments that could impact results of this study as deemed by the PI for at least 1 
week.  If the subject’s primary psychiatrist or treating primary care physician are providing the subject with 
psychotropic medications they will be notified and a discussion about tapering current psychotropic medications 
prior to study enrollment will occur.   
Exclusion Criteria.  
The exclusion criteria is in accordance with the package insert for brexpiprazole and can be located at 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205422s000lbl.pdf  
1) Subjects will be excluded if they have significant medical or neurologic conditions (other than mild to 
moderate TBI), specifically seizures, or movement disorders,  
2) have substance abuse within 12 months of study enrollment,  substance dependence within past three months, 
per DSM-5 criteria (excluding caffeine and nicotine). The absence of substance use will be determined by self-
report and confirmed by the results of urine toxicology at screening.   
3) Women who are pregnant, breast-feeding, or planning to become pregnant while enrolled in this study will 
also be excluded.  

 
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4) Subjects with a history of severe drug allergy or hypersensitivity, or known hypersensitivity to the 
Brexpiprazole or its ingredients.   
5) The subject has a history of tardive dyskinesia.  
6) The subject has clinically significant extrapyramidal symptoms (EPS) including akathisia.  
7) The subject has epilepsy or a history of seizures, except for a single seizure episode (e.g., childhood febrile 
seizure, post traumatic, or alcohol withdrawal).  
8) The subject has chronic, uncontrolled, or unstable clinically relevant medical conditions  Including:  
-Uncontrolled hypertension defined as blood pressure greater than 180/90 
-Hypotension defined as a blood pressure less than 90/60 
-Moderate to severe hepatic impairment (Child-Pugh score ≥7) 
-Moderate, Severe or End-Stage Renal Impairment (CrCL <60ml/min) 
-Known CYP2DG Poor Metabolizers 
-Heart failure NYHA Class III or IV 
-Diabetes mellitus or HbA1c greater than 5.7% (which defines pre-diabetes) 
-Hypertriglyceridemia defined as triglycerides greater than 200mg/dL 
-Low white blood cell count (below lower range of normal) 
-History of leukopenia or neutropenia 
-Arrhythmia with heart rate greater than 100bpm 
-Myocardial infarction in the past 6 months 
-Cerebrovascular accident in the past 6 months   
-Recurrent syncope 
-Seizure disorder 
-Currently receiving treatment for malignancy 
-QTc interval of greater than 450ms on electrocardiogram  
9) The subject has a neurodegenerative disorder (Alzheimer disease, Parkinson’s disease, multiple sclerosis, 
Huntington disease, etc.). 

 
Version:  2/3/2017 
 
 
 
5.2 Study Components: There are 3 treatments (placebo, 2mg, 4mg), each for six weeks (±3 days), separated 
by a 1 week (±3 days) wash-out period. Each subject will be randomly assigned to three of the treatments. 
Subjects will undergo three treatments and receive 42 doses of study drug during each of the three treatment 
phases. Each treatment phase lasts for 6 weeks (±3 days). For each subject, they will receive a total of 126 doses 
of study drug. For the brexpiprazole treatment arms, we will begin with 1mg PO q Day on Days 1 through 4 and 
titrate to 2mg q Day on Days 5 -7 (i.e., the 2mg brexpiprazole group will continue on 2mg daily for the 
remainder of the 6 weeks), and then to 4mg/day on Day 8 (i.e., this will be for the 4mg brexpiprazole group 
who will continue on this dose for the remainder of the 6 weeks). Irrespective of the treatment group, including 
placebo, subjects will be assigned three medication bottles indicated to be taken during days 1-4, days 5-7, and 
days 8 and up to ensure blinding during the three treatment arms.  Otsuka will be providing the study 
medication as a bulk supply and each medication dose and placebo will look identical to each other.  The study 
drug will be stored in a double locked medicine cabinet in the Duke Sleep Lab (Duke Clinic, 5th floor Red 
Zone).  Dr. Szabo will be creating a randomization algorithm that will be given to an unblinded study staff 
member to use during randomizations.  The unblinded study member will prepare the study drug to be 
dispensed to the subjects.   
 
