Clinical trial NCT02466685
Conditions: Bipolar Disorder
Keywords: Bipolar Depression Cognition Cognitive
Sponsor: Herbert Meltzer
Start date: 2015-09-01; Completion date: 2022-12-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goals of this study are to evaluate the efficacy of JNJ-18038683 in an 8 week trial to ameliorate the cognitive deficit and reduce residual depressive symptoms in 60 stable bipolar outpatients receiving treatment for depression. JNJ-18038683 will be studied and compared with placebo as adjunctive treatment to standard pharmacologic treatment for bipolar disorder.

Detailed description:
Most, but not all, patients with bipolar disorder (BPD) have clinically significant cognitive impairment. Impairment is present in both the manic and depressed phases of BPD, as well as in euthymic periods. The percentage of BPD patients with cognitive impairment (CIBD) varies among studies, with 40-60% representing the best estimate. The weight of the evidence supports no overall difference in the type and severity of cognitive impairment in any phase of BPD, i.e. it is a stable trait feature of BPD, albeit variable from one patient to another. The most commonly affected cognitive domains are speed of processing, declarative memory, attention and working memory. Although CIBD is milder in severity than the cognitive impairment associated with schizophrenia (CIAS), on average, as in schizophrenia, CIBD has a major impact on function and quality of life in most patients, particularly because the greater preservation of function of BPD enables them to engage in activities which are more dependent on intact cognitive function. Thus, it is highly likely that improvement in CIBD will have valuable clinical benefit, especially with regard to quality of life measures. It is reasonable to predict that treatments effective to improve CIBD could also be beneficial for CIAS. Efficacy for cognitive impairment is likely to be greater in BPD than schizophrenia, because the baseline severity is milder in the former. Despite this strong rationale for targeting CIBD, there has been minimal focus on clinical trials to improve CIBD, perhaps because so many resources have been devoted to the effort to treat CIAS, but lack of appreciation of the severity of CIBD and its importance as a determinant of functional outcome in BPD may be the most important factors.

In a recent study of CIBD, using the MATRICS Consensus Cognitive Battery (MCCB), impairment was found in both treatment resistant BP I and II depressed inpatients within all MCCB domains. The greatest impairment was evident in speed of processing, declarative memory and attention. The impairment was numerically greater in BP I than BP II patients but the difference was not significant. Compared to normal controls, the deficits, in BP 1 patients, in speed of processing was 1.2SD, in attention, 1.0 SD, and in verbal learning, 1.8 SD. The least affected domain was visual learning, with a mean deficit of 0.8SD compared to normal controls. The mean composite score deficit was 1.25 SD. Medication for BPD, particularly mood stabilizers, may adversely affect some domains of cognition in BPD. However, antidepressant medications have not been found to affect the severity of cognitive impairment in major depression or BPD.

Based on the pre-clinical, pro-cognitive effects of 5-HT7 antagonism in our laboratory, along with the reported pre-clinical antidepressant effects of JNJ-18038683, we propose to conduct a randomized, placebo- controlled parallel, design study to assess the effects of JNJ-18038683 on multiple domains of cognition and mood symptoms. Since our preclinical studies show that 5-HT7 receptor blockade is highly effective in improving declarative memory in rodents, the declarative memory measures will be the primary outcome measures.

Due to the effect of JNJ-18038683 on depressive symptoms in preclinical paradigms, we will investigate the following in the clinical trial the potential antidepressant effect of JNJ-18038683 on patients with baseline MADRS score between 8 and 20.

Arms: arm 1: Subjects will be randomized to receive JNJ-18038683 or placebo after the completion of the baseline assessments. Subjects randomized to JNJ-18038683 will receive 10 mg for one week, then titrate to 20 mg for the duration of the trial, with the provision for a single, downward dose adjustment for intolerance, based upon investigator judgment. arm 2: Placebo treatment for 8 weeks.
Interventions: intervention 1: JNJ-18038683 intervention 2: Placebo
Intervention descriptions: intervention 1: JNJ-18038683 10-20 mg/day tablet for 8 weeks intervention 2: placebo tablet daily

Protocol documents:
ICF_002.pdf: 
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Title of Research Study:  Testing the ability of JNJ-18038683, a selective serotonin (5-HT)7 
antagonist, to improve cognition and reduce residual depressive symptoms in stable bipolar 
patients
Investigator: Herbert Meltzer, MD 
Supported By: This research is supported by Northwestern University and Janssen Research 
and Development, LLC 
Financial Interest Disclosure:  
If your doctor is also the person responsible for this research study, please note that he is 
interested in both your clinical care and the conduct of this research study. You have the right to 
discuss this study with another person who is not part of the research team before deciding 
whether to participate in the research. 
Key Information: 
The first few pages of this document include a summary of this study to help you 
decide whether or not to participate. Detailed information is provided after the 
summary.
Why am I being asked to take part in this research study?
We are asking you to take part in this research study because you have been diagnosed with 
bipolar I or II disorder and may be having difficulty with memory, attention, or concentration. 
What should I know about a research study?

Someone will explain this research study to you.

Whether or not you take part is up to you.

You can choose not to take part.

You can agree to take part and later change your mind.

Your decision will not be held against you.

You can ask all the questions you want before you decide.
Why is this research being done?
This study is being conducted in order to determine if an investigational drug, JNJ-18038683, 
improves mental function and is safe in people who have bipolar disorder and are taking other 
medications for their illness.  Mental function is how your brain works and includes your mood, 
memory and how you think and concentrate.  An investigational drug is one that is not approved 
for sale by the US Food and Drug Administration (FDA) or any other regulatory or health 
agency. This study compares an experimental drug to a placebo. A placebo is an inactive 
substance made to look/taste like an active medicine. The placebo in this study looks like JNJ-
18038683 but has no drug or other active ingredient in it.  You will receive either the study 
medication, JNJ-18038683, or the placebo during this study. Researchers use a placebo to see 
if the study drug works better or is safer than not taking anything.  
How long will the research last and what will I need to do?
We expect that you will be in this research study for up to 10 weeks, including the screening 
period. 
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If you participate, you will be closely followed by asking you about any side effects you 
experience, your vital signs,  (BP, heart rate, respiratory rate, temperature), electrocardiograms, 
and clinical lab tests.  
If you decide to participate, you will be in this study for up to 8 weeks (56 days) after the 
screening period with a safety follow-up phone call 4 weeks (28 days) after the completion of 
the study.  The screening period can last up to 2 weeks (14 days).  The total length of your 
participation is up to 14 weeks (98 days).  After the initial screening visit (Visit 1), you will be 
asked to return to the research site at least 6 more times to take part in additional study 
procedures. 
These procedures include but are not limited to: Physical and mental health questions, height 
and weight measurement, electrocardiograms, physicals examinations, blood samples, urine 
samples, pregnancy tests, questionnaires about our thinking, concentration, and memory; your 
thoughts/intentions to do harm to yourself and others; and your mood, feelings, thoughts, and 
symptoms.
You will also be contacted by phone at weeks 3, 5, and 7 of the study during the study to ask if 
you have had any health problems, have started any new medications, and to answer a 
questionnaire about our thoughts/intentions to do harm to yourself and others; and your mood, 
feelings, thoughts, and symptoms.
More detailed information about the study procedures can be found under the section What 
happens if I say “Yes, I want to be in this research”?
Is there any way being in this study could be bad for me?
While taking JNJ-18038683 you may experience side effect. It is important for you to let the 
study team know of any changes in your health. For more information on known side effects see 
“Is there any way being in this study could be bad for me? (Detailed Risks)” 
In addition to these risks, this research may hurt you in ways that are unknown. These may be a 
minor inconvenience or may be so severe as to cause death. The risk of this type of drug 
includes a risk of sexual problems, mood changes, nervousness, and experiencing thoughts of 
hurting yourself which may be life threatening.
If you start experiencing thoughts of hurting yourself or if you have any plan to do so, please call 
911 immediately for assistance, in addition, the study staff should be notified of these issues as 
well.  Please report any concerns at all study visits (on site or via phone).  
More detailed information about the risks of this study can be found under “Is there any way 
being in this study could be bad for me? (Detailed Risks)”
Will being in this study help me any way?
We cannot promise any benefits to you or others from your taking part in this research. 
However, possible benefits include improvement of your mental functioning (mood, thinking, 
concentration, and memory) and providing scientific information that may benefit others in the 
future. The results of your screening evaluation can be made available to your regular doctor at 
your written request.
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What happens if I do not want to be in this research?
Participation in research is completely voluntary. You decide whether or not to participate. If you 
choose to not participate, there will be no penalty to you or loss of benefit to which you are 
entitled.  
There is not an approved treatment for improving mental function in bipolar disorder.  You may 
choose not to participate in this study. 
During the study, you will remain on the current treatment you receive for bipolar disorder.  For 
other available alternative treatments for bipolar disorder symptoms, please contact your doctor.
Detailed Information:
The rest of this document includes detailed information about this study (in addition to the 
information listed above).
Whom can I talk to?
If you have questions, concerns, or complaints, or think the research has hurt you, talk to the 
research team.
You can call us with your questions or concerns. 
Dr. Herbert Meltzer is the person in charge of this research study. You can call him at 
312.503.0309 during Monday through Friday, from 8:30 am to 5:00 pm.  
You can also call Katie Nikolajuk at 312-503-9076 with questions about this research study. 
For problems arising evenings or weekends, you may call the Stone Institute psychiatric 
emergency number at 312-926-9670.
If you have any illness or injury during your time on this study, you should call us promptly. 
If you experience an emergency, please call 911 immediately for assistance.
This research has been reviewed and approved by an Institutional Review Board (“IRB”). You 
may talk to them at (312) 503-9338 or irb@northwestern.edu if:
Your questions, concerns, or complaints are not being answered by the research team.
You cannot reach the research team.
You want to talk to someone besides the research team.
You have questions about your rights as a research participant.
You want to get information or provide input about this research.
How many people will be studied?
We expect about 60 people in total.  Northwestern University and Beacon Medical Group 
Behavioral Health South Bend will be the sites conducting the research. 
What happens if I say “Yes, I want to be in this research”?
You must give written consent to participate before any of the following tests are performed. The 
following procedures or tests will be done during the study. All study procedures and tests will 
take place at either the Northwestern University Feinberg School of Medicine suites at either 
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680 N. Lake Shore Drive, Suite 1520, Chicago, Illinois, 60611 or the Stone Mental Health 
Center at 446 E Ontario St, Rooms 6-344 and 6-343, Chicago, IL 60611. 
These procedures and tests are to establish your eligibility for the study, safety and effects of 
the study drug.  

Physical and mental health questions.  You will be asked questions about your:
o
Current and past health
o
Age 
o
Drug use (including prescription, over-the-counter, and other drugs).  You may be 
asked to stop taking some medications.  You should discuss the risk of stopping any 
medication with your doctor.

Height and weight measurement: how tall you are, the size of your waist, and how much 
you weigh.

Electrocardiograms (ECGs), a painless way to measure your heart rhythm and check for 
heart problems. 

Physical examinations will be done.  Examinations will not include pelvic or breast 
examinations in females, genital examinations in males, or rectal examinations.

Blood pressure, temperature, pulse, and breathing rate will be measured.

Blood samples will be drawn to check your health before and during the study.

Blood will be taken at three (3) different times over the course of the study.  
Approximately two and a half (2.5) tablespoons (about 36 mL) of blood will be drawn 
over the course of the study.  A needle stick will be used for the blood draws.

Serum pregnancy will be done at screening visit if you are a woman and can have 
children

Urine pregnancy test will be done at baseline visit:  a pregnancy test will only be 
performed if you are a woman and can have children. 

Urine samples will be collected and tested to:
o
Check your health
o
Test whether certain drugs, including illegal substances, are present in your body
o
During the study, the study staff will perform interviews where they will ask you questions and 
have you perform tasks.  These questions and tasks are described below.

The study staff will ask you questions and have you perform tasks to test your thinking, 
concentration, and memory.

You will be asked for any thoughts/intentions to do harm to yourself or others.  Please 
share with your doctor any thoughts you have to do harm to yourself or others.

You will also be asked about your mood, feelings, thoughts, and symptoms.  These 
questions will help the study doctor and study staff to understand the severity of your 
bipolar disorder, whether it has become worse or better, how it affects your life, and your 
everyday activities.

A study staff member will assess your movements (the way you move and whether you 
have movements you cannot control).

Blood pressure, temperature, pulse, and breathing rate will be measured.
You will be randomly assigned to 1 of 2 groups (like drawing names out of a hat or flipping a 
coin).  
Group 1: Placebo – After 1 week of 1 tablet per day, 2 tablets once per day by mouth
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Group 2: study drug – After 1 week of 1 tablet (10 mg) per day, 2 tablets, each 
containing 10 milligrams of JNJ-18038683, once per day by mouth. 
The treatment you get will be chosen by chance, like flipping a coin. Neither you nor the study 
doctor will choose what treatment you get. Neither you nor the study doctor will know which 
treatment you are getting, but the information about which group you are in (whether you are 
receiving placebo or the study drug) can be made available to the study doctor in the case of an 
emergency. 
A Safety Follow-up phone call will take place 4 weeks after the final visit.
If you choose to be in this study, you have the right to be treated with respect, including respect 
for your decision whether or not you wish to continue or stop being in the study.  You are free to 
choose to stop being in the study at any time.  
Any new findings developed during the course of this research that may affect your willingness 
to continue in this study will be shared with you. 
If you want to speak with someone who is not directly involved in this research, or have 
questions about your rights as a research subject, please contact the Northwestern University 
Institutional Review Board (IRB) Office. You can call them at 312-503-9338.
What are my responsibilities if I take part in this research?
In this form, both JNJ-18038683 and placebo will be called “study drug.”  The study drug will be 
available to you only during your participation in the study.  You must return all study drug at the 
end of the study.  After the study is over, Northwestern University will not continue to provide 
you with the study drug.  Your doctor will discuss your future medical care options with you.
While you are in this study, you will continue to take your regular medications as prescribed by 
your doctor.  If you start a new medication while in the study, you and the study doctor will talk 
about if it affects your ability to continue participating.  This includes medications that do not 
require a prescription (over-the-counter medications, vitamins, dietary supplements, etc.).  Your 
study doctor may discuss stopping certain medications with your other doctors.  If it is 
determined that you need a medication not allowed in this study, you might need to discontinue 
your participation in this study.
What happens if I say “Yes”, but I change my mind later?
You can leave the research at any time it will not be held against you.
If you stop being in the research, already collected data may not be removed from the study 
database. You will be asked whether the investigator can collect data from your routine medical 
care. If you agree, this data will be handled the same as research data. 
Choosing not to be in this study or to stop being in this study will not result in any penalty to you 
or loss of benefit to which you are entitled.  Specifically, your choice not to be in this study will 
not negatively affect your right to any present or future medical treatment.
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Detailed Risks: Is there any way being in this study could be bad for me?
Overall, seven completed clinical studies in 405 individuals (245 men and 160 women) have 
been completed with the study medication.  In general, side effects (adverse events) were mild 
to moderate in severity; the investigational drug was well tolerated at doses of up to 20 mg/day 
for up to 7 weeks treatment in both men and women. This dose (20 mg/day) is similar to the 
dose that you will be receiving if you choose to participate in this study. There have been no 
deaths reported with the use of the study drug.  Most side effects were mild to moderate in 
severity.
This research may hurt you in the following ways:
In a previously completed clinical trial with the study drug which evaluated JNJ 18038683, active 
comparator escitalopram, and placebo, the most common side effects (>5%) reported were 
similar in all treatment groups:
headache 

nausea

nasopharyngitis (stuffy nose and sore throat)

insomnia

somnolence (sleepiness) 

dyspepsia

dizziness

dry mouth

constipation

diarrhea

vomiting

back pain

upper respiratory tract infection

palpitations

fatigue 
The side effects that were reported more frequently in the JNJ-18038683 treatment group 
compared with the placebo or escitalopram groups included:

dyspepsia (upset stomach)

constipation

upper respiratory tract infection 

palpitations 
In addition to these risks, this research may hurt you in ways that are unknown. These may be a 
minor inconvenience or may be so severe as to cause death. The risk of this type of drug 
includes a risk of experiencing thoughts of hurting yourself which may be life threatening.  In 
addition, there may be changes in your mood such as euphoria (a feeling or state of intense 
excitement and happiness), sexual problems, nervousness, and/or inappropriate affect 
(emotions that do not properly fit a circumstance, such as smiling in reaction to a tragedy, or 
failing to show emotion at a time when an emotional reaction would normally be called for).  
If you start experiencing thoughts of hurting yourself or if you have any plan to do so, please call 
911 immediately for assistance, in addition, the study staff should be notified of these issues as 
well.  Please report any concerns at all study visits (on site or via phone).  
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There have been no reports of death with use of study drug thus far. 
Also, there have been a fewevents associated with syncope (temporary loss of consciousness 
caused by a fall in blood pressure) and orthostatic hypotension (temporary lowering of blood 
pressure, usually related to suddenly standing up)  and in several studies these events were 
severe and/or serious and led to early discontinuation from study.  There was one adverse 
event of elevated blood levels of creatine kinase, an enzyme present in the body muscles, 
which was  not related to investigational  drug JNJ 18038683
Risks Associated With Blood Draws
During this study, blood samples will be taken from a vein in the arm with a sterile needle.  For 
blood samples drawn by needles, several sites of blood drawing on both arms may be required.  
Risks associated with having blood drawn include pain, bruising, swelling, or infection at the site 
where the needle is inserted.  Rarely, some people feel lightheaded or faint.
Risks Associated with Interviews, Tests, and Questionnaires
There is the possibility that you might find the evaluations stressful. The likelihood of this 
occurring is low and for most of the evaluations, you can stop and take as many breaks as you 
wish. 
This study involves the use of your identifiable, personal information and there is a chance that 
a loss of confidentiality could occur. The researchers have procedures in place to lessen the 
possibility of this happening.  See the section below titled: “What happens to the information 
collected for the research?”. 
What do I need to know about reproductive health and/or sexual activity if I am in 
this study
The procedures in this research  may affect a pregnancy or fetus in the following ways: The 
effect of the study drug on human sperm and eggs has not been studied. The research may 
also hurt a pregnancy or fetus in ways that are unknown. These may be a minor inconvenience 
or may be so severe as to cause death. Therefore, both men and women should not attempt 
pregnancy and women should not be pregnant or breast-feeding while taking part in this study 
If you are sexually active, both men and women should use at least one effective means of birth 
control while participating in this research study. According to the World Health Organization 
and the United States Center for Disease Control and Prevention, the most effective forms of 
birth control include complete abstinence, surgical sterilization (both male and female), 
intrauterine devices (IUDs), and the contraceptive implant.  The next most effective forms of 
birth control include injectables, oral contraceptive pills, the contraceptive ring, or the 
contraceptive patch.  Acceptable but least effective methods of birth control include male 
condoms (with or without spermicide) and female condoms.
If you or your partner become pregnant while participating in this research study or for 6 months 
after you complete the study, it is important that you tell the study doctor or other research team 
member immediately. You may be required to stop participation in this study; however, other 
treatment options will be discussed with you at that time if necessary. You are encouraged to 
use condoms to protect against sexually transmitted diseases.
If you or your partner [are/is] considered to be postmenopausal, you are not required to use 
contraception while participating in this research study. Postmenopausal women rarely become 
pregnant. If you or your partner become pregnant while participating in this research study or for 
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6 months after you complete the study, it is important that you tell the study doctor or other 
research team member immediately. You may be required to stop participation in this study; 
however, other treatment options will be discussed with you at that time if necessary.
Will it cost me anything to participate in this research study?
You and your insurance company will be charged for the health care services that you would 
ordinarily be responsible to pay. In some cases, insurance will not pay for services ordinarily 
covered because these services were performed in a research study. You should check with 
your insurance to see what services will be covered by your insurance and what you will be 
responsible to pay. 
There will be no costs to you for being in this study.
Will being in this study help me in any way?
We cannot promise any benefits to you or others from your taking part in this research. 
However, possible benefits include:  include improvement of your mental functioning (mood, 
thinking, concentration, and memory) and providing scientific information that may benefit others 
in the future. The results of your screening evaluation can be made available to your regular 
doctor at your written request.
What happens to the information collected for the research?
Efforts will be made to limit the use and disclosure of your personal information, including 
research study and medical records, to people who have a need to review this information. We 
cannot promise complete secrecy. Organizations that may inspect and copy your information 
include the IRB and other representatives of this institution.
Monitors, auditors, the IRB, the Northwestern University Office for Research Integrity, the US 
Office of Research Integrity, the US Office for the Protection of Human Research Protections, 
the US Food and Drug Administration may be granted direct access to your medical records to 
conduct and oversee the research. By signing this document, you are authorizing this access. 
We may publish the results of this research. However, we will keep your name and other 
identifying information confidential.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
Data Sharing 
De-identified data from this study may be shared with the research community at large to 
advance science and health. We will remove or code any personal information that could 
identify you before files are shared with other researchers to ensure that, by current scientific 
standards and known methods, no one will be able to identify you from the information we 
share. Despite these measures, we cannot guarantee anonymity of your personal data.
Can I be removed from the research without my OK?
The person in charge of the research study can remove you from the research study without 
your approval. Possible reasons for removal include if your symptoms of bipolar disorder get 
worse, you lose the ability to consent, or if the study is harming you
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We will tell you about any new information that may affect your health, welfare, or choice to stay 
in the research.
What else do I need to know?
If you become ill or are injured as a result of this study (medications, devices or procedures), 
you should seek medical treatment through your doctor or treatment center of choice. You 
should promptly tell the study doctor about any illness or injury.  
The hospital  will not pay for medical care required because of a bad outcome resulting from 
your participation in this research study. This does not keep you from seeking to be paid back 
for care required because of a bad outcome.
If you agree to take part in this research study, we will pay you up to $280 for your time and 
effort. You will get $40/visit for taking part in this research study.  All visit payments will be made 
via a check that will be mailed to you. Processing for checks can take approximately 4 weeks 
after each visit.  If you withdraw from the study, you will be paid for the portions that you 
completed, depending upon how many visits were done.
You will be given assistance for expenses related to parking, taxi or public transportation. 
Parking for study participation will be provided to the participant by the study through University 
Services. You will not be responsible for parking expenses. You will be provided with a 
validation ticket, which will allow you to park for free if you park at one of two Northwestern 
Memorial Hospital parking garages: 

Huron-St. Clair Self Park located at 222 E. Huron Street, Chicago, IL 60611, or 

Erie-Ontario Self Park located at 321 E. Erie St, Chicago, IL 60611 
Expenses for taxis will be reimbursed by cash at the end of each visit, as long as 
reimbursement receipts are received. 
If public transportation is used, single-use CTA cards will be provided for transportation to and 
from each visit. 
Up to $20 per visit will be provided to cover your transportation and parking expenses.
$10 will be provided to cover lunch expenses for visits lasting over 4 hours.
The Accounting Services at Northwestern University will be given your name, address, and 
Social Security Number in order to issue a check for your study participation. Study payments 
are considered taxable income and reportable to the IRS. A Form 1099 will be sent to you if 
your total payments are $600 or more in a calendar year. 
HIPAA Authorization
We are committed to respect your privacy and to keep your personal information confidential.  
When choosing to take part in this study, you are giving us the permission to use your personal 
health information that includes health information in your medical records and information that 
can identify you. For example, personal health information may include your name, address, 
phone number or social security number. Your health information we may collect and use for 
this research includes: 

Results of physical examinations

Medical history

Lab tests, or certain health information indicating or relating to a particular condition

Records about study medication or drugs

Substance abuse information: Results of drug tests  
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
Mental Health information:   Diagnosis, previous treatment, medication history
You have the right to inspect and copy the mental health and developmental disabilities records 
that will be collected as part of this study.
This consent expires on December 31,2060.  After this date, Northwestern University may not 
gather new information about you, use or disclose your personal health information collected in 
this study for any purpose other than the research study described in this consent unless 
Northwestern University obtains permission to do so from you.  Illinois State Law permits use 
and disclosure of your mental health information only to the extent specified in this document.
The following clinical providers may give the researchers information about you:  all current and 
previous health care providers, including but not limited to the Shirley Ryan AbilityLab 
(SRALAB), Northwestern Medical Group (NMG), Northwestern Memorial Hospital (NMH), and 
Northwestern Lake Forest Hospital (NLFH).
Once we have the health information listed above, we may share some of this information with 
the following offices or entities outside of Northwestern University and its clinical partners (or 
affiliates):  the Northwestern University Institutional Review Board Office and Office for 
Research Integrity; the US Office of Research Integrity; the US Office for Human Research 
Protections; the US Food and Drug Administration.  
Any research information shared with outside entities will not contain your name, address, 
telephone or social security number or any other personal identifier unless disclosure of the 
identifier is necessary for review by such parties or is required by law or University policy 
[except that such information may be viewed by the Study sponsor and its partners or 
contractors at the Principal Investigator’s office].
The following entities may receive your health information: 

Authorized members of the Northwestern University workforce, who may need to see 
your information, such as administrative staff members from the Office for Research, 
Office for Research Integrity and members of the Institutional Review Board (a 
committee which is responsible for the ethical oversight of the study), 

Clinical affiliates, including but not limited Northwestern Memorial Hospital (NMH), or 
Northwestern Memorial Physicians Group (NMPG).  Your participation in this clinical trial 
will be tracked in an electronic database and may be seen by investigators running other 
trials that you are enrolled in and by your healthcare providers.

Clinical affiliates, including but not limited to Northwestern Memorial Hospital (NMH), for 
purposes including, but not limited to, the affiliate’s provision of care to you and/or the 
affiliate’s scheduling of appointments and/or billing activities. 

Janssen Research and Development, LLC with whom Northwestern University shares a 
collaborative research agreement. Janssen is the manufacturer of the study medication, 
JNJ-18038683 and the placebo.

Other University research centers and University contractors who are also working on 
the study.