Subjects will be screened and will undergo pupil measures with rating scales on Day 1. Subject must be free of 
all psychotropic medications for one week before Day 1 assessment, except that prior fluoxetine treatment will 
require 4 weeks of abstinence, and MAOIs will require 2 weeks of abstinence. They will be randomized to 
study drug and issued six weeks of study medication on Day 1 to take home. A phone call will then occur for 
safety assessment and medication adherence at every week. They will present back to the study site on Day 42 
and undergo pupil measures with rating scales. They will then undergo a one week washout 
period. On Day 49 they will then be given another study drug to take home with rating scales and pupil 
measures obtained that day. A phone call will then occur for safety assessment and medication adherence at 
every week. They will present back to the study site on Day 91 and undergo pupil measures with rating scales. 
They will then undergo a one week washout period. On Day 98 they will then be given another study drug 
to take home with rating scales and pupil measures obtained that day. A phone call will then occur for safety 
assessment and medication adherence at every week. They will present back to the study site on Day 140 and 
undergo pupil measures with rating scales. No more study medication will be provide on Day 140 and a final 
visit will be scheduled for on Day 147, one week later, for and end of study interview with labs and 
physical exam. At each visit, other than the final visit, subjects will complete the CAPS-5, LEC-5, MADRS, 
Insomnia Severity Index, Columbia Suicide Severity Rating Scale, and Clinician Assessment for Adverse 
Effects. 
   
5.3 Pupillometry Procedure. We will employ Tobii Tracker Eyeglasses 2 (Stockholm, Sweden) fully mobile 
Eye-tracking Glasses, a non-invasive system designed to be used like a common pair of glasses (weight 75 g) in 
a wide range of environments, both indoors and outdoors. Pupil diameter will be recorded continuously from 
the each eye at a sampling rate of 50 - 100 Hz via glasses on the subject’s face in a darkened room.   
 
Primary Hypothesis:  Brexpiprazole treatment will be associated with dose-dependent reduction in resting 
pupil diameter as a reflection of LC NE neuron target engagement in a group of subjects with PTSD. 
 
Secondary Hypothesis:  Brexpiprazole therapy will be associated with a dose-dependent decrease in CAPS-5 
scores  
 
Tertiary Hypothesis: The pre-post treatment change in resting pupil diameter will be statistically significantly 
correlated with the pre-post change in CAPS-5 score.  

 
Version:  2/3/2017 
 
 
5.4  Sample Size Justification and Power Analysis: We chose an effect size of 0.3 as 6/8 prior trials of the 
effects of atypical antipsychotic medications on PTSD using the CAPS-5 had effect sizes larger than this and 
we felt that an effect of this size or larger would be clinically relevant (Liu et al., 2014). The effect-size 
calculation was based on the Cohen's D measure of effect size (mean difference divided by overall standard 
deviation). We are enrolling a sufficient number of subjects in a 3-way cross-over design study so that we could 
both detect this effect AND be able to detect the pupil size effect with at least 80% power. In order to address 
the issue of powering for 2 outcome measures we will employ Bonferoni correction to be conservative and to 
achieve 80% power to detect BOTH the CAPS-5 and pupil size effects at the alpha=0.025 level of significance 
(Bonferoni correction for 2 tests dictates that we divide the alpha=0.05 level by 2). We calculated that with 36 
subjects we could achieve greater than 80% power to detect effects with BOTH the CAPS-5 and pupil measure 
at the alpha=0.025 level in a one-tailed test of significance (we are only interested in whether brexpiprazole is 
associated with lower CAPS-5 scores and pupil diameters than placebo and will only test this hypothesis and 
will not test whether placebo has a greater therapeutic effect than brexpiprazole). This calculation assumed an 
effect size of 0.3 for both the CAPS-5 score and for the pupil measure. It should be noted that the assumption of 
an effect size of 0.3 for the pupil measure is highly conservative. We can estimate the effect size for the 
between group differences in pupil size based on our pilot work where we compared pupil size in a group of 
patients with depression and anxiety (n=5) and healthy controls (n=5) using the pupillometric measure to be 
used in the proposed study. We hypothesize that the difference in locus coeruleus norepinephrine activity 
(which determines pupil size in this test) in PTSD subjects will be comparable to or larger than the differences 
in locus coeruleus activity in patients with depression associated anxiety. The basis for this hypothesis is that 
the patients we studied likely have less severe arousal-system dysfunction than PTSD patients who manifest 
symptoms of hypervigilance which is likely to activate locus coeruleus to a comparable or greater degree and be 
reflected in pupillometry. The effect size for the difference in resting pupil diameter in our anxious/depressed 
patients and healthy controls is 2.98 based on Cohen's D. However, it is appreciated that this is derived from a 
very small sample of subjects who are not the identical patient population that we will be studying so we 
assumed that it was most conservative to assume a lower effect size than 2.98. As a result, we assume an effect 
size of 0.3 which is likely quite conservative for power with respect to the pupil size measure. Thus, we propose 
to enroll 36 subjects in our study and believe that this is conservative for having more than 80% to detect effect 
sizes of 0.3 for both the CAPS-5 and pupil measures with an alpha=0.025, which is adjusted from 0.05 for 
detecting effects on 2 primary outcomes at the 0.05 level, in one-tailed tests of significance. 
 