Government agencies and public health authorities, such as the Food and Drug 
Administration (FDA) and the Department of Health and Human Services (DHHS).
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Do not sign this consent if today’s date is later than the stated expiration date above.
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Version Date 2.4.2019

Research results from the study may be shared with research partners working with the 
Northwestern University.  Research results shared with research partners working with 
Northwestern University will not contain personal identifying information.
Those persons who get your health information may not be required by Federal privacy laws 
(such as the Privacy Rule) to protect it. Some of those persons may be able to share your 
information with others without your separate permission.
However, Illinois law does not allow the re-release of HIV/AIDS, genetic testing, mental health 
and developmental disabilities information by the receivers of the information except in precise 
situations allowed by law. 
Also, Federal Confidentiality Rules, 42 CFR Part 2, prohibit making any further disclosure of 
substance use disorder information unless further disclosure of this information is expressly 
permitted by written consent of the person to whom it pertains or as otherwise permitted by 42 
CFR Part 2. 
The results of this study may also be used for teaching, publications, or for presentation at 
scientific meetings.  
Unless you revoke your consent, it will expire December 31 2060.
Although you may revoke consent to participation in this research at any time and in any format, 
you must revoke authorization for use or disclosure of your health information in writing. To 
revoke your authorization, write to:

PI’s Name:
Herbert Meltzer, MD

Institution: 
Northwestern University

Department: Psychiatry and Behavioral Sciences

Address:
680 N. Lake Shore Drive Suite 1520, Chicago, IL 60611
You do not have to authorize the use or disclosure of your health information; however, you will 
not be allowed to take part in this research study. If you do not authorize the use or disclosure of 
your health information, it will not affect your treatment by health care providers, or the payment 
or enrollment in any health plans, or affect your eligibility for benefits.
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Signature Block for Capable Adult:
Your signature documents your permission to take part in this research.  You will be provided a 
copy of this signed document.
_______________________________________________      __________________
Signature of Participant                                                               Date
_______________________________________________
Printed Name of Participant
____________________________________________            __________________
Signature of Person Obtaining Consent                                     Date
______________________________________________________
Printed Name of Person Obtaining Consent
My signature below documents that the information in the consent document and any other 
written and information was accurately explained to, and apparently understood by, the 
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Prot_000.pdf: 
1 
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 PROTOCOL TITLE:
Testing the ability of JNJ-18038683, a selective serotonin (5-HT)7 antagonist, to 
improve cognition and reduce residual depressive symptoms in stable bipolar patients 
(18038683BCD2001)
PRINCIPAL INVESTIGATOR:
Herbert Meltzer, MD
Northwestern University Feinberg School of Medicine
Department of Psychiatry and Behavioral Sciences
303 E. Chicago Ave. #12-104
312.503.0309
312.503.0348
h-meltzer@northwestern.edu
VERSION NUMBER:
1.13
VERSION DATE:
Initial version:
November 22, 2014
Revised 
January 27, 2015
Revised 
March 5, 2015
Revised 
April 2, 2015
Revised
May 7, 2015
Revised 
August 31, 2015
Revised
November 5, 2015
Revised
March 7, 2016
Revised 
September 8, 2016 
Revised                              October 31, 2016
Revised
February 16, 2018
Revised
May 9, 2018
Revised
July 2, 2018
Revised
February 4, 2019
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Table of Contents
1.0
Objectives
3
2.0
Background
3
3.0
Inclusion and Exclusion Criteria
8
4.0
Study-Wide Number of Individuals
10
5.0
Study-Wide Recruitment Methods
10
6.0
Multi-Site Research
10
7.0
Study Timelines
10
8.0
Study Endpoints
11
9.0
Procedures Involved
11
10.0
Data and Specimen Banking
22
11.0
Data and Specimen Management
22
12.0
Provisions to Monitor the Data to Ensure the Safety of Individuals
 
23
13.0
Withdrawal of Individuals*
24
14.0
Risks to Individuals*
24
15.0
Potential Benefits to Individuals
25
16.0
Vulnerable Populations
25
17.0
Sharing of Results with Individuals
26
18.0
Setting
27
19.0
Resources Available
27
20.0
Prior Approvals
28
21.0
Recruitment Methods
28
22.0
Local Number of Individuals
29
23.0
Confidentiality
29
24.0
Provisions to Protect the Privacy Interests of Individuals
29
25.0
Compensation for Research-Related Injury
29
26.0
Economic Burden to Individuals
29
27.0
Consent Process
30
28.0
Process to Document Consent in Writing
30
29.0
Drugs or Devices
30
30.0
References
32
31.0
Appendices
34
32.1
Appendix 1
34
32.2
Appendix 2
35
32.3
Appendix 3
37
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1.0
Objectives
The goals of this study are to evaluate the efficacy of JNJ-18038683 in an 
8 week trial to ameliorate the cognitive deficit and reduce residual 
depressive symptoms in 60 stable bipolar outpatients receiving treatment 
for depression.  JNJ-18038683 will be studied and compared with placebo 
as adjunctive treatment to standard pharmacologic treatment for bipolar 
disorder.  
2.0
Background
2.1.1 Cognitive impairment in bipolar disorder 
Most, but not all, patients with bipolar disorder (BPD) have clinically significant 
cognitive impairment [1, 2]. Impairment is present in both the manic and depressed 
phases of BPD, as well as in euthymic periods  [3]. The percentage of BPD patients 
with cognitive impairment (CIBD) varies among studies, with 40-60% representing 
the best estimate [3]. The weight of the evidence supports no overall difference in 
the type and severity of cognitive impairment in any phase of BPD, i.e. it is a stable 
trait feature of BPD, albeit variable from one patient to another. The most 
commonly affected cognitive domains are speed of processing, declarative 
memory, attention and working memory [3, 4]. Although CIBD is milder in severity 
than the cognitive impairment associated with  schizophrenia (CIAS), on average, 
as in schizophrenia, CIBD has a major impact on function and quality of life in most 
patients, particularly because the greater preservation of function  of BPD enables 
them to engage in activities which are more dependent on intact  cognitive function 
[5]. Thus, it is highly likely that improvement in CIBD will have valuable clinical 
benefit, especially with regard to quality of life measures. It is reasonable to predict 
that treatments effective to improve CIBD could also be beneficial for CIAS. 
Efficacy for cognitive impairment is likely to be greater in BPD than schizophrenia, 
because the baseline severity is milder in the former [6] . Despite this strong 
rationale for targeting CIBD, there has been minimal focus on clinical trials to 
improve CIBD, perhaps because so many resources have been devoted to the 
effort to treat CIAS, but lack of appreciation of the severity of CIBD and its 
importance as a determinant of functional outcome in BPD may be the most 
important factors.  
In a recent study of CIBD, using the MATRICS Consensus Cognitive Battery 
(MCCB), impairment was found in both treatment resistant BP I and II depressed 
inpatients within all MCCB domains [4]. The greatest impairment was evident in 
speed of processing, declarative memory and attention.  The impairment was 
numerically greater in BP I than BP II patients but the difference was not significant.  
Compared to normal controls, the deficits, in BP 1 patients, in speed of processing 
was 1.2SD, in attention, 1.0 SD, and in verbal learning, 1.8 SD.   The least affected 
domain was visual learning, with a mean deficit of 0.8SD compared to normal 
controls.   The mean composite score deficit was 1.25 SD. Medication for BPD, 
particularly mood stabilizers, may adversely affect some domains of cognition in 
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BPD [7]. However, antidepressant medications have not been found to affect the 
severity of cognitive impairment in major depression or BPD [8].
2.1.2 Preclinical Rationale for Studying JNJ-18038683 to treat CIBD and CIAS 
Serotonin (5-HT)7 receptors are one of 14 5-HT receptors. This Gs-protein coupled 
receptor is widely distributed in brain, with high density in the thalamus, 
hypothalamus, hippocampus, suprachiasmatic nucleus, amygdala and septum, 
with lower levels in the cerebral cortex. The HTR7, is positively coupled to 
adenylate cyclase (as are the dopamine (DA) D1, 5-HT4 and 5-HT6 receptors), and 
has aroused considerable interest as a target for drugs to treat depression, as well 
as some for cognitive impairment and psychosis [9-11]. For example, there has 
been considerable interest in 5-HT7 antagonists as stand-alone antidepressants 
[10, 12, 13] or as contributor to multireceptor antidepressant drugs [14-16]. JNJ 
18038683 and other selective 5-HT7 receptor antagonists have been reported to 
be effective antidepressants in a variety of animal models, including tail suspension 
[13]. JNJ-18038683 potentiated the ability of a sub-effective dose of the SSRI 
citalopram to increase extracellular levels of 5-HT in rat cortex. JNJ-18038683 had 
no effect by itself on 5-HT efflux in a microdialysis study.  In a failed clinical trial, 
JNJ-18038683 did not differentiate from placebo, but the active comparator also 
did not differentiate, possibly because of a high placebo response rate. Importantly, 
no safety concerns emerged for the compound [13]. 
Of key relevance to this proposal, 5-HT7 receptor selective drugs  have  been 
shown to be active in animal models of psychosis, learning, and memory [10]. 5-
HT7 receptor blockade has been postulated to be a  key component of the cognitive 
enhancement due to atypical APDs, e.g. amisulpride, clozapine, lurasidone, and 
risperidone, which are potent 5-HT7 antagonists [17-19] and as a stand-alone 
cognitive enhancer [20]. We will report key additional evidence in the Preliminary 
Studies section. With regard to animal models of antipsychotic activity, the 
selective 5-HT7 antagonist, SB-258471, prevented the disruption of prepulse 
inhibition (PPI) in phencyclidine (PCP)-but not amphetamine-treated rats, 
indicating positive influence on the glutamate, but not DA, component of PPI, a 
model of the sensory gating deficit in BPD and schizophrenia which has bearing 
upon antipsychotic activity and attention, a key component of CIBD [9]. However, 
the selective, 5-HT7 antagonist SB269970 [21] was able to reverse the effect of 
amphetamine to disrupt PPI in C57BL/6 mice [9]. It has been reported that SB-
269970 significantly reversed the NMDA receptor antagonist dizocilpline (MK-
801)-induced deficits in the delayed non-matching to position task, a measure of 
working memory, but augmented the deficit induced by low dose scopolamine, a 
muscarinic antagonist [22]. These authors also showed that SB-269970 
normalized MK-801-induced glutamate but not DA efflux in the prefrontal cortex.  
SB269970 improved reference memory in a radial arm maze [9, 12] and a PCP-
induced reversal learning deficit in rats [23]. SB-656104-A, another 5-HT7 
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antagonist, improved learning and memory deficits induced by an NMDAR 
antagonist, in the rat passive avoidance test alone and with a subeffective dose of 
lurasidone [24]. Sarkisyan and Hedlund [25] reported a deficit in spatial memory in 
a novel location test in 5-HT7 knock out mice and mice treated with SB-269970. 
However, we have found no deficit in novel location in HTR7 knock out mice.  In a 
recent publication, Andressen et al There is some conflicting evidence about the 
role of 5-HT7 antagonism in cognition. 5-HT7 agonism has been suggested to be 
an effective target for improvement of cognitive impairment in aging mice and in 
an Alzheimer’s mouse model, as the 5-HT7 agonist AS19 enhanced memory 
formation in an autoshaping task, an effect blocked by SB269970 [26]. Gasbarri et 
al [27] suggested that the role of the 5-HT7 receptor in cognition will vary depending 
upon the task and brain regions involved.  Eriksson et al [28] suggested that 5-HT7 
receptor blockade can intensify impairments in emotional memory that are induced 
by 5-HT1A receptor stimulation. 
2.1.3 Preclinical Evidence:
The predominant strategy to develop pharmacologic treatments for CIAS and by 
extension, CIBD, relies upon ameliorating cognitive impairment induced in rodent 
models which have some relation to the psychotic spectrum disorders, especially 
drug- or transgenic-induced abnormalities in cognition. Evidence from animal 
models suggests that serotonin (5-HT)7 receptor(R) antagonism is a promising 
target to treat CIBD and CIAS. We have extensively studied SB-269970, the 
protypical 5-HT7 selective antagonist, in the sub-chronic (sc) phencyclidine (PCP) 
rat and mouse models of CIAS.  PCP, an NMDAR antagonist, is widely studied for 
this purpose because of the extensive evidence that abnormalities in glutamate 
and GABA neurotransmission in cortex and hippocampus may be the prime cause 
of CIAS. Acute or scPCP produces a wide range of documented deficits in NMDAR 
and GABA neurotransmission. We recently reported that SB269970 (0.1-1 mg/kg) 
dose-dependently reversed scPCP-induced novel object recognition (NOR) 
deficits in rats [17]. NOR is a model of human declarative memory. We have 
replicated these results in mice treated with PCP or ketamine for 7 days and 
washed out 7 days or longer (Figure 1).  SB-269970 can also reverse PCP-induced 
deficits in novel location detection. Our data contrasts with results from the 
Hedlund lab.  In addition, we reported that the ability of two atypical antipsychotic 
drugs (APDs), lurasidone (0.1 mg/kg) and amisulpride (3 mg/kg), to reverse the 
NOR deficit was blocked by co-treatment with the 5-HT7 receptor agonist, AS19, 
(5-10 mg/kg). None of these compounds affect NOR in naive rats.   There is also 
extensive evidence supporting the cognitive benefits from 5-HT7 receptor blockade 
from other labs, e.g. restoration of reversal learning in PCP-treated rats.  
Furthermore, we have been breeding 5-HT7 knock out mice for a year and now 
have many studies with these mice which replicate the results with SB-269970, 
including prevention of the NOR deficit produced by acute or sub-chronic PCP 
(Figure 2).   In addition, the 5-HT7 knockout mice, from adolescence to adulthood, 
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Dose response: Acute studies
1
2
3
4
5
6
-0.1
0.0
0.1
0.2
0.3
0.4
*
###
1. Vehicle+vehicle
2. PCP+vehicle
3. PCP+SB269970(0.3 mg/kg): sub-effective dose
4. PCP+SB269970(0.5 mg/kg): partially effective dose
5. PCP+SB269970(1 mg/kg): effective dose
6. PCP+SB269970(1 mg/kg): effective dose - 48 hr ITI
*P<0.05: significant reduction in DI compared to vehicle
##-###P<0.01 - P<0.001: significant increase in DI compared to PCP
##
24 hr ITI
48 hr ITI
Treatment
DI
V+V P+V W1
W2
W3
W4
W5
W6
W7
W8
0.0
0.1
0.2
0.3
0.4
0.5
*
###
#
#
#
#
#
#
##
SB269970+PCP:Weeks1-8
DI
Figure 2: SB269970 co-administered 
with sub-chronic PCP Prevents Deficit 
in NOR produced by sub-chronic PCP 
for at least 8 weeks.
Figure 1: Effect of SB269970 to restore 
NOR at 24 and 48 hrs after Acquisition
show superior duration of memory for NOR compared to wild type mice 
(Supplemental Figure 1). Figures referenced below include the discrimination 
index of the NOR experiments, which quantifies the animal’s ability to recognize 
and explore the novel object more than the familiar. 
Our lab has also conducted studies with JNJ-18038683 which indicate that it is as 
effective as SB269970 to restore NOR in scPCP-treated mice (Figure 3).
Discrimination Index
V+V
P+V
P+JNJ(0.3) P+JNJ(1)
-0.1
0.0
0.1
0.2
0.3
0.4
***
##
Treatment
DI
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Additional Evidence for Pro-cognitive effects of JNJ-18038683 on Executive 
Function:
Reversal learning: See Abdul-Monim et al., and Brigman et al., [29, 30] for 
detailed methodology. Apart from the declarative memory deficits, there is a range 
of cognitive deficits in  BPD and schizophrenia, including impaired executive 
functioning [31], which can be assessed by operant reversal learning tasks in 
rodents [32]. We found that both JNJ-18038683 and SB269970 (4 mg/kg) were 
able to reverse sub-chronic PCP induced decrease in percentage correct 
responding in the reversal phase of the task (Figure 4). 
2.2
Rationale for Randomized Controlled Trial of JNJ-18038683 on Cognition and 
Residual Depressive Symptoms in Bipolar Disorder
Based on the pre-clinical, pro-cognitive effects of 5-HT7 antagonism in our 
laboratory, along with the reported pre-clinical antidepressant effects of JNJ-
18038683, we propose to conduct a randomized, placebo- controlled parallel, 
design study to assess the effects of JNJ-18038683 on multiple domains of 
cognition and mood symptoms.  Since our preclinical studies show that 5-HT7 
receptor blockade is highly effective in improving declarative memory in rodents, 
the declarative memory measures will be the primary outcome measures.  As 
previously discussed Andressen et. al [39] noted differential functional selectivity 
of the 5-HT7 receptor, suggesting that the effects of atypical APDs with known 5-
HT7 antagonism, such as lurasidone, ziprasidone and risperidone, are modulated 
via different HTR7 subunits than JNJ1083868. In light of this new information, we 
proposed to allow some individuals currently prescribed treatment with atypical 
APDs with 5-HT7 antagonism to be eligible for screening and randomization.  
1
2
3
4
5
6
1
2
3
4
5
6
0
50
100
150
*
#
initial
reversal
1. Vehicle+vehicle
2. PCP+vehicle
3. PCP+SB269970 (0.5 mg/kg) - sub-effective dose
4. PCP+SB269970 (4 mg/kg) -effective dose
5. PCP+JNJ18038683(1 mg/kg) - sub-effective dose
6. PCP+JNJ18038683 (4 mg/kg)-Effective dose
*P<0.05: significant reduction in percentage correct responding compared to vehicle group;
#P<0.5; ##0.01: significant increase in percentage correct responding compared to PCP
group.
##
%correct responses
Figure 4: Effect of 5-HT7 antagonists on executive function in PCP treated animals 
Figure 3: Acute reversal of sub-chronic PCP with JNJ-18038683: Determination of 
effective and sub-effective doses (1.0 mg/kg and 0.3 mg/kg, respectively)
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Due to the effect of JNJ-18038683 on depressive symptoms in preclinical 
paradigms [12], we will investigate the following in the clinical trial the potential 
antidepressant effect of JNJ-18038683 on patients with baseline MADRS score 
between 8 and 20.
3.0
Inclusion and Exclusion Criteria
All patients will meet criteria for DSM-V diagnosis of Bipolar I or Bipolar II 
disorder.  At the time of enrollment, patients will be relatively stable, and may be 
in a mild-moderate depressed state. 60 patients will be enrolled, and randomized 
in a 1:1 ratio to one dose of JNJ-18038683 or placebo.  Randomization will be 
stratified by the presence / absence of atypical APDs with 5-HT7 antagonism so 
that there is a balance in the assignment of active treatment and placebo in 
individuals who are, and are not, receiving atypical APDs with 5-HT7 antagonism. 
The percentage of those enrolled that are prescribed these atypical APDs will be 
35% of the overall enrollment.
Individuals must meet all of the inclusion and exclusion criteria to be registered to 
the study. Study treatment may not begin until a subject is registered.
3.1
Inclusion Criteria
1. All participants must have signed an informed consent document indicating they 
understand the purpose of the study and the procedures required for the study 
and are willing to participate by complying with the study procedures and 
restrictions. 
2. Male or female individuals of any race; between 18 to 60 years of age, inclusive.
3. Resides in a stable living situation, according to the investigator’s judgment. 
4. Diagnosis of bipolar disorder I or II for at least 1 year in duration, as established 
by the SCID-I, and verified with medical records and/or confirmation of diagnosis 
by treating clinician. Patients will be in a nonacute phase at the time of initial 
screening and have been so for at least 1 month.  
5. No more than moderate clinical symptom burden severity, as defined by the 
following:

Montgomery Asberg Depression Rating Scale < 20 

Young Mania Rating Scale <12 
6. Individuals medically stable enough to complete an 8 week clinical trial, in the 
judgment of the investigator
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7. Women of childbearing potential must have a negative pregnancy serum test at 
screening, negative pregnancy urine test at baseline, and agree to use adequate 
protection (i.e. double barrier method) for birth control.  
8. Antidepressant (AD) medications are allowed if the subject has been treated with 
a stable dose for at least 2 months before screening. 
9. Individuals receiving a single mood stabilizer (e.g., lithium. valproate, or lamictal) 
are allowed if a stable dose has been maintained for at least 2 months prior to 
screening. 
10.Individuals may be receiving one treatment of each the following groups: 
antidepressants, mood stabilizers, and atypical antipsychotics other than 
clozapine, but not more than one from each group. 
11.Individuals taking ripseridone, lurasidone, or ziprasidone must be currently taking 
< doses of 3mg, 40mg, and, 80mg, respectively. 
12.Subjects may be treated with inclusionary antipsychotic drugs as long as they are 
on a stable dose of injectable medication for 2 months or a sable dose of an oral 
medication for 1 month. Exclusionary antipsychotic drugs are listed in Appendix 
2. 
13.Patients with a history of compliance with a drug treatment regimen for bipolar 
disorder, as noted in medical/psychiatric history. 
14.CNS stimulants (e.g., Adderall, Ritalin) are permitted if the participant is stable on 
their dosage of medication for 1 month before screening and cannot change 
dosage throughout the study. 
15.Able to complete cognition assessments in English
16.Individuals must demonstrate a substantive cognitive deficit, as measured by the 
Trails A, Hopkins Verbal Learning Test (HVLT), and the Letter Number Span, 
administered at the screening visit. Eligible individuals will have an established 
cognitive deficit as measured by one or more of these tests, scoring below the 75th 
percentile, using comparative norms according to age, gender, and education. 
17.Able to understand and complete cognition assessments 
3.2
Exclusion Criteria
1. Failure to perform screening or baseline examinations 
2. Hospitalization within 8 weeks before screening, or change in mood stabilizing or 
antidepressant medication or dose within 2 months prior to screening 
3. Individuals who have participated in another clinical study within the past 2 
months. 
4. Individuals with tardive dyskinesia.
5. Individuals with other DSM-V Axis I or Axis II primary diagnoses. 
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6. Diagnosis of alcohol or substance use disorder within the past 3 months. 
7. Subject assessed to be at significant suicide risk based on responses to the 
Columbia Suicide Severity Rating Scale (C-SSRS). 
8. History of myocardial infarction, unstable angina, uncontrolled hypotension or 
hypertension within 3 months before screening. 
9. Clinically significant abnormality on screening ECG.
10.Alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5 times the 
upper limit of normal (ULN).
11.History of stroke, brain tumor, head trauma with loss of consciousness, or other 
clinically significant neurological condition within 12 months before screening. 
12.Individuals with other uncontrolled medical conditions, in the opinion of the 
investigator. 
13.Use of drugs known to be metabolized by CYP2D6 (see Appendix 2)
4.0
Study-Wide Number of Individuals
4.1
There will be 60 total participants
5.0
Study-Wide Recruitment Methods
5.1
This is a multi-center study. We will be using referrals directly from 
the providers and recruitment materials by posting in the clinics. We will 
utilize referrals from primary care or psychiatry providers, or from 
participant interest and consent. We will also be recruiting individuals 
through the NU-SRG Recruitment Pipeline (STU00059328) for the 
Northwestern University site.
6.0
Multi-Site Research
6.1
This is a multi-center study. There are two study sites where the 
research procedures will take place: Northwestern University, Chicago, IL 
and Beacon Medical Group Behavioral Health South Bend, South Bend, 
IN.  Northwestern University will be the coordinating center and Beacon 
Medical Group Behavioral Health South Bend will be a satellite site. 
7.0
Study Timelines
Schedule of Assessments:
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Study Day
Screen 1
7
14
21
28
35
42
49
56
84
Event/Assessment
Phone 
Call
Phone 
Call
Phone 
Call
Phone Call
Informed Consent
X
 
 
 
 
 
 
 
 
 
Medical History & 
Demographics
X
 
 
 
 
 
 
 
 
 
Physical Examination
X
 
 
 
 
 
 
 
 
 
Electrocardiogram
X
 
 
 
 
X
 
 
 
X
Vital Signs
X
X
X
X
 
X
 
X
 
X
Clinical Safety 
Laboratory Tests
X
 
 
 
 
X
 
 
 
X
Serum Pregnancy Test
X
Urine Pregnancy Test
X
Urine Drug Screen
X
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria
X
 
 
 
 
 
 
 
 
 
SCID-I
X
 
 
 
 
 
 
 
 
 
Screening 
neurocognitive 
assessments
X
Montgomery Asberg 
Depression Rating 
Scale
X
 
 
 
X
 
 
 
X
SLOF
X
X
C-SSRS
X
X
X
X
 X
X
X 
X
X 
X
X
AIMS
 
X
 
 
 
X
 
 
 
X
Neurocognitive battery
X
X
 
 
 
 
 
 
 
X
CGI-BP
 
X
 
 
 
X
 
 
 
X
Young Mania Rating 
Scale
 
X
 
 
 
X
 
 
 