6. Subject Consent and Compensation: Those who appear to meet basic study criteria will be asked to the 
Duke Sleep Lab where they will be provided a full description of the study, asked to read and sign the consent 
form, and undergo a qualifying interview. The reviewed information will be obtained from the subject via face-
to-face interview or over the phone and will be restricted to answers to questions intended to determine whether 
subjects meet entry criteria.  All information obtained during this review will be handled confidentially.  
Subjects will be compensated $115 for each of the 8 visits for a total of $920 for partaking in the study. 
6.1 Consent Process: Written Informed Consent will be obtained from each subject prior to enrollment into the 
study.  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.  Once a subject has been consented, the 
screening process will begin. Verification consists of a detailed interview with the patient to obtain history of 
illness and treatments. When possible, and with the subjects permission, verification may be supplemented by a 
phone interview with the subject’s attending physician/psychiatrist and a full review of the subject’s medical 
records of present history, including pharmacy records. The Investigator will retain the original copy of the 
Informed Consent Form signed by the patient, a duplicate will be provided to the patient and a document signed 
by the Investigator confirming receipt of patient consent will be returned to the Sponsor. Only the consent form 
approved by the IRB will be used. 

 
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6.2 Subject’s Capacity to Give Legally Effective Consent: Potential subjects who do not have the capacity to 
give legally effective consent will not be included in this study.   
6.3 Risk/Benefit Assessment: Risks:  Brexpiprazole may cause some, all, or none of the side-effects listed 
below. In the previous studies in patients with depression or other medical conditions, the reported side effects 
expected to occur during treatment with brexpiprazole are listed below: 
• Low blood pressure, or dizziness, or loss of consciousness when standing up 
• Fast heartbeat. 
• Constipation, diarrhea, indigestion, dry mouth, nausea, vomiting 
• Dehydration 
• Exhaustion, irritability, difficulty sleeping, abnormal dreams 
• Allergic reaction 
• Stuffy or runny nose, upper respiratory tract infection like common cold or bronchitis 
• Abnormal liver function test (a blood measurement for the state of the liver), blood creatine phosphokinase 
increase (a blood test to diagnose for example muscular damage).  
• Increased appetite, weight gain 
• Elevated blood sugar or development of diabetes mellitus 
• Increase in blood cholesterol levels 
• Back pain  
• Restlessness, seizure, dizziness, movement disturbances, headache, sedation, drowsiness or fatigue 
trembling. 
• Seizures 
• Agitation, anxiety  
 
For some patients, who have not responded to treatment with brexpiprazole, have experienced a re-occurrence 
of disease symptoms have been reported such as symptoms associated with schizophrenia, psychotic disorder, 
depression or suicidal thoughts. 
Although a placebo has no known risk, it may be associated with higher rates of suicidal thoughts.  Risks 
associated with drawing blood from the arm may include momentary discomfort and/or bruising.  Infection, 
excess bleeding, clotting, or fainting are also possible, although unlikely.  There is also a risk that psychiatric 
symptoms may worsen during the study, particularly during the period where individuals may be tapering off of 
medications.   
6.4 SOP for Increased Suicidality 
Any patient meeting clinical worsening criteria per interviews will be seen for a safety assessment by a study 
team psychiatrist experienced in working with patients with PTSD. If the patient is determined to be a 
significant suicide risk, one of the following three courses of action will be pursued: 
A. Patients who contract for safety with the study physician and will be observed 24 hours/day by a responsible 
family member will be sent home and monitored by phone or added office visits as determined by the study 
physician. 