X
Assessment of 
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
Assessment of Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
8.0
Study Endpoints
The declarative verbal memory subscales will be the primary endpoints. 
Secondary outcome measures will include cognition composite score, the 
MADRS total score (for those with a MADRS score between 8 and 20 at the time 
of enrollment) and individual scores for each of the other neuropsychological 
tests. We will assess JNJ-18038683 effects on functional ability and clinical 
global severity scores as additional endpoints, as measured by the SLOF and 
CGI-BP. Further, we will analyze the effect on drug tolerability as determined by 
the following: body weight, body mass index (BMI), waist circumference, and 
movement rating scales.
9.0
Procedures Involved
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Study visits will include screening and 6 visits (baseline, Weeks 1, 2, 4, 6, and 8). 
Please see Appendix 1 – Schedule of Assessments
At screening, the Structured Clinical Interview for Diagnosis for DSM Disorders 
(SCID) will be completed for confirmation of psychiatric diagnosis. A 
medical/psychiatric history will also be collected and a physical exam will be 
performed. Vital signs including weight, height, waist and hip measurement will be 
obtained at screening to record body mass index. The Hopkins Verbal Learning 
Test (HVLT) and Trail Making Test A (TMT-A), will be administered to screen for 
severity of cognitive impairment.  Only individuals who score between the 25th and 
75th percentile as compared to normative data on these tasks will be enrolled.  
If the subject is determined eligible during the screening procedure, which can last 
for up to two weeks, a baseline visit will be scheduled. Baseline assessments of 
cognitive function, psychopathology and global function will be administered along 
with movement ratings at the baseline visit.  Functional outcome will be assessed 
with Specific Level of Function Scale (SLOF) [33]. Adverse events will be collected 
and recorded from the time the subject signs the informed consent to the final 
safety follow-up visit, and motor side effects will be monitored by the Abnormal 
Involuntary Movement Scale at the following visits: baseline, Weeks 4 and 8.
Individuals will be randomized to receive JNJ-18038683 or placebo after the 
completion of the baseline assessments. Individuals will be stratified for 
randomization as either being treated with an AD or not being treated with an AD.  
As in the previous study of JNJ-18038683 for depression, individuals randomized 
to JNJ-18038683 will receive 10 mg for one week, then titrate to 20 mg, with the 
provision for a single, downward dose adjustment for intolerance, based upon 
investigator judgment. No antipsychotic drugs which are 5-HT7 antagonists will be 
permitted to avoid effects upon 5-HT7 receptors from enhanced 5-HT 
concentrations and possible down regulation of 5-HT7 receptors. As JNJ-
18038683 is a competitive inhibitor of CYP2D6, there will be a 2 week washout 
period requested after the trial prior to initiation of any CYP2D6 substrates (see 
Appendix 2).
Individuals will be asked to return to the clinic at study weeks 1, 2, 4, and 6 after 
baseline to monitor for side effects and compliance. At the Week 4 visit, efficacy 
assessments will be completed (MADRS, YMRS and CGI-BP). Between clinic 
visits, research staff will complete phone calls with individuals at study Weeks 3, 
5, and 7. Individuals will return for a final study visit 8 weeks after initiation of the 
randomized study medication. A Safety Follow-up phone call will take place 4 
weeks after the final visit and safety assessments will be completed (C-SSRS, 
Adverse Events, Concomitant Medications). The assessments completed at 
baseline will be repeated at this Week 8 visit (See Appendix 1 – Schedule of 
Assessments). Reasons for early termination will be recorded. Every effort will be 
made to obtain appropriate rating scale data at the final visit of early terminators.  
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9.1
Outcome Measures: 
A)
Comprehensive cognition battery (measuring executive functioning, speed 
of processing, attention/vigilance, working memory, verbal learning, visual 
learning, reasoning and problem solving) 
B)
Montgomery Asberg Depression Rating scale
C)
Young Mania Rating Scale
D)
Clinical Global Impression - BP
E)
Columbia Suicide Severity Rating Scale
F)
AIMS scale for tardive dyskinesia 
G)
Specific Level of Functioning
H)
Weight, height, waist circumference, triglycerides, FBS, LFTs
9.2
Randomization Method:
Those who meet the study inclusion criteria will be randomized into one of two 
treatment groups, one to receive adjunctive therapy of JNJ-18038683 and the 
other to receive placebo.  Individuals will be stratified for randomization as either 
being treated with an AD or not being treated with an AD. Using SAS software, a 
computer-generated randomization sequences for each treatment arm will be 
assigned using permuted block method limiting imbalance in numbers between 
groups. To assign the randomization, the SAS procedure PROC PLAN will be 
used [34]. Until the trial is concluded, the randomization sequence will be blind to 
the study participants as well as the Principal Investigator, research coordinators 
and raters. Randomization list will be provided by assigned statistician, Karu 
Jayathilake, and will be held by unblinded study drug manager at 680 N. 
Lakeshore Dr., Suite 1410; Chicago, IL 60611-7101 and at 707 N. Michigan St 
Suite 400 South Bend, IN 46601 for the Beacon Medical Group Behavioral 
Health South Bend site. 
9.3
Adverse Events
In a 7 week, randomized, placebo controlled trial comparing JNJ-18038683 with 
placebo and escitalopram (an active comparator), a total of 6 serious adverse 
events were reported during the study (placebo group: spontaneous abortion and 
suicidal ideation; escitalopram group: spontaneous abortion, suicidal ideation, 
suicide attempt, and chest discomfort). A total of 10 individuals (3 in the placebo 
group, 4 in the JNJ-18038683 group, and 3 in the escitalopram group) were 
withdrawn from the study prematurely due to adverse events. The 4 events 
leading to drop out of individuals on JNJ-18038683 were one instance each of 
the following: bundle branch block, panic attack, upper respiratory infection, and 
insomnia.  
Only 3 individuals receiving the 20-mg dose of JNJ 18038683 required dose 
reductions at any point during the study.
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Adverse events that were reported in more than 5% of individuals in any 
treatment group included headache, nausea, nasopharyngitis, insomnia, 
somnolence, dyspepsia, dizziness, dry mouth, constipation, diarrhea, vomiting, 
back pain, upper respiratory tract infection, palpitations, and fatigue. The 
treatment-emergent adverse events that were reported more frequently in the 
JNJ 18038683 group compared with the placebo or escitalopram groups included 
dyspepsia, constipation, upper respiratory tract infection, and palpitations. 
9.3.1 Contraindications: 
None known
9.3.2 Special Warnings and Precautions for Use
JNJ-18038683 is an investigational drug, with safety data available from 
nonclinical animal studies, as well as single and multiple dose clinical studies in 
healthy volunteers. 
All individuals should be closely monitored by means of adverse events, vital 
signs, ECGs, and clinical laboratory safety tests of blood and urine. 
The liver, lung, prostate, mammary gland, hematologic system, and thymus in 
rats (mainly at high dose), and the hematologic system and spleen in dogs, were 
identified as potential target organs for JNJ-18038683 in repeat-dose oral toxicity 
studies (see Other Effects in Investigator Brochure). Female animals appeared to 
be more susceptible than males.
Thus far in clinical trials, there have been no laboratory abnormalities of concern, 
but the following safety tests should be monitored:

Hematologic parameters: red blood cell (RBC), hemoglobin, hematocrit, 
unconjugated bilirubin, reticulocyte, and platelet counts;

Liver function: aspartate transaminase (AST), alanine transaminase (ALT), 
gamma glutamyltransferase (GGT), prothrombin time, total bilirubin, lactic 
dehydrogenase, serum albumin, and protein.
9.3.3 Interaction with other medications
After single and multiple doses of JNJ-18038683, limited or no inhibition of 
CYP3A4 and CYP2C9 activity may be expected, while moderate inhibition of 
CYP2C19 activity, and strong inhibition of CYP2D6 activity may be likely. JNJ-
18038683 increased the rate of T4 glucuronidation. There was no induction of 
CYPs 1A2, 3A4, 2C9, and 2C19 by JNJ-18038683.
9.3.4 Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of individuals enrolled in the studies as 
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well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care. 
All individuals experiencing an adverse event, regardless of its relationship to 
study drug, will be monitored until: 

the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the 
changes observed; or

death.
9.3.5 Definitions
9.3.5.1
Definition of Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which 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 an experimental intervention, whether or not related to 
the intervention. 
9.3.5.2
Severity of Adverse Events
The severity of an AE is graded as follows:
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.
Fatal (grade 5): the event caused death.
9.3.5.3
Serious Adverse Events
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that:
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
Results in death.

If death results from (progression of) the disease, the disease 
should be reported as event (SAE) itself.

Is life-threatening.

(the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it 
were more severe).

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect

Is an important medical event
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency.
9.3.6 Steps to Determine If an Adverse Event Requires Expedited 
Reporting
Step 1: Identify the type of adverse event  
Step 2: Grade the adverse event 
Step 3: Determine whether the adverse event is related to the protocol therapy 
Attribution categories are as follows:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
Note: This includes all events that occur within 30 days of the last dose of 
protocol treatment. Any event that occurs more than 30 days after the last dose 
of treatment and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported accordingly.
Step 4: Determine the prior experience of the adverse event. 
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Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity 
of the event is not listed in:

the current known adverse events listed in the Agent Information Section 
of this protocol;

the GRAS dossier for the supplement;
9.3.7 Reporting Requirements for Adverse Events
Expedited Reporting

The Principal Investigator must be notified within 24 hours of learning of 
any serious adverse events, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study drug. 

The investigator or site personnel will inform Janssen within 24 hours of 
notification of any serious adverse event by phone or fax, with follow-up with a 
written narrative of the event within 48 hours.

The Northwestern University Institutional Review Board must be notified 
within 10 business days of “any unanticipated problems involving risk to 
individuals or others” 
The following events meet the definition of Unanticipated Problem Reporting 
(UPR):
1.
Any serious event (injuries, side effects, deaths or other problems), which 
in the opinion of the Principal Investigator was unanticipated, involved risk to 
individuals or others, and was possibly related to the research procedures.
2.
Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk.
3.
Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject.
4.
Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an unexpected 
change to the risk/benefit ratio for the research.
5.
Any breach in confidentiality that may involve risk to the subject or others.
6.
Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator.

The FDA will be notified within 7 business days of any unexpected fatal or 
life-threatening adverse event with possible relationship to study drug, and 15 
business days of any event that is considered: 1) serious, 2) unexpected, and 3) 
at least possibly related to study participation.
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Routine Reporting

All other adverse events- such as those that are expected, or are unlikely 
or definitely not related to the study participation- are to be reported annually to 
the Northwestern IRB as part of regular data submission.
9.3.8 Unblinding Procedures
The blind should not be broken unless subject has completed all study 
procedures and the data has been locked. Emergency unblinding is expected to 
be infrequent.
Emergency unblinding should occur only if the principal investigator (or other 
treating physician) considers breaking the blind medically relevant. All individuals 
who have the blind broken will be discontinued from the study. Documentation of 
the reasons for unblinding, including date and time will be recorded in the source 
documents and the electronic case report form (eCRF).
9.4
Study Materials 
9.4.1 Structured Clinical Interview for DSM-IV (SCID) 
The SCID-CT is a short semi-structured interview. With an administration time of 
approximately 15 minutes, it was designed to meet the need for a short but 
accurate structured psychiatric interview for multicenter clinical trials and 
epidemiology. The SCID-CT will be administered by raters at the study site. The 
SCID-CT must be administered by a site study staff member listed on the site 
delegation of authority log with at least 2 years of experience with the population 
under study. The results of this assessment will be used to confirm the diagnosis 
of bipolar disorder I or II and rule out any exclusionary diagnosis. The SCID will be 
administered at the screening visit. 
9.4.2 Cognition battery 
The “Cleveland” cognition battery will be administered in this trial, which the PI 
has used over the past 30+ years as measures of the following cognitive 
domains: executive functioning, speed of processing, attention/vigilance, working 
memory, verbal learning, visual learning, reasoning and problem solving
This battery includes the following assessments:

Wisconsin Card Sorting Test (WCST)

Digit Symbol Task

Rey Auditory Verbal Learning Test (Rey-AVLT)

WISC-III Mazes

Category Fluency Test

Verbal Fluency

Brown-Peterson Consonant Trigram Memory Task
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The cognition battery will be administered at baseline and end of study. 
9.4.3 Montgomery Asberg Depression Rating Scale (MADRS) [35] - 
The MADRS will be utilized to assess a subject’s level of depressive symptoms 
and must be administered using a structured interview guide. This scale consists 
of 10 items each with 7 defined grades of severity
9.4.4 Young Mania Rating Scale (YMRS) [36]- 
The YMRS consists of 11 items assessing the core symptoms of mania and is 
based on the subject’s subjective report of his or her clinical condition. Additional 
information is based upon clinical observations made during the course of the 
clinical interview. Each item has 5 defined categories of severity with 4 items 
graded on a 0 to 8 scale (irritability, speech, content, and disruptive-aggressive 
behavior) and 7 items graded on a 0 to 4 scale.
9.4.6 Clinical Global Impression Scale – Bipolar (CGI-BP) [37] - 
The CGI-BP scale refers to the global impression of the subject with respect to 
bipolar disorder. The scale rates the subject’s Severity of Illness (CGI-BP-
Severity: mania, depression, and overall bipolar illness) and Change from 
Preceding Phase (CGI-BP Change from Preceding Phase: mania, depression, 
and overall bipolar illness) based on a 7-point scale. Severity of Illness (CGI-BP-
Severity) will be rated at the baseline visit. The Change from Preceding Phase 
(CGI-BP Change from Preceding Phase) will be rated at the end of study visit 
(Week 9).
9.4.7 Specific Levels of Functioning (SLOF) [33] -
The SLOF is a clinician-rated assessment that evaluates functional behaviors in 
the context of the individual’s skills and abilities. It consists of 43 items 
categorized into 6 subscales: Physical functioning; Personal care skills; 
Interpersonal relationships; Social acceptability; Activities of community living; 
and Work skills. Each question is rated on a 5-point scale. The higher the total 
score, the better the overall functioning of the subject. According to the original 
version of the scale, the time frame covered by the survey is the past week. 
While an informant is not required for this trial, access to a person that can 
provide collateral (caseworker, caregiver, etc.) is preferred, as the SLOF asks 
them for any other relevant information, and also includes a rating for how well 
the informant knows the subject. The SLOF will be performed at the baseline and 
end of study visits. 
9.4.8 Physical Examination 
The physical exams must be performed by the PI or designee (or a licensed 
medical practitioner such as a physician’s assistant or nurse practitioner) listed 
on the site delegation of authority log. 
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A complete physical examination includes the following assessments: general 
appearance, head, eyes, ears/nose/throat, neck, lymph nodes, skin, lungs, heart, 
abdomen, musculoskeletal, and neurologic evaluations. If the subject is 
discontinued for any reason during the treatment phase, every attempt should be 
made to perform a final physical examination.
9.4.9 Vital Signs 
Arterial systolic and diastolic blood pressure and radial artery pulse rate will be 
measured while the patient is seated at the scheduled visits designated in the 
Schedule of Events in Appendix 1. 
9.4.9.1
Height and Body Weight 
Height will be measured at the screening visit. Patients will be measured without 
shoes. Body weight will be recorded at screening, baseline and every visit through 
the 9-week treatment phase. 
9.4.9.2
Body Mass Index (BMI) 
Body mass index (BMI) will be determined with the patient’s height and weight at 
the screening visit and subsequent treatment visits. BMI must be calculated using 
the following formula: A person’s (Weight in pounds divided by their height in 
inches squared) x 703. 
9.4.9.3
Waist and Hip Circumference 
Waist and hip circumference will be recorded at screening, baseline, and all study 
visits. 
9.4.10 Electrocardiogram (12-Lead ECG) 
The PI or a physician listed on the site delegation of authority log must review, 
initial, and date the report, which must be filed in the subject’s study chart. 
Results will be captured in the subject’s study chart, not in the electronic 
database. Clinically significant findings from the screening report must be 
captured in the medical history. Eligibility for study entry must be assessed by the 
principal investigator. Any clinically significant changes compared with baseline 
must be captured as AEs in the electronic database. 
Individuals are to be supine for at least 5 minutes prior to ECG assessments. A 
central facility will be used in this study for interpretation and analysis of ECGs. 
All individuals will have standard resting 12-lead ECGs performed and 
interpreted. The time the ECG is performed will be recorded (using a 24-h clock). 
In addition, the time that the subject took their last dose of study medication (prior 
to the ECG) will be recorded on the CRF page.
9.4.11 Adverse Event (AE) Monitoring 
The PI or a designee (eg, a licensed, qualified medical practitioner such as a 
physician’s assistant or a nurse practitioner) listed on the site delegation of 
authority log must assess the severity and relationship to study medication(s) of 
all AEs. All observed or volunteered AEs regardless of treatment group or 
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suspected causal relationship to the investigational product(s) will be recorded on 
the AE page(s) of the electronic database. 
For all AEs, the investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as an SAE requiring immediate notification to the Sponsor or its 
designated representative. 
For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE. The investigator is required to assess causality 
and indicate that assessment on the source document and electronic database. 
For AEs with a causal relationship to the investigational product, follow-up by the 
investigator is required until the event or its sequelae resolve or stabilize at a 
level acceptable to the investigator. 
Adverse events (serious and non-serious) should be recorded on the source 
document and electronic medical record from the date the informed consent form 
(ICF) was signed until the end of their participation in the study, ie, the subject 
has discontinued or completed the study. 
9.4.12 Concomitant Medications 
Concomitant Medications will be documented using the Concomitant Medications 
form at Baseline and all study visits. 
9.4.13 Study Medication Adherence 
Participants will be asked about his/her medication adherence at each 
appointment. Study personnel will count and record the number of pills in the 
patient’s study medication bottles and provide immediate feedback, reinforcing 
the behaviors of patients who appear to be taking medications as prescribed and 
problem-solving with those who appear not to be. Clinicians will review with 
patients the use of pill-minder boxes, as needed.
9.4.14 Laboratory Test Assessments 
Northwestern Medicine Laboratory and South Bend Medical Foundation will be 
used for analysis of fasting lab assessments required during the study. Blood will 
be drawn from each patient at the screening visit, and at end of study as noted in 
the study Schedule of Events in Appendix 1. The tests will include: Chemistry 
panels; Hematologic parameters: red blood cell (RBC), hemoglobin, hematocrit, 
unconjugated bilirubin, reticulocyte, and platelet counts; Liver function: aspartate 
transaminase (AST), alanine transaminase (ALT), gamma glutamyltransferase 
(GGT), prothrombin time, total bilirubin, lactic dehydrogenase, albumin, protein, 
creatinine.  A  urine drug screen (UDS) will be obtained at screening only.
In women of childbearing potential, serum pregnancy testing will occur at 
screening; urine pregnancy will occur at study baseline.   
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Note: At screening and throughout study participation, a positive UDS is not 
necessarily exclusionary and/or may not require a subject be withdrawn from the 
study. This decision will be per the discretion of the principal investigator.
9.5
Safety Scales 
9.5.1 Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a clinician-rated assessment of abnormal movements consisting of 
unobtrusive observation of the subject at rest (with shoes removed) and several 
questions or instructions directed toward the subject. Using a severity scale 
ranging from 0 (none) to 4 (severe), clinicians rate dyskinesia in several body 
regions, including the facial area, extremities, and trunk. 
9.5.2 Columbia Suicide Severity Rating Scale 
The C-SSRS was developed by a team of researchers at Columbia University to 
address the need for standardized classification of suicide reports to assess 
suicide risk. This scale consists of a baseline evaluation that assesses the 
lifetime experience of the subject with suicide events and suicidal ideation and a 
post-baseline evaluation that focuses on suicidality since the last study visit. A 
baseline C-SSRS will be completed at the screening visit. The C-SSRS Since 
Last Visit form will be completed at all subsequent visits and telephone calls (Day 
21, Day 35, and Day 49).
10.0 Data and Specimen Banking
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Janssen-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study.
Government agency regulations and directives require that the study investigator 
must retain all study documentation pertaining to the conduct of a clinical trial. In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of 
marketing application in an International Conference on Harmonization (ICH) 
region. In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study.
11.0 Data and Specimen Management
11.1 Data Analysis Plan
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The primary analysis will be a mixed model repeated measures ANCOVA 
adjusting for baseline differences in dependent measures, sex and race. Missing 
data will be imputed by MMRM. We would also examine some variables 
categorically. 
Assumptions for the power analysis included random assignment into one group 
receiving placebo and one JNJ-18038683. The cognitive battery, as the primary 
instrument, will be collected at baseline and at end point (8 weeks).  Using 
repeated measure ANCOVA, the time average difference in the response 
variable will be compared between groups to detect treatment difference. Based 
on Javitt et al, 2012, we assume the mean baseline verbal learning score will be 
36.2, SD 9.4 for both groups.  We are assuming the placebo group will show no 
improvement while the treatment group will improve a mean of 5 points, a 
medium effect.  We assume the correlation coefficient of repeated observation to 
be 0.5 and the covariance structure to be compound symmetry. The power 
calculation was conducted with alpha level of 0.05 using one-sided and two-sided 
tests. Full results are available upon request. With a one sided test, 33 
individuals per group are required assuming 5 points improvement of the 
treatment group compared to the placebo for the desired power of 80% with 
alpha level of 0.05. We plan to recruit 36 per group to account for drop outs. In 
the two sided test the sample size per group is 42. 
Numeric Results based on one-sided test
One-Sided Test. Null Hypothesis: D = 0. Alternative Hypothesis: D > 0 (or D < 0).
Covariance Type = Compound Symmetry
Group 1
Group 2
Sample
Difference
Sample
Sample
Allocation
Time
to be Standard
Auto-
Size
Size
Ratio
Points
Detected Deviation
corr.
Power(N1)
(N2)
(R)
(M)
(D1)
(Sigma)
(Rho)
Alpha
Beta
0.8023533
33
1.000
2
5.000
9.400
0.500
0.050
0.19765
11.2
Data Management and Monitoring/Auditing
A database in the RedCap system will be used for data entry and will be formatted 
to simulate the hard copy data entry forms.  Once entered into this database, the 
data files can be extracted into Excel or SAS project databases, which are 
maintained on a networked directory under the direct supervision of the PI and 
biostatistician.  Back-ups are routinely performed to assure the preservation of the 
database. Data are checked for range, consistency, missing values, etc. During 
data analysis, combined datasets are created as needed.  Data are maintained in 
the master system datasets using a source/derived data approach, where source 
datasets are maintained unmodified, while the derived datasets are modified as 
needed.  Thus, alterations that prove to be incorrect are easily rectified. The 
confidentiality of all data is maintained using the HIPAA compliance standards of 
Northwestern University. No confidential information is posted to the web under 
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any circumstances.  All possible efforts are made to retain only the necessary 
information in all cases.
Regarding de-identification of the data set: No identifiable information for any 
individuals (i.e. name, initials or date of birth) will be collected in the analyzable 
RedCap database or directly linked to study data. Individuals will be coded only 
with study-specific unique ID numbers. 
12.0 Provisions to Monitor the Data to Ensure the Safety of 
Individuals
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification of 
proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data.
13.0 Withdrawal of Individuals*
Individuals can be taken off the study treatment and/or study at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for 
safety, behavioral or administrative reasons. The reason(s) for discontinuation will 
be documented and may include:

Individual voluntarily withdraws from treatment (follow-up permitted); 

Individual withdraws consent (termination of treatment and follow-up);

Individual is unable to comply with protocol requirements;

Individual experiences toxicity that makes continuation in the protocol 
unsafe;

Physician judges continuation on the study would not be in the patient’s best 
interest;