 
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B.  Patients who are unwilling or unable to contract for safety will be accompanied by a staff member to the 
Duke Emergency Department.  
C.  Patients who are unwilling or unable to contract for safety and are unwilling to go to the Duke Emergency 
Department will be involuntarily committed via the Duke Medical Center protocol for Involuntary 
Commitment: 
1. MD or appointed staff member remains with patient at all times 
2. Staff member contacts Katherine Fisher 970-0010 or Tawanda Eley 684-0100 , Notary to begin process 
of IC forms 
3. Staff member notifies Duke Public Safety., 681-2444 
4.  Staff member notifies Duke Emergency Department, 684-2413 
5. Staff member collects patient demographics for police report custody order papers 
6. MD does custody order papers 
7. Petition notarized by Katherine Fisher or Tawanda Eley 
8. Police officer escorts patient to Duke Emergency Department 
9. MD to put report in CRMI database 
The complete SOP for Increased Suicidality can be found in the Duke Sleep Center SOP book. 
 
6.5 Safety Evaluations: Adverse effects will be assessed at every visit by study physician interview. Between 
visits, subjects will be called and a safety assessment will be carried out by the study coordinator during the 
call. The regular safety assessment calls will include assessment of suicidality, using the Columbia Suicide 
Severity Rating Scale items 4/5.  If any adverse effects are identified, this will be discussed with a study 
physician and appropriate steps will be taken. 
 
Benefits:  Brexpiprazole has shown benefit in patients with schizophrenia and depression and it may also help 
PTSD symptoms.  An improvement in PTSD symptoms, depression symptoms or in both may occur. The 
information learned from this study may benefit other patients with PTSD in the future. 
6.6 Reproductive Risks: Although there is no human data available, caution should be advised in 3rd trimester 
pregnancies.  Risk of neonatal extrapyramidal and withdrawal symptoms based on human data with other 
antipsychotics are known, there is currently no known risk of fetal harm based on animal data at up to 73x and 
143x the maximum recommended human dose.   
6.7 Costs to the Subject: There will be no charge to subjects for any of the tests, procedures, or professional 
services related to this study. 
6.8 Subject Recruitment: Study participants will be recruited via bulletin/poster advertisements. 
7. Privacy, Data Storage & Confidentiality: 
1. Serious adverse events (SAEs) and other safety information will be collected and reported to the relevant 
government authority in accordance with the current Code of Federal Regulations 
2. Safety Information is defined as, any information from any source containing information such as:  
• Adverse event or suspicion thereof 
• Lack of efficacy 
• Overdose/incorrect dosage (accidental or intentional) 
• Abuse/misuse (e.g., patients sharing medication) even without resulting adverse reaction 

 
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• Accidental exposure (e.g., child takes parent’s medication) 
• Medication error 
• Withdrawal reactions 
• Disease progression/exacerbation of existing disease 
• Drug-drug/Drug-food interaction 
• Reports of unexpected benefit 
• Exposure to drug during pregnancy, where the embryo or fetus may have been exposed to medicinal 
products (either through maternal exposure or transmission of a medicinal product via semen following 
paternal exposure). 
• Exposure to drug during lactation (including uneventful) 
• Suspected counterfeit product 
• Suspected transfer of infectious disease/agent by the medicinal product concerned. 
• Product complaint report (any deficiencies related to the identity, quality, labeling, durability, reliability, 
efficacy, performance of a medicinal product, suspected counterfeit product) 
• Pediatric use (if not an approved use) 
• Occupational exposure 
• Off-label use (if not part of the study design)  
 
3. SAEs and safety information will be collected from first use of an Otsuka product until 28 days after 
discontinuation. 
 
8. Privacy, Data Storage & Confidentiality: Study records identifying subjects will be kept confidential by law. 
Federal Privacy Regulations provide safeguards for privacy, security, and authorized access. Subjects will not be 
identified by name, social security number, address, telephone number, or any other direct personal identifier in 
study records disclosed outside of Duke University Health System (DUHS), except when required by law. For 
records disclosed outside of DUHS, subjects will be assigned a unique code number and key code kept in a locked 
file in Dr. Szabo's office.  Study records may be reviewed to meet federal or state regulations. Reviewers may 
include representatives of the FDA and representatives of DUHS IRB.  If subject records are reviewed by any of 
these groups, they may also need to review the entire medical record. Study results will be retained in research 
records and kept indefinitely.