Individual becomes pregnant (pregnancy to be reported along same 
timelines as a serious adverse event).
14.0 Risks to Individuals*
The risks from the study procedures include:
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In a 7 week, randomized, placebo controlled trial comparing JNJ-18038683 with 
placebo and escitalopram (an active comparator), a total of 6 serious adverse 
events were reported during the study (placebo group: spontaneous abortion and 
suicidal ideation; escitalopram group: spontaneous abortion, suicidal ideation, 
suicide attempt, and chest discomfort). A total of 10 individuals (3 in the placebo 
group, 4 in the JNJ-18038683 group, and 3 in the escitalopram group) were 
withdrawn from the study prematurely due to adverse events. Only 3 individuals 
receiving the 20-mg dose of JNJ 18038683 required dose reductions at any point 
during the study.
Adverse events that were reported in more than 5% of individuals in any 
treatment group included headache, nausea, nasopharyngitis, insomnia, 
somnolence, dyspepsia, dizziness, dry mouth, constipation, diarrhea, vomiting, 
back pain, upper respiratory tract infection, palpitations, and fatigue. The 
treatment-emergent adverse events that were reported more frequently in the 
JNJ 18038683 group compared with the placebo or escitalopram groups included 
dyspepsia, constipation, upper respiratory tract infection, and palpitations. 
The clinical interview questions may result in temporary discomfort when asking 
the subject about a potentially difficult time in the past or the psychiatric symptoms 
they experience in the case of psychiatric participants.  There may be temporary 
discomfort/ bruising at the site of venipuncture.  
It is believed the potential benefits outweigh the risks for this trial.
In case of a medical emergency and risk of suicidality, the study team will follow 
the emergency protocol outlined in the Appendix 3.  
15.0 Potential Benefits to Individuals
The possible benefits to the individuals who participate in this study are 
improvement in cognitive function and residual depressive symptoms, but there 
may be no direct benefit.  Research staff could provide information from screening 
evaluations to the subject’s clinical treatment team if requested by the subject. 
Findings from this study may benefit others.  Participation will allow us to learn 
about the potential cognitive enhancing effects of JNJ-18038683 in patients with 
bipolar disorder, and its effect on depressive symptoms, which would inform further 
studies evaluating its use to treat cognitive deficits among various clinical 
populations.
16.0 Vulnerable Populations
This research study does involve cognitively impaired adults, as the 
primary endpoint is examining the effect of the study medication on the 
cognitive impairment associated with bipolar disorder (CIABP).
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To ensure that each subject’s rights and welfare are protected, we confirm 
the following:
The competency of patients to give informed consent will be evaluated in a 
multifaceted manner. The majority of patients who participate in our research are 
referred to us by clinicians.  Prior to participating in any protocol-related 
procedures, and as per the standard operating procedure, research clinicians 
explain the nature of the protocol to the patient, the risks and benefits, and the 
option not to participate in research. They have been instructed by us not to refer 
patients they believe are incompetent or grossly disorganized. This process of 
assessment and explanation is then repeated by the clinician involved in the 
research project, often in the presence of clinical staff, and by the research 
assistant involved in the research project. They first do a clinical assessment to 
determine if the patient might be appropriate for the project in terms of its 
inclusion and exclusion provisions. During this clinical assessment, they do a 
mental status examination, which assesses the patient’s memory, attention, and 
thinking processes. If these are impaired to the point where the person appears 
to be unable to understand the nature of the research project, its risks and 
benefits, or the option not to participate, they will not be approached to be in 
research.  If they are not excluded for this or other reasons, e.g. patient is a risk 
to themselves or others, one of the subinvestigators on the study or the PI will 
explain the protocol, go carefully over the consent form, provide help to the 
patient, if needed, to review the written protocol and consent, ask question to the 
patient to determine their level of comprehension, and then answer all questions 
the patient may have about the study. This will often be done in the presence of a 
clinical staff member not directly connected to the research or minimally involved. 
This type of assessment is repeated as needed during the course of the protocol 
if there is a question about loss of competency, although it is expected that 
competency will increase rather than decrease because of the beneficial effects 
of the treatments. Where the research staff feels the decision as to competency 
is questionable, the patient will be excluded from research. In a few cases, we 
may ask a clinician not connected to the research to do an independent 
evaluation their decision will be decisive. 
Individuals will be regularly evaluated for the increase of cognitive deficits.   If 
and when increased cognitive deficits emerge, the P.I. or sub-investigator will 
assess for any impairments in judgment that might affect the subject’s ability to 
judge if he or she should continue to participate.  If there are any conflicts about 
the impairment of a given patient, the P.I, Herbert Y. Meltzer, will request Dr. 
John Csernansky, Chairman of the Feinberg School of Medicine Department of 
Psychiatry, to evaluate the patient.  Dr. Csernansky will then independently 
determine if he believes that the patient is continuing to give consent and if 
continued participation is in the patient’s best interest.  If Dr. Csernansky 
determines that the patient has withdrawn consent or that continuing is not in his 
or her best interest, the subject will be withdrawn from continued participation 
and referred for appropriate follow-up treatment. If and when increased cognitive 
deficits emerge in a subject at the Beacon Medical Group Behavioral Health 
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South Bend site, the same process will take place as at the Northwestern 
University. If there are any conflicts about the impairment of a given patient, the 
P.I will ask an independent psychiatrist from the Beacon Medical Group 
Behavioral Health South Bend, South Bend, IN to evaluate the patient. This 
psychiatrist will then independently determine if he/she believes that the patient 
is continuing to give consent and if continued participation is in the patient’s best 
interest.  
The risk of the study is low, and are reasonable in relation to the potential 
benefits. Individuals cannot access alternative pharmacologic treatment 
for CIABP, as there is no approved treatment.
17.0 Sharing of Results with Individuals
All information will be kept confidential except such as is necessary to disclose in 
order to provide appropriate medical care to a study participant, in which case 
the participant will be notified and their healthcare provider will be contacted via 
phone and/or fax. If a participant is found to have severe depression, they will be 
referred to appropriate health care providers. If a participant’s blood tests positive 
for Hepatitis B, local laws may require that the result be reported to local health 
authorities.
18.0 Setting
Participants will be identified as eligible according to diagnosis, severity of 
symptoms and ability to give informed consent. Staff affiliated with this 
research study will conduct chart reviews as allowed by mental health 
centers to determine eligibility based on treatment history.
All research procedures will be performed at either the Northwestern 
University Department of Psychiatry and Behavioral Science offices 
located at 680 N. Lake Shore Dr., Suite 1410, Chicago, IL 60611 or the 
Stone Mental Health Center, located at 446 E Ontario St, Rooms 6-344 
and 6-343, Chicago, IL 60611. For the Beacon Medical Group Behavioral 
Health South Bend site all research procedures will be done at either the 
Beacon Medical Group Behavioral Health South Bend 707 N. Michigan St 
Suite 400 South Bend, IN 46601 or the South Bend Medical Foundation 
530 N. Lafayette Blvd South Bend, IN 46601.
19.0 Resources Available
19.1 Staff and qualifications
Herbert Meltzer, MD
Principal investigator
45+ years in 
psychiatry clinical 
trials, acting as 
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principal and sub-
investigator.
Marko Mihailovic
Project Manager
10+ years of 
research experience 
as a rater and 
budget contact. 
Experience in 
management, 
coordination, and 
rating in clinical 
trials.
Ahmed Elmaadawi, 
MD
Principal Investigator 
Beacon Medical 
Group Behavioral 
Health South Bend
10+ years in 
psychiatry clinical 
trials, acting as 
principal and sub-
investigator.
Suhayl Nasr, MD
Sub Investigator 
Beacon Medical 
Group Behavioral 
Health South Bend
15+ years in 
psychiatry clinical 
trials, acting as 
principal and sub-
investigator.
19.2 Patients will be recruited from several clinical sites with whom we have 
worked closely over the last three years. Our lab has trained and certified 
coordinators and research assistants who will be assigned to this study as 
their primary responsibility. We have used a variety of cognitive batteries 
for schizophrenia and bipolar disorder in many studies over the last five 
years.  Our project statistician and research staff are proficient at electronic 
data capture (RedCap) which we will utilize for this study.  
20.0 Prior Approvals
Approval will be obtained from the Northwestern University IRB and the 
study sponsor, Janssen Research and Development, before commencing 
the research study.
21.0 Recruitment Methods
Participants aged 18-60 with bipolar disorder of at least one year duration, as 
established by SCID-I, will be recruited for this study. Participants will be 
identified as eligible according to diagnosis, severity of symptoms and ability to 
give informed consent. The clinical treatment providers of potentially eligible 
participants will be notified of the inclusion and exclusion criteria for the study, by 
way of written communication or regularly scheduled presentations to the 
providers (e.g. lunch presentations, weekly therapist meetings, etc.), and will be 
asked to discuss the study with potential candidates. The research staff will meet 
with the participants only after notification of the current provider of psychiatric 
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services and after the participants have expressed interest in taking part in 
research. 
We will utilize referrals from primary care or psychiatry providers, or from 
participant interest and consent. We will also be recruiting individuals through the 
NU-SRG Recruitment Pipeline (STU00059328).
As part of the NU-SRG Recruitment Pipeline, research staff will first read 
individuals a verbal consent, where they can indicate if they are interested in 
completing a screening form and if we can hold onto their information and 
contact them for future research opportunities. We have prepared handouts with 
a flow chart to help guide candidates and clinicians to determine if candidates are 
preliminarily eligible for the study.  We then complete a 5-10 minute screening 
form to determine eligibility for the study. The PI, the sub-investigator, and fully 
trained research staff will determine initial prescreen eligibility. The PI will 
personally review and approve all enrollees prior to randomization.
22.0 Local Number of Individuals
After screening for eligibility and providing written informed consent, 60 stable 
outpatients, who may have mild-moderate depressive symptoms, will be 
randomized to receive adjunctive treatment with either JNJ-18038683 or placebo. 
We propose to study a total of 60 randomized participants, 30 receiving JNJ-
18038683 and 30 randomized to placebo.   
23.0 Confidentiality
All data that will be stored on sites and will be maintained in locked cabinets (double lock 
rule applies). Blood specimens will be processed locally at Northwestern Memorial 
Hospital and South Bend Medical Foundation.  Only NU-IRB approved members of the 
study team will have access to the study data. De-identified data will be kept separately 
from the identified data. De-identifiable data will be entered into a RedCap data base 
that serves as an Electronic Data Capture (EDC) system,
24.0 Provisions to Protect the Privacy Interests of Individuals
Participants will be reminded whenever appropriate that they are at liberty to opt 
out of answering any questions or undergoing any procedures with which they 
are not comfortable, up to and including their right to rescind their participation in 
the study without any penalty unto them.
Participants must sign an authorization for release of information before any 
sources of information can be contacted about the participant.
25.0 Compensation for Research-Related Injury
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25.1 If the research involves more than Minimal Risk to individuals, 
describe the available compensation in the event of research-related 
injury.
25.2 Provide a copy of contract language, if any, relevant to compensation 
for research-related injury.
26.0 Economic Burden to Individuals
Participants may incur costs related to transportation by participating in this 
study, and they will be reimbursed for part or all of such incurred expenses.
Individuals will be compensated at the rate of $40/visit for their time and effort. 
The total amount for visit compensation will be prorated based on subject’s 
participation. Up to $20 per visit will also be provided to cover individuals’ 
transportation and parking expenses. For any visit lasting over 4 hours $10 will 
be provided to cover subject’s lunch costs. 
27.0 Consent Process
The informed consent form will typically first be discussed with a potential 
participant over telephone, and after the participant has considered their ability to 
participate in the study, will again formally be reviewed with the participant during 
an in-person screening visit at the Northwestern University Department of 
Psychiatry and Behavioral Science offices or at the Beacon Medical Group 
Behavioral Health South Bend. Any time that there is a change in the protocol or 
the informed consent form, the revised consent form will again be reviewed with 
and signed by the participant. Individuals obtaining consent will follow ‘SOP: 
Informed Consent Process for Research (HRP-090).’
No non-English speaking participants, minors, cognitively impaired adults, or 
adults unable to provide consent will be considered for participation in this study, 
nor will any waivers or alterations of the consent process be applied for.
28.0 Process to Document Consent in Writing
Individuals documenting the consent in writing will follow ‘SOP: Written 
Documentation of Consent (HRP-091).’
29.0 Drugs or Devices
JNJ-18038683 will be provided by Janssen Research and Development, the 
makers of JNJ-18038683, and will provide a detailed Certificate of Analysis 
attesting to the contents of the product.
The investigational product has been assigned the number JNJ-18038683-ADC. 
The suffix ADC denotes the citrate salt form and JNJ-18038683-ADC is referred 
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to as JNJ-18038683 unless stated otherwise. Alternatively, the number RWJ-
800054 may also be used to denote the citrate salt form.
The full International Union of Pure and Applied Chemistry (IUPAC) chemical 
name is 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-
d]azepine 2-hydroxy-1,2,3-propanetricarboxylate (1:1). JNJ-18038683 has been 
assigned the Chemical Abstract Service (CAS) registry number
851376-05-1.
An oral solid dosage formulation has been manufactured as tablets containing 10 
mg of JNJ-18038683, lactose monohydrate, croscarmellose sodium, povidone, 
silicified microcrystalline cellulose, and magnesium stearate. The placebo 
formulation will be supplied as matching tablets. Detailed instructions for storage 
conditions and oral dose administration will accompany the clinical drug supplies 
to the clinical study sites.
The target dosage will be 20 mg/day, or 2 tablets of 10 mg once per day. This will 
preserve the blind, as the placebo comparator will be also given as 2 tablets 
once per day. Individuals will receive 10 mg/day for the first week, and 20 mg 
from weeks 2-7 with a provision for a single, downward, dose adjustment.
Study clinicians will be responsible for dispensing JNJ-18038683 at our research 
office. An unblinded study drug manager will receive and label and distribute the 
product for dispensing during the study.
At the baseline and end of study visits, measures of safety and effectiveness will 
be administered and individuals will be evaluated for response and side effects to 
the treatment. To assess adherence to dosing of the agent, the study medication 
will be returned and counted.
Study drugs sent by the sponsor to the study site will be stored in a locked 
cabinet and be handled only by the study coordinator, who will also 
maintain drug accountability logs and drug destruction/return logs that will 
be verified by the site monitor to ensure that study drugs have only been 
used on individuals and only by authorized investigators.
Study Drug/Study Device: JNJ-18038683
IND/IDE Number:
126601
IND/IDE Holder Name:
Herbert Meltzer, MD
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22.
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of 5-HT(1A) receptor stimulation on contextual learning in mice. Eur J Pharmacol, 2008. 596(1-3): 
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induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in 
the rat. J Psychopharmacol, 2007. 21(2): p. 198-205.
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and Operant Discrimination and Reversal Learning in C57BL/6J Mice. Front Behav Neurosci, 2009. 
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Leeson, V.C., et al., Discrimination learning, reversal, and set-shifting in first-episode 
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133: p. 429-35.
37.
Spearing, M.K., et al., Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar 
illness (BP): the CGI-BP. Psychiatry Res, 1997. 73(3): p. 159-71.
38.
Ingelman-Sundberg, M., Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical 
consequences, evolutionary aspects and functional diversity. Pharmacogenomics J, 2005. 5(1): p. 
6-13.
39.
Andressen, K.W., et al., The atypical antipsychotics clozapine and olanzapine promote down-
regulation and display functional selectivity at human 5-HT7 receptors. Br J Pharmacol, 2015 
172(15): p.3846-60
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Appendix 1
Schedule of Assessments:
Study Day
Screen
1
7
14
21
28
35
42
49
56
84
Event/Assessment
PC
PC
PC
PC
Informed Consent
X
 
 
 
 
 
 
 
 
 
Medical History & 
Demographics
X
 
 
 
 
 
 
 
 
 
Physical Examination
X
 
 
 
 
 
 
 
 
 
Electrocardiogram
X
 
 
 
 
X
 
 
 
X
Vital Signs
X
X
X
X
 
X
 
X
 
X
Clinical Safety Laboratory 
Tests
X
 
 
 
 
X
 
 
 
X
Serum Pregnancy Test
X
Urine Pregnancy Test
X
X
Urine Drug Screen
X
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria
X
 
 
 
 
 
 
 
 
 
SCID-I
X
 
 
 
 
 
 
 
 
 
Screening neurocognitive 
assessments
X
Montgomery Asberg 
Depression Rating Scale
X
 
 
 
X
 
 
 
X
SLOF
X
X
C-SSRS
X
X
X
X
 X
X
X 
X
X 
X
X
AIMS
 
X
 
 
 
X
 
 
 
X
Neurocognitive battery
X
 
 
 
 
 
 
 
X
CGI-BP
 
X
 
 
 
X
 
 
 
X
Young Mania Rating Scale
 
X
 
 
 
X
 
 
 
X
Assessment of Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
Assessment of Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X


35 
Version Date 02.04.2019
Appendix 2: Prohibited medications:
CYP2D6 Inhibitors 
Moderate to potent CYP2C19 inhibitors 
Bupropion 
Fluconazole
Celecoxib 
Fluvoxamine
Cinacalcet
Ticlopidine
Chloroquine
Esomeprazole 
Chlorpheniramine
Moclobemide
Clemastine
Omeprazole 
Clomipramine 
Voriconazole
Diphenhydramine
Duloxetine
Atypical Antipsychotics
Fluoxetine
Clozapine
Halofantrine 
Hydroxyzine
Methadone
Moclobemide
Paroxetine
Pyrilamine
Quinidine
Terbinafine
Tripelennamine
Aripiprazole
Major substrates and inhibitors for CYP2D6 [38]
Specific drugs as substrates
Inhibitors, drugs
Alprenol
Chinidin
Amiflamine
Fluoxetin
Aprindine
Levomepromazine
Atenolol
Lobelin
Bufuralol
Methadone
Bupranolol
Quinidine
Chlorpropamide
Trifluperidol
Clomipramine
Codeine
Inhibitors, alkaloids
Debrisoquine
Ajmalicine
Desimipramine
Berberine
Desmethylcitalopram
Coniine
Dextromethorphan
Ergotamine
Dihydrocodeine
Gramine
Encainide
Harmaline
Ethylmorphine
Sempervirine
Flunarizine
Vincamine
Fluperlapine
Vinblastine
Guanoxan
Haloperidol
Hydrocodone
Imipramine
Indoramin
Maprotiline
Methoxyamphetamine
Methoxyphenamine
Metiamide
Metoprolol
Mexiletine
IRB #: STU00200919 Approved by NU IRB for use on or after 3/8/2021 through 3/7/2022.


36 
Version Date 02.04.2019
Nortriptyline
Ondansetron
Otycodone
Perhexiline
Perphenaxine
Phenacetin
Phenformin
Propafenone
Propranolol
Quinidine
Thioridazine
Timolol
Tomoxetine
Tropisetron
Zuclopenthixol
IRB #: STU00200919 Approved by NU IRB for use on or after 3/8/2021 through 3/7/2022.


37 
Version Date 02.04.2019
Appendix 3: Emergency protocol:
This procedure will be followed whenever the research staff is in contact with the study 
participants either in person or via phone
Emergency procedures:
If there is an apparent imminent medical risk, call 911. A research team member must watch on 
the subject until Police/Ambulance arrives. 
If there is an imminent medical risk, the other immediate safety procedures to be followed by 
clinical research staff.  
If there is no apparent imminent risk, the following protocol will be followed:

Alert the Principal Investigator (PI) and/or Study Doctor about the problem (provide 
with demographics and relevant medical information such as suicidal, homicidal 
ideation/intent, diagnosis, medical condition, etc.)  

Based on the clinical judgment of PI and/or Study Doctor, 911 may be called at any 
time during this procedure or appropriate care will provided at the site. 

Alert the Research Manager (provide with relevant information)

Contact the primary treating psychiatrist.

Pending response (if recommended to proceed to the Emergency Department 
(ED), discuss the issue with all relevant research staff and participant as well as 
the participant’s family members and/or caregivers if appropriate.

Call 911

In the case of an involuntary hospitalization/ED evaluation - call Police – a 
research team member should go with police since “Petition” is required.

In the case of a voluntary hospitalization/ED evaluation - call Ambulance to 
escort the patient.

In the case of suicidal ideation/intent, a research team member must watch on the 
subject until Police/Security/Ambulance arrives.

Contact the building security and inform them that Police and/or Ambulance was 
contacted. 

A Clinical Research Team Member needs to provide documentation from the 
investigator to give to the police/security regarding the investigator 
recommendation.

A Clinical Research Team Member calls ED to alert that patient is on the way and 
to provide with all necessary information.

A Clinical Research Team Member follows up with crisis team/on call resident to give 
information about the patient.
IRB #: STU00200919 Approved by NU IRB for use on or after 3/8/2021 through 3/7/2022.


38 
Version Date 02.04.2019

A Clinical Research Team Member documents all activities for the study file and for 
correspondence with clinicians/, sponsor, IRB and Janssen Research and 
Development, LLC.
IRB #: STU00200919 Approved by NU IRB for use on or after 3/8/2021 through 3/7/2022.

SAP_001.pdf: 
Data Analysis Plan for Northwestern- Janssen R&D Collaboration Study 
Protocol Title:  Testing the ability of JNJ-18038683, a selective serotonin (5-HT)7 antagonist, to 
improve cognition and reduce residual depressive symptoms in stable bipolar patients 
Protocol Identifier Number: 18038683BCD2001 
Northwestern University IRB Number: STU00200919-MOD0042 
Version:  1.13 
Date: 08.04.2021 
 
Goals:  
The goals of this study are to evaluate the efficacy of JNJ-18038683 in an 8-week trial to ameliorate the 
cognitive deficit and reduce residual depressive symptoms in 60 stable bipolar outpatients receiving 
treatment for depression. JNJ-18038683 will be studied and compared with placebo as adjunctive 
treatment to standard pharmacologic treatment for bipolar disorder. Sixty patients will be enrolled and 
randomized with a 1:1 ratio to one dose of JNJ-18038683 or placebo providing 30 subjects for each 
treatment arm. The initial intention was to follow stratified randomization based on the 
presence/absence of atypical APDs with 5-HT7 antagonism so that there is a balance in the assignment 
of active treatment and placebo in individuals who are and are not, receiving atypical APDs with 5-HT7 
antagonism.  However, due to recruitment difficulties, the stratified randomization method was not able 
to be followed as anticipated and was amended.  
Assessments and Events: 
Demographics, medical history, physical examination, serum pregnancy test, urine drug test, SCID-I 
diagnosis, and screening neurocognitive assessments will be done only during the screening visit. Urine 
pregnancy testing is performed at the baseline visit. 
Table 1: Assessments completed during the screening visit only 
Event /Assessment 
Screen 
Medical History & Demographics 
X 
Physical Examination 
X 
Serum Pregnancy Test 
X 
Urine Drug Screen 
X 
Inclusion/Exclusion Criteria 
X 
SCID-I 
X 
Screening neurocognitive assessments 
X 
 
 


Neurocognitive battery will be the primary measure of interest and evaluated at baseline and 8 weeks. 
The clinical global severity scores (CGI-BP), Young Mania Rating (YMRS), Scale for Tardive Dyskinesia 
(AIMS), Montgomery Asberg Depression Rating Scale (MADRS), Electrocardiogram and Clinical Safety 
Laboratory Tests will be collected at screening or baseline, and at 4 and 8 weeks. A measure of 
functional ability (SLOF) also will be assessed at baseline and 8 weeks.  The schedule of these 
assessments is listed in table 2. 
Table 2: Assessments completed during the screen visits/baseline visits and at week 4 and/or week 8 
Event/Assessment 
Screen 
Day 1* 
Day 28 
Day 56 
Electrocardiogram 
X 
  
X 
X 
Clinical Safety Laboratory Tests 
X 
  
X 
X 
Montgomery Asberg Depression Rating Scale 
  
X 
X 
X 
SLOF 
  
X 
  
X 
AIMS 
  
X 
X 
X 
Screening neurocognitive assessment 
X 
  
  
  
Neurocognitive Assessments Cleveland Battery 
  
X 
  
X 
CGI-BP 
  
X 
X 
X 
Young Mania Rating Scale 
  
X 
X 
X 
*Day 1 is equal to Baseline 
 
Vital signs, C-SSRS (suicide tendency), concomitant medication, and adverse events experienced by 
patients will be collected during study visits at screening, baseline, and at weeks 1, 2,4, 6, and 8.  In 
addition, data will be collected at weeks 3, 5, 7, and 12 via phone calls for C-SSRS (suicide tendency), 
concomitant medication, and adverse events.  
Table 3: Assessments completed during the screen visits/baseline visits and at weeks 1,2,4,6 and 8 
Event/Assessment 
Screen Day 1 
Day 7 
Day 14 Day 28 Day 42 Day 56 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
C-SSRS* 
X 
X 
X 
X 
X 
X 
X 
Assessment of Concomitant 
Medication* 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events* 
X 
X 
X 
X 
X 
X 
X 
* assessments will also be collected at 21, 35, 49 and 84 days via phone calls.   
 
 


Statistical Analysis: 
 
Screening data and drop out data: 
Screen assessments listed in table 1 will be summarized for all the patients including reasons for screen 
failures.  Concomitant medications were the reasons for most screen failures and will be documented. 
Included patients will be compared with excluded patients based on appropriate statistical methods 
(parametric or non-parametric) for the variables in table 1. During the study period, all dropouts and 
reasons for drop out will be tabulated. 
In this blinded RCT, individuals with bipolar disorder received active drug (JNJ-18038683) or a placebo 
after screening and the completion of baseline assessments. Subjects in the two treatment arms will be 
compared on all the baseline efficacy measures, measures of psychopathology related to bipolar 
disorder, e.g., YMRS, MADRS, CGI-BP, SLOF measures, demographic variables, and suicide status.  
Primary analysis for efficacy: 
The primary outcome measure for this study is verbal fluency performance as assessed with the Rey 
Auditory Verbal Learning Test, Rey Verbal Learning Test – Recognition Form, Verbal Fluency Test 
“Letterforms”, and Animal Naming Test. The 8-week evaluation of verbal fluency after randomization is 
the primary outcome measure.  Since the main interest is to measure the treatment effect for verbal 
fluency improvement from baseline and there is only one follow-up time point for the primary outcome 
variable, an ANCOVA model will be best suited for this study to compare the treatment effect using 
baseline value as a covariate. Alternatively, an ANOVA model will be used to compare the percent 
improvement and changes in the verbal fluency scores across treatment groups.  Also, we plan to 
compare the treatment effect on verbal fluency performance over time using a mixed model. The 
missing evaluations will be imputed with the last value carried forward method, while model fit statistics 
will be used to estimate the appropriate covariance structure for this model. 
There is both preclinical and clinical evidence that age has an important influence on 5-HT7 receptor 
function, which is the target of JNJ-18038683. Capacity to respond to JNJ-18038683 may decline with 
age.  Thus, we predict the age of the subject will be related to the extent of improvement in verbal 
fluency and other measurements in the cognition battery.  The relationship of age and percent 
improvement and the direct change of verbal fluency from baseline to 8 weeks in each treatment arm 
will be assessed using correlation analysis. The age variable will be used as a continuous variable in the 
analysis. If the distribution of the age variable is skewed, then age groups will be formed appropriately. 
In the above described ANCOVA and repeated measures models, age will be use as a covariate to assess 
the treatment effect. Graphical methods will be used to check for any inflection points of improvement 
of verbal fluency score in the treatment group compared to placebo. In the treatment group, better 
improvement is expected in younger patients compared to older patients. This relationship is not 
expected in placebo-treated patients. Additionally, with the above-mentioned models, the effect of 
covariates, MADRS total score, YMRS and Clinical Global Severity score on cognition will be examined 
because baseline mania or depression severity may influence performance on cognitive testing. 
 
 


Secondary analyses related to efficacy: 
The secondary analyses regarding change in verbal fluency test scores will include identification of   
patients in each arm who improved in verbal fluency scores. The analysis plan includes exploring the 
effect of concomitant meds, gender or race that might contribute to treatment response. For this 
purpose, improvement in verbal fluency can be grouped as a dichotomous response and used as a 
dependent variable in a logistic regression model. The usual method of grouping will be improvement of 
≥0.5 SD from the baseline scores. Using this model, the odds of improvement in verbal fluency can be 
compared in the active treatment group against the placebo group. In this model, the variables, age, 
gender, lab values and presence/absence of concomitant meds, baseline MADRS total score, YMRS and 
Clinical Global Severity score mania or depression severity may influence performance on cognitive 
testing and will be tested as potential covariates using one or few covariates at a time due to sample 
size restrictions.  
Additional secondary analyses will study the effect of treatment group on other cognitive and behavioral 
measures including: 1) Digital Symbol Task, 2) Brown-Peterson Consonant Trigram Memory Task,  3)  
WISC-III Mazes; 4) Wisconsin Card Sorting Test; 5) MADRS total score,6) YMRS, and 7) Clinical Global 
Severity score using a mixed model repeated measure ANCOVA as described above.  If indicated, 
variables such as age, gender, concomitant meds, will be examined, as will be done for the primary 
outcome measure. 
 
Adverse Events: 
A tabular summary of all anticipated and unanticipated serious or non-serious adverse events will be 
presented, including drop-outs due to any side effects or safety reasons. For each serious or other 
adverse events, the summary includes the adverse event term, affected organ system, number of 
participants at risk, and number of participants affected, by the study arm or comparison group. Using 
appropriate parametric or non-parametric methods, each type of adverse event will be compared 
between groups. All adverse events, e.g. development of suicidal ideation or behaviors or switch to 
mania/hypomania, will be examined thoroughly for impact on primary and secondary outcome 
measures.  We will assess group differences, excluding subjects without these two side effects.